STARLING'S LAW OF THE HEART REVISITED

Transcription

1 STARLING'S LAW OF THE HEART REVISITED

2 Developments in Cardiovascular Medicine VOLUME 89

3 STARLING'S LAW OF THE HEART REVISITED edited by HENK E.D.J. ter KEURS Department of Medical Physiology, Medical Faculty, The University of Calgary, Calgary, Alberta, Canada MARK I.M. NOBLE Consultant Physician, King Edward VII Hospital, Midhurst, United Kingdom KLUWER ACADEMIC PUBLISHERS DORDRECHT / BOSTON / LONDON

4 Library of Congress Cataloging in Publication Data Starling'S law of the heart revisited / edited by Henk E.D.J. ter Keurs. Mark I.M. Noble. p. cm. -- (Developments in cardiovascular medicine) Inc 1 udes index. ISBN-13: DOl: 10.l007/ e-isbn-13: Heart--Muscle. 2. Heart--Contraction. ter. II. Noble. Mark I. M. III. Series. OP113.2.S '.17--dc19 I. Keurs. H. E. D. J CIP Published by Kluwer Academic Publishers, P.O. Box 17,3300 AA Dordrecht, The Netherlands. Kluwer Academic Publishers incorporates the publishing programmes of D. Reidel, Martinus Nijhoff, Dr W. Junk and MTP Press. Sold and distributed in the U.S.A. and Canada by Kluwer Academic Publishers, 101 Philip Drive. Norwell, MA 02061, U.S.A. In all other countries, sold and distributed by Kluwer Academic Publishers, P.O. Box 322, 3300 AH Dordrecht, The Netherlands. All Rights Reserved 1988 by Kluwer Academic Publishers Softcover reprint of the hardcover 15t eidition 1988 No part of the material protected by this copyright notice may be reproduced or utilized in any form or by any means, electronic or mechanical including photocopying, recording or by any information storage and retrieval system, without written permission from the copyright owner.

5 Table of Contents List of major contributors Introduction IX XI 1. The contribution of myofibrillar properties to the sarcomere length-force relationship of cardiac muscle J.C. Kentish, H.E.D.J. ter Keurs and D.G. Allen Appendix (Sarcoplasmic reticulum calcium release) A. Fabiato 2. The mechanism of the length-tension relation in cardiac muscle 18 of Rana Catesbeiana T.lwazumi 3. Intracellular calcium concentration following length changes in 28 mammalian cardiac muscle D.G. Allen, G.L. Smith & C.G. Nichols 4. Some dynamic effects of length and isotonic motion on cardiac 43 sarcomere shortening J. W. Krueger & T. Okado 5. The relation between contraction dynamics and the intracellular 60 calcium transient in mammalian cardiac muscle P.R. Housmans 6. The effects of sarcomere length on force and velocity of shorten- 67 ing in cardiac muscle H.E.D.J. ter Keurs, B. Wohlfart, L. Ricciardi & J.J.J Bucx 7. Similarity and dissimilarity between muscle force-length relation- 80 ship and ventricular pressure-volume relationship K. Sagawa, W.C. Hunter, W.L. Maughan, D. Burkoff & D. Yue 8. The importance of the geometry of the heart to the pump 94 T. Arts & R.S. Reneman 9. Cardiac pump function and ventricular dimensions 112 G. Elzinga, G.J. van der Horn & N. Westerhof 10. The pressure-volume relationship of the intact heart 123 M.l.M. Noble Index of Subjects 140

6 The greater the length of the fibre, and therefore the greater amount of surface of its longitudinal contractile elements at the moment when it begins to contract, the greater will be the energy in the form of contractile stress set up in its contraction, and the more extensive will be the chemical changes involved. This relation between the length of the heart fibre and its power of contraction I have called "the law of the heart." E.H. Starling (1920) On the circulatory changes associated with exercise J. Roy. Army Med. Corps 34:

