clinical cardiac electrophysiology in the young...clinical cardiac electrophysiology in the young...

Clinical Cardiac Electrophysiologyin the Young

Developments in Cardiovascular Medicine

232. A. Bayes de Luna, F. Furlanello, B.J. Maron and D.P. Zipes (eds.): Arrhythmias and SuddenDeath in Athletes. 2000 ISBN: 0-7923-6337-X

233. J-C. Tardif and M.G. Bourassa (eds.): Antioxidants and Cardiovascular Disease. 2000ISBN: 0-7923-7829-6

234. J. Candell-Riera, J. Castell-Conesa, S. Aguade Bruiz (eds.): Myocardium at Risk and ViableMyocardium Evaluation by SPET. 2000 ISBN: 0-7923-6724-3

235. M.H. Ellestad and E. Amsterdam (eds.): Exercise Testing: New Concepts for the New Century.2001 ISBN: 0-7923-7378-2

236. Douglas L. Mann (ed.): The Role of Inflammatory Mediators in the Failing Heart. 2001ISBN: 0-7923-7381-2

237. Donald M. Bers (ed.): Excitation-Contraction Coupling and Cardiac Contractile Force, SecondEdition. 2001 ISBN: 0-7923-7157-7

238. Brian D. Hoit, Richard A. Walsh (eds.): Cardiovascular Physiology in the Genetically EngineeredMouse, Second Edition. 2001 ISBN: 0-7923-7536-X

239. Pieter A. Doevendans, A.A.M. Wilde (eds.): Cardiovascular Genetics for Clinicians 2001ISBN 1-4020-0097-9

240. Stephen M. Factor, Maria A. Lamberti-Abadi, Jacobo Abadi (eds.): Handbook of Pathology andPathophysiology of Cardiovascular Disease. 2001 ISBN: 0-7923-7542-4

241. Liong Bing Liem, Eugene Downar (eds.): Progress in Catheter Ablation. 2001ISBN: 1-4020-0147-9

242. Pieter A. Doevendans, Stefan Kaab (eds.): Cardiovascular Genomics: New PathophysiologicalConcepts. 2002 ISBN: 1-4020-7022-5

243. Daan Kromhout, Alessandro Menotti, Henry Blackburn (eds.): Prevention of Coronary HeartDisease: Diet, Lifestyle and Risk Factors in the Seven Countries Study. 2002

ISBN: 1-4020-7123-X244. Antonio Pacifico (ed.), Philip D. Henry, Gust H. Bardy, Martin Borggrefe, Francis E. Marchlinski,

Andrea Natale, Bruce L. Wilkoff (assoc. eds.): Implantable Defibrillator Therapy: A ClinicalGuide. 2002 ISBN: 1-4020-7143-4

245. Hein J.J. Wellens, Anton P.M. Gorgels, Pieter A. Doevendans (eds.): The ECG in Acute MyocardialInfarction and Unstable Angina: Diagnosis and Risk Stratification. 2002 ISBN: 1-4020-7214-7

246. Jack Rychik, Gil Wernovsky (eds.): Hypoplastic Left Heart Syndrome. 2003ISBN: 1-4020-7319-4

247. Thomas H. Marwick: Stress Echocardiography. Its Role in the Diagnosis and Evaluation ofCoronary Artery Disease 2nd Edition. ISBN: 1-4020-7369-0

248. Akira Matsumori: Cardiomyopathies and Heart Failure: Biomolecular, Infectious and ImmuneMechanisms. 2003 ISBN: 1-4020-7438-7

249. Ralph Shabetai: The Pericardium. 2003 ISBN: 1-4020-7639-8250. Irene D. Turpie, George A. Heckman (eds.): Aging Issues in Cardiology. 2004

ISBN: 1-4020-7674-6251. C.H. Peels, L.H.B. Baur (eds.): Valve Surgery at the Turn of the Millennium. 2004

ISBN: 1-4020-7834-X252. Jason X.-J. Yuan (ed.): Hypoxic Pulmonary Vasoconstriction: Cellular and Molecular

Mechanisms. 2004 ISBN: 1-4020-7857-9253. Francisco J. Villarreal (ed.): Interstitial Fibrosis In Heart Failure 2004 ISBN: 0-387-22824-1254. Xander H.T. Wehrens, Andrew R. Marks (eds.): Ryanodine Receptors: Structure, function and

dysfunction in clinical disease. 2005 ISBN: 0-387-23187-0255. Guillem Pons-Llado, Francesc Carreras (eds.): Atlas of Practical Applications of Cardiovascular

Magnetic Resonance. 2005 ISBN: 0-387-23632-5256. Jose Marın-Garcıa : Mitochondria and the Heart. 2005 ISBN: 0-387-25574-5257. Macdonald Dick II: Clinical Cardiac Electrophysiology in the Young 2006

ISBN: 0-387-29164-4

Previous volumes are still available

Clinical Cardiac Electrophysiologyin the Young

Edited by

Macdonald Dick II M.D.With past and presentFellows and Faculty

of theDivision of Pediatric Cardiology

University of Michigan

Macdonald Dick II, MD Professor of Pediatrics University of Michigan C.S. Mott Children’s Hospital Womens L1242, Box 0204 1500 East Medical Center Drive Ann Arbor, MI 48109-0204 USA

Library of Congress Cataloging-in-Publication Data

Clinical cardiac electrophysiology in the young / edited by Macdonald Dick II; with past and present fellows and faculty of the Division of Pediatric Cardiology, University of Michigan. p. ; cm. – (Developments in cardiovascular medicine; v. 257) Includes bibliographical references and index.ISBN -13: 978-0-387-29164-2 (alk. paper) e-ISBN 978-0-387-29170-3 ISBN -10: 0-387-29164-4 (alk. paper) e-ISBN 0-387-29170-9 1. Pediatric cardiology. 2. Electrophysiology. 3. Heart conduction system 4. Children—Diseases--Diagnosis. 5. Heart--Diseases--Diagnosis. I. Dick, MacDonald. II. University of Michigan. Mott Children’s Hospital. Division of Pediatric Cardiology. III. Series. [DNLM: 1. Heart--physiology--Child. 2. Heart--physiology--Infant. 3. Electrophysiology--methods--Child. 4. Electrophysiology--methods--Infant. 5. Heart Conduction System--physiology--Child. 6. Heart Conduction System--physiology--Infant. 7. Heart Diseases—physiopathology--Child. 8. Heart Diseases--physiopathology--Infant. WG 202 C641 2006] RJ421.C555 2006 618.92’12--dc22 2005054106 Printed on acid-free paper.

© 2006 Springer Science+Business Media, LLC. All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

Printed in the United States of America.

9 8 7 6 5 4 3 2

springer.com

This book was written by all of usbecause of our parents and teachers,

with our spouses and partners,for our and all children.

Contributors

Mohamad Al-Ahdab, M.D., Lecturer, Uni-versity of Michigan Medical School, AnnArbor, Michigan

David Bradley, M.D., Assistant Professor ofPediatrics, Pediatric Cardiology, Universityof Utah Medical School, Salt Lake City, Utah

Burt Bromberg, M.D., Pediatric Cardiolo-gist and Electrophysiologist, St. Louis, MO

Craig Byrum, M.D., Associate Professorof Pediatrics, Upstate Medical School, NewYork University, State University of NewYork, Syracuse, New York.

Robert M. Campbell, M.D., Associate Pro-fessor of Pediatrics, Children’s Heart Center,Emory University, Atlanta, Georgia

Macdonald Dick II, M.D., Professor ofPediatrics, University of Michigan MedicalSchool, Ann Arbor, Michigan

Parvin Dorostkar, M.D., Associate Profes-sor of Pediatrics, Rainbow Babies and Chil-dren’s Hospital, University Hospitals HealthSystems, Cleveland, Ohio

Peter S. Fischbach, M.D., Assistant Profes-sor of Pediatrics and Pharmacology, Univer-sity of Michigan Medical School, Ann Arbor,Michigan

Carlen Gomez, M.D., Associate Professor ofPediatrics, University of Michigan MedicalSchool, Ann Arbor, Michigan

Ian H. Law, M.D., Associate Professor ofPediatrics, University of Iowa MedicalSchool, Iowa City, Iowa

Sarah Leroy, Clinical Nurse Specialist andNurse Practitioner, Pediatric Electrophysiol-ogy and Anti-Arrhythmia Device Clinics,University of Michigan Medical School, AnnArbor, Michigan

Mark Russell, M.D., Associate Professor ofPediatrics, University of Michigan MedicalSchool, Ann Arbor, Michigan

Elizabeth V. Saarel, M.D., Assistant Profes-sor of Pediatrics, Cleveland Clinic Founda-tion, Cleveland, Ohio

William A. Scott, M.D., Professor of Pedi-atrics, Southwestern Texas Medical School,Dallas, Texas

Gerald Serwer, M.D., Professor of Pe-diatrics, University of Michigan MedicalSchool, Ann Arbor, Michigan

Christopher B. Stefanelli, M.D., PediatricCardiologist, Tacoma, Washington

Margaret Strieper, D.O., Associate Profes-sor of Pediatrics, Children’s Heart Center,Emory University, Atlanta, Georgia

Stephanie Wechsler, M.D., AssociateProfessor of Pediatrics, University ofMichigan Medical School, Ann Arbor,Michigan

vii

Preface

It takes a certain hubris to come forth with abook entitled Clinical Cardiac Electrophys-iology in the Young. There are a numberof excellent texts, monographs, and reviewson cardiac arrhythmias in both adults andchildren—Josephson’s and also Zipes andJalife’s comprehensive texts come to mind, aswell as a number of others, including Deal,Wolff, and Gelband’s, the several volumesfrom Gillette, and the recent text from Walsh,Saul, and Triedman, the latter three texts fo-cusing on children.

