Fundamental mechanisms in congestive heart failure

Funda.mental

Mechanisms

in Congestive

Heart Failure* PETER E. POOL, M.D. and EUGENE BRAUNWALD, M.D., F.A.C.C. Bethesda,

Maryland

I

T IS generally agreed that heart failure is the disease state in which an abnormality of myocardial function is responsible for the heart’s failure to pump blood at a rate commensurate with the body’s requirements. However, the fundamental mechanisms are not clear, and the aim of this review is to outline those that may be involved in the decreased performance of the failing heart. Much of our knowledge of the failing myocardium is descriptive. Although a number of abnormalities have been identified, their causal relation to the state of heart failure is still uncertain. Many investigations have been conducted in experimental models of heart failure which resemble in varying degrees the clinical state. Moreover, becau:se “heart failure” in man is a common term for a wide variety of clinical conditions, it may be difficult to evaluate findings in one form of heart failure that are not present in In addition, because the severity other forms. of the state of heart failure is difficult to quantify comparisons between various experimental models and clinical forms are difficult.

left ventricle of patients with heart failure exhibited lowered maximal active tension.2 Nevertheless, there has only recently been definitive evidence documenting the contractile state of the hypertrophied and failing ventricle per unit of myocardium. In a study from this laboratory, the pulmonary arteries of cats were constricted, thereby producing right ventricular hypertrophy or overt right ventricular failure.3 In both conditions the contractile activity of the heart per unit of weight was reduced. This was reflected in a reduction of the maximal velocity of shortening of fibers (V,,,) and in the development of maximal isometric tension (PO) of isolated papillary muscles that had been removed from these animals. These changes were more marked in the animals in heart failure than in those with hypertrophy alone (Fig. 1). This depression of contractile state per unit of myocardium in heart failure has also been quantified in the intact heart by Krames et a1.4 and Spann et a1.5 Thus, it appears that ventricular hypertrophy, in the absence of heart failure, is associated with a depression of the contractile state of each unit of myocardium, although the absolute increase of total muscle mass maintains cardiac compensation. In addition, when isolated cat papillary muscles from animals with heart failure are fixed at the top of their Frank-Starling curves, sarcomere lengths are found to be normal by Thus, the conelectron microscopic analysis. tractile abnormalities do not appear to be produced by an alteration of the normal relation between sarcomere length and active tension. In the presence of Ventricular Dilatation: heart failure, the Frank-Starling mechanism can be considered one of the first defense mechanisms employed in maintaining cardiac output when

MECHANICAL FACTORS Ventricular Hyp&rop&: When an abnormal load is imposed upon the ventricle, the development of myocardial hypertrophy provides the ventricle with a fundamental compensatory mechanism. When the ventricle is subjected to an extremely high load, such as that found in severe stenosis of a semilunar valve, this compensation may no longer be adequate and the ventricle may be unable to deliver an adequate output. Meersonl suggested that the intensity of myocardial function is depressed in cardiac hypertrophy, and studies in this laboratory revealed that papillary muscles removed from the

* From the Cardiology Branch, National Heart Institute, National Address for reprincs: Peter E. Pool, M.D., Department of Medicine, Calif. 92037.

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Institutes of Health, Bethesda, Md. 20014. University of California, San Diego, La Jolla,

Pool

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Even after the performance of the tension. failing heart is increased by the administration of drugs with potent positive inotropic properties such as digitalis, norepinephrine, or calcium, the contractile properties of the failing heart are reduced when compared to those of the normal Although the significance of these heart.3 deficits in the failing heart is clear, their basis is not clear and might be found at several levels of the contractile process, such as activation, energy provision, or the interaction of the contractile proteins.

6-

PO

4-

2-

1.0

BIOCHEMICAL

r

T

NORMAL HYPERTROPHY FAILURE Figure 1. Results from studies of muscle mechanics on right ventricular papillary muscles isolated from normal cats and cats with right ventricular hypertrophy alone or right ventricular hypertrophy and congestive heart failure secondary to chronic constriction of the pulmonary artery. A, maximal isometric force of contraction (PO in gm./mm.z). B, velocity of contraction at small (0.5 pm.) preload (V,., in muscle lengths/xc.).