7 IX List of Major Contributors Dr. D.G. Allen, Department of Physiology, University College of London, London, Gower Street, London WClE-6BT, United Kingdom Dr. T. Arts, Biomedical Centre, University of Limburg, 6200 MD Maastricht, The Netherlands Dr. G. Elzinga, Laboratory for Physiology, Free University of Amsterdam, 1081 BT Amsterdam, The Netherlands Dr. P.R. Housmans, Department of Anesthesiology, Mayo Foundation, Rochester, MN 55905, U.S.A. Dr. T. Iwazumi, Department of Medical Physiology, Health Science Centre, University of Calgary, Calgary, Alberta, Canada T2N-4Nl Dr. J.C. Kentish, Department of Physiology, University College of London, Gower Street, London WC1E-6BT, United Kingdom Dr. J.W. Krueger, Albert Einstein College of Medicine, Bronx, New York, NY 10461, U.S.A. Dr. M.I.M. Noble, King Edward VII Hospital, Midhurst, West Sussex GU29-0BL, United Kingdom Dr. K. Sagawa, Department of Biomedical Engineering, Johns Hopkins University Medical School, Baltimore, MD 21205, U.S.A. Dr. H.E.D.J. ter Keurs, Department of Medical Physiology, Faculty of Medicine, Health Science Centre, University of Calgary, Calgary, Alberta, Canada T2N-4Nl

8 Introduction H.E.D.J. TER KEURS & M.I.M. NOBLE The "Starling's Law of the Heart" and "The Frank-Starling Mechanism" have long been the cornerstone of cardiac mechanical physiology. It is often forgotten that Frank and Starling carried out fundamentally different experiments. Frankl measured the isovolumic pressure developed by frog heart at different volumes. He therefore discovered the pressure-volume-volume relationship which depends directly on the force-length relationship of the sarcomeres. Starling 2,3 studied cardiac shortening as manifest by cardiac output and its relationship to end-diastolic conditions as manifest by right atrial pressure. Thus he was studying the ability of cardiac muscle to shorten more at a given load from a greater initial length. Starling in the promulgations of his law 4 implied a common mechanism for these two phenomena and spoke of the "energy liberated" being a function of initial muscle fiber length. However, there has been much confusion about the interrelationship between the two different aspects studied by Frank and Starling. The 1960s saw the era of isolated cardiac muscle mechanics, beginning with the paper of Abbott and Mommaerts. 5 Whole muscle length-tension relations were equated with sarcomere-length-tension relations by fixation of muscle at a particular point on the curve and determination of sarcomere length by electronmicroscopy.6 When the Ciba Symposium "Physiological Basis of Starling's Law of the Heart" was held in 1973 (published 1974),1 the field was at a very exciting stage as the first attempts at instantaneous sarcomere length, measured during the experiment on the living muscle, were reported. In the decade since that publication, definitive data collected with these methods have appeared. 8,9 These advances are summarized and brought up to date in the present volume. Chapter I of the Ciba Symposium 7 contained considerable discussion on the mechanism of the increased mechanical performance of cardiac muscle when stretched. These were summarized by Jewell 10, who predicted that variations in activation of the myofilaments by calcium ions would probably prove to be the mechanism. Nevertheless, Jewell was the first to disprove this H.E.D.J. ter Keurs and M.I.M. Noble (eds), Starling's Law of the Heart Revisited. ISBN , Kluwer Academic Publishers, Dordrecht

9 XII idea. In his paper with Hibberd, II it was shown that in chemically skinned cardiac muscle, a shift in the relationship of force to calcium ion concentration was found. This was confirmed in much greater detail by Kentish et al. 12 whose data also explain the change in shape of sarcomere length-force curves with increasing extracellular Ca 2 + in intact fibres. These new findings are summarized and brought up to date in Chapter 4; those factors other than a change in sensitivity of the myofilaments to Ca 2 + which may still be considered to contribute are explained. Furthermore, disproof of Jewell's hypothesis is given by (1) the lack of effect of instantaneous length changes on intracellular Ca2+ (Chapter 3); (2) the failure of changes in length to change calcium induced calcium release from the sarcoplasmic reticulum (Chapter 1); and (3) the presence of a positive sarcomere length-tension curve at constant Ca 2 + in isolated myofibrils (Chapter 2). We are most grateful to Dr. A. Fabiato for carrying out further experiments on this point with his latest methods and for allowing us to publish his negative results. The new methods of instantaneous sarcomere length measurement have produced a lower yield of new information on shortening behavior of cardiac muscle. Effects of shortening per se on contractile properties continue to be perplexing (Chapters 4 and 5). Velocity of sarcomere shortening at zero load (V m V max) has been well characterized in rat muscle (Chapter 6) but not in other species. The development of understanding of the Frank and Starling phenomena in the intact heart has attracted less attention, both prior to and since the 1973 Ciba Symposium. 7 The major contributions have been: (1) the development of the pressure-volume diagram of the left ventricle as the best means for understanding, integrating, and interpreting cardiac muscle length-tension and length shortening characteristics (Chapters 7, 10); (2) greater accuracy in the study of the geometric factors relating muscle fibres to whole heart function (Chapter 8); and (3) the approach to the whole subject from engineering criteria for assessment of the heart as a pump (Chapter 9). The idea of collecting these contributions into a book arose from a widespread feeling that there was a need to update the classic book from the Ciba Symposia This feeling manifested itself in a series of meetings in recent years. The Cardiac Muscle Research Group in the United Kingdom held a meeting at Bath in 1985 entitled "Frank and Starling Revisited" followed by an indepth small Symposium at Midhurst for the speakers. These meetings were preceded and followed by Symposia of the Physiological Society at St. Andrews and Leiden. None of these meetings were published apart from the abstracts of the CMRG.13 We have therefore tried to obtain contributions to a new book that would be an appropriate update to the Ciba publication. We are very grateful to those contributors to the meeting who did not feel able to submit Chapters to the present publication. We would

