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A mechanism of hypertrophy and wear of the myocardium
The American Volume
15
Journal JUNE
1965
of Cardiology Number
6
EDITORIAL
A Mechanism
of Hypertrophy the Myocardium
and Wear of
FELIX Z. MEERSON, M.D.
Moscow, USSR
C
OMPENSATORY hyperfunction of the heart is an important factor in the development of the general compensation observed clinically It regularly in various cardiovascular diseases. leads to the development of cardiac hypertrophy and later to a gradual weakening of the myoIn the course of the last ten years in cardium. collaboration with a group of physiologists, biochemists and morphologists, we have investigated the dynamics and mechanism of the process of hyperfunction and weakening of the myocardium in experimental cardiac defects reproduced in animals of various species.l-X The results of physiologic investigations show that the events developing in the myocardium in the process of hyperfunction of the heart depend upon the type of load on the heart.g A mainly isometric ty@e of hyperfunction is produced by increased resistance to ventricular ejection. This response is characterized by a marked increase in contractile function of the (estimated from the tension myocardium developed) proportional to the increase in The maximal load to which the resistance. heart can adapt is determined by the maximal tension which may be developed by the myocardium. Cardiac insufficiency occurs only after a complete mobilization of the functional reserve of the myocardium, as observed in hypertension and in stenosis of the valvular orifices. A mainly isotonic type of hyperfunction is produced by increased inflow of blood into a chamber. This response is characterized by a relatively * From the Institute of Normal and Pathologic
small increase in contractile function of the myocardium (estimated from the tension developed) as blood inflow increases. The maximal load to which the heart can adapt is determined by the distensibility of the myocardium rather than by its ability to develop tension. The onset of cardiac insufficiency occurs long before the functional reserve of the myocardium is completely mobilized; and it occurs not as a result of exhaustion of the cardiac reserve but because of inability to mobilize it, as observed in valvular insufficiencies, arteriovenous shunts and anemia. From these observations it may be inferred that in the process of evolution the heart has become adapted to respond to increasing work loads in two different ways. It can accommodate an abrupt increase in cardiac output while sparing mobilization of myocardial resources; but increased resistance in the aorta and pulmonary artery may be overcome by the heart only at the expense of a direct mobilization of energetic and structural resources of the myocardium. We have, therefore, concluded that the process of adaptation of cardiac muscle to an increased level of functioning (i.e., the process of hypertrophy and the subsequent wear of the myocardium) should be studied in a type of hyperfunction in which the myocardial reserve would be most completely mobilized: isometric hyperfunction. Therefore, all biochemical, physiologic and morphologic investigations in our laboratory have been made in this type of hyperfunction, produced by Physiology, Academy of Sciences, Moscow, USSR.
Meerson surgical stenosis of the aortic conus in rabbits or dogs or of the subdiaphragmatic aorta in rats. This experimental method led to a three to fourfold narrowing of the cross section of the aorta and to marked hyperfunction characterized by a one and a half- to twofold increase in left ventricular pressure and wall tension. The study of the dynamics of the myocardium under these conditions of mainly isometric hyperfunction of the heart enabled us to define a concept of three stages in the process of compensatory hyperfunction. STAGESINCARDIACHYPERTROPHYANDWEAR FIRST STAGE
The first or damage stage of isometric hyperfunction lasts about five to ten days and is characterized by hyperfunction of the still nonhypertrophied heart. This is effectuated by an increase in intensity of function per unit of myocardial mass, estimated as the ratio of contractile force to ventricular weight.16f17 The increase in intensity of function of structures (IFS) leads to a considerable increase in breakdown of myocardial proteins and in consumption of energy in the form of adenosine triphosphate (ATP). The increase in breakdown of proteins constituting the myocardial structure is manifested by the accelerated liberation of incorporated amino acids from the myocardium, by the six-fold increase in number of mitochondria undergoing destruction, and by the phenomena of protein and fatty dystrophy of the myocardium.i0J~~20~21 These shifts in turn become factors producing mobilization of the production of energy and the protein synthesis in the myocardium.’ t2*‘pi The activation of protein and nucleic acid synthesis is expressed by the one and a half to twofold increase in degree of incorporation of tagged precursors into proteins and acids ; by a rapid increase in total content of ribonucleic acid (RNA), protein and desoxyribonucleic acid (DNA) in the ventricular myocardium; and by an increase in the total content of specialized muscle proteins in the ventricular myocardium (myosin, actomyosin and proteins of the T-fraction, discovered by Iranov,26” made up of tropoThe concentration myosin and Zao protein). of mitochondrial protein and the area occupied by mitochondria in electron microscopic sections increase sharply during activation of protein and nucleic acid synthesis. These observations2~4~riJ4~20J2indicate that activation of the
apparatus for protein synthesis (i.e., the genetic apparatus of the myocardial cells) not only ensures the maintenance of myocardial cell differentiation but also a primary increase in mass and capacity of the energy-producing structures. Morphologically, the activation of the genetic apparatus is expressed by a rapidly developing hypertrophy of the myocardium. The activation of energy production and utilization is expressed by a marked increase in oxygen consumption per unit of myocardial mass, increased uptake of substrates for oxidation, and a shift in substrate utilization toward preponderance of carbohydrates. There is mobilization of 50 to 70 per cent of glycogen and 80 to 90 per cent of creatine phosphate reserves of the myocardium. Owing to the simultaneous activation of processes of respiratory and glycolytic phosphorylation, the myocardial concentration of ATP remains unchanged. Thus, conditions necessary to ensure production of energy for the increased contractile function and protein synthesis are maintained during cardiac hypertrophy. The maximal attainable level of contractile function of the heart (maximal contractile force or tension-time index of the left ventricle during complete aortic compression) is always decreased in this first stage of hyperfunction. The maximal intensity of function of myocardial structures (maximal contractile force per gram of left ventricle) is also decreased.25 The loss of functional capacity of the muscle is due to a sudden increase in protein breakdown and to the limitation imposed by the increased use of ATP. The first stage of the process of compensatory hyperfunction is characterized by a normal concentration of noradrenalin in the myocardium, with some decrease