The myocardium in congestive heart failure

The Myocardium

in Congestive

Heart Failure

Arnold M. Katz, MD

It is now apparent that the myocardium in patients with congestive heart failure (CHF) is not normal, because important structural and molecular changes modify function in these hearts. It appears likely that the myocardium in these patients with CHF becomes unable to provide enough chemical energy to meet its mechanical requirements. If this interpretation is correct, the resulting condition of “energy starvation” would have several important implications for therapy. For example, inotropic stimulation, by increasing energy expenditure, could contribute to the progressive myocardial cell death that characterizes end-stage cardiac hypertrophy. Conversely, the reduction in myocardial contractility that develops in the chronically overloaded heart reduces myocardial energy expenditure, and changes in the expression of myosin isoforms improve cardiac efficiency. Therefore, an important goal of therapy in. the patient with CHF is to reduce energy expenditure by unloading the failing heart and, in some cases, by administration of negative inotropic drugs. (Am J Cardiol 1989;63:12A-16A)

he clinical picture in congestive heart failure (CHF), in which cardiac abnormalitiesreducethe performance of the heart, is generally dominated by signs and symptomsrelated to a decreasein cardiac output and an increasein systemicand pulmonary venous pressures. Fatigue, dyspnea and anasarca most often bring the patient to the physician, and therapy is usually tailored to minimize these symptoms. Less apparent, and therefore easily overlooked, are important changesin the composition of the cells of the hypertrophied and failing myocardium. These changes play an important role in the pathogenesisof the abnormal cardiac function seenin patients with CHF. These cellular changesare hard to quantify, sotheir progression is difficult to follow. Attention is therefore generally directed to the circulatory and renal responsesto the impaired cardiac function.’ However, the poor long-term prognosis in most patients with CHF is probably determined primarily by deterioration of the myocardium, which culminates in myocardial cell death. This article discusses2 interrelated aspectsof the myocardial responsein patients with chronically overloaded and failing hearts: altered cellular energeticsand changesin the myocardial cell composition.Both of these must be understood by the physician who seeksto optimize therapy in patients with CHF.

T

ENERGETICS AND FAILING

From the Cardiology Division, Department of Medicine, University of Connecticut, Farmington, Connecticut. Address for reprints: Arnold M. Katz, MD, Cardiology Division, Department of Medicine, University of Connecticut, Farmington, Connecticut 06032.

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In most.patients with heart failure, whether due to hemodynamic overloading, lossof functional myocardial tissue or a valve abnormality, the work of the active myocardial cells is chronically increased.‘This chronic increase in energy expenditure makes it likely that the cells of the hypertrophied and failing heart. are in an energy-starved state.2Whereas hypertrophy distributes the increased load among a greater number of sarcomeres,important changesthat occur in the hypertrophied and failing heart influence the ability of the myocardial cells to provide for their energy needs. Increased intercapillary distance: It was shown over 50 years ago that the number of capillaries supplying the hypertrophied heart doesnot increasein proportion to the increased mass of the myocardium3*4;it also was postulated that these hearts are inadequately perfusede5 More recently, morphometric studiesof the hypertrophied myocardium have shownthat the number of transverse capillary profiles per mm2 is decreased,so that intercapillary distance is increased.6By increasing the diffusion distance for substrates and metabolites, the most important of which is oxygen,this deficit in capillaries can contribute to a relative deficiency of energy for

phy counterbalances

the inability of the overloaded

d heart meets the chronically

increased

requirements

contraction by the hypertrophied heart. This view is supported by findings that the increasedenergy demandsof the overloadedheart are met by increasedoxygen extraction rather than by increased coronary flow.ls These findings also suggestthat these hearts may be operating under conditions of relative anaerobiosis. Altered

contents

of myofibrils

and mitochondria:

With the developmentof established myocardial hypertrophy, the fraction of cell volume occupied by myofibrils increases,whereas the mass of mitochondria decreases.6,9J0 The resulting disproportionate increase in the volume fraction of the cardiac myocyte occupied by energy-consumingmyofibrils, relative to the volume of mitochondria (which regenerate adenosinetriphosphate [ATP]), could contribute to a deficit of chemical energy in the failing heart.” Decrease

in high-energy

phosphate

heart to meet the increased demands of the circulation

compounds:

More direct evidencethat the cells of the hypertrophied and failing heart are in an energy-starvedstate has been obtained in studies of animal models of heart failure. These studies show decreasedmyocardial high-energy phosphatecontentsafter pressureoverloading of the left’* and right13ventricles. Endomyocardial biopsies taken from the hearts of patients with CHF have shown a correlation between decreasedATP content and impaired contraction and relaxation,14aswould be predicted by the hypothesisthat energystarvation plays a role in the myocardial response in heart failure. Natural history of the myocardium in the response to heart failure: The likelihood that hypertrophied and fail-

ing hearts are in an energy-depletedstate is of considerable importance to our understanding of the prognosis and managementof CHF. The most important clinical implication of this energy deficit is the possibility that it hastensthe deterioration of the chronically overloaded myocardium and may thus lead to death. Almost a century ago, Osler15 recognized that the clinical statein patients with CHF could be divided into 3 stages(Table I): After a period of “development,” during which the myocardium hypertrophies to meet a chronically increasedload, the heart enters a period of “full compensation,” in which hypertrophy has “helped” the heart to meet its newly increasedwork load. Osler recognized, however, that the hypertrophied heart was not normal, and that it could undergo a spontaneousand progressivedeterioration that he called the phaseof “broken compensation.” More recently, Meerson’ l,i6,17examined the mechanism for theseprocessesin an animal model of systemic

of the circulation

hypertension produced by aortic banding, and provided a clear description of the heart’s responseto chronic hemodynamic overloading. He characterized the 3 phasesdescribed by Osler as (1) a “short-term stage of damage,” (2) a “long-term stage of relatively constant hyperfunction,” and (3) a “long-term stage of progressivecardiosclerosis and exhaustion” (Table II). From a clinical standpoint, understanding the mechanisms that give rise to the third stage in the myocardial responseto a chronic overload is of the greatest significancein planning therapy for the patient with CHF; that is because this stage, which appears to be progressive, probably represents a vicious cycle that ends with the death of myocardial cells and their replacement with fibrous tissue. In the light of evidencethat the failing heart is energystarved,the ultimate deterioration of the heart in patients with CHF probably arises, at least in part, from inadequate provision of chemical energy to meet the abnormal and sustained increase in cardiac work. The possibility that energy starvation contributes to the broken compensation described by Osler raises the further possibility that therapeutic measures that increase energy expenditure hasten the clinical deterioration so often seenin CHF. Conversely, efforts to reduce energy expenditure by the overloaded myocardium could prolong life in patients with CHF and therefore reduction of energy expenditure may be a major goal of therapy in the management of CHF. RELAXATION AND CONTRACTION ARE BOTH IMPAIRED IN THE FAILING HEART

In the failing heart, relaxation, like contraction, is impaired by a deficit in chemical energy within the myocardial cell.* This fact may explain observationsthat the hemodynamic abnormalities in patients with heart failure arise from impaired relaxation in the overloadedmyocardium.18-24While both contraction and relaxation are active processes,energy is used quite differently during the systolic and diastolic phasesof the cardiac cycle. Energy expenditure during systole: Energy must be expended to pump blood under pressure into the aorta and the pulmonary artery. This is apparent since the generation of mechanical work by the contractile proteins occurs when the chemical energy of ATP is released by the myosin cross bridges as they interact with actin to causeshortening and tension development in the walls of the heart. Whereassystoleis an active process,activation is not. Muscular contraction is initiated when calcium ion

