PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE HEART, SECOND EDITION

Developments in Cardiovascular Medicine

Perry, H. M. ,ed.: Lifelong management of hypertension. ISBN 0-89838-582-2. Jaffe, E.A., ed.: Biology of endothelial cells. ISBN 0-89838-587-3. Surawicz, B., Reddy, c.P., Prystowsky, E.N., eds.: Tachycardias. ISBN 0-89838-588-1. Spencer, M.P., ed.: Cardiac doppler diagnosis. ISBN 0-89838-591-1. Villareal, H.V., Sambhi, M.P. , eds.: Topics in pathophysiology of hypertension. ISBN 0-89838-595-4. Messerli, F.H., ed.: Cardiovascular disease in the elderly. 1984. ISBN 0-89838-596-2. Simoons, M.L., Reiber,] .H.C., eds.: Nuclear imaging in clinical cardiology. ISBN 0-89838-599-7. Ter Keurs, H. E. D.). , Schipperheym,).)., eds.: Cardiac left ventricular hypertrophy. ISBN 0-89838-612-8 . Sperelakis, N., ed.: Physiology and pathophysiology of the heart. ISBN 0-89838-615-2. Messerli, F.H., ed.: Kidney in essential hypertension. 1983. ISBN 0-89838-616-0. Sambhi, M.P., ed.: Fundamental fault in hypertension. ISBN 0-89838-638-1. Marchesi, D., ed .: Ambulatory monitoring: Cardiovascular system and allied applications. ISBN 0-89838-642-X . Kupper, W., Macalpin, R.N: , Bleifeld, W., eds .: Coronary tone in ischemic heart disease. ISBN 0-89838-646-2. Sperelakis, N., Caulfield,] .B., eds.: Calcium antagonists: Mechanisms of action on cardiac muscle and vascular

smooth muscle. ISBN 0-89838-655-1. Godfraind, T., Herman, A.S., Wellens, D., eds.: Entry blockers in cardiovascular and cerebral dysfunctions.

ISBN 0-89838-658-6. Morganroth,]., Moore, E. N., eds.: Interventions in the acute phase of myocardial infarction. ISBN 0-89838-659-4. Abel, F.L., Newman, W.H., eds.: Functional aspects of the normal, hypertrophied, and failing heart.

ISBN 0-89838-665-9. Sideman, S., and Beyar, R. , eds.: Simulation and imaging of the cardiac system. ISBN 0-89838-687-X. van de Wall, E. , Lie, K.I. , eds.: Recent views on hypertrophic cardiomyopathy. ISBN 0-89838-694-2. Beamish , R.E., Singal, P.K., Dhalla, N.S . , eds .: Stress and hean disease . ISBN 089838-709-4. Beamish, R.E . , Panagia, V., DhaIla, N.S., eds.: Pathogenesis of stress-induced heart disease. ISBN 0-89838-710-8. Morganroth,]., Moore, E.N., eds.: Cardiac arrhythmias: New therapeutic drugs and devices. ISBN 0-89838-716-7_ Mathes, P., ed.: Secondary prevention in coronary artery disease and myocardial infarction. ISBN 0-89838-736-1. Stone, H. Lowell, Weglicki, W.B., eds.: Pathobiology of cardiovascular injury. ISBN 0-89838-743-4. Meyer,]., Erbel, R., Rupprecht, H.]., eds.: Improvement of myocardial perfusion. ISBN 0-89838-748-5. Reiber, ].H.C., Serruys, P. W., Slager, C.] . : Quantitative coronary and left ventricular cineangiography . .

