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British HeartJournal, I971, 33, Supplement, ioo-io8.

Mechanism of hypertrophy of the heart' andexperimental prevention of acutecardiac insufficiency

F. Z. MeersonFrom the Institute of Normal and Pathological Physiology,Academy of Medical Sciences, Moscow, U.S.S.R.

It is known that hyperfunction of the heartarising from cardiac defects, systemic hyper-tension, pulmonary hypertension, and overactivity of non-affected regions of the heartin cardiac infarction, is regularly followed bymyocardial hypertrophy, which after a pro-longed period not infrequently results inchronic cardiac insufficiency. Thus hyper-function, hypertrophy, and cardiac insuffici-ency represent three links of a unique processhaving a fundamental importance in modemcardiology. The dynamics of structural, bio-chemical, and physiological alterations consti-tuting this process has already been the objectof extensive investigations and has beendescribed in numerous reviews and mono-graphs (Meerson, I960; Sonnenblick, I968;Spann et al., I965; Meerson, I969a, b; Gud-bjarnason, Telerman, and Bing, I964; Buch-ner and Weyland, I968). This allows us torestrict our paper to analysis of the principalmechanism of development of cardiac hyper-trophy and to the consequences of the currentconcept of this mechanism in the preventionof acute cardiac insufficiency in overload ofthe heart.

Basis of hypertrophyMore than I0 years ago it was shown that thebasis of hypertrophy of the heart was theactivation of nucleic acid and protein syn-thesis arising in myocardial cells in responseto hyperfunction of the heart (Meerson andZajats, I960). Soon it became obvious thatthis activation of nucleic acid and protein syn-thesis in response to augmented physiologicalfunction was common to all cells, organs, andphysiological systems of a whole organism,and that in particular it was the basis of com-pensatory hypertrophy of most diverseorgans in their protracted continuous hyper-function.

Essentially, activation of nucleic acid andprotein synthesis in response to augmentedfunction is an expression of interrelation be-tween the genetic apparatus and the physio-

logical function of the cell, the interrelationwhich is the structural basis of various adapta-bility reactions of the organism. This impliesthat the question of the mechanism of cardiachypertrophy is also pertinent in the biologicalproblem concerning the interrelation betweenthe genetic apparatus and the physiologicalfunction of the cell. Here a direct and aninverse relation between the genetic apparatusand the cellular function, definitely expressedin the heart muscle, are distinguishable. Thedirect relation is that the genetic apparatus,on the basis of the known scheme DNA-*RNA-*protein, ensures the formation of basicstructures of the muscle cell, the myofibrils,mitochondria, and membranes of the sarco-plasmic reticulum - that is, of structures ofthe myocardial cell which perform its function.Since it is known that the intensity of thebreakdown of structures of the muscle cellsas well as of other differentiated cells increasesin proportion to the increase in their function(Meerson et al., I964b; Hyden, I962) it isobvious that even the most direct relationcannot ensure an opportune renewal of myo-cardial structures and the persistence of thecontractile function of the heart. This essen-tial effect may be achieved only if the intensityof RNA and protein synthesis is opportunelyaltered after the change in intensity of func-tioning and breakdown of structures, thuspreventing exhaustion of structures and func-tional disturbance. In other words, to ensureperfect structural contractile function, pre-cisely regulated changes in activity of thegenetic apparatus - changes in intensity ofRNA synthesis on active genes of DNA -must occur in due time. For this the geneticapparatus should receive exact and opportuneinformation about the level of the contractilefunction of the myocardial cell. This kind ofinformation about the functional level sentfrom the cytoplasm to the cellular nucleusplays the part of an inverse relation, regulatingthe activity of the genetic apparatus and pre-venting the exhaustion of cellular structures.

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Mechanism of hypertrophy of the heart IO0

In continuous compensatory hyperfunctionof the myocardium, where the abrupt break-down of cellular structures may be welldemonstrated by biochemical (Meerson et al.,I964b) and electronmicroscopical data (Hattand Swynghedauw, I968), it is the realizationof the inverse relation that enables the func-tion 'to lay increased claims to protein syn-thesis' and ensures activation of synthesis andthe development of cardiac hypertrophy. Thedecisive part played by the inverse relationbetween function and genetic apparatus ofmyocardial cells in the development of com-pensatory hypertrophy of the heart has beenthe object of many investigations.