Nonetheless the past three decades havewitnessed enormous advances in the under-standing and management of human cardiacarrhythmias. This development represents thefruits of both basic and clinical investigationsin cardiac impulse formation and propagationat the organ, tissue, and more recently, cel-lular and molecular levels. This informationexplosion may result in information overloadand frustrate the student, the young physi-cian in training, as well as the seasoned prac-titioner. This book focuses on the practical(and theoretical when applicable) aspects ofclinical electrophysiology of cardiac arrhyth-mias in the young. Our intention is that theyoung house officer or mature physician whois faced with a child with a cardiac arrhyth-mia will find this book useful in increasingtheir understanding, sparking their interest,and perhaps leading them to a therapeuticsolution.

This book emerges from the clinicalpractice and research of the pediatric cardiacelectrophysiology group in the Division ofPediatric Cardiology at the C.S. Mott Chil-dren’s Hospital, the University of Michiganin Ann Arbor, and the former pediatric elec-trophysiology fellows from Michigan, nowestablished electrophysiologists in their ownright. It represents a compilation of the clini-cal course, electrocardiograms, electrophysi-ologic studies, pharmacological management,and transcatheter ablation therapy in patientsfrom infancy through young adulthood seen inAnn Arbor and at the current clinical sites ofthe former Michigan fellows. Thus, while theproduct may be idiosyncratic, it is not provin-cial. We are interested in “how it is done” butnot to the exclusion of other approaches. Thisis only one (or several) way to address theclinical problem of arrhythmias in children,and surely not the only way, especially as oneviews the future of emerging energy sourcesfor ablation, non-ionizing radiation imagingtechniques, and molecular diagnostic possi-bilities.

The book is divided into two parts.The first part, Background (Chapters 1–3),discusses the cardiac conduction system—development, anatomy, and physiology.Particular attention is directed to the clinicalelectrophysiology of the cardiac conductionsystem and the techniques of electrophysio-logic study that are specific to children and

ix

x PREFACE

that have been developed and practiced at theUniversity of Michigan and at other centers.The second part, Cardiac Electrophysiologyin Infants and Children (Chapters 4–23),focuses on the clinical science of cardiacarrhythmias in infants and children.

Chapters 4–12 discuss the mechanism,the ECG characteristics, the electrophysio-logic findings, the treatment, and the progno-sis of tachyarrhythmias. Chapters 13–16 focuson bradyarrhythmias. Chapters 17–20 addresscertain specialized subjects, including, syn-cope, cardiac pacemakers, implantable car-diac defibrillators, genetic disorders of thecardiac impulse, fetal arrhythmias, and sud-den cardiac death as it occurs in the young.Chapters 21–22 center on the pharmacologyof antiarrhythmic agents, indications for use,doses, side effects and toxicity, as well ason transcatheter arrhythmia ablation. Finally,what the practitioner can expect to see fromthe impact of cardiac arrhythmias on the lifeof the patient and family is discussed from thenursing point of view in Chapter 23.

The intent of the book is practical andthus the suggested readings are selected andnot encyclopedic. They are meant as a startingplace for the interested reader. Examples andtables are included in the anticipation that thereader will rapidly be able to match the clinicalproblem to the examples and the accompany-ing text.

A text or technical book is rarely theproduct of a single individual. With that inmind, any value or sense that can be made ofthis work is solely due to the terrific effortsof the authors; any error or fault can be cor-rectly attributed to me. I am deeply gratefulto all of the authors for their contributions, aswell as their patience in bringing the projecttogether. I want to recognize the generosity ofmy colleagues at Michigan in providing cov-erage when I would hide out (including a sab-batical) to work on the text. Thanks also to themedical electrophysiology group at Michiganfor encouragement and support for the pedi-atric program. I also want to thank my localeditor, Kathryn Clark, for all her efforts inkeeping me on task, endlessly and repeatedlyformatting the multiple revisions of the text,and finding and eliminating too many exam-ples of “nonsense” to count. Finally, I want tothank Melissa Ramondetta at Springer for hergreat patience, great good humor, and soundadvice throughout the course of the project.Carolin, my wife, graciously permitted me toweed the book of its unwanted wordage (prob-ably missed a bit) rather than our yard of un-wanted plant life on numerous weekends.

Macdonald Dick II, M.D.Ann Arbor, MI

August, 2005

Foreword

The text of Clinical Cardiac Electrophysiol-ogy in the Young provides a systematic ap-proach to the anatomy, pathophysiology, ba-sic electrophysiology, diagnosis and therapyof atrial and ventricular arrhythmias as wellas conduction abnormalities in the young. Itelucidates the broad spectrum of rhythm dis-turbances that may occur from the fetus toyoung adult, as an isolated abnormality, in thepresence of underlying congenital heart dis-ease, both prior to and subsequent to surgicalrepair. The clinical manifestations, diagnosisand appropriate pharmacologic and interven-tional therapy by a trained healthcare team arefully discussed. Science is consistently usedto explain the electrophysiologic diagnoses,pharmacologic, interventional and surgicaltreatment. Some prior knowledge and under-standing of electrophysiology and rhythm dis-turbances is helpful and the information pro-vided here may be utilized as a guidebook,resource and reference for residents, cardiol-ogy fellows, trained cardiologists and elec-trophysiologists as well as other allied health

professionals. The rapid advances in the fieldin such areas as interventional and surgicalcryoablation techniques, complexity of rhy-thm disturbances,newmonitoringdevices andpharmaceuticals make it an invaluable text.

Dr. Macdonald Dick as an author and edi-tor of the book is an internationally recognizedscholar and clinical pediatric electrophysiol-ogist. A superb teacher and role model fortrainees and faculty his affability and diligenteffort have brought about the compilation andpublication of the book. The majority of theknowledgeable and experienced contributorshave received their training in pediatric car-diology at the University of Michigan. Theauthors are indebted to their medical and sur-gical colleagues, fellows, family members andrespective institutions for the support and en-couragement in the endeavor.

Amnon Rosenthal, MDProfessor of Pediatrics

University of Michigan Medical SchoolAnn Arbor, MI

xi

Contents

I. BACKGROUND

1 Development and Structure of the Cardiac Conduction System 1Parvin Dorostkar

2 Physiology of the Cardiac Conduction System 17Peter S. Fischbach

3 Clinical Electrophysiology of the Cardiac Conduction System 33Macdonald Dick II, Peter S. Fischbach, Ian H. Law, and William A. Scott

II. CLINICAL ELECTROPHYSIOLOGY IN INFANTS AND CHILDREN

4 Atrioventricular Reentry Tachycardia 51Ian H. Law

5 Atrioventricular Nodal Reentrant Tachycardia 69David J. Bradley

6 Persistent Junctional Reciprocating Tachycardia 83Parvin C. Dorostkar

7 Sinoatrial Reentrant Tachycardia 91Macdonald Dick II

8 Intra-atrial Reentrant Tachycardia—Atrial Flutter 95Ian H. Law and Macdonald Dick II

9 Atrial Fibrillation 115Peter S. Fischbach

10 Atrial Ectopic Tachycardias/Atrial Automatic Tachycardia 119Burt Bromberg

xiii

xiv CONTENTS

11 Multifocal Atrial Tachycardia 135David J. Bradley

12 Ventricular Tachycardia 139Craig Byrum

13 Sick Sinus Syndrome 153William A. Scott

14 First- and Second-Degree Atrioventricular Block 163William A. Scott

15 Complete Heart Block—Third-Degree Heart Block 173Mohamad Al-Ahdab

16 Syncope 183Margaret Strieper, Robert M. Campbell, William A. Scott

17 Cardiac Pacemakers and Implantable Cardioverter-Defibrillators 195Gerald S. Serwer and Ian H. Law

18 Genetic Disorders of the Cardiac Impulse 217Mark W.W. Russell and Stephanie Wechsler

19 Fetal Arrhythmia 241Elizabeth V. Saarel and Carlen Gomez

20 Sudden Cardiac Death in the Young 257Christopher B. Stefanelli

21 Pharmacology of Antiarrhythmic Agents 267Peter S. Fischbach

22 Transcatheter Ablation of Cardiac Arrhythmias in the Young 289Macdonald Dick II, Peter S. Fischbach and Ian H. Law

23 Nursing Management of Arrhythmias in the Young 315Sarah Leroy

Index 327

I

Background

1

Development and Structure of theCardiac Conduction System

Parvin Dorostkar

In the adult mammalian heart, the primary car-diac impulse is ultimately driven by the sinoa-trial (SA) node, which contains the leadingpacemaker cells of the mature human heart.The generated impulse then travels throughthe atrial myocardium to the atrioventricular(AV) node. Here a delay in conduction occurs,after which the impulse is rapidly transmittedfrom the AV node through the His-Purkinjesystem to the ventricular myocardium. It is theperipheral His-Purkinje system that transmitsthe impulse to the ventricular myocardium,which, in conjunction with electromechani-cal coupling, results in myocardial contractionfrom the apex of the heart toward the base ofthe heart, generating cardiac output with eachbeat.

