American Heart Journal April, 1971, Volume 81, Number 4

Editorial

Recent studies on cardiac hypertrophy

Barry L. Panburg, M.D.” Boston, Mass.

A major postembryonic adaptation of the heart is the ability of this organ

to respond to various stimuli by an increase in tissue mass. The mechanism by which this occurs and the composition and physio- logic properties of the hypertrophied heart have been studied extensively.1 Three relatively contemporary developments have aided investigators of the heart in approach- ing this subject in more detail: (1) knowl- edge of the molecular biology of protein and nucleic acid synthesis in both mam- malian tissues and bacteria has increased immensely; (2) information about the bio- chemistry and ultrastructure of skeletal muscle has advanced considerably and has paved the way for similar studies of heart muscle; and (3) physiologic studies first developed for isolated skeletal muscle now have been adapted to the heart.

The purpose of this communication is to review briefly and comment on the infor- mation that is now available on experi- mental cardiac hypertrophy in the labora- tory animal. The data were obtained from many laboratories although only a partial bibliography is given. While it is likely that information gained from such studies ulti- mately will be useful in evaluating the clinical situation, such a relationship at the moment must be viewed as tentative. Furthermore, it should be kept in mind that information gained about the response

of the heart to one type of stimulation for hypertrophy need not apply to the response to another type of stimulation.

Several methods have been used to pro- duce cardiac hypertrophy in the experi- mental animal. Among these are constric- tion of the aorta or pulmonary artery, partial ligation of the renal artery after unilateral nephrectomy, treatment with thyroid hormone and related compounds, treatment with sympathomimetic drugs, production of anemia, creation of nutri- tional deficiency states, exposure to hypoxic conditions, production of myocardial isch- emia, and exposure to stress.

The imposition of an increased afterload on the heart is frequently used for produc- ing hypertrophy. With an increase in after- load, such as that caused by aortic con- striction, one of the earliest biochemical changes that can be identified is an increase in RNA synthesis. Although the increase in total RNA or RNA concentration is insufficient to be measured until 1 to 2 days after imposing an increased work load, there is a stimulation of radioactive pre- cursor labeling of RNA within the first few hours.2s3 Several studies indicate that the early increase in RNA synthesis affects all types of cellular RNA (ribosomal, soluble, and messenger) to about the same extent. However, some evidence suggests that stimulation of messenger RNA precedes

From the New England Medical Center Hospitals, 171 Harrison Ave., and the Department of Medicine, Tufts Uni- versity School of Medicine, Boston, Mass. 02111.

This investigation was supported by Grants ST01 HE06924 and 3TOl HE05391 from the National Heart Institute, National Institutes of Health, United States Public Health Service.

*Recipient of Research Career DeveLopmat Award, National Institutes of Health.

Vol. Sl,.No. 4,$q. 447-450 April,1971 American Heart Journal 447

that of the other types of RNA4; confirma- tion of this finding awaits more specific means for identifying messenger RNA. The activity of RNA polymerase, which catalyzes RNA synthesis from precursor nucleotides, increases after an elevation in work ljoad,5 but present information sug- gests that the stimulation of RNA labeling precedes, rather than follows, the increase in activity of the polymerase.

An increase in protein synthesis also occurs soon after an increase in cardiac work load. The question of whether the increase in RNA or the increase in protein synthesis comes first is not fully resolved. In vivo labeling experiments suggest that an increase in RNA precedes that of pro- tein. In studies with the isolated heart, it has been found that increased labeling of protein with radioactive amino acid occurs as early as 3 hours after an elevation in work load.6 In vivo studies have shown that increased labeling of protein with radioactive amino acids usually does not occur until 1 to 2 days after an increase in work load.7*s The interpretation of many of these studies is hindered by the lack of information about the specific activity of precursor amino acid inside the cell.

There is an increase in ribosomes in the hypertrophying heart, and these provide additional sites for protein synthesis. It appears that there is no increase in protein synthesis per ribosome when this is deter- mined on the basis of RNA content.g Furthermore, there is no evidence for stimulation of soluble factors in cell sap to account for increased protein synthesis.

Measurements of DNA indicate, for the most part, that the total quantity of heart DNA increases with hypertrophy pari passu with the increase in tissue mass; hence, DNA concentration either remains un- changed or decreases with hypertrcphy. There has been long-standing uncertainty as to whether the increase in tissue mass in the hypertrophied heart represents an increase in the number of heart muscle cells or an increase in muscle cell size. Recently, it has been demonstrated by radioautography that new DNA synthesis takes place during cardiac hypertrophy almost entirely in interstitial as opposed to muscle cells.lOJ1 There probably has been

insufficient appreciation that interstitial cells outnumber muscle cells by about 3 to 1 in the heart.

The majority of studies on changes in nucleic acid and protein synthesis in hearts subjected to an increased work load have been done in the intact animal. However, there have been some studies with the isolated perfused lzeart.6 With the isolated system, careful regulation of mechanical parameters may be obtained. Hence, it would appear that such a system could offer many advantages for a detailed study of the influence of heart mechanics on nucleic acid and protein synthesis. For example, it might be possible to determine if any particular parameter of contraction plays a predominant role in the syntheses of these substances and if specific modifica- tions in contraction alter their production. Such studies have not yet been reported.