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(Ca2+) enters the cytosol of the heart through channels ognition of the importance of changing molecular properin the sarcolemmal and sarcoplasmic reticulum mem- ties of highly purified myocardial proteinsraised the posbranes.Becausecytosolic Ca*+ concentration in the rest- sibility that functionally significant alterations of protein structure in the heart participated in the adaptation of the ing heart is much lower than that in the extracellular spaceand the sarcoplasmicreticulum (where the activa- myocardium to long-term circulatory changes such as tor Ca*+ is stored), activation is effectedby the very rapid chronic hemodynamic overloading.31 Variability of gene expression in the heart: Rapid passivediffusion of Ca2+ into the cytosol.25Thus, while energy is usedby the contractile proteins during contrac- developmentsin molecular biology have already revolution, systole is initiated by downhill Ca*+ fluxes that do 1tionized our understanding of cardiovascular regulation.32Growing knowledge of the mechanismsresponsinot require the direct expenditure of energy. ble for the remarkable variability of gene expressionin Energy expenditure during diastole: The heart relaxes when activator Ca2+ is transported out of the cytosol the heart is beginning to illuminate the nature of the back into the sarcoplasmicreticulum and the extracellu- changesin the proteins of the heart that are responsible lar space.As this Ca*+ leaves the cell against a strong for the changesin myocardial function in patients with electrochemical gradient, relaxation requires energy.26,27 heart failure. The best understood of these changesare The fact that energy must be expended by the heart those involving cardiac myosin, a large protein that is during both systole and diastole makes it possible for readily isolated from heart muscle. Myosin has a number of important structural and energy starvation to contribute to both contraction and biochemical properties.Each myosin moleculeis madeup relaxation abnormalities in patients with heart failure. of heavy and light chains. The heavy chain is responsible for the intrinsic rate of energy liberation by myosin both CHANGES IN THE COMPOSITION OF THE in vitro (ATPase activity) and in vivo (muscle-shortening HYPERTROPHIED AND FAILING HEART velocity). Morphologic studies have demonstrated important It is now known that the myosin heavy and light and complex changesin hypertrophied and failing hearts. For example,Linzbach28observedthat in milder forms of chains represent families of isoformsthat are encodedby hypertrophy, the myocardial cells are uniformly and different genefamilies, and that expressionof thesegenes moderately enlarged, whereasin diiated hearts, weaken- during ontogeny differs among different musclesand at ing of connective tissue and destruction of myofibers different times in a single muscle.33In the mammalian causesthinning of the wall of the heart in a process.that heart, the atria and ventricles contain distinct families of myosin isoforms,34and it has been found that different resemblesthe formation of a cardiac aneurysm. In addition to the well-known morphologic abnormal- myosin isoforms are expressedin adjacent myocardial ities seen in these hearts, subtle changes occur in the cells.35,36 Cells containing myosins of different heavy-chainimstructures of the individual proteins of the hypertrophied and failing heart. It is now clear that these molecular munologic crossreactivities, light-chain compositionand alterations can causechronic changesin myocardial cell ATPase activities are found side by side in the human heart.37 This remarkable heterogeneity in the cellular function in the patient with CHF. The existence of a regulatory mechanism based on compositionof the heart is made possibleby variability in plasticity in the structures of individual myocardial pro- the expression of the genesthat code for different isoteins was initially suggestedby findings that the ATPase forms of the peptide chains of myosin3s and by such activity of cardiac myosin could change in responseto mechanismsas alternate genesplicing, which allows literpathophysiologic abnormalities such as chronic hemody- ally dozensof protein isoforms to be synthesizedby the namic overloading, aging and endocrinopathies.29,30 Rec- heart.39 Response of the myocardium TABLE II Three Stages in the Response to a Sudden Hemodynamic Overload Stage 1: (days) Circulatory: Cardiac: Myocardial: Stage 2: (wks) Circulatory: Cardiac: Myocardial: Stage 3: (mos) Circulatory: Cardiac: Myocardial:

transient breakdown acute heart failure, pulmonary congestion, low output acute left ventricular dilatation, early hypertrophy increased content of mitochondria relative to myofibrils stable hyperfunction improved pulmonary congestion and cardiac output established hypertrophy increased content of myofibrils relative to mitochondria exhaustion and progressive cardiosclerosis progressive left ventricular failure further hypertrophy with progressive fibrosis cell death

Based on studies of aortic constriction

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to chronic overloading:

Long-standing hemodynamicoverloadingof the myocardium leads to changes in the expressionof genesthat encodecardiac myosin,40-45the sodium pump46and creatine phosphokinase.47,48 Functional studiesalso suggestthat the calcium pump of the sarcoplasmicreticulum may changein responseto altered physiologic states.49Whereasthe functional significance of these changes is still incompletely understood, it is likely that they play an important role in the adaptation of the heart to a chronically increasedhemodynamic load. Functional significance of myosin isoforms: The

of changes in the expression

ability of changing myocardial composition to adjust the performance of the heart in responseto a chronic overload has been most clearly studied in the case of myosin. Each myosin molecule contains 2 heavy chains.As indicated previously, the spe-