myocardial contractility declines. An increase in the end-diastolic volume of the ventricle permits the ejection of a larger stroke volume, even in the presence of slightly decreased shortening of fibers. However, because of geometric factors, the maintenance of systolic ventricular pressure in the presence of an enlarged chamber must be associated with increased wall tension. Therefore, the functional reserve of the failing heart is also limited because increasing wall tension associated with ventricular dilatation may approach the limited capacity of the failing heart to generate tension. Thus, the mechanical deficit of the hypertrophied and failing heart consists of a diminished velocity and extent of shortening of fibers accompanied by a reduced ability to generate

FACTORS

Energy Production, Storage and Utilization: A major unresolved question concerning the fundamental mechanism of heart failure is whether or not a specific biochemical abnormality is responsible for this condition. Numerous investigations have involved the study of patients with naturally occurring decompensation as well as animals with experimentally produced forms of heart failure. At various times it has been suggested that defects exist in the production,6-g or utilization of energy.i5ai6 Prostorage,‘+l4 duction of energy is the conversion of the energy of substrates such as glucose, lactate and fatty acids into the energy of the high energy phoscompounds, adenosine triphosphate phate (ATP) and creatine phosphate (CP). Storage of energy is the steady state concentration of these high energy phosphate compounds in the heart, and utilization of energy is the rate and efficiency with which this chemical energy is converted to the mechanical energy (work) of cardiac function. By contrast, other studies have suggested that these three basic metabolic functions are entirely normal during heart failure.15J7J8 Furthermore, in those instances in which evidence for specific defects in energy metabolism was obtained, it was unclear whether the observed defect was causally related to the state of heart failure. Coronary sinus catheteriEnergy Production: zation studies in patients as well as dogs with low output heart failure have revealed that the coronary blood flow per gram of myocardium and the myocardial extraction of various substrates do not differ significantly from normal values.1g*20 In the mitochondria of the heart, the energy of substrate oxidation is converted into the terminal-bond energy of CP and of ATP, the immediate source of chemical energy utilized by heart muscle. This process is known as oxidative phosphorylation. THEAMERICANJOURNALOF

CARDIOLOGY

Fundamental

Mechanisms

Impairment of mitochondrial function has been reported in the hearts of guinea pigs,* rats6 and dogs7 with aortic constriction and left ventricular hypertrophy or failure. In more recent studies, however, oxidative phosphorylation has been found to bee normal in guinea pigs with heart failure produced by aortic constriction,21 in cats with heart failure after pulmonary artery constriction21 (Table I), in dogs with heart failure secondary to pulmonic stenosis and tricuspid regurgitation22 and in patients with heart failure secondary to valvular rheumatic disease.23 Oxidative

TABLE I Phosphorylation in Cat Heart Mitochondria* P/O

Normal Heart failure

2.9zhO.5 2.9 ztr0.4

R.C.

qC2

5.63~1.0 6.0 f0.6

0.124f0.010 0.126 f0.005

* Glutamate as substrate, 25” C. P/O = JLM. adenosine diphosphate (ADP) phosphorylated per patom of 0, consumed; R.CI. = ratio of Or consumption in the presence of adenosine diphosphate (ADP) to that after the ADP has been utilized; q02 = Fatoms of 0, consumed per mg. of mitochondrial protein per minute.

The effects of congestive heart failure on the oxygen consumption of the heart (MvOz) and on over-all efficiency have been a matter of controversy. Although it is recognized that the useful minute work of the left ventricle is reduced in heart failure, IBlain et al.,ig Levine and Wagman24 and Messer and Nei1125showed the MVOz/ 100 gm. of heart to be unchanged. Since minute work is generally reduced, one might conclude that efficiency was reduced.

-

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Coupling *

A

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In summary, then, there has been controversy concerning the status of the various factors that contribute to the production of energy in the state of heart failure. In most recent work, however, no abnormalities have been found. In addition, it is clear that well documented depressions of cardiac function due to heart failure may be found when no evidence of limited energy production is present. Thus, disorders of energy production probably cannot be implicated in the contractile defects of the state of heart failure. Energy Storage: The chemical energy that is produced by the process of oxidative phosphorylation in the mitochondria (see coupling B, Fig. 2) is stored in the myocardium in the form of ATP and CP. CP is a larger store of chemical energy in equilibrium with ATP and serves as a reservoir to maintain ATP stores. Thus, when ATP supplies energy for contraction, the resultant adenosine diphosphate (ADP) is rephosphorylated by CP. The recent studies of Fox et a1.13 in dogs, Feinsteinr2 in guinea pigs and in this laboratory26 in cats all show that the experimentally induced state of chronic heart failure is associated with modest depressions of myocardial CP stores and, in some cases, mild depressions of ATP stores. In addition, consistent depressions of total myocardial creatine stores have been found. These may account in part for the fall in CP concentration since the fraction of total creatine in the form of CP is quite similar in hearts from normal animals and those with heart failure. There is evidence derived from the acutely failing heart, however,