in acetylcholine content and lowered cholinesterase activity. The heart is normally reactive to sympathetic influences, whereas it is less reactive to vagal effects. Thus there is a preponderance of sympathetic autonomic regulation of cardiac activity corresponding to the marked increase in IFS.lsJD Hypertrophy due to activation of the protein synthesis leads to distribution of the increased function of the myocardium in its enlarged massIFS is decreased. This leads to a decrease of intensity of protein synthesis and energy production. Further development of hypertrophy does not occur; the first stage of the process is completed. Clinical manifestations of the damage stage are THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Cardiac Hypertrophy most marked when there is an acute increase in the load on the heart (i.e., in experimental and traumatic defects, insufficiency following infarction of the papillary muscle, hypertensive crises and significant overloading in untrained subjects). In rheumatic cardiac disease, gradually developing hypertension and highaltitude hypoxia, the load on the heart increases gradually. Augmentation of IFS is then less, and all phenomena characterizing the damage stage are not as pronounced as in experimental defects. However, the main features of this stage are the same as in our experimental model : In all cases a prolonged increase in IFS is observed. This produces activation of protein synthesis and energy production without which the cardiac hypertrophy regularly developed in clinical diseases would be impossible. SECOND
STAGE
The second stage or stage of relatively stable hy@fumtion in rabbits and rats lasts four to ten months, and in dogs about one and a half to two years. It is characterized by a normal level of IFS; hyperfunction of the organ as a whole is maintained without further augmentation of its mass, and is not accompanied by hyperfunction of the cellular elements. This conclusion is based upon observations that protein breakdown and the use of ATP by the myocardium approach the normal. There is a normal rate of liberation of tagged amino acids incorporated into the myocardial a normal number of mitochondria proteins, undergoing destruction, and no fatty or protein dystrophy. There is no activation of the genetic apparatus of myocardial cells, since incorporation of tagged precursors into protein and nucleic acids proceeds normally. Concentration of nucleic acid, mitochondrial and contractile proteins is also normal, and their total content in the myocardium is increased in proportion to the increase in its mass (i.e., about two-fold) .I.* ,9,11--13 There is also a pronounced increase in ATPase activity of myosin and in concentration of proteins of the T-fraction (which includes the assumed precursor of myosin, tropomyosin) . No acceleration occurs in energy production and utilization in the tissue since consumption of oxygen and oxidative substrates per unit of cardiac mass is normal, and for the organ as a whole is increased in proportion to the increase in mass. Myocardial concentration of glycogen, creatine phosphate and ATP is normal, and VOLUME
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JUNE
1965
their total content is increased in proportion to the mass of the myocardium.’ v3z4J* r14 The maximal attainable level of contractile futlction of the heart is increased in comparison to that of the intact heart. The maximal IFS is normal or slightly decreased. Thus the increase of maximal contractile force of the hypertrophied heart is due only to augmentation of its mass and not to increased functional capacity of the cellular elements. Regulation of cardiac activity in this second stage is characterized by an insignificant fall in noradrenalin concentration in the myocardium, the concentration of acetylcholine and cholinesterase activity being normal. The reactivity of the heart of sympathetic and parasympathetic influences remains unchanged.iJsJg An important feature of the stage of relatively stable hyperfunction is that regressive shifts preparing the next stage of the process are gradually developing. The earliest changes of this kind include the decrease of concentration of coronary capillaries ; abrupt increase of concentration of lactic acid, slight decrease of DNA concentration and accumulation of nonprotein nitrogen in the myocardium;14J3 and, as was first shown by Wollenbergernf2a and later by us 716.*0 appearance of slight destructive changes in mitochondria and some decrease in noradrenalin content.lg The stage of relatively stable hyperfurution constitutes the most protracted period of hyperfunction in most cardiovascular diseases in man. Its duration depends on the extent and acuteness of the development of the damage stage, on the degree of hyperfunction and hypertrophy, on the presence or absence of additional injuries of the heart and regulatory mechanisms and on Clinically, the period of stable other factors. compensation usually corresponds to this stage. THIRD
The
STAGE
third stage of gradual exhaustion and procardiosclerosis is characterized primarily by inhibition of activity of the genetic apparatus of myocardial cells and, as a result, by the development in the hypertrophied myocardium of a “complex of wear.” This complex includes pathologic alterations in the nuclei of muscle fibers, sometimes a fall in DNA concentration, inhibition of protein synthesis and destructive changes in the most intensely renewed myothe mitochondria.’ ,* J* v*O cardial structures, There is also a moderate decrease in ATP a decrease in ATP-ase activity concentration;
gressive
Meerson of the myosin of myofibrils;
gradual atrophy, vacuolar degeneration and clumping breakdown of some muscle fibers with simultaneous increase in the extent of hypertrophy of the remaining fibers; and progressive cardiosclerosis, most pronounced in those myocardial zones which have undergone a significant hyperfunction and hypertrophy .’ .4z5 The maximal level of contractile function of the heart may be either increased or normal or decreased, depending on the extent of wear; but the maximal IFS is always decreased.*” This observation indicates that the development of the “complex of wear” regularly decreases the functional capacity of the myocardium. For a time, this shift is compensated for by the increase in myocardial mass, but later it is progressive and leads to decreased contractile capacity of the heart as a whole. This stage is characterized by a three- to fourfold fall in noradrenalin concentration in the myocardium, normal concentration of acetylcholine and cholinesterase activity being maintained. The reactivity of the heart to sympathetic influences decreases abruptly, while the heart is normally reactive to vagal effects.1,1ka19 Thus there is a preponderance of parasympathetic autonomic regulation of cardiac activity and a profound disturbance of myocardial catecholamine metabolism corresponding to the decreased contractile capacity. Pathologic and btochemical studies indicate that many characteristics of the “complex of wear” observed by us in experimental cardiac insufficiency are marked in the hypertrophied myocardium of human subjects suffering from deficiencies and hypertension for a long time. Frequently the “complex of wear” corresponds to various stages and forms of clinical decompensation, but it may also be observed under conditions of complete compensation.