TABLE III Cross-Bridge Mechanics in Hypertrophied V3/Vl Ratio

Preparation Pressure overload Thyrotoxic

and Thyrotoxic

Hearts

Cycling Frequency

Tension-Time Integral

Economy of Force Development

Increased

65%

1.54

Increased

Decreased

156%

0.47

Decreased

V3/Vl ratio: rat0 of slow (V3) to fast (Vl) myosins. Cyclingfrequency: percent cycling frequency of control hearts. Tension-time Integral: tension integral during a single contraction. Economy of force development: a rough index of “efficiency”; viz. tension-time integral/tension-dependent initial heat. Modiftedfrom Hamrell and Alpert (1986).

cific heavy-chain isoform that is expresseddetermines both myosin ATPase activity and the velocity of muscleshortening.In the rat ventricle, the presenceof the Vl (or ol) myosin heavy chain determines a high rate of myosin ATPaseactivity and a rapid shortening velocity, while the V3 (or p) myosin heavy chain determines a low myosin ATPase activity and slow shortening velocity. (The V2 myosinheavychain is a hybrid containing oneVl and one V3).

It is reasonable to postulate, although it has not yet beenestablished,that energy starvation contributes to the progressivemyocardial cell death that characterizesendstagecardiac hypertrophy (Table II). If in fact this causal relation exists, then reducing energy expenditure by unloading the hypertrophied and failing heart may explain the ability of somevasodilators to prolong life in patients with heart failureSs4 It is also possible (though certainly not yet proven) that the remarkable ability of converting-enzyme inhibitors to prolong survival in patients with severe CHF55 may arise in part from their inhibition of the ability of neurotransmitters and hormones to stimulate the myocardium, thus preserving myocardial cell viability. While still unproven, these considerations should be taken into account in tailoring therapy for the patient with CHF.

The ATPase activity of myosin and the shortening velocity of musclethat this enzymatic activity determines are modified by the working conditions of the heart. In the rat ventricle, chronic pressure-overloadingand hypothyroidism increase the expressionof the gene that encodesthe V3 isoform, thereby increasing the proportion of this “slow” myosin heavy chain in the ventricle. Conversely, exercise and hyperthyroidism increase the expressionof the genethat encodesthe Vl isoform, thereby increasing the proportion of the “fast” myosin heavy chain.38 REFERENCES In the pressure-overloadedheart, replacement of fast 1. Harris P. Evolution and the cardiac patient. Cardiovasc Res 1983;/7:313m319, 437-445. V 1 myosinheavy chains by slow V3 myosin heavy chains 2.373-378, Katz AM. Cellular mechanisms in congestive heart failure. Rm J Cardiol increases mechanical efficiency of the pressure-over- 1988;62:3A-8A. 3. Shipley RA, Shipley LJ, Wearn JT. The capillary supply in normal and loaded heart, although at the expense of a slowing of hypertrophied hearts of rabbits. J Exp Med 1937;65:29-42. cross-bridgecycling (Table III).5o Changesin myocardi- 4. Roberts JT, Wearn JT. Quantitative changes in the capillary-muscle rclational composition similar to those shown in Table III have ship in human hearts during normal growth and hypertrophy. Am Heart J beenobservedto accompanythe clinical responseof the 5.1941;21:617-633. Wearn JT. Morphological and functional alterations of the coronary circulahuman atrium to overload, where a direct relation has tion. Harvey Lect 1939m1940:35:243-270. beenobservedbetweenthe proportion of slow myosin in 6. Anversa P, Olivetti G, M&sari M, Loud AV. Stereological measurement of and subcellular hypertrophy and hyperplasia in the papillary muscle of the atria of patients with left atria1 enlargement and the cellular adult rat. J Mel Cell Cardiol 1980;12:781-795. 7. Blain JM, Schafer H, Siegel AL, Bing RJ. Studies on myocardial metabolism. size of the left atriumS51 Myocardial metabolism in congestive failure. Am J Med 1956;20:820-833. This finding, which demonstrates that myocardial 8.VI. Chatterjee K, DeMarco T, Roulcau JL. Vasodilator therapy in chronic congescomposition changesin clinical CHF, is in accord with tive heart failure. Am J Cardiol 1988;62:46A-54A. the view that a reduction in contractility is part of the 9. Rabinowitz M. Protein synthesis and turnover in normal and hypertrophicd Am J Cardiol 1973;31:202-210. responseof the heart to overload. Whereas this adapta- heart 10. Page E, McCallistcr LP. Quantitative electron microscopic description of tion to a chronic overload impairs myocardial contractili- heart muscle cells. Application to normal, hypertrophied and thyroxin-stimulated ty, it is likely that the resulting energy-sparing effect hearts. Am J Cardioi 1973;31:172-181. 11. Mccrson FZ. On the mechanism of compensatory hypcrfunction and insufficould prolong survival in a patient with CHF.52,53 ciency of the heart. Car Vasa 1961;3:161-177. LINICAL

lMPLlCATlONS

The possibility of a deficit of chemical energy in the hypertrophied or failing heart has important implications for the patient with CHF. The most important of theseis the likelihood that inotropic stimulation, by increasing energyexpenditure in an energy-starvedheart, can exacerbate the detrimental effects of a deficit in chemical energy.