I I I

Coupling

B

I---_

Substrates

IExcitation .(Calcium Release)

INITIAL

PROCESS

RECOVERY 8 MAINTENANCE PROCESSES

Eigure 2. Representation of the sequential processes providing energy for muscle conhuhon. Coupling A is the coupling between chemical energy and work performance. Couphng B is the coupling between oxidation of substrates and phosphorylation. VOLUME 22,

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that these modest depressions of high energy phosphate stores cannot, of themselves, be the cause of heart failure.12s27*28 Acute hypoxic and ischemic heart failure has been produced in dogs at a time when no alterations of high energy phosphate compounds were present, 27,2s and, conversely, recovery of mechanical function after prolonged hypoxia has been shown to occur at a time when high energy phosphate stores were still severely depressed.12 Similar conclusions have also been reached in chronic heart failure from the observation that papillary muscles isolated from cats with right ventricular failure may have normal stores of energy at a time when contractility is significantly depressed. 26 Energy Utilization: In the light of the absence of a definitive abnormality of energy production or storage in the failing myocardium, attention has naturally been directed to the possibility that utilization of energy is abnormal. This could occur if the contractile proteins themselves were altered, and, indeed, this was once believed to be the basic biochemical abnormality in congestive heart failure.2g However, at the present time and with present methods it has not been possible to document any abnormalities in the physical properties of the contractile proteins of the failing heart.st’*31 There is a remaining link in the chain of chemical energy between the oxidation of substrates on the one hand and the production of mechanical force on the other : the mechanochemical coupling link (Coupling A, Fig. 2). It is possible that the mechanochemical coupling is disturbed, or that both muscle contraction and ATP hydrolysis are slowed. Both of these areas have been investigated recently. To determine whether an inefficient process of energy conversion might be involved in producing heart failure, the utilization of CP and ATP was studied in the right ventricular papillary muscle of the cat under conditions in which no production of net energy could occur.32 This was accomplished by inhibiting the net synthesis of ATP by blockade of both oxidative phosphorylation and anaerobic glycolysis and then determining the utilization of energy stores at rest and during activity. It was observed that the basal rate of energy utilization in muscles obtained from cats with experimental right ventricular failure was not greater than normal. In fact, a slightly higher basal rate was found in the normal animal. Similar results were obtained in muscles that were stimulated to contract and

perform work. The mechanical function of the muscles from cats with heart failure was severely depressed, but despite the fact that these muscles performed only 13 per cent as much mechanical work and were activated 64 per cent less often, they used only 7 per cent as much energy as did those muscles from normal cats (Table II). These results clearly indicate that the failing heart is not inefficient in the conversion of chemical energy to mechanical work. Thus, it is likely that mechanochemical uncoupling (Coupling A, Fig. 2) is not present in the failing heart. What of the possibility that both muscle contraction and ATP hydrolysis are slowed in heart failure? TABLE II Comparative Values for Average Muscles from Normal Cats and Those with Heart Failure

A-P (ccM/gm.) No. of contractions Work performed (gm.-cm./gm.) A -

Normal

Failure

3.15

0.23

34.4 312 -.

Failure/ Control x 100 7

21.9

64

41

13

P = total high energy phosphate

stores used.

Alterations in ATPase Activity of Contractile Proteins: The release of energy from ATP in the contractile process is known to be controlled by a specific ATPase within the myofibril, and the rate of energy release may be related to the activity of this enzyme. This ATPase is an enzyme that splits the terminal phosphate bond of ATP and thereby liberates the energy of this bond. The mechanical and energetic studies of A. V. Hi1133have suggested that there is an intimate relation between the rate of energy release and the intrinsic velocity of muscle contraction. An extension of these concepts would imply that the ATPase activity of the contractile proteins is tightly coupled to the mechanical interactions that are responsible for the intrinsic velocity (V,,,) of muscle contraction; in fact, this correlation has been demonstrated in striated muscle.34 Since the contractility (intrinsic velocity) of cardiac muscle is clearly depressed in heart failure, a corresponding alteration in the ATPase activity of the contractile proteins of this muscle might be anticipated. This possibility, suggested by Alpert and Gordon,35 was recently THE AMERICANJOURNAL OF CARDIOLOGY