EFFECTS OF PRECURSORSOF NUCLEIC ACID AND CO-FACTORS SYNTHESISON CONTRACTILE FUNCTION The hypothesis that the development of a “complex of wear” is the basis for decreased contractile capacity of the hypertrophied myocardium contradicts the widespread concept that insufficiency of the hypertrophied heart is determined exclusively by a disturbance in the use of ATP energy for contractile function, the process of energy production being quite normal. In fact, there is inhibition of protein synthesis in myocardial cells, which leads to a disturbance in the
renewal of the energy-producing as well as the contractile structures of the myocardium. This is manifested by a destruction and decrease in enzymal activity of mitochondria, and by a decrease in ATP-ase activity of myofibrils. Naturally, since mitochondria are organelles having a much more intense rate of renewal than myofibrils, their structure and function are affected by disturbed protein synthesis earlier than are myofibrillar structure and function. Therefore, in prolonged isometric hyperfunction of the heart, the decrease in myofibrillar ATPase activity and probable disturbance in utilization of ATP energy for contractile function is combined with decreased ATP concentration. In this manner, the primary inhibition of protein synthesis leads to a disturbance in the processes of energy production and utilization. Th result is a decrease in contractile capacity of the myocardium. This hypothesis has been a premise for studying the action of precursors and co-factors of nucleic acids and protein synthesis, and for energy production, on the contractile function or metabolism of the myocardium23-26 in three different situations: fatigue of the normal heart, acute experimental cardiac insufficiency of several days’ duration, and finally under conditions of wear of the hypertrophied myocardium in experimental insufficiency lasting about five months. The factors chosen were vitamin B12, folic and erotic acids and cardiotonic nucleosides and bases29130 alone and in combination with strophanthin. In the majority of experiments, three essential indices of the contractile function of the left ventricle were determined : maximum attainable contractile force, maximum intensity of function of myocardial structures (maximum IFS) and a “staircase of myocardial fatigue.” The first two indices have already been de-
scribed. The maximum contractile force of the left ventricle expressed by the systolic ventricular pressure or tension-time index characterizes the maximally attainable contractile force of the ventricle as a whole; the maximal IFS characterizes the contractile capacity of the tissue constituting the ventricle. The third index, “staircase of fatigue,” was determined by repeated numerous 30-second occlusions of the ascending aorta at intervals of five minutes. With each occlusion, the maximal systolic intraventricular pressure becomes lower, producing a staircase characteristic of the development of a process of myocardial fatigue. Effect of Nucleosides
on Fatigue of Normal Heart:
THE AMERICAN JOURNALOF CARDIOLOGY
Cardiac
Hypertrophy
The effect of a mixture of uridine, uracil, inosine and hypoxanthine on the “staircase” in normal animals was compared to the effect of saline or strophanthin. *’ Strophanthin alone or the mixture of nucleosides and bases halted the trend toward myocardial failure, while a combination of all five agents completely reversed this The injected nucleosides are precursors trend. of nucleic acids and may stimulate their synExperiments with tagged nucleosides3’ thesis. showed that on entering the myocardium, uridine is rapidly incorporated into uridine triphosphate and inosine into ATP. The rapid inotropic effect of ATP and UTP observed on isolated hearts”-” suggest that the rapid inotropic effect of nucleosides depends mainly on their influence on the biosynthesis of macroergic phosphates. EJect of Xucleosides in Acute Cardiac Insu@iency: Another series of experiments compared the effect of a mixture of uridine, uracil, inosine and hypoxanthine on the contractile function of the myocardium in the acute damage stage of experimental insufficiency with the effect in normal animals.25 In the “breakdown” stage of compensatory hyperfunction in untreated animals, two days after creation of experimental stenosis of the aorta, the maximal contractile function of the heart was decreased by 14 per cent. This decrease could be accounted for on the basis of the previously described biochemical changes. It could be prevented by daily intravenous injection of the nucleoside-base mixture in a dose which had no effect on the maximal contractile function of normal hearts. These observations indicate that under conditions of acute overloading of the heart, the precursors and stimulators of nucleic acid synthesis may eliminate the characteristic defect in contractile function. effect of Folk and Orotic Acids on Acute Cardiac Insujkiency : In a recent series of investigations (in cdllaboration with M. G. Pshennikova and N. G. Tarayeva), we have studied the effect produced on cardiac contractile function by a combination of two substances which are known stimulators of nucleic acid and protein synthesis: folic and erotic acids. Daily injections with these two compounds during the four days after creation of experimental aortic stenosis led to a shift upward of the “staircase” for treated as compared to untreated animals. In addition, the maximal IFS was always greater in the treated animals. Therefore, since the injection of the combination of erotic and folic VOLUME15,
JUNE 1965
759
acids increased the IFS, the improved contractile function could not be accounted for on the basis of increased rate of hypertrophy but of improved cellular function. Biochemical studies (carried out in our laboratory by Dergatchev) have shown that folic acid administered in this stage of the process of compensatory hyperfunction produces a distinctly marked effect on the protein and nucleic acid synthesis in the myocardium. Consequently, these factors may both accelerate myocardial hvpertropb and increase its contractile function per unit mass. Protracted Experimental Cardiac InsujSciency: A final object of our studies has been to inhibit the development of the “complex of wear.” We have already investigated the effect of injection of a combination of vitamin B12, ATP and methionine on biochemical changes in hypertrophied hearts of animals with pratracted experimental stenosis of the aorta.6s8 Prolonged treatment with this combination of substances prevented to some extent the decrease in ATP-ase activity and DNA concentration of the myocardium, that is, it inhibited the development of changes essential to the “complex of wear.” Further investigations on experimental prophylaxis of the “complex of wear” in the process of hyperfunction and hypertrophy of the heart are being carried out. The various experiments summarized here are particularly relevant to clinical situations associated with acute overloading, rapid hypertrophy, and regional hyperfunction of intact areas after myocardial infarction. The results obtained suggest that a careful clinicophysiologic study of the joint administration of glycosides and precursors and co-factors of nucleic acid synthesis would be very promising. REFERENCES 1. MEERSON, F. Z. Compensatory Hyperfunction and Insufficiency of the Heart. Moscow, 1960. Academy Medical Sciences. 2. MEERSON, F. Z. and ZAYATZ, T. L. The changes in intensity of protein synthesis in myocardium in the compensatory hyperfunction of the heart.