82. Furchgott RF, Lee KS. High energy phosphates and the force of contraction of cardiac muscle. Circulation 1961;24:416-432. 13. Pool PE, Spann JF Jr. Buccino RA. Sonnenblick EH. Braunwald E. Mvocardial high energi phosphate stores in cardiac hypertroph; and heart failure. Circ Rrs 1967:21:365-373. 14. Bashore TM, Magorien DJ, Letterio J, Shaffcr P, Unverferth DV. Histologic and biochemical correlates of left ventricular chamber dynamics in man. JACC 1987;9:734-742. 15. Osier W. The Principles and Practice of Medicine. New York: D. Applemn, 1892;634. 16. Meerson FZ. The myocardium in hyperfunction, hypcrtrophy, and hzart failure. Circ Res 1969:25:suppl II:Il-l-11-163.

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17. Meerson FZ. Adaptation of the heart to physical loads. In: Katz AM, ed. The Failing Heart: Adaptation and Deadaptation. New York; Raven Press 1983;128179. 18. Brutsaert DL, Meijler FL. Introduction: relaxation and diastole II. Proceedings of the fifth workshop on contractile behaviour of the heart. Eur Heart J 198O;l:suppl A:1 19. Grossman W, Barry WH. Diastolic pressure-volume relations in the diseased heart. Fed Proc 1980;39:148-155, 20. Rankin JS, Olson CO. The diastolic filling of the left ventricle. Eur Heart J 198O:Isuppl A:95-105. 21. Bonow RO, Bacharach SL, Green MV, Kent KM, Rosing DR, Lipson LC, Leon MB, Epstein SE. Impaired left ventricular diastolic filling in patients with coronary artery disease. Assessment with radionuclide angiography. Circulation 1981x54:315-323. 22. Smith VE, Katz AM. Inotropic and lusitropic abnormalities in the genesis of heart failure. Eur Heart .I 1983:4:suppl A:7-17. 23. Smith VE, Schulman P, Karimeddini MK, White WB, Meeran MK, Katz AM. Rapid ventricular filling in left ventricular hypertrophy. II Pathologic hypertrophy. JACC 1985;5:869~874. 24. Grossman W, Lore11 B. Diastolic Relaxation of the Heart. Boston: Martinus Nijhoff, 1988. 25. Katz AM. Potential deleterious effects of inotropic agents in the therapy of chronic heart failue. Circulation 1986;73auppl III:III-184-111-188. 26. Tada M, Yamamoto T, Tonomura Y. Molecular mechanisms of active calcium transport by sarcoplasmic reticulum. Physiol Reu 1978;58:1-79. 27. Katz AM. Calcium fluxes across the sarcoplasmic reticulum. In: Opie LH, ed. Calcium Antagonists and Cardiovascular Disease. New York: Rauen Press. Persp Cardiouasc Res 1984;9:53-66. 28. Linzbach AJ. ijber das Langenwachstum der Herzmuskelfasern und ihrer Kerne in Beziehung zur Herzdilatation. Vi&tows Arch 1956;328:165~181, 29. Alpert NR, Gordon MS. Myofibrillar adenosine triphosphatase activity in congestive heart failure. Am J Physiol 1962;202:940-946. 30. Katz AM. Contractile proteins of the heart. Physiol Reu 1970;50;63-158. 31. Katz AM. ‘Tonic’ and ‘phasic’ mechanisms in the regulation of myocardial contractility. Basic Res Cardiol 1976;71:447-455. 32. Katz AM. Molecular biology in cardiology, a paradigmatic shift. J Mel Cell Cardiol 1988;20:355-366. 33. Emerson CP Jr, Bernstein SI. Molecular genetics of myosin. Annu Reu Biorhem 1987;56:695-726. 34. Swynghedauw B. Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscles. Physiol Reu 1986;66:710-771. 35. Sartore S, Gorza L, Bormioli SP, Libera LD, Schiaffino S. Myosin types and fiber types in cardiac muscle. J Cell Biol 1981;88:226-233. 36. Bouvagnet P, Leger J, Pons F, Dechesne C, Leger JJ. Fiber types and myosin types in human atria1 and ventricular myocardium. An anatomical description. Circ Res 1984:55:794-804. 37. Dechesne C, Leger J, Bouvagnet P, Claviez M, Leger JJ. Fractionation and characterization of two molecular variants of myosin from adult human atrium. J Mel Cell Cardiol 1985;17:753-767. 38. Bugaisky L, Zak R. Biological mechanisms of hypertrophy. In: Fozzard H, Haber E, Katz A, Jennings R, Morgan HE, eds. The Heart and Cardiovascular System. New York: Rauen Press, 1986:1491-1506. 39. Breitbart RE, Andreadis A, Nadal-Ginard B. Alternative splicing. A ubiqui-