ISBN 0-89838-760-4. Fagard, R.H., Bekserr, I.E. , eds.: Sportscardiology. ISBN 0-89838-782-5. Reiber, ).H.C., Serruys, P. W., eds.: State of the art in quantitative coronary arteriography. ISBN 0-89838-804-X. Roelandt,]., ed.: Color doppler flow imaging. ISBN 0-89838-806-6. van der Wall, E.E., ed.: Noninvasive imaging of cardiac metabolism. ISBN 0-89838-812-0. Liebman,)., Plonsey, R., Rudy, Y., eds., Pediatric and fundamental electrocardiography. ISBN 0-89838-815-5. Higler, H., Hombach, V., eds., Invasive cardiovasculartherapy. ISBN 0-89838-818-X. Serruys, P. W ., Meester, G. T., eds . , Coronary angioplasty: a controlled model for ischemia. ISBN 0-89838-819-8. Tooke, ).E., Smaje, L.H. , eds.: Clinical investigation of the microcirculation. ISBN 0-89838-833-3. van Dam, Th., van Oosterom, A., eds.: Electrocardiographic body surface mapping . ISBN 0-89838-834-1. Spencer, M.P. , ed.: Ultrasonic diagnosis of cerebrovascular disease. ISBN 0-89838-836-8. Legato, M.J., ed.: The stressed heart. ISBN 0-89838-849-X. Safar, M.E., ed.: Arterial and venous systems in essential hypertension. ISBN 0-89838-857-0. Roelandt,]., ed.: Digital techniques in echocardiography. ISBN 0-89838-861-9. DhaIla, N .S., Singal, P. K., Beamish, R. E., eds.: Pathophysiology of heart disease. ISBN 0-89838-864-3 . Dhalla, N.S., Pierce, G.N., Beamish, R.E., eds .: Heart function and metabolism. ISBN 0-89838-865-1. DhaIla, N.S. , Innes, I.R., Beamish, R.E. , eds.: Myocardial ischemia. ISBN 0-89838-866-X. Beamish, R.E., Panagia, V., Dhalla, N.S., eds. : Pharmacological aspects of heart disease. ISBN 0-89838-867-8. Ter Keurs, H.E.D.]., Tyberg,]. V., eds.: Mechanics of the circulation. ISBN 0-89838-870-8. Sideman, S., Beyar, R. , eds.: Activation metabolism and perfusion of the heart. ISBN 0-89838-871-6. Aliot, E., Lazzara, R., eds.: Ventricular tachycardias. ISBN 0-89838-881-3. Schnneweiss, A., Schettler, G.: Cardiovascular drug therapy in the elderly. ISBN 0-89838-883-X. Chapman,]. V., Sgalambro, A., eds.: Basic concepts in doppler echocardiography. ISBN 0-89838-888-0. Chien, S. , Dormandy,]., Ernst, E., Matrai, A. , eds. : Clinical hemorheology. ISBN 0-89838-807-4. Morganroth,]. , Moore, E. Neil, eds.: Congestive heatt failute. ISBN 0-89838-955-0. Heintzen, PH, Bursch,] . H. eds.: Progress in digital angiocardiography. ISBN 0-89838-965-8. Scheirman, M., ed.: Catheter ablation of cardiac arrhythmias. ISBN 0-89838-967-4. Spaan, ].A.E., Bruschke, A. V.G., Gittenberger, A.C., eds.: Coronary circulation. ISBN 0-89838-978-X. Bayes de Luna, A., ed.: Therapuetics in cardiology. ISBN 0-89838-98 I-X.

PHYSIOLOGY AND PATHOPHYSIOLOGY

OF THE HEART

Second Edition

Edited By

Nicholas Sperelakis

t....

" Kluwer Academic Publishers

BOSTON DORDRECHT I.ANCASTER

Distributors

for North America

Kluwer Academic Publishers 101 Philip Drive

Assinippi Park Norwell, Massachusetts 02061 USA

for the UK and Ireland

Kluwer Academic Publishers Falcon House, Queen Square

Lancaster LA 1 1 RN, UNITED KINGDOM

for all other countries

Kluwer Academic Publishers Distribution Centre Post Office Box 322

3300 AH Dordrecht, THE NETHERLANDS

Library of Congress Cataloging-in-Publicarion Data

Physiology and pathophysiology of the heart.

(Developments in cardiovascular medicine) Includes bibliographies and index. 1. Heart - Physiology. 2. Heart - Pathophysiology.

3. Coronary circulation. I. Sperelakis, Nick, 1930- {DNLM: I. Heart-physiology. 2. Heart-physiopathology. WI DE997VME I WG 202 P5787} QPll1.4.P53 1989 612'.17 88-12808

ISBN-13:978-1-4612-8222-8 e-ISBN-13:978-1-4613-0873-7 001: 10,1007/978-1-46\3-0873-7

Copyright 1989 by Kluwer Academic Publishers Softcover reprint of the hardcover 2nd edition 1989

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, photocopying,

recording, or otherwise, without the prior written permission of the publisher, Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, Massachusetts 02061.