Effect of increased functionThe first question to be answered is whetherthe activating effect of the increased functionis really directed to the genetic apparatus. Inother words, is it true that the increased ten-sion of myofibrils in cardiac cells activatesthe RNA synthesis on the genes of chromo-somal DNA through a definite mechanism?

Since the increase in function is regularlyfollowed by the rise of RNA concentrationin the cell, while the whole RNA, in particularthe ribosomal one, is synthesized only on thematrices of DNA - that is, on genes - it ap-peared some years ago, when the concept ofthe inverse relation was advanced, that thisquestion might be answered affirmatively(Meerson, I963). However, the scepticismwhich met the proposed formulation of'interrelation of function and the geneticapparatus' served as a stimulus for under-taking special experimental work in thisdirection.At the first stage of investigation in our

laboratory the antibiotic actinomycin, whichinhibits with relative selectivity the RNA andDNA synthesis - that is, the process of tran-scription - was used. Introduction of thispreparation into the animal organism in non-toxic doses does not decrease the concentra-tion of RNA in such organs as heart and kid-ney, and does not disturb therein the proteinsynthesis, since protein continues to be syn-thesized on available matrices of the messen-ger RNA formed before injection of actino-mycin. At the same time, in animals in whichhyperfunction of the heart was produced byaortic stenosis, or hyperfunction of the leftkidney by removal of the right kidney, actino-mycin fully prevented activation of RNA andprotein synthesis which usually arises in in-tensely working myocardium, and inhibitedthe development of hypertrophy (Meerson etal., I964a). This evidence has confirmed that

the activating influence of the increased func-tion may be effected through some inter-mediate links and is directed to the geneticcellular apparatus. Some years later these ex-periments were successfully developed by agroup of workers (Schreiber, Oratz, andRothschild, I967; Schreiber et al., I968)who imposed an overload on the isolated ratheart and at the first stage reproduced ourresults. They obtained activation ofRNA andprotein synthesis under the influence of theoverload, and prevented this activation byadding actinomycin to the perfusing fluid.Later they showed that the ability of ribo-somes obtained from isolated hearts to syn-thesize protein had grown one hour after theoverload had been imposed on the organ. Thehyperactivity of ribosomes was fully preven-ted by actinomycin and this action was notfollowed by an increase in the number ofribosomes.

Since one of the probable causes of increasein synthesizing activity of ribosomes is theprogramming of the increased number ofribosomes of the messenger RNA, an experi-ment was performed to discover the extent ofprogramming. Synthetic polyuridin (poly-U)was added to ribosomes. This polynucleotide,like natural messenger RNA, programmes theribosomes, activating not the protein synthe-sis but that of the polypeptide, consistingonly of phenylalanine-polyphenylalanine.Poly-U elicited this effect on the ribosomes

obtained from the group of control hearts: in-corporation of labelled precursor-phenylala-nine was increased. On ribosomes obtainedfrom intensely working heart such an effectwas not produced. It has been assumed thatthe poly-U could not enter into activatedribosomes since they had been programmedbeforehand by the normal information ofRNA, which was synthesized in increasedamounts on DNA and within an hour couldreach the ribosomes. In other words, inhyperfunction of the heart the messengerRNA is very rapidly transported into ribo-somes, ensuring the activation of proteinsynthesis and by this the structural basis of theheart's hyperfunction.The work of Nair and his colleagues (Nair

et al., I968) was the next step, identifyingmore precisely the influence activating theincreased function. The authors determinedthe polymerase activity of nuclei isolated fromthe myocardium of animals in which an in-tense hyperfunction and extensive hyper-trophy of the heart were produced by aorticstenosis. It was found that I2 hours after theonset ofhyperfunction the polymerase activityof such nuclei - that is, their ability to syn-



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thesize RNA on matrices of DNA - wasessentially increased, especially in relation toribosomal RNA synthesis.