Fundamental

Mechanisms

confirmed in a study comparing the contractile state of heart from normal cats and cats with right ventricular hypertrophy and heart failure with the ATPase activity of myofibrils derived from these hearts.36 It was found that right ventricular myofibrillar ATPase activity was significantly depressed in the presence of right ventricular hypertrophy and heart failure (Fig. 3). In addition these depressions were correlated with the depressions in contractility found in these hearts. Small but significant depressions of left venricular ATPase activity were also present (Fig. 3). Thus, from a review of the available data, it appears that the processes of energy production in the heart are sufficient to meet energy demands and may be normal. Although myocardial energy stores may be slightly depressed in heart failure, this depression may be related more closely to a disorder of creatine metabolism than of energy metabolism, and there is no evidence that these reducti,ons in energy stores are causally related to heart failure. Finally, it is now clear that failing myocardium may be at least as efficient as normal heart muscle in converting The chemical energy into mechanical work. rate at which these processes proceed, however, may be considerably reduced, as indicated by the depressions cd myofibrillar ATPase activity that have been found. Finally, the Excitation-Contraction Cou$ing: possibility that an abnormality of excitationcontraction coupling occurs in heart faihtre must also be considered. The chain of events leading to the contraction of heart muscle is In the restthought to involve several steps. ing state calcium ions are highly concentrated in the sarcoplasmic reticulum surrounding each myofibril. The electrical depolarization of the muscle membrane in some way causes the release of calcium ions from the sarcoplasmic reticulum into the vicinity of the contractile The increase in concentration of proteins. calcium ions in the vicinity of the contractile proteins then results in contraction. Although no experimental data are available to support or refute the hypothesis that heart failure is associated with an abnormality of excitationcontraction coupling, there is evidence that the release of calcium by the sarcoplasmic reticulum may be affected by pharmacologic agents.s7 It is possible that the state of heart failure is related to an inadequate release of calcium from the sarcoplasmic reticul.um and, consequently, an inadequate activation of the contractile process. VOLUME

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HYPERTROPHY

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Figure 3. A, maximum Mgf f-actiuated myoJibrillar A TPase actiuity of normal, hypertrophied and failing right ventricles in the presence of 5 mM. sodium azide ( * standard error). B, the same data for normal left ventricle and left ventricle in presence of right ventricular failure,

SUPPORTING FACTORS: THE ADRENERGIC NERVOUS SYSTEM The important influence of the neurotransmitter substance norepinephrine (NE) on the mechanical properties of the myocardium is well known. The responses of the intact heart to augmented adrenergic influences have been defined during hypothalamic stimulation, with stellate ganglion stimulation and during exercise, and it has been demonstrated that these adrenergic influences improve myocardial contractility profoundly.38 In the intact animal, these adrenergic effects are evidenced by tachycardia, a reduction in cardiac dimensions, increased velocity of ejection and increased rate of tension development.3g However, denervated hearts in situ or isolated papillary muscles taken from denervated hearts do not exhibit depression of their intrinsic contractile properties,40 and despite denervation of the heart the intact animal appears capable of augmenting its output during muscular exercise.41 The mechanisms by which the denervated heart increases its output differ from those of the intact animal, however. Tachycardia is less marked, and in animals subjected both to denervation and adrenalectomy, the Frank-Starling mechanism is called upon to increase the stroke volume and cardiac output.41

12

Pool

and Braunwald

Cardiac Stores of Norepinephrine (NE): Because of the importance of the adrenergic nervous system in stimulating the contractility of the normal myocardium, the activity of this system has been studied intensively in patients with congestive heart failure. In this condition, the activity of the adrenergic nervous system is augmented, as reflected in elevated concentrations of NE in arterial blood42 and increased urinary excretion of this compound.43 The cardiac stores of NE, however, were shown to be severely depressed, both in atria1 tissue and in papillary muscles removed from the left ventricles of patients undergoing mitral valve replacement. Subsequent studies in animals with experimentally produced congestive heart failure44t45 have confirmed the clinical findings (Fig. 4) and FLgfgm Norepmephrine

Concentration

A.