10 XIII particularly like to mention Dr. Brian Jewell, Chairman of the CMRG meeting at Bath and leader and instigator of studies of the subject over the years, Dr. A. Guz, his co-chairman and also Chairman of the Ciba Symposium, 1973, and Dr. D.J. Miller18 and to Dr. Denis Noble, Chairman of the Leiden Symposium. Important contributions not included here were those of Matsubara, Maughan and Yagi14 and of Lloyd HefnerY The discussions during these meetings foreboded a considerable number of future developments, both to address important unanswered questions and to resolve some points of disagreement between participants, e.g.: (1) when muscle length is increased there is an immediate fast response of force followed by a more slowly developing further force increase which is accompanied by an increase in calcium release. This phenomenon was found by the groups of Allen, Nichols and Hefner but not by those of Krueger, Sagawa or Noble. "Why are the results of these groups different" (2) Miller found hysteresis in the calcium versus tension relationship of chemically "skinned" cardiac muscle18 whereas Kentish and ter Keurs did not. "Which result is correct" Both of these controversies are of considerable importance, and have a potentially large effect on our present ideas of how the heart behaves within the pressure-volume diagram. At the time of writing, the force-sarcomere length relationship of cardiac muscle appears to be mainly attributable to a length dependent change in the sensitivity of the contractile proteins to calcium Some evidence points to this being a change in the affinity of troponin for Ca2+ (Chapters 1, 6). Mechanical data suggests cooperativity between force generation and Ca 2 + binding. We expect that the answer to the question whether this mechanism determines the force-sarcomere length relation may emerge in the next years. The role of restoring forces in the force-sarcomere length relationship is postulated at present on the basis of indirect findings and more by exclusion than by direct evidence (Chapter 1). Improved measurement techniques (Chapter 2) may be expected to yield the relevant data on the magnitude of restoring forces as a function of sarcomere length in the near future. Little is known about the effects of activation and sarcomere length on the relation between force and velocity. We anticipate that the combination of studies of sarcomere dynamics with the use of caged compounds in the analysis of the kinetics of myofibrillar A TP hydrolysis will reveal exciting insights into the molecular mechanism of cardiac contraction in the next decade. To what extent does the behavior of intact rat heart muscle (Chapter 1) represent heart muscle in general and human heart muscle in particular. This question follows from the higher level of activation found in rat compared to other mammalia. We should therefore expect the modern techniques summarized in these pages to be extended to such species as rabbit, cat, dog and