Intensity of functioning of the structuresOn the whole the data obtained seem toagree with the original concept that the acti-vating influence of the increased physio-logical function is directed through some in-termediate links to the genetic cellular appara-tus. The second question, in considering theinfluence of function on the genetic apparatus,is by which parameter of function the geneticapparatus is determined. This aspect of theproblem was first encountered during thestudy of the dynamics of nucleic acid and pro-tein synthesis in the development of com-pensatory hyperfunction and hypertrophy ofvisceral organs. It was found that the impor-tant feature of the process of hyperfunction- hypertrophy of the heart in aortic stenosis,of the single kidney after unilateral nephrec-tomy, of the hepatic lobe after partial hepa-tectomy, and of the single lung after removalof the other lung - is that the activation ofnucleic acid and protein synthesis arisingduring the subsequent hours and on the dayafter the onset of hyperfunction graduallyceases in the course of development of hyper-trophy of the organ. Such dynamics of theprocess is determined by the fact that at thebeginning of the process the hyperfunction iseffected by a still unhypertrophied organ andthe amount of function per unit of mass of theorgan is sharply increased. Just such an in-crease in amount of function per unit of massof cellular structures produces activation ofthe genetic apparatus of differentiated cells.After full development of hypertrophy of theorgan its function is distributed within theincreased mass of cellular structures, and as a

result the amount of function performed bythe mass unit of structures returns to or

approaches the normal level. Then activationof the genetic apparatus ceases and the nucleicacid and protein synthesis also returns to thenormal level (Meerson, I960, I968).

If hyperfunction of the organ still subjectedto hypertrophy is eliminated, the amount offunction performed by i g. of the myocardiumwill become abnormally low. As a result, theprotein synthesis in differentiated cells of theorgan is decreased and the mass of the organ

begins to decrease.Owing to this decrease the amount of func-

tion per unit of mass is gradually increased,and after it becomes normal the inhibition ofprotein synthesis in the organ cells ceases:

its mass is not decreased further (Meerson,I969a, I965).

The data presented suggest that in differen-tiated cells and mammalian organs formed bythe latter, the amount of function performedby the mass unit of the organ - the intensityof functioning of the structures (IFS) - playsan important part in regulating the activity ofthe genetic cellular apparatus. The increasein IFS corresponds to the state when 'thereis restriction of space for function in the struc-ture'. This involves activation of protein syn-thesis and increase in mass of functioning,energy-producing, and supporting structures.The decrease in the given parameter corre-sponds to the situation when 'there is tooample space for function in the structure',which results in decrease in intensity of syn-thesis with a subsequent removal of excessivestructure. In both cases the intensity of func-tioning of the structures returns to the optimalvalue proper to a normal organism.Thus the intracellular mechanism effecting

bilateral interrelation between physiologicalfunction and genetic apparatus of the differen-tiated cell ensures the state in which 'the in-tensity of functioning of the structures' (IFS)is simultaneously the determinant of activityof the genetic apparatus and the physiologicalconstant maintained at a permanent levelowing to opportune changes in activity of thisapparatus (Meerson, I965).There are other factors concerning the

interrelation of function and the geneticapparatus of myocardial cells. They are con-sidered elsewhere, and represent but a premiseto the essential main question about the inter-relation of function and genetic apparatus,namely: In what manner and through whichintracellular mechanism does the intensity offunctioning of the structures exert its influ-ence upon the activity of the genetic apparatusof myocardial cells ?

Two conceptsIn an attempt to answer the main questiontwo further concepts should be considered:

i) In intense compensatory hyperfunction of theheart (Meerson, I964b), of neurones (Hyden,I962), and apparently of other differentiated cells,there regularly occurs an increase in the break-down of cellular structures. This breakdown ofstructures itself serves as a stimulus to activationof the genetic cellular apparatus, as has beendemonstrated in recent experiments which showedthat by itself the increased breakdown of myo-cardial structures caused by moderate ischaemiaof the heart regularly produces activation ofnucleic acid and protein synthesis and the develop-ment of hypertrophy of the heart without hyper-function of this organ (Gudbjarnason, Braasch,and Bing, I968). It has also been shown that