LV

have also indicated that the uptake, release and subcellular distribution of NE in the NEdepleted heart are depressed to an extent similar to the depression in the total stores of NE. Thus, there is no evidence for any qualitative abnormality in the distribution of the reduced quantities of NE taken up by the failing heart. Biosynthesis of Norepinephrine (NE) in the Failing Heart: In view of the common reduction of most metabolic processes involving NE in the heart, suggesting a total loss of adrenergic nerves from the failing heart, it was of interest to investigate the biosynthesis of NE in the failing heart. It is now clear that tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of NE.46 Marked reductions in the activity of this enzyme have recently been shown to accompany the NE depletion in the myocardium of dogs with experimental heart failure (Fig. 5). No alterations in enzyme concentrations occurred in the hearts of animals in which NE depletion had been produced with reserpine. Thus, it appears likely that this reduction of enzyme concentration is responsible for the cardiac NE depletion in 6

T

TYROSINE HYDRDXYLASE ACTIVITY m/mu4es/g/hr

NOREPINEFHRINE

6

tb

;;o

3b

40

5’0

6’0

70

DAYS 4. Effect of left ventricular failure produced by chronic constriction of the aorta in guinea pigs on uentriculm norepinephrine concentration. Time course of changes in norepi-

0.6

CONCENTRATION I44

04

Figure

nephrine concentration in rgm./gm. (A and B) in each ventricle. Solid circles and vertical bars represent the mean values * 1 standard error of the mean obtained from animals with congestive heart failure. Horizontal lines and hatched areas represent the mean f 1 standard error of the mean obtained from 15 normal animals. Numbers in parentheses at bottom of panel A refer to the number of animals sacrificed at each point in time which provided the data shown in both panels.

0.2

0 NORMAL

FAILIRE

RESERPIW

OENERVATION

Figure 5.

Tyrosine hydroxylase activity and norepinephrine concentration in the right ventricles of normal dogs, dogs with

chronic heart failure secondary to pulmonic stenosis and tricdpid insufficiency, dogs treated for 10 days with reserpine and dogs in which total cardiac denervation had been performed. THE

AMERICAN

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CARDIOLOGY

Fundamental

Mechanisms

heart failure.47 It is still not clear, however, whether the prolonged increase in sympathetic activity that accompanies heart failure is responsible for the reduction of myocardial tyrosine hydroxylase activity. Adrenerpic Receptors and Circulating Catecholamines: Although the mechanism ultimately responsible for .:he reduction of tyrosine hydroxylase activity in the heart in congestive heart failure remains to be elucidated, there is evidence to suggest that the failing myocardium, in contrast to the normal heart, is both limited in its response to physiologic stimulation of the adrenergic nerves and perhaps partly dependent upon circulating norepinephrine of adrenal origin to maintain normal function. In dogs with experimentally produced heart failure, stimulation of the postganglionic nerves to the heart produces only minor positive inotropic and chronotropic effects compared to those of normal animals.48 In patients with congestive heart failure propranolol or guanethidine given in doses that did not lower arterial pressure frequently intensified heart failure.4gs50 Recently Chidsey et aL51 have shown that the administration of propranolol to calves with progressive pulmonary hypertension leading to congestive heart failure causes a deterioration of cardiac function which may be associate’d with an increased concentration of circulating norepinephrine. This implies that the beta adrenergic receptor in the failing heart may be intact and may be stimulated by circulating catecholamines. Thus, in heart failure, the myocardium is depleted of its intrinsic adrenergic neurotransmitter store and has a decreased ability to replace this store. Although the adrenergic nervous system does not seem to be a critical factor in the normal function of cardiac muscle, the response of the intact circulation to stress may require adrenergic support. In the presence of congestive heart failure this support may, to a great extent, be lost, and the remaining means of supporting cardiac function may be the FrankStarling mechanism and, in part, adrenergic stimulation derived from circulating norepinephrine. SUMMARY The state of congestive heart failure is associated with clear-cut depressions of intrinsic myocardial function. The production and storage of energy in the failing heart are normal, and although the failing heart converts energy to work at a normal efficiency, the rate of this VOLUME 22, JULY

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process is decreased. This decreased rate may be caused by a reduction of the activity of myofibrillar adenosine triphosphatase, which in turn may be causally related to the depression of cardiac function. In considering the efficiency of the failing heart, the translation of myocardial tension into useful circulatory work must also be considered. In this case, efficiency could be reduced by geometric factors such as ventricular size and shape and wall thickness or asynchrony of contraction. Finally, the failing heart must depend on supporting mechanisms, such as adrenergic stimulation, for normal function, and in the presence of reduced intrinsic norepinephrine stores, the presence of circulating catecholamines may be important.