11 XIV man. It also has been shown that the end-systolic pressure volume relation is non linear (Chapter 7). Further studies of the independence of this relation on diastolic and systolic conditions are still required. For example, the deactivating effect of shortening has been confirmed in isolated muscle (Chapter 6) but it is not clear whether this accounts for differences between the isovolumic and end-systolic pressure-volume relationships of the intact heart (Chapter 7) or whether the latter are merely a manifestation of the limitations of the duration of systole (Chapter 10). The analysis of Chapter 8 suggests the exciting possibility that we can drop complex geometric models of the ventricles when considering force-sarcomere length relationships in the intact heart. We may be able to consider merely a long one-dimensional muscle bundle, wrapped around the cavity, in which only the cavity volume and mass of muscle contribute to the translation of force-sarcomere length to pressure-volume. On the other hand, an increasing body of evidence suggests that the pericardium 19 exerts a constraining effect on the heart under conditions in which it previously has been considered to be of little relevance. Further information regarding the effect of the pericardium on coupling of the function of the cardiac compartments will emerge with new techniques to assess its properties. Finally, we anticipate an answer in the next decade to the question posed by the finding that the working point of the heart corresponds to maximum power transfer from heart to arterial system (Chapter 9). Does this result solely from the pressure-volume diagram (Chapter 10) which will tend to always move the heart towards a maximum pressure-volume loop or must one invoke mechanisms other than the Frank and Starling phenomena The quest for a mechanism that is utilized by the organism to maximize the transfer of power from the heart to the vascular system will provide insight in the regulation of cardiac growth as the adaptive mechanism, which is superimposed on the neurohumoral and length-dependent regulation of cardiac function as was discussed by Starling. 20 References 1. Frank 0 (1885). Zur Dynamik des Heizmuskels, Zeitschrift fur Biologie 32: , translated by Chapman CB and Wasserman E (1959). Am Heart J 58: , Patterson SW, Piper H and Starling EH (1914). The regulation of the heart beat. J Physiol 48: Patterson SW and Starling EH (1914). On the mechanical factors which determine the output of the ventricles. J Physiol 48: Starling EH (1918). The Linacre Lecture on the Law of the Heart, Jougmans, Green and Co, London. 5. Abbott BC and Mommeart WFHM (1959). A study of inotropic mechanisms in the papillary muscle preparation. J Gen Physiol 42:

12 xv 6. Sonnenblick EH and Skelton CL (1974). Reconsideration of the ultra-structural basis of cardiac length-tension relations. Circ Res 35: Ciba Foundation Symposium (1974): The PHysiological Basis of Starling's Law of the Heart. Elsevier: Excerpta Medica: North Holland, Amsterdam. 8. ter Keurs HEDJ, Rijnsburger WH, van Heunigen Rand Nagelsmit MJ (1980). Tension development and sarcomere length in rat cardiac trabeculae. Evidence of length-dependent activation. Circ Res 46: Daniels M, Noble MIM, ter Keurs HEDJ and Wohlfart B (1984). Velocity of sarcomere shortening in rat cardiac muscle: relationship to force sarcomere length, calcium and time. J Physiol 355: Jewell BR (1977). A re-examination of the influence of muscle length on myocardial performance. Circ Res 40: II. Hibberd MG and Jewell BR (1982). Calcium- and length-dependent force production in rat ventricular muscle. J Physiol 329: Kentish JC, ter Keurs HEDJ, Ricciardi L, Bucx JJJ and Noble MIM (1986). Comparison between the sarcomere length-force relations of intact and skinned trabeculae from rat right ventricle. Circ Res 58: Abstracts of symposium organized by the Cardiac Muscle Research Group (1985). Cardiovase Res 19: Matsubara I, Maughan DW and Yagi N (1985). An X-ray diffraction study of chemically skinned cardiac muscle. Cardiovasc Res 19: Reeves RC, Reeves DNS, Walker AA and Hefner LL (1985). The fast and slow components of the force-length curve in cardiac muscle. Cardiovasc Res 19: Housmans PK, Lee NK and Blinks JR (1983a). Active cellular calcium transient in mammalian heart muscle. Science 221: Housmans PK, Lee NK and Blinks JR (1983b). History ofloading in preceding contractions influences intracellular calcium transients in cat papillary muscle. Fed Proc 42: Harrison SM, Lamont C and Miller DJ (1985). Hysteresis in the Ca vs. tension relationship of chemically "skinned" cardiac muscle. J Physiol 364: 91P. 19. Tyberg JV, Taichman GC, Smith ER, Douglas NWS, Smiseth OA, and Keon WJ (1986). The relationship between pericardial pressure and right atrial pressure: an intraoperative study. Circulation 73: Starling EH (1919). On the circulatory changes associated with exercise. Lecture given at the Army Medical College In "Starling on the Heart". CB Chapman, JH Mitchell, Dawsons of Pall Mall, London.