Even though the cardiac conduction sys-tem in its function and anatomy is consideredquite separate from the working myocardiumof the heart, it is virtually indistinguishablefrom adjacent myocardial tissue by gross visu-alization. Even on a cellular and microscopiclevel the cells are indistinguishable. Cells ofthe conduction system as well as all other my-ocardial cells are capable of contraction, au-tomaticity, intercellular conduction, and elec-tromechanical coupling. These similarities

in characteristics make a focused study ofthe specialized conduction system very dif-ficult. However, the conduction system cells,once matured, exhibit subcellular elementsthat differentiate these cells from other work-ing myocytes, such as connexins (in the my-ocardial cell membrane), and contractile andcytoskeletal proteins (intramyocardial).

A number of investigators have stud-ied the embryologic formation and develop-ment of the heart. Animal models have beenused extensively to study the development ofthe heart and the cardiac conduction system.However, interspecies variability and multi-ple challenges associated with the study ofthe early embryo have made the quest to un-ravel the many interrelated factors of cardiacdevelopment difficult.

In the chick embryo, which has beenstudied in detail, the earliest development ofthe heart occurs in the cardiac progenitor cellsoriginating from the embryonic mesoderm.There are specific “heart-forming fields”where the cells will develop and produce beat-ing tissue. In chicks, cells designated to formthe heart arise lateral to the primitive streak,which can be identified during HamburgerHamilton (HH) stage 3 of chick embryo

3

4 DEVELOPMENT AND STRUCTURE OF THE CARDIAC CONDUCTION SYSTEM

a

b

d

e

c

v

f

VP

AP

VP

FIGURE 1. Formation of the cardiac tube. Transforma-tion of the flat cardiogenic crescent into a cardiac tubeis displayed. During this process the red outer contourof the myocardial crescent (grey) folds around the fusingendocardial vesicles (yellow) and passes the blue innercontour of the crescent, thereby forming the cardiac tube.AP = anterior pole, VP = venous pole, V = future ven-tricle. Reprinted with permission from AFN Moormanet al., Development of the cardiac conduction system,Circulation Research 1998; 82:629–644.

development (Figure 1). These cells migraterostrolaterally to form the lateral plate. Colorpatterns in Figure 1 show the region of theembryo that gives rise to precardiac cells,which will eventually contribute to the devel-opment of myocardium. The relative anterior–posterior positions of precardiac cells in theprimitive streak is maintained in the heartfield in the mesoderm and continues duringHH stage 5 through 7 of development. At HHstage 8, the embryo folds ventrally, generat-ing the foregut and somatic and splanchniclayers of the mesoderm. The splanchnic layerof the mesoderm contains myocardial precur-

sors. By HH stage 10, the chick heart primor-dia fuse to form a tubular heart with the ante-rior most region of the cardiac tube giving riseto an outflow region or conotruncus or bulbuscordis. In the chick embryo, the most cau-dal portion contributes to the most posteriorend of the heart and will result in the inflowregion or the sinoatrial region. This primaryheart tube undergoes peristalsis-like contrac-tions that support unidirectional flow. In themammalian heart, the formation of the cardiactube occurs in six, similar, successive stages,which support transformation of a flat cardio-genic crest into a cardiac tube. During thisprocess the outer contour of the myocardialcrescent folds around the fusing endocardialvesicles. This primitive heart tube consists ofthe endocardium with adjacent myocardiumand has slowly conducting contractions thatsupport peristaltic movements. Within thisprimitive heart tube fast-conducting atrialand ventricular myocytes develop. The fast-conducting atrial and ventricular myocytes,however, remain next to the slowly conduct-ing tissue, which eventually gives rise to theinflow tract, AV canal area, and outflow tract.As development proceeds, the slow conduct-ing areas give rise to the SA node (aroundthe inflow area), the AV node, and the slowlyconducting outflow tract, whereas the fastconducting atrial and ventricular cells giverise to the His-Purkinje system and its ramifi-cations. During development, alternating slowand fast conducting segments support unidi-rectional flow and are responsible for the em-bryonic ECG. Alternating fast and slow con-duction also prevent relaxation of the atrialor ventricular segments before contraction ofa downstream segment, therefore, minimiz-ing regurgitating blood. As polarity developsin the vertebrate heart, there is an increase inphenotypic atrial cells posteriorly and an in-crease of phenotypic ventricular cells anteri-orly. Highest pacemaker activity (highest beatfrequency) can then be observed in cells as-sociated with the intake portion of the cardiactube (atrial cells); this phenomenon occurs atthe human embryonic age of about 20 days.

DEVELOPMENT AND STRUCTURE OF THE CARDIAC CONDUCTION SYSTEM 5

DEVELOPMENT OF IMPULSEGENERATION

The early cardiac mesoderm arises fromectodermal tissue and subsequently forms thecardiac tube, which has polarity along its ante-rior posterior axis. As mentioned previously,a straight heart tube is present at about day20 of human embryonic life, while cardiaclooping occurs at about day 21. The polarityof the mammalian heart is characterized bythe predominance of an atrial tissue pheno-type posteriorly at the inflow region of theheart or upstream side of the heart and ofthe ventricular tissue phenotype anteriorly atthe outflow or downstream region of the heart.Dominant pacemaker activity and highest beatfrequency are found at the intake of the hearttube. Here an efficient contraction wave isgenerated. Cells of the primary cardiac tubeand the future sinus node region show actionpotentials resembling those of the adult pace-maker cells. These action potentials displayslow depolarization and are similar to those ofpacemaker cells that are associated with slowvoltage-gated calcium ion channels. Cells ofthe future ventricles, however, show actionpotential behavior similar to that of adult ven-tricles exhibiting action potentials that havehigh amplitudes similar to action potentialsassociated with fast voltage-gated sodiumchannels.

As the heart develops, the frequency ofthe intrinsic beat rate increases along the in-flow tract of the heart. In both birds and mam-mals, the leading pacemaker area is initiallyfound on the left side but as soon as the sinusvenosus has formed (at approximately 25 daysin the human), the right side becomes moredominant. Both right and left inflow tracts willbecome incorporated into the future, matureright atrium. “Node-like cells” develop in theright atrium. Such cells have also been foundin the myocardium surrounding the distal por-tion of the pulmonary veins in adult rats andappear to play a role in preventing regurgita-tion of blood into the pulmonary veins fromthe left atrium. How leading pacemaker cells

develop into an anatomically distinct SA nodeis still unclear.

DEVELOPMENT OF IMPULSEPROPAGATION

The primary myocardium is character-ized by action potentials that are primarilysupported by slow voltage-gated calcium ionchannels. As embryonic atrial and ventricularchambers develop, synchronous contractionsof these chambers are characterized by higherconduction velocities, which are more likelyassociated with fast voltage-gated sodiumchannels. These variations in conduction areaccompanied by the development of an adulttype ECG that reflects the sequential activa-tion of the atrial and ventricular chambersrather than the presence of a morphologicallyrecognizable conduction system. For exam-ple, a noted AV delay is present before the de-velopment of a morphologically identifiableAV node. This AV delay occurs in the regionof the AV canal, which is recognized as anarea of slow conduction. Segments of slowlyconducting primary myocardium also persistat both the inflow and outflow area of the heart.

Several theories exist regarding the de-velopment of the specialized conduction sys-tem (i.e., the AV node and its penetratingbundles and bundle branches). Using a mon-oclonal antibody against a specific neuralmarker (G1N2), several investigators havesuggested that there is a process of differ-entiation that supports the development of amyocardial ring that encircles the presump-tive foramen between the developing rightand left ventricles. These investigators sug-gest that the dorsal portion of this ring willdevelop the AV bundle whereas parts cover-ing the septum will give rise to the right andleft bundles (Figures 2 and 3). However, sev-eral investigators suggest that ventricular de-polarization undergoes a transition, where themyocardium undergoes a switch from base-to-apex depolarization of the ventricular my-ocardium to an apex-to-base depolarization


a b

dC

OFT

OFT

ERA

ERA

IFT

IFT

AVC

AVC

ELA

ELA

ERV

ERV

ELV

ELV

FIGURE 2. Formation of the cardiac chambers. Scan-ning electron photomicrographs (a and c) and schematicrepresentations (b and d) of a 3-day embryonic chickenheart, where the first signs of the ventricles emerge (aand b), and of a 37-day embryonic human heart withclearly developed ventricles (c and d). ERA = indicatesembryonic right atrium; ELA = embryonic left atrium;ELV = embryonic left ventricle; and ERV = embryonicright ventricle. The atrial segment is indicated in blue;the ventricular segment, in red; and the primary hearttube, encompassing the flanking segments, IFT, AVC,and OFT, as well as the atrial and ventricular parts, inpurple. Reprinted with permission from AFN Moormanet al., Development of the cardiac conduction system,Circulation Research 1998; 82:629–644.

in the mature, intact His-Purkinje system. Atransition in the ventricular myocardial de-polarization pattern was demonstrated usingmonoclonal antibodies to the polysialylatedneural cell adhesion molecule and the HNK-1sulfated carbohydrate epitope. In the chickembryo, HH stage 30 appears to represent acritical period in the morphogenesis of theheart. The primitive myocardium has slowconduction; however, faster conduction alongventricular myocardium has been observed asearly as HH stage 23. This fast conductionis functionally distinct from slow conductionaround HH stage 28, just before the transi-tion period. Because activation of the ventri-cles occurs base-to-apex, the developing His-Purkinje system is still thought to be relativelyimmature at this stage. At HH stage 30, thissequence reverses and becomes apex-to-base.