There are several inherent difficulties in this type of an evaluation. First, the muscle is in an abnormal situation in the isolated state. Second, any bacterial contamination may cause a considerable problem since bacteria incorporate radioactive precursor much more rapidly than mammalian tis- sue, and small numbers of bacteria, which may be insensitive to antibiotics, can cause a marked alteration in labeling of extracted nucleic acids.r2 Labeling of bacterial RNA, extracted along with that of the mammalian tissue, would be undetected unless a more specific analysis of the RNA, such as by density gradient separation, were per- formed. Another consideration is that alter- ations in the mechanics of contraction may alter membrane transport of radioactive precursor; and unless the intracellular pre- cursor specific activity is taken into ac- count, labeling of nucleic acids or proteins may only reflect changes in transport of the labelled precursors.

There have been several studies to evalu- ate possible changes in cellular organelles and chemical constituents of the hypertro- phied heart. Although the number of muscle cells does not seem to be increased, the number of myofibrils per muscle cell is increased.r3 There does not appear to be an alteration in the geometry of thick or thin filaments, and the electron-microscopic appearance of myosin is unchanged.14 Dis-

V&me 81 Namber 4 Recent studies on cardiac hypertrophy 449

tention of the sarcotubular system has been reported, and various changes in tlhe ap- pearance of mitochondria have been de- scribed.ls

Although the data have been somewhat variable, there is at present no compelling reason to believe that there is a defect in mitochondrial oxidative phosphorylation or ATP availability in the hypertrophied heart. The calcium transporting activity of the isola.ted sarcoplasmic reticulum has not been studied in hypertrophy. Such a. study would ble of interest although small changes may be difficult to detect.

Several biochemical alterations have been found in the hypertrophied heart. There is often an. increase in collagen, but the extent of this change appears to be related to the method for inducing hypertrophy. For ex- ample, Iconstriction of the aorta results in an increase in both content and concentra- tion of collagen while there mav ble little change in content and a decrease-in concen- tration of collagen in hypertrophy pro- duced by sideropenic anemia.16 The con- centration of catecholamines has been found to be depressed in hypertrophy.17 Amino acid concentration has been found to be increased.l* Although there is little, if any, available information on glucose and fatty acid transport or metabolism in the hypertrophied heart, studies with the isolated perfused heart have shown glucose and fatty acid uptake and utilization to be work-dependent.1gs20

Several studies have related hormonal function to cardiac hypertrophy. It appears that growth hormone is not a requirement for mu.scle hypertrophy produced by an increasle in work load.21-23 The lesser extent of induced heart growth in the hypophysec- tomized as compared to the normal. animal appears to be primarily a function of hemo- dynamic and mechanical differences. It has been suggested, however, that thyroid hor- mone may participate in heart growth by its direct action on protein synthesis.24 A defect in protein synthesis by heart ribo- somes has been demonstrated in the dia- betic animal,25 but there is no information about .the effect of diabetes on the response of the heart to a stimulus for hypertrophy.

Studies on the mechanics of the hyper- trophied heart in the intact animal have

been hampered by difficulties in the control of variables such as initial muscle length and differences in muscle mass between hypertrophied and control hearts. The iso- lated muscle preparation, in which these variables can be readily controlled, has been useful in studying the performance of hypertrophied muscle. Investigations to date suggest that there is a decrease in the maximum velocity of contraction of hy- pertrophied muscle while the isometric developed tension per unit of cross-sec- tional area remains unchanged.26s27 The decrease in maximum velocity has been interpreted as evidence of a depressed contractile state, although alternate expla- nations are possible depending upon the analogue model of muscle employed to derive contractile element velocities. Pro- longation of the active state may compen- sate for the decrease in contractility thus enabling the hypertrophied heart to sustain a normal stress. The basis for the depression of contractility in hypertrophied heart mus- cle has not been established. It has been proposed that the reduced contractility is related to a decrease in cardiac myofibrillar ATPase activity. Further studies on iso- lated contractile proteins may be useful. The relation of function to structural and biochemical alterations is uncertain at present.

It appears that the development of hypertrophy is a method of temporary compensation for an increased cardiac work load. It is quite possible that any increase in work load, regardless of its duration, sets in motion a sequence of biochemical altera- tions of the muscle cell. Whether the initial transmission of a mechanical to a biochemi- cal change occurs at the cell membrane or in the interior of the cell is, at the moment, unknown. If the increased work load is not sustained, the biochemical alterations may be readily reversible. With maintenance of an increased work load, there are altera- tions in the ultrastructure, in the organelles, and in the biochemical composition of the muscle cell. The extent of reversibility of these changes is not known. As knowledge about these alterations increases, we may gain a clearer understanding of the process by which the heart becomes incompetent and heart failure ensues.

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