Dedication

This book is dedicated to my wife, Dolores, whose constant encouragement and help were essential to completion of

this work.

ACKNOWLEDGMENT

The author is grateful to Rhonda S. Hentz and Anita Lutz for excellent assistance in preparation of

the second edition.

CONTENTS

Contributing Authors XI

Foreword to the Second Edition P.M. Abboud

XVll

Foreword to the First Edition R.J. Bing

Preface to the Second Edition N. S perelakis

Preface to the First Edition N. S perelakis

1. CARDIAC MUSCLE

XIX

XXI

XXlll

1. Ultrastructure of Mammalian Cardiac Muscle 3 M.S. Porbes and N. Sperelakis

2. Basic Pathological Processes of the Heart: Relationship to Cardiomyopathies 43 L.M. Buja

3. Basis of the Resting Potential N. Sperelakis

59

4. Ionic Basis of Electrical Activity 10 the Heart 81 R.S. Kass

5. Role of Calcium-Activated Ion Currents in the Heart 95 w. T. Clusin

6. Electrogenesis of the Pacemaker Potential as Revealed by Atrioventricular Nodal Experiments 115 H. Irisawa, A. Noma, and H. Matsuda

7. A Matrical Perspective of Cardiac Excit­ability, Cable Properties, and Impulse Propagation 133 M.P. Arnsdorf

8. The Electrocardiogram and Its Relationship to Excitation of the Heart 175 R.C. Barr

9. The Slow Action Potential and Properties of the Myocardial Slow Ca Channels 195 N. SPereiakis and I. Josephson

10. Excitation-Contraction Coupling: Rela­tionship of Slow Inward Current to Con-traction 227 T.P. McDonald

11. Role of N a-Ca Exchange in Heart L.J. Mullins

12. Calculated T ranssarcolemmal Movements in Cardiac Muscle C. M. Baumgarten and A. Pabiato

341

Calcium 253

13. Uptake of Calcium by Sarcoplasmic Reti­culum and Its Regulation and Functional Consequences 267 M. Tada, M. Shigekawa, M. Kadoma and, Y. Nimura

14. Control and Modulation of Contractile Acti-vity of Cardiac Myofilaments 291 R.J. Solaro and B-S. Pan

15. Contractile and Mechanical Properties of the Myocardium 305 A.J. Brady

16. Substrate and Energy Metabolism of the Heart 327 L.H. Opie

17. Autonomic Neural Control of Cardiac Function 361 M.N. Levy and P.J. Martin

18. Development of Post junctional Cardiac Autonomic Receptors and their Regulation of Cardiac Function During Fetal and Neo-natal Life 381 A.J. P appano

19. Developmental Changes in Alpha-Adrener­gic Modulation of Cardiac Rhythm 413 M.R. Rosen, R.B. Robinson, I.S. Cohen and J.P.

Bilezikian

20. Mechanisms of Adrenergic and Cholinergic Regulation of Myocardial Contractility 423 J. P. Linckmann and A. M . Watanabe

VlI

viii

21. Pharmacology of Cardiac Glycosides 453 T. Akera and T.M. Brody

CONTENTS

22. Effects of and the Mechanism of Action of Calcium Antagonists and Other Antianginal Agents 471 A. Fleckemtein and G. Fleckemtein-Griin

33. Effects of the Volatile Anesthetic Agents on the Heart 671 M. G. Pratila and V. Pratilas

34. Effects of Toxic Substances on the Heart 691 v J. Ferrans

II. CORONARY CIRCULATION 709 23. Cellular Electrophysiology and Ischemia

493 R. Lazzara and B J. Sherlag

24. Mechanism of Action of Antiarrhythmic Drugs 509 L.M. Hondeghem and B.G. Katzung

25. Calcium and the Injured Cardiac Myocyte 527 W.G. Nayler and MJ. Daly

26. Cell Coupling and Healing-Over in Cardiac Muscle 541 w.e. De Mello

27. Action of Natural Toxins on Cardiac Ionic Channels 55 1 J.F. Renaud and M. Lazdumki

28. Cardiac Hypertrophy and Altered Cellular Electrical Activity of the Myocardium: Pos­sible Electrophysiological Basis for Myo-cardial Contractility Changes 573 R.E. Ten Eick, S.R. Houser and A.L. Bassett