FIGURE 3. Development of the ventricular conductionsystem. a. Drawing of a prototypical heart, in which theposition of the ventricular conduction system is indicated,including those parts that are only present in the fetalmammalian heart. The entire system persists in the adultchicken heart. b. Section of a 5-week human heart im-munostained for the presence of GlN2 in which the posi-tion of the developing conduction system is representedin brick red. c–e. Drawings representing the developmentof the ventricular conduction system based on reconstruc-tions of GlN2 expression in developing hearts at ≈5 (c),≈6 (d), and ≈7 (e) weeks of development. See text forexplanation. RAORB = retro-aortic root branch; SB =septal branch; RAVRB = right atrioventricular ring bun-dle; LBB and RBB = left and right bundle branches,respectively; LA = left atrium; LV = left ventricle;RA = right atrium; RV = right ventricle; AO = aorta;and PT = pulmonary trunk. Reprinted with permissionfrom AFN Moorman et al., Development of the cardiacconduction system, Circulation Research 1998; 82:629–644.

The authors suggest that the switch may occurbecause the His-Purkinje system has matured,and the muscular AV junction is then able tosupport and limit the avenue of AV conductionto the His-Purkinje system, allowing rapid im-pulse propagation to the apical myocardium.The mature AV node as a nodal structurebecomes only gradually identifiable afterabout Carnegie stage 15 (5 weeks of humandevelopment).

In summary, during the process of cham-ber formation, fast conducting atrial and ven-tricular segments are being formed withinslowly conducting primary myocardium ofthe embryonic heart tube so that the car-diac tube becomes a composite of alternatingslow and fast conducting segments that persistin a more specialized fashion in the matureheart. The molecular basis underlining such


compartmentalization is still poorly under-stood and continues to be studied.

CELLULAR DEVELOPMENTOF “NODAL” PHENOTYPE

In the mature heart, the nodal myocytesdisplay a number of embryonic characteris-tics. Nodal cells are poorly distinguishablefrom surrounding myocardium in the earlyembryonic heart as they exhibit many of thesame characteristics as the surrounding my-ocardium. However, with development, it ap-pears that nodal cells retain some of the samecharacteristics as early embryonic myocytessuch as organized actin and myosin filamentsand poorly developed sarcoplasmic reticu-lum. In addition, nodal cells express differ-ent structural and cellular markers which arespecies-specific. Several classes of markershave been identified including connexins, spe-cific contractile proteins, desmin, and neuro-filament that provide specific markers for thestudy of conduction system development. Inaddition, antibodies to carbohydrate markerssuch as the polysialylated neural cell adhe-sion molecule and HNK1 have been used tostudy the development of specific regions ofthe specialized conduction tissue.

Connexins

The transmission of the electrical actionpotential is thought to be primarily associ-ated with gap junctions. Gap junctions areaggregates of membrane channels, composedof protein subunits named connexins that areencoded by a multi-gene family. Five dif-ferent connexins are expressed in the mam-malian heart including connexin 37, 40, 43,45, and 46. In the early myocardium, bothnumber and size of gap junctions are smallbut they increase during development. Thenumber of gap junctions remains scarce in thedeveloping SA node and the AV node. Thelow abundance of connexin expression in thenodes corresponds with both the slow con-duction velocities observed in the nodes and

the absence of fast sodium currents. The poorcoupling of nodal cells appears to be a require-ment for the expression of an action potentialby these nodal myocytes, which differenti-ates itself from the much more abundant atrialand/or ventricular working myocardium. Thisdifference in connexin concentration has beenan important marker for nodal-specific tissue.An abrupt rather than gradual increase in thenumber of gap junctions is found at the transi-tion of nodal tissue to working myocardium.This boundary is thought to be due to a de-crease in the number of nodal cells towards theatrial working myocardium rather than a gra-dient due to a change in molecular phenotype.

Cytoskeletal Proteins

Nodal-specific developmental expres-sion of contractile proteins such as myosinheavy chain and its isoforms, desmin andneurofilament, has been used to delineatethe sinoatrial and AV nodes. However, inter-species variability in the staining of thesemarkers does not allow enough consistent datato draw a definitive global conclusion in rela-tion to development or morphologic changesthat are specific to the conduction system orits development and differentiation.

Cell Markers

Nodal tissue seems to acquire uniquecharacteristics during development, includingthe expression of higher amounts of calcium-release channel/type-1 inositol triphosphatereceptor, gamma enolase, alpha 1 and alpha2 of the sodium pump, G-protein alpha sub-unit, and angiotensin II receptor. The role ofthese differences remains to be studied.

ANATOMIC DEVELOPMENTOF THE SPECIALIZEDCONDUCTION TISSUE

The AV node structure appears to arisefrom “primordia cells” that originate from themyocardium of the posterior wall of the AV


canal or primitive endocardial cushions. Theprimordia later forms both the AV node andthe His bundle. The Tendon of Todaro and thecentral fibrous body are later formed from theinferior endocardial cushions.

Although several authors have suggestedthat the specialized conduction tissue mayoriginate from neural crest tissue, the originof the myocytes of the specialized conductionsystem has been established by recent studiesto be from the cardiomyocyte, rather than theneural crest. By a process that may involveET-1 (endothelin-1) signaling, neural crest-derived cells have been reported to migrateto regions of the central conduction systemand may play an as yet undefined role in thedevelopment of the definitive mature structureof the AV conduction system.

Genetic, molecular, functional, and mor-phologic evidence suggests that the ventric-ular conduction system develops separatelyand may originate from the trabecular com-ponent of the developing ventricles. Whilethe trabecular portion of the heart contractswithout a specialized conduction system viaslow, homogeneous cell-to-cell propagationduring early embryogenesis, a faster more ma-ture form of conduction occurs when the His-Purkinje system is engaged and involved incontraction. An important transition time hasbeen described (stage 30) where a specializedHis-Purkinje system emerges (in both formand function), defining a critical time period indevelopment at which time the electrical acti-vation of the myocardium switches from base-to-apex to apex-to-base with preferential elec-trical activation over the His-Purkinje system.

In summary, recent evidence suggeststhat the specialized conduction system de-velops from further differentiation of localmyocytes. The molecular signals for thisdifferentiation are unknown. The exact stimu-lants for differentiation, selective cellular po-tency, and variable cell protein and channelexpression and their roles in differentiationwarrant further study. The variable role andinteractions of these factors in embryogene-sis and differentiation continue to be poorly

understood and provide the groundwork forfurther investigation using advanced tech-niques to increase understanding of the de-veloping conduction system.

ANATOMY OF THE MATURECARDIAC CONDUCTION SYSTEM

The specialized conduction system of thehuman heart consists of a single SA node,atrial and intra-nodal pathways, the AV node,the His-Purkinje system, the right and leftbundle branches of the His-Purkinje system,and the peripheral His-Purkinje system.

The SA node is the dominant pacemakerof the heart and lies in the right atrium at thesuperior vena cava/right atrial junction, onemm below the epicardium of the sulcus ter-minalus. It was first described in the early1900s. The SA node appears to have the shapeof an inverted comma, descriptively contain-ing a head, body, and tail. It tapers both me-dially and laterally and bends backwards to-ward the left and then downward. The SAnode is supplied by a relatively large artery,which courses through the node giving offbranches to the sinus node and adjacent atrialmyocardium. It originates from the right coro-nary artery about 55% of the time and from theleft circumflex artery in about 45% of cases.

It is still somewhat controversial whetherpreferential intranodal pathways exist. Prefer-ential conduction or impulse propagation maybe associated with the underlying anatomicdifferences in muscle density or muscle fiberorientation and/or the thickness of the rightatrial wall and its pectinate muscles. Someauthors argue that “specialized pathways” arethought to consist of aggregations or concen-trations of myocardial muscle fibers, bridgingthe SA and AV nodes or the right atrium to theleft atrium. These authors propose three in-ternodal tracts: the anterior internodal fibers,thought to have two components: Bachman’sBundle, which bridges right and left atriumand “descending branches,” which descend inthe intra-atrial septum. The middle internodal


tracts, also known as Wenchebach’s bundle,are thought to arise from the posterior portionof the sinus node and then descend within theinta-atrial septum, anterior to the fossa ovale.The posterior internodal tracts, also known asThorel’s pathway, are thought to exit the si-nus node posteriorly and then descend withinthe crista terminalis, traversing through theEustachian ridge, entering the AV node pos-teriorly in the mouth of the coronary sinus.

The AV node is located in the posterosep-tal area, primarily on the right atrial side,in the region known as the triangle of Koch.This triangle is defined by the Tendon ofTodaro, the edge of the tricuspid valve andthe edge of the mouth of the coronary sinus,which marks the base of the triangle. In theadult, the triangle measures 14–20 mm in itslongest apex-to-base dimension. The AV nodeis located mostly at the base of this triangleand on the right side of the central fibrousbody. In children, the triangle of Koch varieswith age and size of the child. It is consid-ered to be a complex structure. Descriptively,the AV node abuts the mitral valve annulusand tricuspid valve annulus with its poste-rior margin abutting the coronary sinus. Un-like the bundle of His, the AV node cannot beseen visually, nor does it generate a distinct,recordable signal during electrophysiologictesting. Therefore, the knowledge of its loca-tion is discerned by implied mechanisms dur-ing electrophysiologic mapping techniques.The anterior portion or distal ends of the AVnode blend with the bundle of His, which pen-etrates the central fibrous body. The AV nodeis thought to be a flattened, oblong structurewith multiple extensions, some extending tothe left atrium. The AV node is also thoughtto have extensions with a compact portion ofthe node existing more closely associated withthe perimembranous portion of the ventricularseptum. The AV node is usually supplied byan AV nodal artery, which arises from the rightcoronary artery in 90% of cases, and from theleft circumflex artery in 10% of the cases.