REFERENCES 1. MEERSON, F. 2. A mechanism of hypertrophy and wear of the myocardium. Am. J. Cardial., 15:

755, 1965.

2.

CHIDSEY,

3.

SPANN,

4.

C. A., SONNENBLICK, E. H., MORROW, A. G. and BRAUNWALD, E. Norepinephrine stores and contractile force of papillary muscle from the failing human heart. Circulation, 33: 43,

1966.

J. F., JR., BUCCINO, R. A., SONNENBLICK, E. H. and BRAUNWALD, E. Contractile state of

cardiac muscle obtained from cats with experimentally produced ventricular hypertrophy and heart failure. Circulation Res., 21: 341, 1967. KRAMES, B. B., NORTHUP, D. W. and VAN LIERE, E. J. Pressuredevelopment in the hypertrophied heart. Pm. Sot. Exper. Biol. & Med., 124: 150,

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SPANN, J. F., JR., COVELL, J. W., ECKBERG, D. L., SONNENBLICK, E. H., Ross, J., JR. and BRAUNWALD, E. Myocardial contractility in hypertrophy and heart failure. Physiologist, 10: 310,

1967. 6. ARGUS,M. F., ARCOS, J. C., OVERBY, J. L. Oxidative

SARDESAI, V. M. and rates and phosphorylafrom experimentally-induced

tion in sarcosomes failing rat heart. Pm.

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WOLLENBERCER, A., KLEITKE, B. and RAABE, G. Some metabolic characteristics of mitochondria from chronically overloaded, hypertrophied hearts.

8.

SCHWARTZ, A. and LEE, K. S. Study of heart mitochondria and glycolytic metabolism in experimentally induced cardiac failure. Circulation

9.

GERTLER, M. M. Differences in efficiency of energy transfer in mitochondrial systems derived from normal and failing hearts. Proc. Sot. Exper. B&l.

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B Med., 106: 109, 1961.

FLECKENSTEIN, A.

Die Bedeutung der energiereithen Phosphate fur Kontraktilitat und Tonus des Myokards. Verhandl. deutsch. Gesellsch. inn. Med., 70: 81, 1964.

Pool and Braunwald

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F. and LEE, K. S. High energy phosphates and the force of contraction of cardiac muscle. Circulation, 24: 416, 1961. FEINSTEIN,M. B. Effects of experimental congestive heart failure, ouabain, and asphyxia on the high-energy phosphate and creatine content of the guinea pig heart. Circulation Res., 10: 333, 1962. Fox, A. C., WIKLER, N. S. and REED, G. E. High energy phosphate compounds in the myocardium during experimental congestive heart failure. Purine and pyrimidine nucleotides, creatine, and creatine phosphate in normal and in failing hearts. J. Clin. Invest., 44: 202, 1965. FURCHGOTT,R. F. and DEGUBAREFF, T. The high energy phosphate content of cardiac muscle under various experimental conditions which alter contractile strength. J. Pharmacol. & Exper. Therap., 124: 203, 1958. OLSON, R. E. Myocardial metabolism in congestive heart failure. J. Chron. Dis., 9: 442, 1959. MINTON, P. R., ZOLL, P. M. and NORMAN, L. R. Levels of phosphate compounds in experimental cardiac hypertrophy. Circulation Res., 8 : 924, 1960= BUCKLEY,N. M. and TSUBOI,K. K. Cardiac nucleotides and derivatives in acute and chronic ventricular failure of the dog heart. Circulation Res., 9: 618, 1961. BING, R. J. Cardiac metabolism. Physiol. Rev., 45: 171, 1965. BLAIN, J. M., SCHAFER,H., SIEGEL,A. L. and BING, R. J. Studies on myocardial metabolism. VI. Myocardial metabolism in congestive failure. Am. J. Med., 20: 820, 1956. BING, R. J. Metabolic activity of the intact heart. Am. J. Med., 30: 679, 1761. SOBEL,B. E., SPANN, J. F., JR., POOL, P. E., SONNENBLICK,E. H. and BRAUNWALD,E. Normal oxidative phosphorylation in mitochondria from the failing heart. Circulation Res., 21: 355, 1967. OLSON, R. E. Abnormalities of myocardial metabolism. Circulation Res., 14 (Suppl. II): 109, 1964. CHIDSEY, C. A., WEINBACH,E. C., POOL, P. E. and MORROW, A. G. Biochemical studies of energy production in the failing human heart. J. Clin. Invest., 45: 40, 1766. LEVINE, H. J. and WAGMAN, R. J. Energetics of the human heart. Am. J. Cardiol., 9: 372, 1962. MESSER, J. V. and NEILL, W. A. Oxygen supply of the human heart. Am. J. Cardiol., 9: 382, 1962. POOL, P. E., SPANN, J. F., JR., BUCCINO, R. A., SONNENBLICK, E. H. and BRAUNWALD,E. Myocardial high energy phosphate stores in cardiac hypertrophy and heart failure. Circulation Res., 21: 365, f 967. POOL, P. E., COVELL, J. W., CHIDSEY, C. A. and BRAUNWALD, E. Myocardial high energy phosphate stores in acutely induced hypoxic heart failure. Circulation Res., 17: 221, 1966. COVELL, J. W., POOL, P. E. and BRAVNWALD, E. Effects of acutely induced ischemic heart failure on myocardial high energy phosphate stores. Proc. Sot. Exper. Biol. B Med., 124: 89, 1967. OLSON, R. E., ELLENBOCEN,E. and IYENGAR, R. Cardiac myosin and congestive heart failure in the dog. Circulation, 24: 471, 1961.