29. Developmental Changes in Membrane Electrical Properties of the Heart 595 N. S perelakis

30. Aging of the Adult Heart 625 E.G. Lakatta

3 1. Hormonal Effects on Cardiac Performance 643 E. Morkin

32. Cardioplegia: Principles and Problems 655 M.-M. Gebhard. HJ. Bretschneider and P.A. Schnabel

35. Vascular Smooth-Muscle Cells and Other Peri endothelial Cells of Mammalian Heart 711 M.S. Forbes

36. Pathogenesis of Coronary Atherosclerosis 737 S.D. Gertz and A. Kurgan

37. Endothelial Cell Regulation of Vascular Smooth Muscle 755 R.F. Highsmith and O.M. FitzGerald

38. Electrophysiology of Vascular Smooth Muscle 773 N. Sperelakis and Y. Ohya

39. Electromechanical and Pharmacomechanical Coupling in Vascular Smooth Muscle 813 G. Droogmans and R. Casteels

40. Cyclic Nucleotides and Protein Phosphory­lation in Vascular Smooth-Muscle Relaxa-

41.

42.

43.

tion 825 B.M. Bennett. e.R .• Molina, S.A. Waldman and F. Murad

Vascular Muscle Membrane Properties in Hypertension 847 K. Hermsmeyer

Contractile Proteins of Smooth Muscle 855 M.P. Walsh

Mechanical Properties and Regulation of Vascular Smooth-Muscle Contraction 879 S.P. Driska

CONTENTS

44. Metabolism and Energetics of Vascular Smooth Muscle 899 }. W. Pc/mon and R J. Paul

45. Control of the Coronary Circulation 917 H. V. Sparks, Jr .• R.D. Wangler and M. W. Gorman

46. Extravascular Coronary Resistance

}.M. Downey

939

IX

47. Myocardial Infarction 955 T. Miura, D.M. Yellon and }.M. Downey

48. Inappropriate Coronary Vasomotion: Exces­sive Constriction and Insufficient Dilation 975 P.D. Henry

Index 993

CONTRIBUTING AUTHORS

Dr. Francois M. Abboud University of Iowa College of Medicine Iowa City, IA 52242

Dr. Tai Akera Medical Research Center National Children's Hospital 3-35-31 Taishido Setagaya-bu Tokyo 154, Japan

Dr. Morton F. Arnsdorf Department of Medicine School of Medicine University of Chicago Chicago, IL 60637

Dr. Roger C. Barr Department of Biomedical Engineering Duke University School of Medicine Durham, NC 27706

Dr. Arthur L. Bassett Department of Pharmacology Northwestern University Medical School Chicago, IL 60611

Dr. Clive Marc Baumgarten Department of Physiology Medical College of Virginia Box 551 Richmond, VA 23298

Dr. Brian M. Bennett Departments of Medicine and Pharmacology Stanford University and Veterans Medical Center (111) 3801 Miranda Avenue Palo Alto, CA 94301

Dr. John P. Bilezikian Departments of Pharmacology, Pediatrics,

and Medicine Columbia University College of Physicians and Surgeons New York, NY 10032

Dr. Richard]. Bing Huntington Memorial Hospital 100 Congress Street Pasadena, CA 91105

Dr. Allan]. Brady Medical Center University of California Los Angeles, CA 90024

Dr. Hans Ji.irgen Bretschneider Institute of Physiology University of Giittingen D-3400 Gottingen WEST GERMANY

Dr. Theodore M. Brody Department of Pharamacology and Toxicology Life Sciences Building Michigan State University East Lansing, MI 48824

Dr. L. Maximilian Buja Department of Pathology School of Medicine University of Texas 5232 Harry Hines Blvd. Dallas, TX 75235

Dr. R. Casteels Laboratorium voor Fysiologie K. U.L. Campus Gasthuisberg Herestraat B-300 Leuven, BELGIUM

Dr. William Clusin Division of Cardiology Falk Cardiovascular Research Center Stanford University School of Medicine 300 Pasteur Drive Stanford, CA 94305

Dr. Ira S. Cohen Department of Physiology & Biophysics State University of New York Stonybrook, NY

Dr. M.]. Daly Department of Medicine University of Melbourne Austin Hospital Heidelberg Victoria, AUSTRALIA