The bundle of His consists of extensionsof the AV node. These extensions occur distal

to the compact AV node. The bundle of His ischaracterized by fibers, which are organizedin parallel channels or strands. These fibersare surrounded by a fibrous sheath more prox-imally and are, therefore, well insulated. Thebundle of His penetrates the fibrous body andproceeds anteriorly descending towards theAV septum where it divides into the right andleft bundle branches.

The right bundle is a relatively well de-fined and easily dissectible structure situatedbeneath the epicardium on the right side. Theright bundle branch proceeds along the freeedge of the moderator band to the base of theanterior papillary muscles in the right ventri-cle and along the septal band to the apex ofthe right ventricle.

The left bundle passes down the left sideof the intraventricular septum and emerges be-low the posterior cusp of the aortic valve. Incontrast to the right bundle, the left bundlebreaks up almost immediately into a numberof small fan-shaped branches, which proceeddown the smooth aspect of the left side ofthe intraventricular septum. The bundle con-tains two major branches including an antero-superior division and a postero-inferior divi-sion. The antero-superior division is relativelylong and thin whereas the postero-inferior di-vision is relatively short and thick. The antero-superior division is closer to the aortic valvewhereas the postero-inferior division suppliesthe posterior and inferior aspect of the leftventricle.

Parasympathetic supply to the my-ocardium arises from branches from the rightand left vagus nerves. The right vagus nervesupplies primarily the SA node; the left va-gus nerve supplies primarily the AV node. TheSA node is thought to originate from the righthorn of the sinus venosus and is, therefore,connected with the right vagus nerve. The AVnode is thought to originate from the left hornof the sinus venosus. The sympathetic systeminnervates the atrial and ventricular muscula-ture as well.

With the advent of newer technologyand the possibility of curative radiofrequency


ablation of anomalous conduction, it is veryimportant to have a sound understanding ofthe AV junction, since the description andtreatment of arrhythmias is crucially depen-dent on an accurate understanding of theunderlying anatomy. A consensus statementfrom the cardiac Nomenclature Study Grouphas been advocated and published in Circula-tion. This nomenclature divides the AV junc-tion into anatomically distinct and separateregions for description of accessory pathwaylocation and better health care professionalcommunication. In addition, it is importantto appreciate developmental changes, as thesehave important implications for the study ofthe electrophysiologic structures in the pedi-atric age group and associated approach toablation of an underlying abnormal substrate,such as that seen in dual AV nodal physiology.

ANATOMY OF THE CONDUCTIONSYSTEM IN CONGENITAL HEARTDISEASE

With congenital heart disease, develop-ment of the AV node and His-Purkinje systemdepend on appropriate atrial and ventricularorientation and proper alignment of the atrialand ventricular septum with appropriate clo-sure of septal defects.

Atrioventricular Septal Defects

A most obvious abnormality occurs inassociation with AV septal defects (otherwiseknown as canal defects or endocardial cushiondefects) where abnormalities in AV conduc-tion system occur in association with abnor-mal development of the endocardial cushions.In these defects, the AV node is inferiorly andposteriorly displaced. The AV node is situatedanterior to the mouth of the coronary sinus ata site just below where the base of the triangleof Koch would have occurred if the crux ofthe heart were properly formed. A commonHis bundle extents along the lower rim of the

inlet portion of the ventricular septal defectresulting in a posterior course of the intraven-tricular conduction network. The classic ECGpattern inscribes a superior axis (vector) as-sociated with this course of the His-Purkinjesystem.

In patients with ventricular septal de-fects, the AV node is usually in its anatomi-cally correct position. The exceptions includeventricular septal defects that are inlet in typeand, therefore, support a more inferior andposterior propagation of initial ventricular ac-tivation. The course of the common bundle orits branches relative to the ventricular septaldefect may exhibit a longer common bundle.In patients with either inlet, perimembrane-ous, or outlet ventricular septal defects, theHis bundle and its branches will typically befound on the lower crest of the effect, and willtend to deviate slightly towards the left sideof the defect. Therefore, in postoperative pa-tients, a ventricular septal patch may overlaythe region of interest where a His bundle couldbe recorded. In these patients, the amplitudeand frequency of a His signal may be variableand perhaps diminished.

Atrioventricular Discordance

Other abnormalities of the conductionsystem are associated with AV discordanceeither in biventricular hearts or in hearts withsingle ventricle physiology. In these patients,the AV node is situated outside the triangle ofKoch and is elongated in morphology. Usu-ally, the conduction system extends mediallyand runs along the right-sided mitral valve andpulmonary valve. If there is a ventricular sep-tal defect, conduction usually occurs along theupper border of the septal defect. It is wellknown that the AV conduction system is tena-cious in these patients and is sometimes asso-ciated with the development of spontaneousAV block.

Another type of AV discordance occursin atrial situs inversus with D-loop ventri-cles. Because there is evidence to suggestembryologic development of more than one


AV node with one main node predominantlyremaining in this malformation, the posteriorAV node seems to persist. These patients will,therefore, have a left-sided triangle of Koch,but will usually have an associated AV nodelocated posteriorly and inferiorly and may beinferiorly displaced; if there is the presenceof a ventricular septal defect, the conductionsystem will run along the inferior border ofthe septal defect. These findings suggest thatthe AV node follows or is associated primarilywith the morphologic right atrium.

Ventriculoatrial Discordance orTransposition of the Great Arteries

Abnormalities of outflow, and otherconotruncal abnormalities and septal defectsremote from the crux of the heart, usually donot effect the position and the location of theconduction system. In isolated transpositionof the great arteries without a ventricular sep-tal defect, there is minimal influence on thelocation of the conduction system. The AVanatomy is normal and there is normal AVconcordance allowing for normal AV conduc-tion system development. These patients haveabnormalities of the outflow tracts. Many pa-tients with D-transposition of the great ar-teries have undergone surgical repairs witheither a Mustard or a Senning procedure, dur-ing which the atrial blood is rechanneled viaa baffle to the appropriate ventricle. There isa high incidence of SA node dysfunction lateafter Mustard or Senning procedures. Thesepatients are also at higher risk for the develop-ment of atrial flutter in association with thesesurgeries. It is important to understand theatrial surgery performed in such patients atthe time of electrophysiologic studies to max-imize outcomes of ablation therapies.

For both Mustard and Senning proce-dures, superior caval blood and inferior cavalblood are directed via an intra-atrial baffle tothe left ventricle. This baffle usually excludesthe AV conduction system. This precludes di-rect catheter access to the His bundle area bya standard transvenous approach. In these pa-

tients, a proximal left bundle may be recordedfrom the left ventricular septum from the me-dial aspect of the mitral valve annulus from thevenous side. A His signal can also be recordedor obtained from the non coronary cusp of theaortic valve or from the right ventricle after thecatheter has been advanced through the aorticvalve into the right ventricle and back towardsthe right-sided tricuspid valve (via a transar-terial approach) to a position near the centralfibrous body. Formal landmarks of triangle ofKoch remain present, but can be distorted byprevious surgery, and by the fact that the eu-stachian valve is often cut or intersected aspart of the Mustard or the Senning procedures.In these patients, the coronary sinus can be leftto drain to the pulmonary venous atrium orthe systemic atrium. Regardless, recognitionof these postoperative changes is crucial forpatients with supraventricular tachycardia inassociation with transposition of the great ar-teries, which may include atrial tachychardiasor AV node reentry tachycardias.

Twin Atrioventricular Nodes

These anatomic variants can be associ-ated with dual compact AV nodes where bothan anterior and posterior nodal structures arepresent. In these cases, the posterior nodeseems to be a more developed structure and ul-timately forms the connection to the His bun-dle. These patients may experience AV reentrytachycardia using both AV nodes.

Tricuspid Atresia

In tricuspid atresia, the AV node is typ-ically associated with the atretic tricuspidvalve in the right atrium. Studies confirm thatthe compact AV node in tricuspid atresia issituated in the right atrium inside the under-developed and diminutive triangle of Koch.The orifice of the coronary sinus can stillbe identified as the base of the triangle, butthe tricuspid valve may be small and diffi-cult to identify. A very short common bun-dle is described running towards the central


fiber body, which then descends along theseptum. Should a ventricular septal defectbe present, the conduction system tends totravel along the lower margin of the ventricu-lar septal defect on the side of the septum be-tween the rudimentary right ventricle and leftventricle.

Ebstein’s Anomaly

Ebstein’s Anomaly is associated with anormal atrioventricular node and triangle ofKoch. However, because of anatomic distor-tions associated with displacement of the sep-tal and posterior leaflets of the tricuspid valvein association with right atrial and right ven-tricular enlargement, identification of the nor-mal anatomy may be difficult. In these cases,the coronary sinus may serve as an especiallyuseful marker for the delineation of the trian-gle of Koch. Because the anatomic and elec-trophysiologic atrioventricular groove may bediscrepant in patients with Epstein’s anomaly,it might be helpful to perform a right coronaryartery angiogram to define the anatomic atri-oventricular groove. This cardiac abnormal-ity is often associated with one or more ac-cessory pathways and carries with it a higherincidence of atrial arrhythmias as well. Anunderstanding of the anatomy and an effortto delineate present distortions can be criti-cal for successful ablation at the time of theelectrophysiologic study.