30. MUELLER, H., FRANZEN,J., RICE, R. V. and OLSON, R. E. Characterization of cardiac myosin from the dog. J. Biol. C’hem., 239: 1447, 1964. 31. DAVIS, J. O., CARROLL, W. R., TRAPASSO, M. and YANKOPOULOS,N. A. Chemical characterization of cardiac myosin from normal dogs and from dogs with chronic congestive heart failure. J. Clin. Znuest., 39: 1463, 1960. 32. POOL, P. E., CHANDLER, B. M., SPANN, J. F., JR., SONNENBLICK,E. H. and BRAUNWALD, E. The mechanochemistry of cardiac muscle. IV. Utilization of high energy phosphates in experimental heart failure. Submitted for publication. 33. HILL, A. V. The heat of shortening and the dynamic constants of muscle. Proc. Roy. Sot. London, s.B, 126: 136, 1938. 34. BARANY, M. ATPase activity of myosin correlated with speed of muscle shortening. J. Gen. Physiol., 50: 197, 1967. 35. ALPERT, N. R., and GORDON, M. S. Myofibrillar adenosine triphosphatase activity in congestive heart failure. Am. J. Physiol., 202: 940, 1962. 36. CHANDLER, B. M., SONNENBLICK,E. H., SPANN, J. F. and POOL, P. E. The association of depressed myofibrillar adenosine triphosphatase and reduced contractility in experimental heart failure. Circulation Res., 21: 717, 1967. 37. NAYLER, W. G. Calcium exchange in cardiac muscle: A basic mechanism of drug action. Am. Heart J., 73: 379, 1967. 38. SARNOFF, S. J. and MITCHELL, J. H. The control of the function of the heart. In: Handbook of Physiology, sect. 2, Circulation, vol. 1, pp. 487532. Edited by HAMILTON, W. F. and Dow, P., Washington, D. C., 1962. American Physiological Society. 39. RUSHMER, R. F. Effects of nerve stimulation and hormones on the heart: The role of the heart in general circulatory regulation. In Ref. 38, pp. 535-550. 40. SPANN, J. F., JR., SONNENBLICK,E. H., COOPER, T., CHIDSEY, C. A., WILLMAN, V. L. ~~~BRAUNWALD, E. Cardiac norepinephrine stores and the contractile state of heart muscle. Circulation Rex., 19:

317, 1966. 41. DONALD, D. E., MILBURN, S. E. and SHEPHERD,J. T. Effect of cardiac denervation on the maximal capacity for exercise in the racing greyhound.