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tous mechanism for the generation of multiple protein isoforms from single genes. Annu Rev Biochem 1987:56:467-495. 40. Lompre AM, Schwartz K, D’Albis A, Lacombe G, Van Thiem N, Swynghedauw B. Myosin isoenzyme redistribution in chronic heart overload. Nature 1979:282:105-107. 41. Rupp H. The adaptive changes in the isoenzyme pattern of myosin from hypertrophied rat myocardium as a result of pressure overload and physical training. Basic Res Cardiol 1981;76:79-88. 42. Scheuer J, Malhotra A, Hirsch C, Capasso J, Schaible TF. Physiologic cardiac hypertrophy corrects contractile protein abnormalities associated with pathologic hypertrophy in rats. J Clin Invest 1982;70:1300-1305. 43. Litten RZ, Martin BJ, Low RB, Alpert NR. Altered myosin isozyme patterns from pressure-overloaded and thyrotoxic hypertrophied rabbit hearts. Circ Res 1982:50:856-864. 44. Tsuchimochi H, Kuro-o M, Takaku F, Yoshida K, Kawana M, Kimata SI, Yazaki Y. Expression of myosin isozymes during the developmental stage and their redistribution induced by pressure overload. Jpn Circ J 1986;50:1044-1052. 45. Izumo S, Lompre AM, Matsuoka R, Karen G, Schwartz K, Nadal-Ginard B, Mahdavi V. Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. J Clin Invest 1987:79:970-977, 46. Charlemagne D, Maixent JM, Preteseille M, Lelievre LG. Ouabain binding sites and (Na+, K+)-ATPase activity in rat cardiac hypertrophy. Expression of neonatal forms. J Biol Chem 1986:261:185-189. 47. Meerson FZ. Javich MP. Isozvme oattern and activitv of mvocardial creatinine phosphokinase under heart adapiation to prolonged overload. Basic Res Cardiol 1982:77:349-358. 48. Ingwall jS, Kramer MF, Fifer MA, Lore11 BH, Shemin R, Grossman W, Allen PD. The creatinine kinase system in normal and diseased human myocardiurn. N Engl J Med 1985:313:1OSO-1054. 49. Penpargkul S, Repke DI, Katz AM, Scheuer J. Effect of physical training on calcium transport by rat cardiac sarcoplasmic reticulum. Circ Res 1977;40;134138. 50. Hamrell BB, Alpert NR. Cellular basis of the mechanical properties of hypertrophied myocardium. In: Fozzard H, Haber E, Katz A, Jennings R, Morgan HE, eds. The Heart and Cardiovascular System. New York: Raven Press, 1986;1507-1524. 51. Mercadier JJ, DeLaBastie D, Menasche P, N’Guyen Van Cao A, Bouveret P, Lorente P, Piwnica A, Slama R, Schwartz K. Alpha-myosin heavy chain isoform and atria1 size in patients with various types of mitral valve dysfunction. A quantitative study. JACC 1987:9:1024~1030. 52. Katz AM. Biochemical “defect” in the hypertrophied and failing heart. Deleterious or compensatory? Circulation 1973;47:1076-1079. 53. Katz AM. A new inotropic drug. Its promise and a caution. N Engl J Med 1978:299:1409-1410. 54. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:15471552. 55. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987:316:1429-1435.