XI

CONTRIBUTING AUTHORS

Dr. H. Irisawa National Institute for

Physiological Sciences Okazaki Myodiji 444, JAPAN

Dr. Ira Josephson Department of Physiology & Biophysics University of Cincinnati 231 Bethesda Avenue Cincinnati, OH 45267-0576

Dr. Masaaki Kadoma First Department of Internal Medicine University of Osaka Kukushima -ku Osaka 553, JAPAN

Dr. Robert S. Kass Physiology Department School of Medicine University of Rochester 601 Elmwood A venue Rochester, NY 14642

Dr. Bertram G. Katzung Department of Pharmacology School of Medicine University of California/San Francisco San Francisco, CA 94143

Dr. S. Kokubun National Institute for Physiological Sciences Okazaki Myodiji 444, JAPAN

Dr. Y. Kurachi National Institute for Physiological Sciences Okazaki Myodiji 444, JAPAN

Dr. Adi Kurgan Department of Anatomy and Embryology Hebrew University Hadassah Medical School P.O. Box 102 Jerusalem, ISRAEL

Dr. Edward G. Lakatta Cardiovascular Section National Institute on Aging 4940 Eastern Avenue Baltimore, MD 21224

Dr. Michel Lazdunski Centre de Biochimie Faculte S.P.C.N.!. Universite de Nice/Pare Val rose F-06034 Nice, FRANCE

Dr. Ralph Lazzara Medical/Cardiology Section Oklahoma University Health Science Center P.O. Box 26901 Oklahoma City, OK 73190

Dr. Matthew N. Levy Department of Investigative Medicine Mount Sinai Hospital Cleveland, OH 44106

Dr. Jon P. Lindemann Richard L. Roudebush Veterans Administration

Medical Center and Krannert Institute of Cardiology

1001 W. 10th Street Indianapolis, IN 46202

Dr. Paul J. Martin Department of Investigative Medicine Mount Sinai Hospital Cleveland, OH 44106

Dr. H. Matsuda National Institute for Physiological Studies Okazaki Myodiji 444, JAPAN

Dr. Terrence F. McDonald Department of Physiology and Biophysics Dalhousie University Halifax NS B3H 4H7 CANADA

Dr. Tetsuji Miura c/o Dr. James M. Downey Department of Physiology College of Medicine University of South Alabama Mobile, AL 36688

Dr. cesar R. Molina Departments of Medicine and Pharmacology Standford University and Veterans Medical Center (111) 3801 Miranda Avenue Palo Alto, CA 94301

Xlll

XIV CONTRIBUTING AUTHORS

Dr. Eugene Morkin Division of Cardiology College of Medicine University of Arizona Tucson, AZ 85724

Dr. Lorin J. Mullins Biophysics Department University of Maryland Baltimore, MD 21201

Dr. Ferid Murad Departments of Medicine and Pharmacology Stanford University and Veterans Medical Center (111) 3801 Miranda Avenue Palo Alto, CA 94301

Dr. Winifred G. Nayler Department of Medicine University of Melbourne Austin Hospital Heidelberg Victoria, AUSTRALIA

Dr. A. Noma National Institute for Physiological Studies Okazaki Myodiji 444, JAPAN

Dr. Yasuharu Nimura National Cardiovascular Research Institute Suita 565, JAPAN

Dr. Yusuke Ohya Department of Physiology & Biophysics University of Cincinnati College of Medicine 231 Bethesda Avenue Cincinnati, OH 45267-0576

Dr. Lionel H. Opie Department of Medicine School of Medicine University of Cape Town Observatory 7925 Cape Town, SOUTH AFRICA

Dr. Bo-Sheng Pan Department of Physiology and Biophysics University of Washington College of Medicine Seattle, WA 98195

Dr. Achilles J. Pappano Department of Pharmacology University of Connecticut Health Center 2 Holcomb Street Farmington, CT 06032

Dr. Richard J. Paul Department of Physiology and Biophysics University of Cincinnati College of Medicine 231 Bethesda Avenue Cincinnati, OH 45267 -0576

Dr. John W. Peterson Neurosurgical Services Warren - 4 Building Massachusetts General Hospital Boston, MA 02114

Dr. Margaret G. Pratila Anesthesiology Department Memorial/Sloane Kettering Hospital New York, NY