Bull. exper. biol. mad., 25: 33, 1960. 3. MEERSON, F. Z. and RAMENSKAY, G. P. tent of nucleic acids in the myocardium pensatory hyperfunction of the heart.
The conin com-
Vo@x~y
medizinskoy khimii, 6: 598, 1960. 4. MEERSON, F. Z., RUBEL, V. M. and TCHEFCNYSHOVA, G. V. Proteins and activity of the ATP-ase of the myocardium in experimental compensatory hyperfunction of the heart. PTOG. Vth Zntnnat.
Congr. Biochemists, Moscow, 1961. 5. MEERSON, F. Z., TCHERNYSHOVA, G. V. and ROSANOVA, L. S. Dynamics of functional composition of proteins of the myocardium in its adenosine tri-
Meerson phosphatase activity in compensatory hyperfunction of the heart. Vestnik Akademii Nauk USSR, 16: 32,
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MEERSON, F. Z., PSHENNIKOVA,M. G., RAMENSKAJA, G. P. and TCHERNYSHOVA, G. V. Experimental prophylaxis of certain changes developing in the myocardmm m chronic cardiac insufficiency. Doklady Akademii Nauk, 141: 509, 1961. 7. MEERSON, F. Z. On the mechanism of compensatory hyperfunction and insufficiency of the heart. Cor et mm, 3: 161, 1961. 8. MEERSON, F. Z. and PSHENNIKOVA,M. G. Senile alterations in the myocardium developing under the influence of hyperfunction of the heart and their experimental prophylaxis. Acta cardiol. 6.
(BTU.), 17: 261, 9. MEERSON, F. Z.
250, 11.
: 621,
Nauk
MEERSON, F. Z., MALOV, G. A., KALEBINA, N. S., SIMONYAN,N. T. and ROMANOVA,L. K. The role of DNA-dependent synthesis of RNA in activation of the genetic apparatus of differentiated cells in their increased physiological function. Doklady
23.
BAZARDJAN, A. G., KALEBINA, N. S. and MALOV, G. A. The effect of vitamin Bi2 on the dynamics of the protein synthesis in the myocardium in compensatory hyperfunction of the heart. Doklady
24.
BUCKLEY, N. M., MEERSON, F. Z., POGOSYAN,L. A. and SHENDEROV,S. M. The effect of nucleosides, strophanthin and combination of these factors on the process of fatigue in the myocardium. Bull.
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MEERSON, F. Z., BUCKLEY,N. M., KEPELKO, V. I. and SHENDEROV,S. M. Effect of nucleosides on the contractile function of the myocardium in the damage stage of the compensatory hyperfunction of the heart. Bull. Eksp. Biol., Med, 1965. MEERSON, F. Z. and PSHENNMOVA,M. G. Effect of myocardial hypertrophy on the contractile function of the heart. Bull. Etsp. Biol. Med., 5: 35, 1965. IRANOV, I. and YURIEV, V. Biochemistry and Pathochemistry of Muscles. Leningrad, 1961. WOLLENBERGER,A. Mitochondria in hypertrophied insufficient heart. In Ref. 16. WOLLENBERGER,A. and SCHULTZE, V. The mass and structure of mitochondria in chronically overloaded hynertrophied heart. In: Ref. 14, p. 126. BUCKLEY, N. M., TSUBOI, K. K. and ZEIG, N. J. Effects of nucleosides on acute left ventricular failure in the isolated dog heart. Circulation Res., 7:
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18: 27, 1963.
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149
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Union Scienbfic Conf. Cardiologist5 SocialiJt Countries, Moscow, 1963.
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with
Scientists
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F. Z., REPIN, I. M. and GODIN, V. P. On the role of interrelation of the physiological function and the genetic apparatus of the cell in the rise and inverse development of hypertrophy of the myocardium. Doklady Akademii Nauk USSR,
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KROKHINA, E. M. and MEERSON, F. Z. The dynamics of cholinesterase activity of intramural nerve elements of the heart in compensatory hyperfuncdon and hypertrophy. Archiu. Path., 25 : 34, 1963. MEERSON, F. Z., MANUCHIN, B. N., PSHENNIKOVA, M. G. and ROSANOVA, L. S. On the mediatory metabolism of the myocardium in compensatory hyperfunction and hypertrophy of the heart. i cxprrimentalnaya
2:. 28.
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BUCKLEY, N. M., TSUBOI, K. K. and ZEIG, N. J. Inotropic effects of purines and pyrimidines on the isolated heart. Circulation Res., 9: 242, 1961. 31. TSUBOI, K. K. and BUCKLEY,N. M. Metabolism of perfused Cr4-labeled nucleosides and bases by the isolated heart. Cirnrlation Res., 1965. In press. 32. STEPANENKO,B. N. and BOBROVA,M. N. On comparative study of the effect of UTP, ATP and UDP on the contractility of the myocardium. 30.