Heterotaxy Syndromes

These syndromes encompass a complexset of defects associated with “sidedness” con-fusion of organs in the thorax and/or abdomen.Two general subgroups exist: those with rightatrial isomerism or “bilateral right sidedness”and those with left atrial isomerism or “bilat-eral left sidedness.” Typical cardiac featuresof bilateral right sidedness or asplenia includean intact inferior vena cava, unroofed coro-nary sinus, total anomalous pulmonary ve-nous return, complete AV septal defect, ven-tricular inversion, transposition of the great

arteries or double outlet right ventricle withpulmonary stenosis/atresia. Features of dou-ble left-sidedness include interrupted inferiorvena cava, total or partial anomalous pul-monary venous return, common or partial AVseptal defects, normally related great vesselsor double outlet right ventricle with or withoutpulmonary stenosis. The mode of inheritanceof heterotaxy syndromes remains uncertain,although there is some suggestion that theremay be autosomal dominant and recessiveforms, with the majority of cases being due tomutations in genes that encode sidedness inassociation with environmental insults. Wrenand colleagues reviewed the electrocardio-grams of 126 patients with atrial isomerism,67 with left atrial isomerism and 59 with rightatrial isomerism. The cardiac rhythm in pa-tients with left atrial isomerism, with sup-posed “absence” of normal sinus nodal tissue,tends to exhibit an atrial rhythm with a varietyof atrial pacemaker locations as manifested inthe wide range of P-wave axes recorded. Incontract, patients with right atrial isomerism,with supposed “bilateral” sinus nodes, tendedto exhibit P-wave axes predictive of either ahigh right-sided (between 0 and 89◦) or highleft-sided (between 90◦ and 179◦) atrial pace-maker location. In addition, patients with dou-ble left-sidedness exhibit sinus node dysfunc-tion (at 10-year follow-up, 80%). In addition,there are instances of AV nodal abnormalities(15%); in contrast there were none noted in pa-tients with double right-sidedness. In asplenia(double right-sidedness), ventricular inver-sion is common. The incidence of completeheart block in patients with L-transpositionhas been reported to be between 17% and22%. Approximately 3% to 5% of patientswith L-transposition are born with completeheart block; heart block thereafter occurs ap-proximately 2% per year. All cases of AVblock were reportedly spontaneous, with nocases as a consequence of heart surgery orother mechanical insult to the AV node.

Finally, an entity of twin AV nodes hasbeen described where there is co-existence oftwo distinct AV nodes (Monckeberg’s sling).


Reciprocating tachycardias involving bothnodes can be the source of supraventriculartachycardia in these patients. Catheter abla-tion can successfully treat these patients. Thisentity seems to be more common in patientswith right atrial isomerism.

In summary, patients with complex con-genital heart disease, with or without hetero-taxy, represent both a challenge to the surgeonfor repair and a window for the developmentalbiologist into the development of the cardiacconduction system.

SUGGESTED READING

1. Anderson RH, Ho SY. The architecture of the sinusnode, the atrioventricular conduction axis, and theinternodal atrial myocardium. J Cardiovasc Elec-trophysiol 1998;9:1233–1248.

Development

2. Moorman AF, de Jong F, Denyn MM, Lamers WH.Development of the cardiac conduction system.Circ Res 1998;82:629–644.

3. Fishman MC, Chien KR. Fashioning the vertebrateheart: earliest embryonic decisions. Development1997;124:2099–2117.

4. Garcia-Martinez V, Alvarez IS, Schoenwolf GC.Locations of the ectodermal and nonectodermalsubdivisions of the epiblast at stages 3 and 4 ofavian gastrulation and neurulation. J Exp Zool1993;267:431–446.

5. Sedmera D, Pexieder T, Vuillemin M, et al. Devel-opmental patterning of the myocardium. Anat Rec2000;258:319–337.

6. Ar A, Tazawa H. Analysis of heart rate in develop-ing bird embryos: effects of developmental modeand mass. Comp Biochem Physiol A Mol IntegrPhysiol 1999;124:491–500.

7. Akiyama R, Matsuhisa A, Pearson JT, Tazawa H.Long-term measurement of heart rate in chickeneggs. Comp Biochem Physiol A Mol Integr Physiol1999;124:483–490.

8. Moriya K, Hochel J, Pearson JT, Tazawa H. Car-diac rhythms in developing chicks. Comp BiochemPhysiol A Mol Integr Physiol 1999;124:461–468.

9. Broekhuizen ML, Gittenberger-de Groot AC, Baas-ten MJ, et al. Disturbed vagal nerve distributionin embryonic chick hearts after treatment withall-trans retinoic acid. Anat Embryol (Berl)1998;197:391–397.

10. Aranega AE, Velez MC, Gonzalez FJ, et al. Mod-ulation of cardiac intermediate filament proteins in

the chick heart by fibric acid derivatives. Eur J Mor-phol 1995;33:421–431.

11. Velez C, Aranega AE, Fernandez JE, et al.Modulation of contractile protein troponin-T inchick myocardial cells by catecholamines dur-ing development. Cell Mol Biol (Noisy-le-grand)1994;40:1189–1199.

12. Anderson RH. The developing heart in chick em-bryos. Circulation 1990;82:1542–1543.

13. Arguello C, Alanis J, Valenzuela B. The early de-velopment of the atrioventricular node and bundleof His in the embryonic chick heart. An electro-physiological and morphological study. Develop-ment 1988;102:623–637.

14. Chuck ET, Freeman DM, Watanabe M, RosenbaumDS. Changing activation sequence in the embryonicchick heart. Implications for the development of theHis-Purkinje system. Circ Res 1997;81:470–476.

15. Van Mierop L. Location of Pacemaker in chick em-bryo heart at the time of initiation of heart beat. AmJ Physiology 1967;212:407–415.

16. Anderson RH AB, AC Weninck, et al. The Devel-opment of the Cardiac Specialized Tissue. In: TheConduction System of the Heart: Structure, Func-tion and Clinical Implications, ed 1: The Hague,Martinus Nijhoff Publishing; 1976:3–28.

17. Moorman AF, de Jong F, Lamers WH. Developmentof the conduction system of the heart. Pacing ClinElectrophysiol 1997;20:2087–2092.

18. Moorman A, Webb S, Brown NA, et al. Develop-ment of the heart: (1) formation of the cardiac cham-bers and arterial trunks. Heart 2003;89:806–814.

19. Manasek FJ, Burnside MB, Waterman RE. My-ocardial cell shape change as a mechanism ofembryonic heart looping. Dev Biol 1972;29:349–371.

20. Manasek FJ, Monroe RG. Early cardiac mor-phogenesis is independent of function. Dev Biol1972;27:584–588.

21. Manasek FJ, Burnside B, Stroman J. The sensitivityof developing cardiac myofibrils to cytochalasin-B (electron microscopy-polarized light-Z-bands-heartbeat). Proc Natl Acad Sci USA. 1972;69:308–312.

22. Moorman AF, Lamers WH. A molecular approachtowards the understanding of early heart develop-ment: an emerging synthesis. Symp Soc Exp Biol1992;46:285–300.

23. Watanabe MDR, Libbus I, Chuck ET. The Form andFunction of the Developing Cardiac ConductionSystem. In: Clark EB NM, Takao A., ed. Etiologyand Morphogenesis of Congenital Heart Disease:Twenty Years of Progress in Genetics and Devel-opmental Biology: Armonk, NY: Futura PublishingCo. Inc.; 2000.

24. Fromaget C, el Aoumari A, Gros D. Distributionpattern of connexin 43, a gap junctional protein,


during the differentiation of mouse heart myocytes.Differentiation 1992;51:9–20.

25. Davis LM, Rodefeld ME, Green K, et al. Gap junc-tion protein phenotypes of the human heart andconduction system. J Cardiovasc Electrophysiol1995;6:813–822.

26. Verheijck EE, Wessels A, van Ginneken AC, et al.Distribution of atrial and nodal cells within the rab-bit sinoatrial node: models of sinoatrial transition.Circulation 1998;97:1623–1631.

27. Domenech-Mateu JM, Arno Palau A, MartinezPozo A. The development of the atrioventricularnode and bundle of His in the human embryonicperiod. Rev Esp Cardiol 1993;46:421–430.

28. Nakagawa M, Thompson RP, Terracio L, Borg TK.Developmental anatomy of HNK-1 immunoreac-tivity in the embryonic rat heart: co-distributionwith early conduction tissue. Anat Embryol (Berl)1993;187:445–460.

29. Development of the Cardiac Conduction Sys-tem. Symposium, held at the Novartis Foundation,London, May 21–21, 2003. Editors: Chadwick DJ,Goode J. John Wiley & Sons, Ltd, Chichester, UK.

Structure

30. Schamroth L. The Disorders of Cardiac Rhythm inDisorders of Impulse Formation. Basic Principles.In: The Disorders of Cardiac Rhythm: BlackwellScientific Publications; 1971.

31. Keith AFM. The form and nature of the muscu-lar connections between the primary divisions ofthe vertebrate heart. J Anat Physiol 1907;41:172–189.

