Basic Research in Cardiology Archiv fiir Kreislaufforschung Official J o u r n a l of t h e G e r m a n A s s o c i a t i o n of C a r d i o v a s c u l a r R e s e a r c h Edited b y R. J a c o b , T i i b i n g e n , a n d W. S c h a p e r , B a d N a u h e i m Volume 71

July/August

Number 4

EDITORIAL Basic Res. Cardiol. 71,343-354 (1976) 9 1976 Dr. Dietrich Steinkopff Verlag GmbH & Co. KG, Darmstadt ISSN 0300-8428 I n s t i t u t e o] G e n e r a l P a t h o l o g y a n d Pathologic P h y s i o l o g y , U S S R A c a d e m y of M e d i c a t S c i e n c e s (A. M. C h e r n u k h , M e m b e r o] the U S S R A c a d e m y o f M e d i c a l S c i e n c e s - Director)

Insufficiency of h~pertrophied heart Insuffizienz des hypertrophierten Herzens F. Z . M e e r s o n

With 7 figures (Received April 9, 1976) Summary

There are two types of compensatory hypertrophy of the heart. In v a l v u l a r diseases, systemic hypertension and pulmonary arterial hypertension, the r esultant h y p er t ro p h y compensates the increased load on the organ and is designated as h y p e r t r o p h y due to overload. In ischemic cardiac disease, hereditary cardiomyopathies and myocarditis, the hypertrophy compensates for the functional insufficiency of the damaged myocardial tissue and is designated as hypertrophy due to damage. It is shown in this paper that increase in cardiac mass in both types of compensatory hypertrophy prevents acute cardiac insufficiency but at the same time is a non-balanced form of growth. As a result, in severe h y p er t ro p h y a disturbance of normal proportions at all levels of cardiac structural integration occurs. Disturbances of this type which gradually become causes of cardiac insufficiency are the main subject of this paper. C a r d i a c i n s u f f i c i e n c y is a c o n d i t i o n in w h i c h t h e l o a d i m p o s e d on t h e heart e x c e e d s t h e a b i l i t y of t h e l a t t e r to p e r f o r m its w o r k of p r o p e l l i n g the b l o o d f r o m t h e v e n o u s b e d i n t o th e a r t e r i a l bed. F r o m this d e f i n i t i o n 630

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it follows that cardiac insufficiency m a y be caused by two essentially different factors, namely, an overload imposed on a relatively sound heart or, on the contrary, direct damage to the heart which proves unable to perform its normal work. An important aspect of the problem is that in chronic development of the process neither of these variants of insufficiency arise on the spot, but are preceded b y a more or less pr0. nounced compensatory h y p e r t r o p h y of the myocardium. This hypertrophy m a y equally well and for a long period of time compensate for both the overload of the heart and the damage to the h e a r t muscle. 9As a m a t t e r of fact, in cases of o v e r l o a d - v a l v u l a r disease, hypertensive vascular disease, arteriovenous shunts, hypertension of the lesser c i r c u l a t i o n - the systolic tension of the heart muscle increases. Because of this change the increased expenditure of A T P in the myofibrils forestalls its resynthesis in the mitochondria. The result is a decrease in the concentration of A T P and CP and a simultaneous increase in the concentration of the products of their b r e a k - d o w n (2, 7) and an increase in the phosphorylation potential (22). This change has two consequences: firstly, t h r o u g h the coupling mechanism it activates the process of A T P resynthesis in the mitochondria, i.e., it turns on the main mechanism of urgent adaptation. Secondly, the increase in the phosphorylation potential through the as yet unknown mechanism results in the formation of a signal which activates the synthesis of nucleic acids and proteins and thereby turns on the main mechanism of prolonged adaptation of the h e a r t - m y o c a r d i a l hypertrophy (22, 27). The biological significance of h y p e r t r o p h y due to overload is that it ensures a distribution of the increased cardiac function through its increased mass, decreasing in this w a y the systolic tension and returning the phosphorylation potential to its initial level. Such a decrease in the initially elevated myocardial tension to normal has now been demonstrated in people with valvular disease and hypertension (10). This important change means that h y p e r t r o p h y compensates for the excessively heavy load on the organ by reducing to normal the function of the muscular tissue of which the organ consists. The action of injurious factors, namely, ischemic heart disease, my0carditis and h e r e d i t a r y cardiomegaly, also give rise to a deficit in energyrich phosphate compounds and a g r o w t h of the phosphorylation potential. This takes place because the injurious f a c t o r s - o x y g e n deficiency, dissociation of oxidation and phosphorylation, h e r e d i t a r y defects of the mitochondria and m y o f i b r i l s - r e n d e r the A T P synthesis insufficient to maintain the normal function. The increase in the phosphorylation potential gives rise to a signal which activates the synthesis of nucleic acids and proteins; cardiac h y p e r t r o p h y develops. The biological significance of this damage h y p e r t r o p h y is determined by the fact that initially it arises against the background of normal functioning, but subsequently leads to a decrease in the systolic tension of the ventricles of the heart to an unusual, abnormally low level. Moreover, owing to the increase in the mass of the heart as a whole, the systolic pressure in its ventricles, as well as the stroke and minute