Doklady
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STEPANENKO,B. N. and BOBROVA, M. N. On new stimulators of cardiac activity. Theses of reports made at the scientific session of the I Moscow Medical Institute on: Cardiovascular Diseases, Their Prevention and Treatment. Moscow, 1963. 34. PUTINTZEVA,G. G. and TURPAYEV, T. M. The role of macroergs in effectuation of parasympathetic influences on the heart. In: Problemy Nervnoy Tropkhiki v Teorii u Practike Mediziny. Moscow, 1963. 33.
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MEERSON, F. Z., MALOV, G. A., PSHENNIKOVA,M. G. and ZALETAYEVA, T. A. Mechanism of hypertrophy and deterioration of the myocardium in cardiac deficiencies. In: Symposium: On insufficiency of the contractile function of the myocardium in cardiac deficiencies. Aoc. II All-
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MEERSON, F. Z., EVNINA, I. I., APANASSJUK, M. P. and SERDJUK, N. A. On energetic ensuring of the compensatory hyperfunction of the heart. In: Physiology and Fathology of the Heart (Symposium dedicated to V. V. Parin on his 60th birthday), p. 141. Moscow, 1963. 15. MEERSON, F. Z., LEYKINA, E. M. and BELOSHAPKINA, T. D. On interrelation of the physiological function and the genetic apparatus of the cell. Dok-
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Akademii
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F. Z. On the Relationships between the Physiological Function and the Genetic Apparatus of the Cell. Moscow, 1963. Academy Medical Sciences. 13. MEERSON, F. 2. et al. Function, structure and protein synthesis of hypertrophied myocardium. MEERSON,
Ve’eJtnik Akademii
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MEERSON, F. Z., MALOV, A. G., PSHENNIKOVA,M. G. and KALEBINA, N. S. Correlation of the intensity of protein synthesis and breakdown in hyperfunction of the heart. Doklady Akadcmii Nauk, 154:
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MEERSON, F. Z. and Po~ossov~, A. V. Incorporation of tagged amino-acids into the total protein and proteins of myocardial nuclei in compensatory hyperfunction of the heart. Voprossy mcdizinskoy khimii,
12.
increased level of Nauk, 157: 3, 1964.
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On the Pathophysiology of Insufficiency of the Heart. Moscow, 1962. Academy Medical Sciences. 10. MEERSON, F. Z. Compensatory hyperfunction and insufIiciency of the heart. Circulation R~J., 10:
MEERSON, F. Z., ZALETAEVA, T. A., LAGUTCHEV, S. S. and PSHENN~KOVA,M. G. Correlation of energy-producing and functional structures in the process of adaptation of differentiated cells to the
terapia, 7: 32, 1963.
THE AMERICANJOURNAL OF CARDIOLOGY
15
Journal JUNE
1965
of Cardiology Number
6
EDITORIAL
A Mechanism
of Hypertrophy the Myocardium
and Wear of
FELIX Z. MEERSON, M.D.
Moscow, USSR
C
OMPENSATORY hyperfunction of the heart is an important factor in the development of the general compensation observed clinically It regularly in various cardiovascular diseases. leads to the development of cardiac hypertrophy and later to a gradual weakening of the myoIn the course of the last ten years in cardium. collaboration with a group of physiologists, biochemists and morphologists, we have investigated the dynamics and mechanism of the process of hyperfunction and weakening of the myocardium in experimental cardiac defects reproduced in animals of various species.l-X The results of physiologic investigations show that the events developing in the myocardium in the process of hyperfunction of the heart depend upon the type of load on the heart.g A mainly isometric ty@e of hyperfunction is produced by increased resistance to ventricular ejection. This response is characterized by a marked increase in contractile function of the (estimated from the tension myocardium developed) proportional to the increase in The maximal load to which the resistance. heart can adapt is determined by the maximal tension which may be developed by the myocardium. Cardiac insufficiency occurs only after a complete mobilization of the functional reserve of the myocardium, as observed in hypertension and in stenosis of the valvular orifices. A mainly isotonic type of hyperfunction is produced by increased inflow of blood into a chamber. This response is characterized by a relatively * From the Institute of Normal and Pathologic
small increase in contractile function of the myocardium (estimated from the tension developed) as blood inflow increases. The maximal load to which the heart can adapt is determined by the distensibility of the myocardium rather than by its ability to develop tension. The onset of cardiac insufficiency occurs long before the functional reserve of the myocardium is completely mobilized; and it occurs not as a result of exhaustion of the cardiac reserve but because of inability to mobilize it, as observed in valvular insufficiencies, arteriovenous shunts and anemia. From these observations it may be inferred that in the process of evolution the heart has become adapted to respond to increasing work loads in two different ways. It can accommodate an abrupt increase in cardiac output while sparing mobilization of myocardial resources; but increased resistance in the aorta and pulmonary artery may be overcome by the heart only at the expense of a direct mobilization of energetic and structural resources of the myocardium. We have, therefore, concluded that the process of adaptation of cardiac muscle to an increased level of functioning (i.e., the process of hypertrophy and the subsequent wear of the myocardium) should be studied in a type of hyperfunction in which the myocardial reserve would be most completely mobilized: isometric hyperfunction. Therefore, all biochemical, physiologic and morphologic investigations in our laboratory have been made in this type of hyperfunction, produced by Physiology, Academy of Sciences, Moscow, USSR.