32. Anderson KR, Ho SY, Anderson RH. Location andvascular supply of sinus node in human heart. BrHeart J 1979;41:28–32.

33. Anderson RH, Ho SY, Smith A, Becker AE.The internodal atrial myocardium. Anat Rec1981;201:75–82.

34. McGuire MA, Johnson DC, Robotin M, et al.Dimensions of the triangle of Koch in humans. AmJ Cardiol 1992;70:829–830.

35. Ho SY. Embryology and Anatomy of the nor-mal and abnormal conduction system. In: GillettePCaGA, ed. Pediatric Arrhythmias: Electrophys-iology and Pacing. Philadelphia: WB Saunders;1990.

36. Goldberg CS, Caplan MJ, Heidelberger KP, DickM, 2nd. The dimensions of the triangle of Koch inchildren. Am J Cardiol 1999;83:117–20, A9.

37. Anderson RH, Becker AE, Brechenmacher C, et al.The human atrioventricular junctional area. A mor-phological study of the A-V node and bundle. EurJ Cardiol 1975;3:11–25.

38. Anderson RH, Brown NA. The anatomy of the heartrevisited. Anat Rec 1996;246:1–7.

39. Anderson RH, Ho SY, Becker AE. Anatomy ofthe human atrioventricular junctions revisited. AnatRec. 2000;260:81–91.

40. Bharati S. Anatomy of the atrioventricular conduc-tion system. Circulation. 2001;103:E63–4.

41. Dean JW, Ho SY, Rowland E, et al. Clinicalanatomy of the atrioventricular junctions. J Am CollCardiol 1994;24:1725–1731.

42. Quan KJ, Lee JH, Van Hare GF, et al. Identificationand characterization of atrioventricular parasympa-thetic innervation in humans. J Cardiovasc Electro-physiol 2002;13:735–739.

43. Quan KJ, Van Hare GF, Biblo LA, et al. Endocardialstimulation of efferent parasympathetic nerves tothe atrioventricular node in humans: optimal stim-ulation sites and the effects of digoxin. J Interv CardElectrophysiol 2001;5:145–152.

44. Quan KJ, Lee JH, Geha AS, et al. Characteriza-tion of sinoatrial parasympathetic innervation in hu-mans. J Cardiovasc Electrophysiol 1999;10:1060–1065.

45. Cosio FG, Anderson RH, Becker A, et al. Liv-ing anatomy of the atrioventricular junctions. Aguide to electrophysiological mapping. A Con-sensus Statement from the Cardiac Nomencla-ture Study Group, Working Group of Arrhythmias,European Society of Cardiology, and the Task Forceon Cardiac Nomenclature from NASPE. NorthAmerican Society of Pacing and Electrophysiology.Eur Heart J 1999;20:1068–1075.

46. Ho SY, McComb JM, Scott CD, et al. Morphol-ogy of the cardiac conduction system in patientswith electrophysiologically proven dual atrioven-tricular nodal pathways. J Cardiovasc Electrophys-iol 1993;4:504–512.

47. Dick M, 2nd, Norwood WI, Chipman C, CastanedaAR. Intraoperative recording of specialized atri-oventricular conduction tissue electrograms in 47patients. Circulation 1979;59:150–160.

48. Feldt RE, Puga WD, Seward FJ, et al. AtrialSeptal Defects and Atrioventricular Canal. In:Adams FE, GC, ed. Heart Disease in Infants,Children and Adolescents: Williams and Wilkins;1983.

49. Allwork SP, Bentall HH, Becker AE, et al. Con-genitally corrected transposition of the great arter-ies: morphologic study of 32 cases. Am J Cardiol1976;38:910–923.

50. Anderson RH, Becker AE, Arnold R, Wilkinson JL.The conducting tissues in congenitally correctedtransposition. Circulation 1974;50:911–923.

51. Anderson RH, Danielson GK, Maloney JD,Becker AE. Atrioventricular bundle in correctedtransposition. Ann Thorac Surg 1978;26:95–97.

52. Suzuki K, Ho SY, Anderson RH, et al. Interventric-ular communication in complete atrioventricular


septal defect. Ann Thorac Surg 1998;66:1389–1393.

53. Moorman AF, de Jong F, Denyn MM, Lamers WH.Development of the cardiac conduction system.Circ Res 1998;82:629–644.

54. Mayer ACRJJ. Cardiac Surgery of the neonateand infant D-Transposition of the Great Arteries.Philadelphia: WB Saunders; 1994.

55. Rhodes LA, Wernovsky G, Keane JF, et al. Ar-rhythmias and intracardiac conduction after the ar-terial switch operation. J Thorac Cardiovasc Surg1995;109:303–310.

56. Collins KK, Love BA, Walsh EP, et al. Locationof acutely successful radiofrequency catheter ab-lation of intraatrial reentrant tachycardia in pa-tients with congenital heart disease. Am J Cardiol2000;86:969–974.

57. Triedman JK, Bergau DM, Saul JP, et al. Efficacyof radiofrequency ablation for control of intraatrialreentrant tachycardia in patients with congenitalheart disease. J Am Coll Cardiol 1997;30:1032–1038.

58. Wenink AC. Congenitally complete heart blockwith an interrupted Monckeberg sling. Eur J Car-diol 1979;9:89–99.

59. Becker MDRAA. The conduction system of theheart. London: Butterworth-Heineman; 1983.

60. Kajitani M, Ezeldin AK, Neuhauser JH. Wolff-Parkinson-White syndrome in previously undi-agnosed Ebstein’s anomaly. J Ark Med Soc2004;100:362–364.

61. Nikolic G. Tachycardia in Ebstein’s anomaly. HeartLung 2003;32:347–349.

62. Ai T, Ikeguchi S, Watanuki M, et al. Successfulradiofrequency current catheter ablation of acces-sory atrioventricular pathway in Ebstein’s anomalyusing electroanatomic mapping. Pacing Clin Elec-trophysiol 2002;25:374–375.

63. Mabo P. Ebstein’s anomaly. Rhythm disordersand their treatment. Arch Mal Coeur Vaiss2002;95:522–524.

64. Chauvaud SM, Brancaccio G, Carpentier AF. Car-diac arrhythmia in patients undergoing surgicalrepair of Ebstein’s anomaly. Ann Thorac Surg2001;71:1547–1552.

65. Ho SY, Fagg N, Anderson RH, et al. Disposition ofthe atrioventricular conduction tissues in the heartwith isomerism of the atrial appendages: its rela-tion to congenital complete heart block. J Am CollCardiol 1992;20(4):904–910.

2

Physiology of the CardiacConduction System

Peter S. Fischbach

The diagnosis and management of cardiac ar-rhythmias has progressed rapidly as a science.Advances in the ability to diagnose and eithersuppress or eliminate arrhythmic substrateshas taken an exponential trajectory. Whetherutilizing three-dimensional electroanatomicmapping systems for examining complex ar-rhythmias in patients with palliated congen-ital heart disease or genetic analysis in asearch for evidence of heritable arrhythmiasyndromes, technological advances have im-proved our ability to observe, diagnosis, andmanage rhythm disturbances in patients fromfetal life through adulthood. To fully harnessthe possibilities offered by these new tech-nologies, a detailed understanding of cardiacanatomy and cellular electrophysiology isimperative.

The orderly spread of electrical ac-tivity through the myocardium is a well-choreographed process involving the coor-dinated actions of multiple intracellular andmembrane proteins. Abnormalities in thephysical structure of the heart or the func-tion of these cellular proteins may serve as thesubstrate for arrhythmias. Cardiac myocyteslike other excitable cells maintain an electri-cal gradient across the cell membrane. Various

proteins including ion channels, ion pumps,and ion exchangers span the membrane con-tributing to the voltage difference between theinside and outside of the cell. Because theseintegral membrane proteins, along with mem-brane receptors and regulatory proteins, formthe basis of the electrophysiologic propertiesof the heart, a knowledge of their structureand function is necessary to understand fullycardiac arrhythmias, as well as for the appro-priate selection of antiarrhythmic pharmaco-logical agents.

RESTING MEMBRANEPOTENTIAL

At rest, cardiac myocytes maintain avoltage gradient across the sarcolemmalmembrane with the inside being negativelycharged relative to the outside of the cell.The sarcolemmal membrane is a lipid bilayerthat prevents the free exchange of intracel-lular contents with the extracellular space.The transmembrane potential is generated byan unequal distribution of charged ions be-tween the intracellular and extracellular com-partments. The maintenance of the resting

17

18 PHYSIOLOGY OF THE CARDIAC CONDUCTION SYSTEM

membrane potential is an active, energy de-pendent process relying in part on ion chan-nels, ion pumps, and ion exchangers, as wellas by large intracellular non-mobile anionicproteins. The ions are not free to move acrossthe membrane and can only do so through theselective ion channels or via the pumps andexchangers. The net result is a resting mem-brane potential generally ranging from −80 to−90 mV. The most important membrane pro-teins for establishing the resting membranepotential are the Na+/K+-ATPase (ion ex-changer) and the inwardly rectifying potas-sium channel (IK). The Na+/K+-ATPase isan electrogenic pump that exchanges threesodium ions from the inside of the cell fortwo potassium ions in the extracellular space,resulting in a net outward flow of positivecharge.

The unequal distribution of charged ionsacross the sarcolemmal membrane leads toboth an electrical and a chemical force causingthe ions to move into or out of the cell. If themembrane is permeable to only a single ionat a time, than for each ion, there is a mem-brane potential, the “equilibrium potential,”at which there is no net driving force actingon the ion. The equilibrium potential may becalculated if the ionic concentrations on bothsides of the membrane are known using theNernst equation:

Ex = RT/F ln[X]o/[X]i.