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Mechanism of hypertrophy of the heart 103

compensatory hyperfunction of the kidney, pro-duced after a brief deprivation of the blood supplyof this organ, leads to a considerably greater acti-vation of nucleic acid and protein synthesis and tothe development of a greater hypertrophy of theorgan, than does hyperfunction of the ischaemickidney (Hubner, I967). In other words, the break-down of structures caused by a hypoxic lesion ofthe tissue, and the breakdown due to hyperfunc-tion of this tissue, together create a stimulus tomuch greater activation of nucleic acid and pro-tein synthesis than can be induced by these factorsseparately.2) In acute pronounced hyperfunction of theheart the use of energy in the form of ATP inmyofibrils exceeds the capacity of mitochondriato effect ATP resynthesis by oxidative phosphory-lation. As a result there is a lack of energy, shownby the fall in concentration of creatine phosphateand glycogen together with activation of glycolysisand accumulation of lactic acid in the myocardium(Vyalykh and Meerson, I960; Fox, Wikler, andReed, I965; Feinstein, I962) - that is, there ariseshifts similar to those occurring under the directaction of hypoxia upon the myocardium, whichlimits the intensity of processes of oxidation andoxidative phosphorylation (Gudbjarnason et al.,I968; Chang, 1938). Recently evidence has beenobtained showing that such lack of energy andassociated decrease in pH regularly produce alysosome effect in the myocardium which isincreased in hyperfunction of the heart (Meersonet al., I970) and under the action of hypoxia(Ravens and Gudbjarnason, I969; Leighty et al.,I967).

In sum, these two ideas suggest that thelack of energy arising in intense and pro-tracted hyperfunction of the organs becomesthe cause of labilization of lysosomes, and thebreakdown of structures produced by lyso-some ferments is the stimulus leading toactivation of nucleic acid and protein syn-thesis in the cells. This activation and theensuing hypertrophy finally result in decreasein intensity of functioning of structures of theorgan and to increase in capacity of themechanisms ensuring energy transformation.Thus the lack of energy and the increasedbreakdown of structures are eliminated andthe hyperfunction of the hypertrophied organbecomes relatively stable.

This concept implies that the breakdown ofstructures caused by the lack of energy is animportant link in the mechanism connectingfunction and genetic cellular apparatus. Thisraises the question, how may the breakdownof structures activate the genetic cellularapparatus ? The study of this still unresolvedquestion is in fact being made on the basis oftwo different hypotheses.The first hypothesis is that the increased

breakdown of structures leads to accumula-

tion in the cell of products of breakdown oforganospecific proteins and RNA - 'meta-bolites of wear'. Metabolites of this kind canplay the part of inductors activating the pro-cesses of transcription - RNA synthesis onstructural genes of DNA. This activation maybe effected by decrease or abolition of the in-hibitory influence exerted by special regula-tory genes upon structural genes - that is, onthe basis of principles formulated for themicrobic cell by Jacob and Monod (I96I).

Mechanism of activationThe ability of breakdown products to stimu-late organospecifically nucleic acid and pro-tein synthesis has been demonstrated in manyinvestigations on mammalian organs (Lahti-harju and Teir, I964; Mahler et al., I958;Polezhaev et al., I962). The phenome-non of synthesis induction under the influ-ence of hormones and other metabolites isalso well known in these organs (Levi-Montalcini, I964; Korner, I969; Naets andWittek, I969). Therefore in the past, whileformulating the concept of connexion offunction of the genetic apparatus, the authorcould assume that 'metabolites of wear'formed in the myocardium in hyperfunctionof the heart activate the nucleic acid and pro-tein synthesis, acting like inductors in theJacob and Monod scheme.The second hypothesis is that in usual con-

ditions the normal concentration of proteinsin the differentiated cell is the factor restrain-ing the synthesis of these proteins. In hyper-function of the organ the increase in IFS in-volves the breakdown or increased 'export ofproteins'. As a result there is a decrease intheir concentration at different points of thecell, and the lack of proteins becomes a factorproducing activation of their synthesis. Inthis circumstance the decrease in concentra-tion of myofibrillary proteins, actually ob-served at the damage stage of hyperfunctionof the heart, may accelerate the rate at whichthe molecules of these proteins leave thematrices of the messenger RNA in polyribo-somes. As a result, the intensity of use of theRNA matrices and of their breakdown mayincrease. As a result, the rate at which avail-able RNA matrices leave the structural genesof chromosomal DNA is accelerated and thewhole process DNA-#RNA--.protein be-comes activated. If this hypothesis, advancedsome years ago, is true, and activation of pro-tein synthesis in polysomes really constitutesthe initial link of the process necessary forrealization of its subsequent links, then