Meerson surgical stenosis of the aortic conus in rabbits or dogs or of the subdiaphragmatic aorta in rats. This experimental method led to a three to fourfold narrowing of the cross section of the aorta and to marked hyperfunction characterized by a one and a half- to twofold increase in left ventricular pressure and wall tension. The study of the dynamics of the myocardium under these conditions of mainly isometric hyperfunction of the heart enabled us to define a concept of three stages in the process of compensatory hyperfunction. STAGESINCARDIACHYPERTROPHYANDWEAR FIRST STAGE
The first or damage stage of isometric hyperfunction lasts about five to ten days and is characterized by hyperfunction of the still nonhypertrophied heart. This is effectuated by an increase in intensity of function per unit of myocardial mass, estimated as the ratio of contractile force to ventricular weight.16f17 The increase in intensity of function of structures (IFS) leads to a considerable increase in breakdown of myocardial proteins and in consumption of energy in the form of adenosine triphosphate (ATP). The increase in breakdown of proteins constituting the myocardial structure is manifested by the accelerated liberation of incorporated amino acids from the myocardium, by the six-fold increase in number of mitochondria undergoing destruction, and by the phenomena of protein and fatty dystrophy of the myocardium.i0J~~20~21 These shifts in turn become factors producing mobilization of the production of energy and the protein synthesis in the myocardium.’ t2*‘pi The activation of protein and nucleic acid synthesis is expressed by the one and a half to twofold increase in degree of incorporation of tagged precursors into proteins and acids ; by a rapid increase in total content of ribonucleic acid (RNA), protein and desoxyribonucleic acid (DNA) in the ventricular myocardium; and by an increase in the total content of specialized muscle proteins in the ventricular myocardium (myosin, actomyosin and proteins of the T-fraction, discovered by Iranov,26” made up of tropoThe concentration myosin and Zao protein). of mitochondrial protein and the area occupied by mitochondria in electron microscopic sections increase sharply during activation of protein and nucleic acid synthesis. These observations2~4~riJ4~20J2indicate that activation of the
apparatus for protein synthesis (i.e., the genetic apparatus of the myocardial cells) not only ensures the maintenance of myocardial cell differentiation but also a primary increase in mass and capacity of the energy-producing structures. Morphologically, the activation of the genetic apparatus is expressed by a rapidly developing hypertrophy of the myocardium. The activation of energy production and utilization is expressed by a marked increase in oxygen consumption per unit of myocardial mass, increased uptake of substrates for oxidation, and a shift in substrate utilization toward preponderance of carbohydrates. There is mobilization of 50 to 70 per cent of glycogen and 80 to 90 per cent of creatine phosphate reserves of the myocardium. Owing to the simultaneous activation of processes of respiratory and glycolytic phosphorylation, the myocardial concentration of ATP remains unchanged. Thus, conditions necessary to ensure production of energy for the increased contractile function and protein synthesis are maintained during cardiac hypertrophy. The maximal attainable level of contractile function of the heart (maximal contractile force or tension-time index of the left ventricle during complete aortic compression) is always decreased in this first stage of hyperfunction. The maximal intensity of function of myocardial structures (maximal contractile force per gram of left ventricle) is also decreased.25 The loss of functional capacity of the muscle is due to a sudden increase in protein breakdown and to the limitation imposed by the increased use of ATP. The first stage of the process of compensatory hyperfunction is characterized by a normal concentration of noradrenalin in the myocardium, with some decrease in acetylcholine content and lowered cholinesterase activity. The heart is normally reactive to sympathetic influences, whereas it is less reactive to vagal effects. Thus there is a preponderance of sympathetic autonomic regulation of cardiac activity corresponding to the marked increase in IFS.lsJD Hypertrophy due to activation of the protein synthesis leads to distribution of the increased function of the myocardium in its enlarged massIFS is decreased. This leads to a decrease of intensity of protein synthesis and energy production. Further development of hypertrophy does not occur; the first stage of the process is completed. Clinical manifestations of the damage stage are THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Cardiac Hypertrophy most marked when there is an acute increase in the load on the heart (i.e., in experimental and traumatic defects, insufficiency following infarction of the papillary muscle, hypertensive crises and significant overloading in untrained subjects). In rheumatic cardiac disease, gradually developing hypertension and highaltitude hypoxia, the load on the heart increases gradually. Augmentation of IFS is then less, and all phenomena characterizing the damage stage are not as pronounced as in experimental defects. However, the main features of this stage are the same as in our experimental model : In all cases a prolonged increase in IFS is observed. This produces activation of protein synthesis and energy production without which the cardiac hypertrophy regularly developed in clinical diseases would be impossible. SECOND
STAGE
The second stage or stage of relatively stable hy@fumtion in rabbits and rats lasts four to ten months, and in dogs about one and a half to two years. It is characterized by a normal level of IFS; hyperfunction of the organ as a whole is maintained without further augmentation of its mass, and is not accompanied by hyperfunction of the cellular elements. This conclusion is based upon observations that protein breakdown and the use of ATP by the myocardium approach the normal. There is a normal rate of liberation of tagged amino acids incorporated into the myocardial a normal number of mitochondria proteins, undergoing destruction, and no fatty or protein dystrophy. There is no activation of the genetic apparatus of myocardial cells, since incorporation of tagged precursors into protein and nucleic acids proceeds normally. Concentration of nucleic acid, mitochondrial and contractile proteins is also normal, and their total content in the myocardium is increased in proportion to the increase in its mass (i.e., about two-fold) .I.* ,9,11--13 There is also a pronounced increase in ATPase activity of myosin and in concentration of proteins of the T-fraction (which includes the assumed precursor of myosin, tropomyosin) . No acceleration occurs in energy production and utilization in the tissue since consumption of oxygen and oxidative substrates per unit of cardiac mass is normal, and for the organ as a whole is increased in proportion to the increase in mass. Myocardial concentration of glycogen, creatine phosphate and ATP is normal, and VOLUME