Dr. Vasilios Pratilas Anesthesiology Department Mount Sinai School of Medicine 1 Gustave Levy Place New York, NY 10029

Dr. Claus Jurgen Preusse Institute of Physiology University of Gottingen D-3400 Gottingen WEST GERMANY

Dr. Jean-Francois Renaud Fondax - Groupe de Recherches Servier 7, Rue Ampere 92800 Puteaux, FRANCE

Dr. Richard Robinson Departments of Pharmacology, Pediatrics

and Medicine Columbia University College of Physicians and Surgeons New York, NY 10032

Dr. Michael Rosen Departments of Pharmacology, Pediatrics

and Medicine Columbia University College of Physicians and Surgeons New York, NY 10032

CONTRIBUTING AUTHORS

Dr. Benjamin J. Scherlag University of Oklahoma College of Medicine VA Hospital Oklahoma City, OK 73104

Dr. Philipp A. Schnabel Institute of Physiology University of Gottingen D-3400 Gottingen WEST GERMANY

Dr. Munekazu Shigekawa National Cardiovascular Research Institute Suita 565, JAPAN

Dr. R. John Solaro Department of Physiology and Biophysics University of Illinois College of Medicine Chicago, IL 60680

Dr. Harvey V. Sparks, Jr. Department of Physiology Michigan State University East Lansing, MI 48824

Dr. Nicholas Sperelakis Department of Physiology and Biophysics University of Cincinnati College of Medicine 231 Bethesda Avenue Cincinnati, OH 45267-0576

Dr. Michihiko Tada First Department of Internal Medicine University of Osaka Kukushima-ku Osaka 553, JAPAN

Dr. Robert E. Ten Eick Department of Pharmacology Northwestern University Medical School Chicago, IL 60611

Dr. Roger D. Wangler Department of Physiology School of Medicine Michigan State University East Lansing, MI 48824

Dr. Scott A. Waldman Departments of Medicine and Pharmacology Stanford University and Veterans Medical Center Oil) 3801 Miranda Avenue Palo Alro, CA 94301

Dr. Michael Walsh Assistant Professor Department of Medicine University of Calgary 3330 Hospital Drive, N.W. Calgary , Alberta T2N 4N 1 CANADA

Dr. August M. Watanabe Department of Medicine and Pharmacology Indiana University School of Medicine 1100 W . Michigan Street Indianapolis, IN 45223

Dr. Derek Yellon Lorex Pharmaceuticals Limited Old Bank House 39 High Street High Wycombe Bucks HPll 2AG ENGLAND

xv

FOREWORD TO THE SECOND EDITION

The expansion of our practical knowledge in the man­agement of cardiovascular diseases has been stagger­ing. Few will not be awed by our ability to prolong life and reduce mortality from cardiovascular diseases . Some may argue that, at an exorbitant price, we are simply postponing death with our "halfway" techno­logy. Our society, however, will continue to demand cardiac transplantation, artificial hearts, bypass sur­gery, intravenous thrombolysis with serep and TPA, balloon angioplasty, automatic defibrillation, and intracardiac pacing. We are bewildered by the effec­tiveness of these "clinical advances," frustrated by their complications, and often ignorant of basic concepts and mechanisms.

Parallel with this revolution in cardiovascular treatment, at a lower cost but without immediate evidence of clinical benefit, is the exci ting and vi tal process of understanding the underlying cellular biology. This book is a repository of the state of the science with respect to function and malfunction of cardiac and vascular muscle cells . The breadth of topics covered is a prerequisite in a textbook; more­over, their depth and the expertise of the authors are indeed impressive. As anticipated from a book edited by Dr. Nicholas Sperelakis, whose contributions to electrophysiology have been nationally and interna­tionally recognized , subjects related to electrophysiol­ogy of cardiac and vascular muscle are emphasized. For example, calcium uptake and release are discussed in three chapters: one on sodium-calcium exchange, another on calcium uptake by sarcoplasmic reticulum, and a third on calcium release by sarcoplasmic reti­culum. For any "student" wishing to be introduced to a comprehensive base of knowledge on the role of this important cation in electromechanical coupling, this book is a superb reference resource. In addition, several other fundamental areas are covered with the comprehensive, analytical, and integrative approach expected from experts . Ultrastructure, pathology, energetics, metabolism, receptor regulation, and mechanics of both cardiac and vascular muscle are

presented in two major parts of the book. One section on cardiac muscle encompasses 30 chapters and the other on the coronary circulation covers 10 chapters . Areas of great importance in pathophysiol­ogy of cardiovascular diseases are presented from a fundamental perspective. These include topics such as calcium injury and the calcium paradox, antiar­rhythmic drugs, calcium channel blockers, cardiac hypertrophy, coronary atherosclerosis, and coronary spasm. The list of authors is a litany of the very best in each of these fields. Dr. Sperelakis takes us in his book to the frontiers of our knowledge of cellular function and pathophysiology. He impresses us by what we know and challenges us by what we do not know.