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volumes, long r e m a i n normal, the h y p e r t r o p h y c o m p e n s a t i n g for the defect of the d a m a g e d m y o c a r d i a l tissue by i n c r e a s i n g its mass. The existence of c a r d i a c h y p e r t r o p h y due to i n j u r y was until recently p o s t u l a t e d on the basis of the g e n e r a l t h e o r y of the process (20, 27) and e x p e r i m e n t a l findings (4). This form of h y p e r t r o p h y has now been demo n s t r a t e d p a t h o m o r p h o l o g i c a ] l y (15) and e c h o c a r d i o g r a p h y c a l l y (1, 30)in people suffering from ischemic h e a r t disease, and by the m e t h o d of twoplane c i n e a n g i o r a d i o g r a p h y in people with i d i o p a t h i c h y p e r t r o p h i e s (10). It is essential t h a t in all these studies the h y p e r t r o p h y d e v e l o p e d without a n y a d d i t i o n a l load on the h e a r t and p r e c e d e d the a p p e a r a n c e of disturbances in the c o n t r a c t i l e function. Thus is now obvious t h a t h y p e r t r o p h y precedes cardiac insufficiency in the main chronic c i r c u l a t o r y diseases and t h a t it can, for a considerable l e n g t h of time, c o m p e n s a t e for the o v e r l o a d imposed on the h e a r t and its d i r e c t damage. This concept of the mechanism and significance of cardiac h y p e r t r o p h y is s u m m a r i z e d by the d i a g r a m in fig. 1. The d i a g r a m makes it possible to e m p h a s i z e t h a t the two v a r i a n t s of h y p e r t r o p h y , differing in etiology, p r e v e n t an e n e r g y deficit in the m y o c a r d i u m , and, t h e r e b y , acute c a r d i a c insufficiency, i.e., t h e y a r e a c o m p e n s a t o r y p h e n o m e n o n . S u b s e q u e n t l y p r o g r e s s i v e c o m p e n s a t o r y h y p e r t r o p h y of the h e a r t may develop into c a r d i a c insufficiency. The question of the mechanism of this t r a n s i t i o n from an a d a p t i v e to a p a t h o l o g i c reaction is e s s e n t i a l l y one of the m a i n questions of the p a t h o g e n e s i s of cardiac insufficiency. In o u r opinion this t r a n s f o r m a t i o n is due to the fact t h a t the hypert r o p h y caused b y the incessant e v o l u t i o n a l l y u n f o r e s e e n load or damage to the m u s c u l a r tissue takes place from the v e r y b e g i n n i n g as an u n b a l a n c e d f o r m of growth. A t the level of the organ this u n b a l a n c e d g r o w t h m a n i f e s t s itself in a d i s t u r b e d r e l a t i o n b e t w e e n the h e a r t and its a d r e n e r g i c nervous a p p a r a t u s - t h e g r o w t h of the neurons, which r e g u l a t e the function of the heart, and of t h e i r axons lags b e h i n d the increase in the mass of the heart, the r e s y n t h e s i s of n o r a d r e n a l i n lagging b e h i n d its e x p e n d i t u r e . As a result the d e n s i t y of a r r a n g e m e n t of s y m p a t h e t i c fibres and the concentration of the m e d i a t o r in the m y o c a r d i u m g r e a t l y decrease (24, 26, 35). A t the level of tissue the u n b a l a n c e d g r o w t h consists of a lag of the g r o w t h of c o r o n a r y c a p i l l a r i e s b e h i n d t h a t of the muscle cells of the heart. As a r e s u l t the n u m b e r of c o r o n a r y c a p i l l a r i e s p e r unit of mass and the c o r o n a r y r e s e r v e of the m y o c a r d i u m diminish, while the diffusion distance for o x y g e n increases (9, 16, 38). A t the level of the cell the results of the u n b a l a n c e d , disproportional g r o w t h a r e p a r t i c u l a r l y great. One of t h e m is t h a t the v o l u m e of the cell increases much m o r e t h a n its surface, and the a r e a of the sarcolemmic m e m b r a n e , in which the most i m p o r t a n t mechanisms of ion t r a n s p o r t are localized, decreases p e r unit of cell mass by 60~ (13). As a result, the c a p a c i t y of the N a K p u m p and the Na-Ca m e t a b o l i c mechanism per unit of cell mass m a y diminish. A t the level of intracellular organelles the u n b a l a n c e d g r o w t h manifests itself in the fact t h a t the increase in the mass of m i t o c h o n d r i a lags behind