J. Appl. Physiol., 19: 849, 1964. 42. CHIDSEY, C. A., HARRISON,D. C. and BRAUNWALD, E. Augmentation of the plasma norepinephrine response to exercise in patients with congestive heart failure. New England J. Med., 267: 650, f 762. 43. CHIDSEY,C. A., BRAUNWALD,E. and MORROW, A. G. Catecholamine excretion and cardiac stores of norepinephrine in congestive heart failure. Am. J. Med., 39: 442, 1965. 44. CHIDSEY,C. A., KAISER, G. A., SONNENBLICK, E. H., SPANN, J. F., JR. and BRAUNWALD, E. Cardiac norepinephrine stores in experimental heart failure in the dog. J. Clin. Invest., 43: 2386, 1964.

45. SPANN, J. F., JR., CHIDSEY, C. A., POOL, P. E. and BRAUNWALD, E. Mechanism of norepinephrine depletion in experimental heart failure produced THE AMERICANJOURNAL OF CARDIOLOGY

Fundamental

Mechanisms

by aortic constriction in the guinea pig. Circulation Ref., 17, 312, 1965. 46. LEVITT, M., SPECTOR, S., SJOERDSMA, A. and UDENFRIEND, S. Elucidation of the rate-limiting step in norepinephrine biosynthesis in the perfused guinea pig heart. J. Pharmacol. GY Exper. The@., 148: 1, 1965. 47. POOL, P. E., CO~ELL, J. W., LEVITT, M. and BRAUNWALD, E. Myocardial tyrosine hydroxylase activity in canine congestive heart failure. Circulation Res., 20: 349, 1967. 48. COVELL, J. W., CHIDSEY, C. A. and BRAUNWALD, E. Reduction of the cardiac response to postganglionit sympathetic nerve stimulation in experimental

in Heart Failure

15

heart failure. Circulation Res., 19: 51, 1966. 49. GAFFNEY, T. E. and BRAUNWALD, E. Importance of the adrenergic nervous system in the support of circulatory function in patients with congestive heart failure. Am. J. Med., 34: 320, 1963. 50. EPSTEIN, S. E. and BRAUNWALD,E. The effect of beta adrenergic blockage on patterns of urinary sodium excretion. Studies in normal subjects and in patients with heart disease. Ann. Int. Med., 65: 20, 1966. 51. CHIDSEY, C. A., JAMIESON,G. and VOGEL, J. H. K. Cardiac adrenergic activity in experimental heart failure assessed with beta-receptor blockade. Circulation, 36 (Suppl. II): 85, 1967.

DRUGS IN USE 32-02-M) Autonomic DrugAntindrenerrc.ic

258 Cardiac Deoressaat;s

u 5019/W Propranolol HCl

2/68-618 INDZRAL Ayerst

(P)

Clinical Phormocology

No. Patients This group

56 56

Iige: 20-42 years (mean-33 yrs.) Dosage: 10 mg. Route: i.v. Duration: 2 single doses Statistical Study (t-test)

Dbrrrvations

ormal subjects Purpose: Xffects of adrenergic receptor 49 activation and bloclcadeon ssstolic Pree>ection period: preejection period, heart rate and arterial P-i&r. avg; 10 msec I-dew. 36 msec before pressure. 4 meet after P E-deer. 30 msec before Zescription of subjects: 15 m.secafter P L-incr. after P at all Volunteers 49 [Excessivecardiac P adrenergic A-incr. after P C-dew. wre after P ' activity 7 6 Sinus tachycardia 1 , Phqchromocytoma P-slowed avg. b beats nin without affecting mean arterial ap P-abolished all responses to I

cross-over Ztudy Partial HCl ('J0245/11) HCl (U 0?36/38) L=Le&terenol bitartrate (U 0339/n) .k,\ngiotensinamide (U 0007/51) C=Lanatoside C (U 0831/9) &o&terenol

262 262 262 262 260

Excessive cardiac activity: 7 Pree,jectionperiod - excessively sho& befork P; incr. by P Heart rate - slowed with XI effect on BP Tables and graphs presented.

_. \ Harris, W.S.; Schoenfeld, C.D. & ideissler,A.M. (Ohio State U., Columbus, unlol Effects of adrener#c receptor activation and blockade on the systolic preejection period, heart rate and arterial pressure in man. J, Clin. Invest. 46: 1704-1714 (Nov.) 1967 Prefiared by Paul de Haen, Inc. for the drug index card system, “de Haen Drugs in Use.” VOLUEAE22, JULY 1968