By selecting as the last chapter in his book the topic of coronary artery spasm, Dr. Sperelakis may be trying to tell us what this book is all about. The suspicion that angina represents not only an imbalance between oxygen supply and demand by the heart, but a phenomenon that can occur without an increase in demand, is about two centuries old. More than three quarters of a century ago, Osler advanced the notion of coronary spasm, but the mechanisms involved have remained a total mystery. Recently, however, the discovery that the endothelium, far from being a simple barrier, is a powerful regulator of vasomotor tone, is leading us ro totally new con­cepts in the understanding of this and other major dysfunctions of vascular muscle. Knowledge of basic mechanisms of biological phenomena are great re­wards for the biomedical scientist. These are amplified several-fold if the understanding leads to treatment and cure of disease. This chapter, and indeed the whole book, shares with us the excitement of under­standing basic cellular mechanisms and the promise of the application of this new knowledge to a better understanding of pathophysiologic states and their treatment.

Francois M. Abboud, MD

FOREWORD TO THE FIRST EDITION

This book emphasizes the fundamental, functional aspects of cardiology. Within the last 30 years, the rift between clinical and investigative cardiology has widened because of the overwhelming development of new clinical procedures, both diagnostic and therapeutic. Almost forgotten is the fact that we owe most of the clinical advances to theoretical and experimental observations. I need not remind the reader of the work of Carrel, who performed the first experimental coronary bypass in 1902, or the work of the brothers Curie in 1880, both physicists, who discovered piezoelectricity, the keystone in ech­ogradiography; of the works of Langley, who intro­duced the receptors concept; of Ahlquist in 1946, who first differentiated between alpha and beta re­ceptors; of Fleckenstein, a physiologist who pioneered the field of Ca2+ antagonists. This list could go on

for sveral pages. Thus the book edited by Sperelakis is a potent reminder of the almost forgotten fact that cardiology has two sites, inextricably related.

The book deals with subjects in which Dr. Sperelakis has pioneered: ultrastructure of heart muscle, electrophysiology, cardiac contractility, and ion exchange. An extension of these subjects is the chapter dealing with fundamental topics of the coronary circulation.

This book is indeed a timely reminder of the importance of the fundamental aspects of cardiology. Emphasis on clinical aspects of cardiology alone will result in a sterile and unproductive future for a field that has made such stunning advances during the last 30 years to the benefit of millions of people.

Richard J. Bing

PREFACE TO THE SECOND EDITION

The first edition of this book was quite successful. Several complimentary book reviews appeared soon after the first edition was published, and written and oral words of praise and appreciation were given both to the publisher and to me by quite a few individuals. It is because of such positive comments and reactions that the publisher and I decided to embark on a second edition of Physiology and Pathophysiology of the Heart. The second edition was long in preparation, taking over a year to complete. All chapter contri­butors were asked to revise, improve, and update their articles, and all have done so with enthusiasm and timeliness. A second edition not only allows for updating chapters and correcting errors and omis­sions, but also enables all contributors to work to­wards a more uniform and more didactic writing style.

In addition, a second edition enables the editor to invite other outstanding researchers of the heart to

contribute articles that will help to fill in any holes or missing areas on the subject that are important and timely. A total of eight such new chapters have been added to the second edition. The new chapters are on the areas of contractile proteins of cardiac muscle (John Solaro), contractile proteins of smooth muscle (Michael Walsh), cyclic nucleotides and protein kinases in smooth muscle (Ferid Murad), calcium­activated ion currents in cardiac muscle (William Clusin), developmental changes in adrenergic modu­lation (M.R. Rosen, R.B. Robinson, I.S. Cohen, and J. P. Bilezikian), endothelial cell interactions with vascular smooth muscle cells (Robert High­smith), myocardial infarction and free radical effects on the heart (T. Miura, Derek Yellin, and James Downey), and extravascular coronary resistance (J ames Downey). In addition, a Foreword to the Second Edition was written by Frank Abboud.