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that in t h e m a s s of m y o f i b r i l s (3) a n d this m a y n e g a t i v e l y affect t h e e n e r g y supply of t h e c o n t r a c t i l e f u n c t i o n . Lastly, at t h e l e v e l o~ m o l e c u l a r s t r u c t u r e s t h e u n b a l a n c e d g r o w t h m a y , as was r e c e n t l y s h o w n , l e a d to t h e fact t h a t t h e n u m b e r of l o n g - l i f e l i g h t chains (L-chains) in t h e m y o s i n h e a d s i n c r e a s e s m o r e t h a n t h a t of t h e short-life h e a v y chains (H-chains) w i t h t h e r e s u l t t h a t t h e A T P a s e a c t i v i t y of the m y o f i b r i l s a n d t h e i r a b i l i t y to u t i l i s e A T P e n e r g y d i m i n i s h (39, 40). Thus t h e g r o w t h of t h e h e a r t in its c o m p e n s a t o r y h y p e r t r o p h y p r e v e n t s , on the one h a n d , a c u t e c a r d i a c insufficiency, while, at t h e s a m e t i m e , t h e u n b a l a n c e d c h a r a c t e r of t h i s g r o w t h r e s u l t s in a d i s t u r b a n c e in t h e p r o p o r tions at all l e v e l s of t h e s t r u c t u r a l o r g a n i z a t i o n of t h e o r g a n ; s u b s e q u e n t l y this d i s t u r b a n c e b e c o m e s t h e c a u s e of chronic i n s u f f i c i e n c y of t h e h y p e r trophied h e a r t . To g e t a m o r e c o n c r e t e i d e a of t h e m e c h a n i s m of this s l o w c h a n g e of the a d a p t i v e r e a c t i o n to a p a t h o l o g i c r e a c t i o n , it is e x p e d i e n t to e x a m i n e in g r e a t e r d e t a i l s o m e of t h e l i n k s of t h e p a t h o g e n e s i s of i n s u f f i c i e n c y of the h y p e r t r o p h i e d h e a r t . The first l i n k of this k i n d , in t i m e of a p p e a r a n c e a n d significance, is the a f o r e m e n t i o n e d d e c r e a s e in t h e c a p a c i t y of t h e ion t r a n s p o r t m e c h anisms, i.e,, t h e d i s t u r b a n c e in e x c i t a t i o n - c o n t r a c t i o n - r e l a x a t i o n c o u p l i n g . The d i a g r a m in fig. 2 a p p r o x i m a t e l y reflects t h e p r e s e n t c o n c e p t i o n s of e x c i t a t i o n c o n t r a c t i o n r e l a x a t i o n c o u p l i n g (29, 32, 36). During the action potential, calcium enters the sarcopIasm from the cistern of t h e s a r c o p l a s m i c r e t i c u l u m a n d t h e e x t r a c e l l u l a r e n v i r o n m e n t . This c a t i o n t r i g g e r s off t w o p r o c e s s e s w h i c h e n s u r e t h e r h y t h m i c f u n c tioning of t h e h e a r t - f i r s t l y , t h e c o n t r a c t i o n of myofibrils, and, s e c o n d l y , ~ts o w n r e m o v a l f r o m t h e sarcopZasm back to the sarcoplasm~c ret~culum and the e x t r a c e l l u l a r e n v i r o n m e n t . This t r a n s p o r t of c a l c i u m f o r m s t h e basis of d i a s t o l i c r e l a x a t i o n ; it is c a r r i e d o u t b y t h e c a l c i u m p u m p of t h e sarcoplasmic reticulum and the so-called sodium-calcium metabolic m e c h a n i s m of t h e s a r c o l e m m a , w h i c h w a s r e c e n t l y s t u d i e d b y R e u t e r et al. (31, 32).