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their total content is increased in proportion to the mass of the myocardium.’ v3z4J* r14 The maximal attainable level of contractile futlction of the heart is increased in comparison to that of the intact heart. The maximal IFS is normal or slightly decreased. Thus the increase of maximal contractile force of the hypertrophied heart is due only to augmentation of its mass and not to increased functional capacity of the cellular elements. Regulation of cardiac activity in this second stage is characterized by an insignificant fall in noradrenalin concentration in the myocardium, the concentration of acetylcholine and cholinesterase activity being normal. The reactivity of the heart of sympathetic and parasympathetic influences remains unchanged.iJsJg An important feature of the stage of relatively stable hyperfunction is that regressive shifts preparing the next stage of the process are gradually developing. The earliest changes of this kind include the decrease of concentration of coronary capillaries ; abrupt increase of concentration of lactic acid, slight decrease of DNA concentration and accumulation of nonprotein nitrogen in the myocardium;14J3 and, as was first shown by Wollenbergernf2a and later by us 716.*0 appearance of slight destructive changes in mitochondria and some decrease in noradrenalin content.lg The stage of relatively stable hyperfurution constitutes the most protracted period of hyperfunction in most cardiovascular diseases in man. Its duration depends on the extent and acuteness of the development of the damage stage, on the degree of hyperfunction and hypertrophy, on the presence or absence of additional injuries of the heart and regulatory mechanisms and on Clinically, the period of stable other factors. compensation usually corresponds to this stage. THIRD
The
STAGE
third stage of gradual exhaustion and procardiosclerosis is characterized primarily by inhibition of activity of the genetic apparatus of myocardial cells and, as a result, by the development in the hypertrophied myocardium of a “complex of wear.” This complex includes pathologic alterations in the nuclei of muscle fibers, sometimes a fall in DNA concentration, inhibition of protein synthesis and destructive changes in the most intensely renewed myothe mitochondria.’ ,* J* v*O cardial structures, There is also a moderate decrease in ATP a decrease in ATP-ase activity concentration;
gressive
Meerson of the myosin of myofibrils;
gradual atrophy, vacuolar degeneration and clumping breakdown of some muscle fibers with simultaneous increase in the extent of hypertrophy of the remaining fibers; and progressive cardiosclerosis, most pronounced in those myocardial zones which have undergone a significant hyperfunction and hypertrophy .’ .4z5 The maximal level of contractile function of the heart may be either increased or normal or decreased, depending on the extent of wear; but the maximal IFS is always decreased.*” This observation indicates that the development of the “complex of wear” regularly decreases the functional capacity of the myocardium. For a time, this shift is compensated for by the increase in myocardial mass, but later it is progressive and leads to decreased contractile capacity of the heart as a whole. This stage is characterized by a three- to fourfold fall in noradrenalin concentration in the myocardium, normal concentration of acetylcholine and cholinesterase activity being maintained. The reactivity of the heart to sympathetic influences decreases abruptly, while the heart is normally reactive to vagal effects.1,1ka19 Thus there is a preponderance of parasympathetic autonomic regulation of cardiac activity and a profound disturbance of myocardial catecholamine metabolism corresponding to the decreased contractile capacity. Pathologic and btochemical studies indicate that many characteristics of the “complex of wear” observed by us in experimental cardiac insufficiency are marked in the hypertrophied myocardium of human subjects suffering from deficiencies and hypertension for a long time. Frequently the “complex of wear” corresponds to various stages and forms of clinical decompensation, but it may also be observed under conditions of complete compensation.
EFFECTS OF PRECURSORSOF NUCLEIC ACID AND CO-FACTORS SYNTHESISON CONTRACTILE FUNCTION The hypothesis that the development of a “complex of wear” is the basis for decreased contractile capacity of the hypertrophied myocardium contradicts the widespread concept that insufficiency of the hypertrophied heart is determined exclusively by a disturbance in the use of ATP energy for contractile function, the process of energy production being quite normal. In fact, there is inhibition of protein synthesis in myocardial cells, which leads to a disturbance in the
renewal of the energy-producing as well as the contractile structures of the myocardium. This is manifested by a destruction and decrease in enzymal activity of mitochondria, and by a decrease in ATP-ase activity of myofibrils. Naturally, since mitochondria are organelles having a much more intense rate of renewal than myofibrils, their structure and function are affected by disturbed protein synthesis earlier than are myofibrillar structure and function. Therefore, in prolonged isometric hyperfunction of the heart, the decrease in myofibrillar ATPase activity and probable disturbance in utilization of ATP energy for contractile function is combined with decreased ATP concentration. In this manner, the primary inhibition of protein synthesis leads to a disturbance in the processes of energy production and utilization. Th result is a decrease in contractile capacity of the myocardium. This hypothesis has been a premise for studying the action of precursors and co-factors of nucleic acids and protein synthesis, and for energy production, on the contractile function or metabolism of the myocardium23-26 in three different situations: fatigue of the normal heart, acute experimental cardiac insufficiency of several days’ duration, and finally under conditions of wear of the hypertrophied myocardium in experimental insufficiency lasting about five months. The factors chosen were vitamin B12, folic and erotic acids and cardiotonic nucleosides and bases29130 alone and in combination with strophanthin. In the majority of experiments, three essential indices of the contractile function of the left ventricle were determined : maximum attainable contractile force, maximum intensity of function of myocardial structures (maximum IFS) and a “staircase of myocardial fatigue.” The first two indices have already been de-
scribed. The maximum contractile force of the left ventricle expressed by the systolic ventricular pressure or tension-time index characterizes the maximally attainable contractile force of the ventricle as a whole; the maximal IFS characterizes the contractile capacity of the tissue constituting the ventricle. The third index, “staircase of fatigue,” was determined by repeated numerous 30-second occlusions of the ascending aorta at intervals of five minutes. With each occlusion, the maximal systolic intraventricular pressure becomes lower, producing a staircase characteristic of the development of a process of myocardial fatigue. Effect of Nucleosides