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104 F. Z. Meerson

apparently elimination of the given link bythe inhibitor of protein synthesis under con-ditions of hyperfunction should prevent notonly the activation of protein synthesis butalso that of the synthesis of RNA. Investiga-tion of the effect of puromycin on the com-pensatory hyperfunction of the heart, pro-duced by stenosis of the aorta by Posner andFanburg (I968), has shown just this result.Another argument in favour of the given

hypothesis is that synthesis of one of themuscle proteins, myoglobin, occurring invitro in the ribosome system, may be activatedby the decrease in concentration of myoglobinand inhibited by the rise of concentration ofthe given protein. Here the change in con-centration of myoglobin does not act on thedegree of synthesis of other proteins, in par-ticular of that of albumin (Kagen and Linder,I969). Actually this hypothesis suggests theexistence of an economic mechanism ofquantitative regulation of transcription of alimited number of genes which are active inthe differentiated cell.

Experimental correlation ofthese two hypo-theses is expected in the future. At the sametime the concept that the breakdown of struc-tures activates in some way the genetic appara-tus of muscle cells already represents a start-ing point for the prophylaxis of acute heartinsufficiency and the active prevention of theprocess of hypertrophy.

Indeed, if at the onset of compensatoryhyperfunction of the heart, at the so-calleddamage stage of this process, there arises alack of energy and as a consequence a break-down of structures with a subsequent activa-tion of synthesis, this situation may be pre-vented by preliminary increase in capacity ofthe mechanisms of oxidation and oxidativephosphorylation in myocardial cells.

Altitude hypoxia and physical loadTwo factors are known which by them-selves .produce an insignificant hypertrophyof the left ventricle but at the same timelead to a considerable increase in capacity ofthe mechanism of energy transformation inthe myocardium. Such factors are adaptationto disrupted action of altitude hypoxia, andtraining to physical load.The adaptation to disrupted action of alti-

tude hypoxia always involves an increase incapacity of the mechanisms responsible forthe transport of oxygen to myocardial cells,namely the increase in number of coronarycapillaries (Valdivia, I962) and conceiitrationof myoglobin (Tappen and Reynafarje, I957;Poupa et al., I966), with simultaneous increase

in concentration of mitochondrial protein(Sobel and Cohen, 1958) and in activity ofenzymes of the respiratory chain (Tappen andReynafarje, I957). The maximal force ofmyocardial contraction of trained animals cal-culated per unit ofweight, as well as the rate ofisotonic contraction, increased considerably(Meerson and Kapelko, I970). In this con-nexion one could assume a priori that at theonset of compensatory hyperfunction of theheart, produced for instance by experimentaldefect in animals previously trained to altitudehypoxia, the lack of energy, breakdown ofstructures, and disturbance of the contractilefunction would be less than in the untrainedanimals, and correspondingly that the activa-tion of nucleic acid and protein synthesiswould be less pronounced.The data represented in Fig. I-5 illustrate

the results of experiments performed on malerats of Wistar line in which, iI months afterpreliminary training in the barocamera (at an' altitude' of 6ooo metres for 6 hours daily), anexperimental coarctation of the abdominalaorta (narrowing to one quarter the cross-section of the abdominal aorta immediatelybelow the diaphragm) was produced. Fig. I(left) shows that one day after coarctation ofthe aorta the concentration of creatine phos-phate in the myocardium of the left ventriclein untrained rats has decreased by almosthalf; on the right it is shown that in ratspreviously trained to hypoxia no decrease in

FIG. I Effect of training to altitude hypoxiaon the decrease in concentration of creatinephosphate in the myocardium produced byaortic coarctation.

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1C000 Control900-

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FIG. 2 Effect of training to altitude hypoxiaon the decrease in concentration of glycogen inthe myocardium after aortic coarctation.

creatine phosphate is occurring; there is evensome increase, still unexplained.

Fig. 2 (left) shows that in untrained ani-mals the concentration of another reserve ofenergy, glycogen, is decreased some days afteraortic coarctation, not sharply, but quiteappreciably by I7 per cent. On the right it isseen that in trained animals there is minimaldecrease in glycogen after aortic coarctation.

Fig. 3 represents data on maximal force of

FIG. 3 Effect of training to altitude hypoxiaon the decrease in maximal contraction forceof the myocardium produced by aortic coarc-tation.