Fig. 2. Diagram of excitation - contraction - relaxation coupling. Explanation in text.

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This c o n c e p t i o n m e a n s t h a t c o n t r a c t i o n a n d s u b s e q u e n t r e l a x a t i o n are c o n t r o l l e d b y the s a m e factor, i.e., Ca ++ c o n c e n t r a t i o n a n d therefore the e m e r g e n c e of each action potential p r e d e t e r m i n e s the occurrence not only o] contraction, but also of relaxation. It is f u r t h e r m o r e e v i d e n t t h a t o t h e r t h i n g s b e i n g e q u a l the removal of Ca ++ f r o m the s a r c o p l a s m a n d m y o f i b r i l s and, hence, the r a t e a n d depth of c a r d i a c r e l a x a t i o n d e p e n d on the s a r c o p l a s m i c r e t i c u l u m c a l c i u m pump, as well as the i n t e r c o n n e c t e d N a - K p u m p a n d the N a - C a metabolic mechanism. I n c o m p e n s a t o r y h y p e r t r o p h y the d e c r e a s e i n t h e r a t i o of the s a r c o l e m m i c a r e a to the mass of the cell a n d a n a l o g o u s changes at the SPR, a n d p o s s i b l y also o t h e r factors m u s t lead to a d e c r e a s e in the capacity of these m a i n m e c h a n i s m s of ion t r a n s p o r t . It t h e r e f o r e s t a n d s to reason t h a t d u r i n g the s t u d i e s of the c o n t r a c t i l e f u n c t i o n of t h e hypertrophied h e a r t facts i n d i c a t i n g a d e c r e a s e i n t h e c a p a c i t y of p r e c i s e l y these m e c h a n i s m s r e s p o n s i b l e for the r e m o v a l of c a l c i u m f r o m t h e sarcoplasm a n d t h e process of r e l a x a t i o n w e r e d i s c o v e r e d (19, 23) in a d d i t i o n to the decrease i n t h e force a n d r a t e of c o n t r a c t i o n (28, 35). T h e first fact is that, w h e n the m e c h a n i s m s of ion t r a n s p o r t were o v e r l o a d e d b y a n i n c r e a s e d c a l c i u m c o n c e n t r a t i o n in t h e p e r f u s i o n solution, t h e r a t e of r e l a x a t i o n of the h y p e r t r o p h i e d h e a r t s decreased, while t h e t i m e n e c e s s a r y for t h e i r r e l a x a t i o n i n c r e a s e d m o r e t h a n for the control hearts. T h e c u r v e s in fig. 3 c h a r a c t e r i z e the d u r a t i o n of r e l a x a t i o n with an i n c r e a s i n g Ca ++ c o n c e n t r a t i o n in the p e r f u s a t e of t h e isolated isovolumic h e a r t s of c o n t r o l rats a n d r a t s w i t h m a r k e d c a r d i a c h y p e r t r o p h y . They s h o w t h a t t h e t i m e of r e l a x a t i o n of a h y p e r t r o p h i e d h e a r t i n c r e a s e s with the increases in calcium concentration more than in control. The second fact of the same significance was discovered upon imposing a high rate of contractions on an isovolumic heart. In such experiments the excessively high rate of contractions leads to the fact that the capacity of the mechanisms of relaxation proves insufficient, i.e., during the short intervals between the contractions the heart does not have enough time to

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Fig. 3. Effect of increase in Ca ++ concentration in the perfusate of isovolumic heart of the rat on the time of relaxation of control hearts and hearts hypertrophied as a result of coarctation of the aorta; v e r t i c a l - time of cardiac relaxation in msec; horizontal - calcium concentration in perfusate.