In this equation, R = the gas constant, T =absolute temperature, F = the Faraday con-stant and X is the ion in question. As anexample, the usual intracellular and extracel-lular concentration of potassium is 4.0 mMand 140 mM, respectively. Substituting thesevalues into the Nernst equation gives thefollowing values:

Ek = −61 ln[4]/[140] = −94.

At rest, the sarcolemmal membrane is nearlyimpermeable to sodium and calcium ionswhile the conductance (conductance = 1/re-sistance) for potassium ions is high. Itis not surprising therefore that the resting

membrane potential of most cardiac myocytesapproaches the equilibrium potential forpotassium. The sarcolemmal membrane,however, is a dynamic structure with chang-ing permeability to various ions with a re-sultant change in the membrane potential. Ifthe cellular membrane were permeable onlyto potassium then the Nernst equation wouldsuffice to describe the membrane potentialfor all circumstances. As the membrane be-comes permeable to various ions at differ-ent moments in time during the action po-tential, the Nernst equation is insufficientto fully describe the changes in the alter-ation of the membrane potential. The mem-brane potential at any given moment maybe calculated if the corresponding instanta-neous intra- and extracellular concentrationsof the ions and the permeability of the respec-tive ion channels are known. The Goldman-Hodgkin-Katz equation describes the mem-brane potential for any given set of concen-trations and permeability’s (P). The equationis:

Vm = − RT/F ln {PK[K+]i + PNa[Na+]i

+ PCl[Cl+]i}/{PK[K+]o + PNa[Na+]o

+ PCl[Cl+]o}.The Goldman-Hodgkin-Katz equation moreclosely approximates the cellular potentialthan the Nernst equation because it accountsfor the permeability of the membrane for allactive ions. This equation can also be usedto computer model single cells and cellularsyncytia.

ION CHANNELS

The lipid bilayer that makes up the sar-colemmal membrane has a high resistance tothe flow of electrical charge and therefore re-quires specialized channels to allow the selec-tive movement of ions into and out of the cell.Ion channels are macromolecular proteins thatspan the sarcolemmal membrane and providea low resistance pathway for ions to enter or

PHYSIOLOGY OF THE CARDIAC CONDUCTION SYSTEM 19

exit the cell. The ion channels are selectivefor specific ions and upon opening providea low resistance pathway that allows ions topass down their electrochemical gradient. Theion channels have three general properties: (1)a central water filled pore through which theions pass; (2) a selectivity filter; and (3) a gat-ing mechanism to open and close the channel.The channels may be classified not only bytheir selectivity for specific ions, but also bythe stimulus that causes the channel to open.Channels may open in response to changes inthe transmembrane potential (voltage gated)in response to activation with various ligands,in response to mechanical forces (stretch ac-tivated), and in response to changes in themetabolic state of the cell (ATP gated potas-sium channels).

Sodium Channels

The sodium current is the principal cur-rent responsible for cellular depolarization inatrial, ventricular, and Purkinje fibers. The

rapid flow of ions through the sodium channelpermits rapid depolarization of the sarcolem-mal membrane and rapid conduction of theelectrical signal. Sodium channels are closedat normal hyperpolarized resting membranepotentials. When stimulated by membrane de-polarization, they open allowing the rapid in-flux of sodium ions, which changes the mem-brane potential from −90 mV towards theequilibrium potential for sodium (+40 mV).The channel inactivates rapidly over a fewmilliseconds in a time dependent fashion.That is, even in the face of a sustained depo-larized membrane potential, the channel willclose after a short time.

The sodium channels are proteins com-posed of a large pore forming an alpha subunitand two smaller regulatory beta subunits. Thealpha subunit consists of four homologous do-mains, each of which consists of six trans-membrane segments (S1–S6, Figure 1), a mo-tif that is consistent across the voltage-gatedion channels. The transmembrane segmentsare hydrophobic and have an alpha-helical

FIGURE 1. Top: Drawing of a voltage-gated sodium channel. The channel is composed of four domains, each of whichhas six membrane spanning hydrophobic helical segments. The fourth transmembrane segment is highly charged andacts as the voltage sensor for the channel. The linker segment between the 5th and 6th transmembrane segment in eachdomain bends back into the channel pore and is important in channel selectivity and gating. Bottom: This idealizeddrawing viewed from the extracellular surface demonstrates how the four domains organize to form a single pore withthe S5–S6 linker segment of each domain contributing to the pore. (Downloaded from the internet).

20 PHYSIOLOGY OF THE CARDIAC CONDUCTION SYSTEM

conformation. The fourth transmembranesegment (S4) in each domain is highly chargedwith arginine and lysine residues located at ev-ery third position. The S4 segment acts as thevoltage sensor for the channel with membranedepolarization causing an outward movementof all of the S4 domains leading to an openingof the transmembrane pore. The channel poreis formed by the S5 and S6 segments of eachof the four domains in addition to the extra-cellular linker between S5 and S6. The trans-membrane segments are linked by short loops,which alternate between intra- and extracellu-lar. The extracellular linker loop between S5and S6 is particularly long and curves backinto the lipid bilayer to line the pore throughwhich the ions pass. The four extracellularS5–S6 linker loops contribute to the selectiv-ity of the channel.

The function of the beta subunit contin-ues to be investigated. Much of the early workon beta subunits was in neuronal cells and re-cently attention has turned to cardiac cells.The beta subunits, in addition to modulatingchannel gating properties, are cell adhesionmolecules that interact with the extracellu-lar matrix serving an anchoring function. Thebeta subunits also regulate the level of channelexpression in the plasma membrane.

The sodium channel opens rapidly in re-sponse to a depolarization in the membranepotential above a threshold value, reachingits maximal conductance within half a mil-lisecond. After opening, the sodium currentthen rapidly dissipates, falling to almost zerowithin a few milliseconds. The inactivationof the sodium channel is the result of twoseparate processes, which may be differenti-ated based on their time constants. An initialrapid inactivation has a fast recovery constantand is, in part, caused by a conformationalchange in the intracellular linker between S3and S4 that acts like a ball valve swinging intoand occluding the pore-forming region. Rapidinactivation may occur without the channelopening, a process known as “closed state in-activation.” A slower, more stable inactivatedstate also exists and may last from hundreds

of milliseconds to several seconds. The mech-anism(s) underlying slow inactivation are notwell understood but likely results from thelinker sequences between S5 and S6 in eachdomain bending back into the pore of thechannel and occluding it.

The SCN5A gene located on chromo-some 3 encodes the cardiac sodium channel.The cardiac sodium channel may be differen-tiated from the neuronal and skeletal musclechannel by its insensitivity to tetrodotoxin,which is isolated from puffer fish. Severaldiseases in humans resulting from sodiumchannel gene defects have been identified(Chapter 18).

Potassium Channels

Potassium channels are more numerousand diverse than any other type of ion channelin the heart (Figure 2). Over 200 genes havebeen identified that code for potassium chan-nels. The channels may be categorized by theirmolecular structure, time, and voltage depen-dant properties, as well as their pharmacologi-cal sensitivities. Potassium channels are majorcomponents in the establishment of the rest-ing membrane potential, automaticity, and theplateau phase of the action potential, as wellas repolarization (phase 3, Figure 5). Withinthe heart a tremendous amount of heterogene-ity exists in the density and expression of thepotassium channels. The varied expressionlevel of potassium channels contributes to thevariability of the action potential morphologyin different regions of the heart includingtransmural differences within the ventricularmyocardium (Figure 3). In addition to the nat-ural variability in the expression of potassiumchannels, many disease processes such ascongestive heart failure and persistent tach-yarrhythmias alter the density of these chan-nels, as well as their functional properties,thereby leading to disruption of the normalelectrical stability of the heart. This alterationin the density and function of these channelshas been termed “electrical remodeling.”

FIGURE 2. Similar to the voltage-gated sodium channels, the voltage-gated potassium channels are composed offour domains (α-subunits) composed of six membrane spanning segments. Unlike the sodium channels, the potassiumchannel domains are separate subunits that co-assemble to form a functional channel (compared with the sodium chan-nel, which is a single large α-subunit composed of four domains. The voltage-gated potassium channels structurallyare very similar to the sodium channels. The four α-subunits assemble to form a single pore with the S5–S6 linkerfrom all α-subunits contributing to the pore. Similar to the voltage-gated sodium channel, the S4 subunit is also highlycharged and serves as the voltage sensor leading to channel opening and closing. (Downloaded from the internet).

Right ventricle

Epicardium

Endocardium

M-cell

0

0

0

0

0

0

200 msec

50mV

Left ventricle

FIGURE 3. Action potential heterogeneity: The action potentials in this figure were recorded from strips of ventricularmyocardium isolated from canine right and left ventricle. The difference in the morphology of the action potentialsacross the ventricular wall is obvious with a longer action potential found in the M-cells, which are located in themid-myocardium. Additionally, the spike and dome configuration of the action potential generated by the activity ofthe transient outward current is prominent in the epicardial cells and nearly absent in the endocardium. Differencesbetween the action potential morphology are also evident between the right and left ventricles. Finally, the actionpotentials were recorded at various paced cycle lengths. The rate adaptation of the cells from the different regions ofthe ventricle is strikingly different. (Reproduced from Antzelevitch C, Fish J. Basic Res Cardiol 2001;96(6):517–527,Springer Science + Business Media, Inc.)

clinical cardiac electrophysiology in the young...clinical cardiac electrophysiology in the young...

Documents