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myocardial contraction of the left ventriclecalculated per unit of myocardial mass. Onthe left it is seen that in untrained rats themaximal contraction force developed by themyocardium in brief aortic coarctation isdecreased by more than half one day aftercoarctation. On the right it is shown that intrained animals this decrease ofthe contractilefunction is 20 per cent and this difference isnot statistically significant.

Fig. 4 shows that two days after the onsetof hyperfunction in animals not adapted toaltitude hypoxia, the RNA content in the leftventricle has increased by 5I per cent and intrained ones by only 9 per cent.

Fig. 5 shows that two days after aorticcoarctation and the onset of hyperfunction ofthe heart, protein synthesis in the myocardiumof untrained animals has increased by 66 percent, while in those first adapted to the actionof altitude hypoxia it has increased by io percent.Thus the preliminary adaptation to the dis-

rupted action of altitude hypoxia has defin-itely prevented the disturbance of metabol-ism, function, and activation of nucleic acidand protein synthesis in the damage stage ofthe compensatory hyperfunction of the heart.

It is known that training to physical loading,like adaptation to altitude hypoxia, is a factorincreasing the capacity of mechanisms trans-porting oxygen to myocardial cells - namely,

FIG. 4 Effect of training to altitude hypoxiaon the increase in RNA content in the leftventricular myocardium produced by aorticcoarctation.

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FIG. 5 Effect of training to altitude hypoxiaon activation of protein synthesis in the myo-cardium produced by aortic coarctation.

the capacity of the coronary vessels (Leon andBloor, i968) and myoglobin concentration(Pattengale and Holloszy, i967). At the sametime, as a result of training there is an increasein mass and number of mitochondria at theexpense of activation of the nucleic acid andprotein synthesis in these organelles (Laguensand Gomez-Dumm, i967, i968; Goilnick andKing, i969) and the increase in capacity ofmitochondrial enzyme systems of oxidationand oxidative phosphorylation (GoUlnick andKing, i969; Hearn and Wainio, i956; Gouldand Rawlinson, 1959; Holloszy, i967).The results of experimental work on the

effect of acute heart overloading, produced byexperimental aortic coarctation, upon themetabolism and function of the heart in ratsfirst trained to physical load (running in atreadmill at the rate of 14 m. per minute for3 hours daily with 5-minute intervals eachhalf-hour during 2 months) have been foundin principle similar to those in experimentswith rats trained to altitude hypoxia. Fig. 6shows that two days after aortic coarctationand the onset of hyperfunction the RNAcontent in the left ventricular myocardiumtaken from untrained animals has increasedby 48 per cent, while that in the left ventricleof trained animals has inot essentially changed.Fig. 7 shows that the intensity of proteinsynthesis two days after onset of hyperfunc-tion has increased in the untrained animals by46 per cent and in trained animals no notice-able activation of protein synthesis is seen.

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FIG. 6 Effect of training to physical load onthe increase in RNA content produced byaortic coarctation.

On the whole, the results of experiments indi-cate that preliminary training to altitude hy-poxia and physical exercise not only increasesthe myocardial resistance to overloading anddecreases the extent of energy lack, character-ized by concentration of glycogen and creatinephosphate, but also significantly lowers the

FIG. 7 Effect of training to physical exerciseson activation of protein synthesis in the myo-cardium produced by aortic coarctation.



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degree of activation of nucleic acid and proteinsynthesis in the damage stage of heart hyper-function.The course of training to altitude hypoxia

used in these experiments led to an insignifi-cant hypertrophy of the left ventricle - itsrelative weight was increased only by i8 percent. Training to physical exercises did notgenerally produce any significant increase inthe left ventricular weight. This means thatthe result cannot be explained by supposingthat in trained animals after coarctation IFSwas lower than in those untrained. The mostprobable explanation is that the developedcapacity of the mechanisms of energy trans-formation in trained animals prevented thelack of energy and as a consequence decreasedthe breakdown of structures and the degreeof activation of nucleic acid and proteinsynthesis.Although the explanation put forward re-

quires confirmation, it is important clinicallyto emphasize two points. The first is that pre-liminary training to altitude hypoxia orphysical exercises is the factor capable of pre-venting the disturbance of metabolism andfunction characteristic of acute heart failurefrom overloading. The second implies that,other conditions being equal, the heart pos-sessing a more active system of energy trans-formation may manifest an intense hyper-function at a lesser degree of activation ofprotein synthesis and consequently at alesser degree of hypertrophy.

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