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hypertrophied heart

349

Fig. 4. Effect of a n i n c r e a s e d r a t e of c o n t r a c t i o n s on t h e systolic ( u p p e r c u r v e ) and the diastolic ( l o w e r c u r v e ) p r e s s u r e of t h e i s o v o l u m e t r i c a l l y b e a t i n g r a t heart. T h e d i a s t o l i c d e f e c t r e p r e s e n t s t h e a r e a b e t w e e n t h e i n c r e a s e d diastolic rnm IIg 9 see pressure a n d i n i t i a l d i a s t o l i c p r e s s u r e . T h e f o r m u l a quantifies the 2 v a l u e of diastolic defect. relax completely and diastole d e v e l o p s .

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Fig. 4 s h o w s t h a t w h e n a h i g h r a t e of c o n t r a c t i o n s is i m p o s e d o n a n o r m a l h e a r t t h e r e l a x a t i o n b e c o m e s i n c o m p l e t e a n d t h e d e f e c t of d i a s t o l e develops. S u b s e q u e n t e x p e r i m e n t s d e m o n s t r a t e d t h a t i n h y p e r t r o p h y t h e defect of d i a s t o l e is m o r e p r o n o u n c e d t h a n i n c o n t r o l . A s a m a t t e r of f a c t , the c u r v e s i n fig. 5 e v i d e n c e t h a t u p o n i n c r e a s e i n t h e r a t e of c o n t r a c t i o n s of h y p e r t r o p h i e d h e a r t s t h e d e f e c t o f d i a s t o l e i n c r e a s e s m u c h m o r e t h a n it does f o r c o n t r o l h e a r t s . A t t h e r a t e of 480 p e r m i n t h e d e f e c t of d i a s t o l e in h y p e r t r o p h i e d h e a r t is t w i c e a s l a r g e as it is i n c o n t r o l . T h e t h i r d f a c t is t h a t t h e s t r i a e f r o m t h e p a p i l l a r y m u s c l e s of h y p e r t r o p h i e d h e a r t s p r o v e d m u c h l e s s e x t e n s i b l e t h a n t h e c o n t r o l s t r i a e of t h e s a m e t h i c k n e s s (12).