on Fatigue of Normal Heart:
THE AMERICAN JOURNALOF CARDIOLOGY
Cardiac
Hypertrophy
The effect of a mixture of uridine, uracil, inosine and hypoxanthine on the “staircase” in normal animals was compared to the effect of saline or strophanthin. *’ Strophanthin alone or the mixture of nucleosides and bases halted the trend toward myocardial failure, while a combination of all five agents completely reversed this The injected nucleosides are precursors trend. of nucleic acids and may stimulate their synExperiments with tagged nucleosides3’ thesis. showed that on entering the myocardium, uridine is rapidly incorporated into uridine triphosphate and inosine into ATP. The rapid inotropic effect of ATP and UTP observed on isolated hearts”-” suggest that the rapid inotropic effect of nucleosides depends mainly on their influence on the biosynthesis of macroergic phosphates. EJect of Xucleosides in Acute Cardiac Insu@iency: Another series of experiments compared the effect of a mixture of uridine, uracil, inosine and hypoxanthine on the contractile function of the myocardium in the acute damage stage of experimental insufficiency with the effect in normal animals.25 In the “breakdown” stage of compensatory hyperfunction in untreated animals, two days after creation of experimental stenosis of the aorta, the maximal contractile function of the heart was decreased by 14 per cent. This decrease could be accounted for on the basis of the previously described biochemical changes. It could be prevented by daily intravenous injection of the nucleoside-base mixture in a dose which had no effect on the maximal contractile function of normal hearts. These observations indicate that under conditions of acute overloading of the heart, the precursors and stimulators of nucleic acid synthesis may eliminate the characteristic defect in contractile function. effect of Folk and Orotic Acids on Acute Cardiac Insujkiency : In a recent series of investigations (in cdllaboration with M. G. Pshennikova and N. G. Tarayeva), we have studied the effect produced on cardiac contractile function by a combination of two substances which are known stimulators of nucleic acid and protein synthesis: folic and erotic acids. Daily injections with these two compounds during the four days after creation of experimental aortic stenosis led to a shift upward of the “staircase” for treated as compared to untreated animals. In addition, the maximal IFS was always greater in the treated animals. Therefore, since the injection of the combination of erotic and folic VOLUME15,
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acids increased the IFS, the improved contractile function could not be accounted for on the basis of increased rate of hypertrophy but of improved cellular function. Biochemical studies (carried out in our laboratory by Dergatchev) have shown that folic acid administered in this stage of the process of compensatory hyperfunction produces a distinctly marked effect on the protein and nucleic acid synthesis in the myocardium. Consequently, these factors may both accelerate myocardial hvpertropb and increase its contractile function per unit mass. Protracted Experimental Cardiac InsujSciency: A final object of our studies has been to inhibit the development of the “complex of wear.” We have already investigated the effect of injection of a combination of vitamin B12, ATP and methionine on biochemical changes in hypertrophied hearts of animals with pratracted experimental stenosis of the aorta.6s8 Prolonged treatment with this combination of substances prevented to some extent the decrease in ATP-ase activity and DNA concentration of the myocardium, that is, it inhibited the development of changes essential to the “complex of wear.” Further investigations on experimental prophylaxis of the “complex of wear” in the process of hyperfunction and hypertrophy of the heart are being carried out. The various experiments summarized here are particularly relevant to clinical situations associated with acute overloading, rapid hypertrophy, and regional hyperfunction of intact areas after myocardial infarction. The results obtained suggest that a careful clinicophysiologic study of the joint administration of glycosides and precursors and co-factors of nucleic acid synthesis would be very promising. REFERENCES 1. MEERSON, F. Z. Compensatory Hyperfunction and Insufficiency of the Heart. Moscow, 1960. Academy Medical Sciences. 2. MEERSON, F. Z. and ZAYATZ, T. L. The changes in intensity of protein synthesis in myocardium in the compensatory hyperfunction of the heart.
Bull. exper. biol. mad., 25: 33, 1960. 3. MEERSON, F. Z. and RAMENSKAY, G. P. tent of nucleic acids in the myocardium pensatory hyperfunction of the heart.
The conin com-
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medizinskoy khimii, 6: 598, 1960. 4. MEERSON, F. Z., RUBEL, V. M. and TCHEFCNYSHOVA, G. V. Proteins and activity of the ATP-ase of the myocardium in experimental compensatory hyperfunction of the heart. PTOG. Vth Zntnnat.
Congr. Biochemists, Moscow, 1961. 5. MEERSON, F. Z., TCHERNYSHOVA, G. V. and ROSANOVA, L. S. Dynamics of functional composition of proteins of the myocardium in its adenosine tri-
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MEERSON, F. Z., PSHENNIKOVA,M. G., RAMENSKAJA, G. P. and TCHERNYSHOVA, G. V. Experimental prophylaxis of certain changes developing in the myocardmm m chronic cardiac insufficiency. Doklady Akademii Nauk, 141: 509, 1961. 7. MEERSON, F. Z. On the mechanism of compensatory hyperfunction and insufficiency of the heart. Cor et mm, 3: 161, 1961. 8. MEERSON, F. Z. and PSHENNIKOVA,M. G. Senile alterations in the myocardium developing under the influence of hyperfunction of the heart and their experimental prophylaxis. Acta cardiol. 6.
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BUCKLEY, N. M., MEERSON, F. Z., POGOSYAN,L. A. and SHENDEROV,S. M. The effect of nucleosides, strophanthin and combination of these factors on the process of fatigue in the myocardium. Bull.
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MEERSON, F. Z., BUCKLEY,N. M., KEPELKO, V. I. and SHENDEROV,S. M. Effect of nucleosides on the contractile function of the myocardium in the damage stage of the compensatory hyperfunction of the heart. Bull. Eksp. Biol., Med, 1965. MEERSON, F. Z. and PSHENNMOVA,M. G. Effect of myocardial hypertrophy on the contractile function of the heart. Bull. Etsp. Biol. Med., 5: 35, 1965. IRANOV, I. and YURIEV, V. Biochemistry and Pathochemistry of Muscles. Leningrad, 1961. WOLLENBERGER,A. Mitochondria in hypertrophied insufficient heart. In Ref. 16. WOLLENBERGER,A. and SCHULTZE, V. The mass and structure of mitochondria in chronically overloaded hynertrophied heart. In: Ref. 14, p. 126. BUCKLEY, N. M., TSUBOI, K. K. and ZEIG, N. J. Effects of nucleosides on acute left ventricular failure in the isolated dog heart. Circulation Res., 7:
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THE AMERICANJOURNAL OF CARDIOLOGY