Incorporating new chapters into the second edition becomes a balance between overall length and cost of the book versus completeness. The editor is usually concerned primarily with completeness, whereas the publisher establishes limits based on cost. Therefore, the final product is a compromise between these two factors.

As in the first edition, the book is divided into two major sections: cardiac muscle and coronary circula­tion. The book is multidisciplinary and includes membrane biophysics, electrophysiology, physiol­ogy, pathophysiology, pharmacology, biochemistry, and ultrastructure. Thus, the book attempts ro integrate all relevant aspects of the factors influenc­ing the function of the heart as a vital organ under normal and various abnormal conditions. The book also attempts to set the foundation for an under­standing of the action and mechanism of action of a number of classes of cardioactive drugs.

I hope that the medical and science research com­munity will find the second edition as useful and worthwhile as the first edition and, of course, im­proved, updated, and more complete. The second edition is intended for the same general audience as the first edition, namely, researchers of the heart, academic cardiologists, cardiologists and related medical specialists in private practice, resident physicians, research fellows, and graduate students. Even medical students at the better medical colleges should find the book useful as a reference volume to

supplement and amplify specific points covered in lectures and broader textbooks. Many clinicians recognize the importance of basic science aspects of the heart that underlie the practice of cardiology. This book attempts to help bridge the gap between basic science and clinical science. Plans are underway to publish the second edition of Physiology and Patho­physiology of the Heart in several foreign languages, including Russian and Japanese.

The chapters have been written by a distinguished group of experts and outstanding researchers from around the world. It has been my great pleasure and honor to work with this distinguished group of in­dividuals in preparation of the second edition. I trust that the reader will recognize that this multidisci­plinary book is a clear, concise, up-to-date, and thorough book on the functioning of the heart in normal and pathological states.

Nicholas SPerelakis

PREFACE TO THE FIRST EDITION

The theme of this book is the physiology and func­tion of the heart in the normal state and in various pathologic states. The two major sections are on (1) cardiac muscle and related tissues,. such as nodal cell and Purkinje fiber systems, and (21 coronary circula­tion, including properties of the vascular smooth muscle cells. Not only are the relevant physiology and biophysics discussed, but, in addition, the ultrastructure, biochemistry, and pharmacology -that is, the book attempts to integrate all relevant aspects of the factors influencing the function of the heart as a vital organ under normal and abnormal conditions and states. The book also attempts to set the foundation for an understanding of the action of, and mechanism of action of, a number of classes of cardioactive drugs, including the calcium antagonis­tic drugs, antianginal drugs, antiarrthythmic drugs, and cardiac glycosides.

Each chapter is written by one or more experts in the area who have been selected·.from around the world. The authors were asked to aim for a clear, concise, accurate, and up-to-date summary of the topic in a didactic and textbook teaching style. It was suggested that the authors present key references only, with heavy emphasis on review-type and summary-type articles. The reader should be able to obtain the important facts, concepts, and hypotheses from the chapters and, if he or she wishes to go into greater depth and examine more of the evidence on some particular aspect, he or she can look up the appropriate reference.

This book is intended for practicing and academic cardiologists, related medical specialists, and re­searchers. However, resident physicians, graduate students, and medical students should find the book useful as a reference volume to supplement and amplify specific points covered in lectures and in broader textbooks. The authors were made aware of the audience intended for the book and were requested to pitch their chapter at the appropriate level. It was suggested that they present sufficient detail, documentation, and illustrations as required for the readership that the book was aimed at. The clinican undoubtedly recognizes the importance of basic science aspects of the heart that underlie his or her practice of cardiology, and this undertaking attempts to help bridge the gap between basic science and clinical science.

As mentioned above, the chapters have been written by a distinguished group of experts and outstanding researchers in their respective fields from around the world. It has been my great pleasure in assembling and working with this distinguished group of individuals in this rather massive under­taking. I hope that the readers will recognize the merits of the book and will agree that it represents a clear, concise, up-to-date, and multidisciplinary book on the heart.

Nicholas Sperelakis