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A l l t h e s e f i n d i n g s w e r e e x p l a i n e d b y t h e r e d u c e d c a p a c i t y of the ion t r a n s p o r t m e c h a n i s m s and, as a n effect, t h e d e c e l e r a t e d a n d incomplete r e m o v a l of c a l c i u m f r o m t h e m y o f i b r i l s . S e v e r a l y e a r s ago this view s u g g e s t e d to us t h e i d e a t h a t t h e s y n d r o m e of i n c o m p l e t e d i a s t o l e is the i n i t i a l s t a g e in t h e d e v e l o p m e n t of i n s u f f i c i e n c y of t h e hypertrophied h e a r t . This i d e a is c o n f i r m e d b y t h e b i o c h e m i c a l f i n d i n g s of Schwartz and o t h e r r e s e a r c h e r s t h a t t h e e l e m e n t s of s a r c o p l a s m i c r e t i c u l u m isolated f r o m t h e h y p e r t r o p h i e d m y o c a r d i u m of a n i m a l s a n d m a n possess a sharply d i m i n i s h e d a b i l i t y to a b s o r b c a l c i u m (6, 33). I t also c o r r e s p o n d s to the e l e c t r o n - m i c r o s c o p i c f i n d i n g s of H a t t (8) a n d V i t a I i - M a z z a (37) that the s a r c o m e r e s of a h y p e r t r o p h i e d h e a r t a r e s h o r t e n e d o w i n g to d i s k s I, many of t h e m b e i n g in a s u b c o n t r a c t u r e . L a s t l y , t h e s t u d i e s c a r r i e d o u t b y Hood et al. (10) a n d t h o s e conducted b y o u r l a b o r a t o r y j o i n t l y w i t h c l i n i c i a n s (21) h a v e s h o w n t h a t in people w i t h h y p e r t r o p h i e d h e a r t s t h e r a t e of d i a s t o l i c r e l a x a t i o n is diminished a n d t h e t e n s i o n a t r e s t is i n c r e a s e d . T h u s t h e i d e a t h a t t h e s y n d r o m e of i n c o m p l e t e d i a s t o l e is one of the i n i t i a l l i n k s of t h e p a t h o g e n i c c h a i n of i n s u f f i c i e n c y of t h e hypertrophied h e a r t is n o w a d e q u a t e l y s u b s t a n t i a t e d . T h e r e t a r d e d r e m o v a l of Ca ++ f r o m h y p e r t r o p h i e d cells and the s y n d r o m e of i n c o m p l e t e d i a s t o l e l e a d to v a r i o u s c o n s e q u e n c e s . One of the m o s t i m p o r t a n t c o n s e q u e n c e s of t h e r e t a r d e d r e m o v a l of c a l c i u m from the s a r c o p l a s m of m y o c a r d i a l cells is t h e i n c r e a s e d p a s s a g e of c a l c i u m into t h e m i t o c h o n d r i a . A s a r e s u l t of t h i s c h a n g e its c o n c e n t r a t i o n in the mit o c h o n d r i a of t h e h y p e r t r o p h i e d m y o c a r d i u m i n c r e a s e s 60 ~ (11). A c c o r d i n g to L e h n i n g e r ' s i d e a s (14), t h e a b s o r p t i o n of c a l c i u m by m i t o c h o n d r i a t a k e s p l a c e b y m e a n s of t h e t r a n s p o r t of e l e c t r o n s of the r e s p i r a t o r y c h a i n a n d m a y l e a d to a d e c r e a s e in o x i d a t i o n - p h o s p h o r y l a t i o n c o u p l i n g . I n t h i s case w e m u s t o b s e r v e a d e c r e a s e in t h e effectiveness Control

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of oxygen consumption by the heart. Such a decrease has actually been demonstrated in cardiac h y p e r t r o p h y by G u n n i n g and Coleman's studies (5) and has been confirmed in our l a b o r a t o r y (25). In h y p e r t r o p h y the decrease in effectiveness of oxygen consumption is accompanied by the already mentioned decrease in the n u m b e r of coronary capillaries and the coronary reserve. Obviously the combination of the reduced effectiveness of oxygen consumption and the decrease in the carrying capacity of the system responsible for its transport must lead to a decrease in the capacity of aerobic A T P resynthesis. The diagram in fig. 6 shows that 30 seconds after complete constriction of the aorta and creation of a critical load on the heart the ATP concentration in the m y o c a r d i u m of control animals decreases 15%, whereas in the hypertrophied m y o c a r d i u m it diminishes about 66 %. The concentration of A D P and inorganic phosphorus increases in hypertrophy about twice as much as in the control. This means that in a critical load on the heart A T P resynthesis in h y p e r t r o p h i e d m y o c a r d i u m lags behind A T P consumption much more than in the control, i.e., the capacity of the ATP resynthesis apparatus in the h y p e r t r o p h i e d heart is decreased. The diagram in fig. 7 shows that the phenomena considered a b o v e disturbance in the processes of ion transport and relaxation of the heart, decrease in coronary reserve, the capacity of energy-supply mechanisms, diminution of the ATPase activity of myofibrils and the disturbance in adrenergic regulation of the h e a r t - p o t e n t i a t e each other. In the end they lead to a 33-50 ~ decrease in the m a x i m u m attainable force and rate of contraction of the muscular tissue of the heart (19, 28, 34). However, this dangerous change m a y not for m a n y years lead to cardiac insufficiency; instead of insufficiency there arises a delicate balance for which we at one time suggested the designation of "cardiac preinsufficiency". The period is characterized by the fact that the changes in the structure and function of the h y p e r t r o p h i e d heart considered above do not for some time lead to m a r k e d h e m o d y n a m i c disturbances. During this period the unstable compensation is achieved by means of two basic factors. Firstly, the defect in the contractile function of hypertrophied myocardium is over a period of m a n y years compensated for by an increase in its mass. Secondly, the initial h e m o d y n a m i c changes inhibit through neuroendocrine regulation the basal metabolism, motor activity, i.e., reduce the organism's demands of the circulatory system, on the one hand, and activate the extracardial factors of compensation - erythropoiesis, the ability of the tissues to extract oxygen from hypoxemic blood, etc., on the other (18). This chain of events shown in the diagram inhibits the development of cardiac insufficiency. With the f u r t h e r development of the disease the progressive depression of the contractile function of the heart leads to such an increase in venous pressure and decrease in the minute volume that they cause an intensive excitation of the renin-aldosterone mechanism, i.e., a loss of potassium and retention of sodium and water in the organism. Combined with hydraulic factors this regulatory change not only plays a direct role in the development of edemas and ascites, but also causes an additional depression of the

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353

contractile f u n c t i o n of t h e h e a r t , t h e c a r d i a c cells b e i n g d e e p l y i n j u r e d by the potassium deficit (7). T h i s c h a in of e v e n t s s h o w n in t h e d i a g r a m potentiates t h e d e v e l o p m e n t of c a r d i a c insufficiency. Thus t h e p a t i e n t ' s c o n d i t i o n at each s t a g e of t h e disease, p r e s e r v a t i o n of p r e i n s u f f i c i e n c y or, on t h e c o n t r a r y , d e v e l o p m e n t of i n s u f f i c i e n c y , is determined b y t h e e x t e n t of t h e changes in t h e m y o c a r d i u m as w e l l as t h e correlation of t h e r e g u l a t o r y r e a c t i o n s a r i s i n g in r e s p o n s e to t h e p r i m a r y hemodynamic changes. The m o d e r n m e a n s of c o n s e r v a t i v e t h e r a p y of car d i ac i n s u f f i c i e n c y a r e essentially a set of f a c t o r s b y m e a n s of w h i c h it is possible to r e g u l a t e this d y n a m i c b a l a n c e . T h e p r o s p e c t f o r r a d i c a l t h e r a p y of c a r d i a c i n sufficiency in e a c h c o n c r e t e case is d e t e r m i n e d b y t h e p o ssi b i l i t y of s u r g i c a l or p h a r m a c o l o g i c e l i m i n a t i o n of t h e " o v e r l o a d " or " i n j u r y " b e c a u s e h y p e r t r o p h y of t h e v e n t r i c l e s of t h e h e a r t is in p r i n c i p l e r e v e r s i b l e ; hence, the n e g a t i v e p h e n o m e n a c o n n e c t e d w i t h h y p e r t r o p h y are also r e v e r s i b l e .

Zusammen]assung Man unterscheidet zwei Typen kompensatorischer Herzhypertrophie. Bei Klappenfehlern, Systemhochdruck und pulmonalem Hochdruck kompensiert die resultierende t t y p e r t r o p h i e die gesteigerte Belastung des Organs und ist als belastungsbedingte Hypertrophie zu bezeichnen. Bei ischtimischen Herzerkrankungen, vererblichen Kardiomyopathien und bei Myokarditiden stellt die Hypertrophie eine Kompensation ffir das funktionelle Versagen des gesch~digten Myokardgewebes dar und ist als sch~digungsbedingte Hypertrophie zu bezeichnen. In der vorliegenden Abhandlung wird gezeigt, dab die Massenzunahme des Herzens bei beiden Typen kompensatorischer Hypertrophie einer akuten Herzinsuffizienz vorbeugt, gleichzeitig jedoch eine unausgeglichene Form des Wachstums darstellt. Infolgedessen ergibt sich bei schwerer Hypertrophie eine StSrung bez~glich der Proportionen auf allen strukturellen Ebenen. St5rungen dieses Types, die allmfihlich als Ursache einer Herzinsuffizienz wirksam werden, stellen den wesentlichen Gegenstand dieser Ubersicht dar.

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F. Z. Meerson, I n s t i t u t e of G e n e r a l P a t h o l o g y a n d P a t h o l o g i c P h y s i o l o g y , U S S R A c a d e m y of M e d i c a l Sciences, 125315 M o s c o w , B a l t i i s k a j a ul. 8