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Abnormalities in the sarcoplasmic reticulum of the failing heart, in which slowed calcium uptake may contribute to impaired relaxation (see “Relaxation Abnormalities”), appear to reflect a reduced concentration of calcium-pump ATPase molecules in this internal membrane, rather than the expression of an altered isoform of the large molecule.82 , 83 Another example of altered membrane assembly in the overloaded heart is suggested by a recent report that the density of voltage-sensitive calcium channels may be increased in the atria of patients with hypertrophic cardiomyopathy.84 This report extends to humans a genetic cardiomyopathy previously described in the Syrian hamster. However, since the density of calcium channels was not found to be altered in renal-hypertensive rats, the increased number of calcium channels described in the human and hamster cardio-myopathies may be related to underlying genetic abnormalities rather than to the hypertrophic response itself.

Role of Proto-oncogenes

Proto-oncogenes, which play a major part in regulating growth and differentiation, provide a remarkably complex control of the many steps between signal recognition and altered gene expression. By allowing protein synthesis to respond to a wide range of influences both outside and within the cells of the heart, the proto-oncogenes regulate the hypertrophic process and may have a pathogenetic role in the cardiomyopathy of overload.
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The proto-oncogenes exert their regulatory effects by encoding a variety of growth factors and their receptors, intracellular transducers, modulators, amplifiers, and DNA-binding factors involved in the control of RNA transcription. Although this field is still in its infancy, it is apparent that hemodynamic overloading increases the expression of c-fos and c-myc, proto-oncogenes that encode short-lived nuclear proteins that promote and regulate cell proliferation and differentiation. In the overloaded heart, the activation of these proto-oncogenes, along with the heat-shock protein gene HSP 70, resembles the early mitogenic responses to a variety of growth factors in other cell types and may be part of a general adaptive response to stress.

The induction of c-fos and c-myc, which occurs within an hour of acute pressure overload, is transient and precedes the expression of fetal isoforms of several contractile proteins and atrial natriuretic factor.76 Thus, in addition to stimulating the overall rate of protein synthesis, proto-oncogenes may control alterations in specific protein isoforms synthesized by the overloaded heart.

Although the roles of the proto-oncogenes in activating and reprogramming gene expression in the overloaded heart remain to be fully elucidated, rapid progress in this important field promises new insights into the pathogenesis of the cardiomyopathy of overload.

Adult myocardial cells respond to overload by accelerating protein synthesis, although at the same time they preferentially synthesize fetal isoforms of several proteins. Abnormal actin and tropomyosin, also synthesized by the overloaded heart, represent isoforms of the proteins that were predominant earlier in development, during fetal life.

This reversion to fetal isoforms may be related to the fact that the adult myocardium is a terminally differentiated tissue that, like mature peripheral-blood granulocytes, cannot divide and that normally synthesizes new protein at only a very slow rate. Unlike the granulocyte, which does not enlarge but is readily replenished by the proliferation and maturation of undifferentiated stem cells in the bone marrow, the adult heart can initiate rapid protein synthesis and so undergo hypertrophy. Thus, for adult myocardial cells to regain the capacity for rapid protein synthesis that they had during development, the pattern of protein synthesis may have to revert to that seen earlier in ontogeny. It is of interest, however, that the hypertrophy induced by hyperthyroidism does not increase the expression of fetal isoforms of myocardial proteins.

The functional consequences of the appearance of primitive isoforms of myocardial proteins in the overloaded heart are poorly understood. It is tempting to postulate that these changes may contribute to the cardiomyopathy of overload, but such speculation must await additional evidence.
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Heterogeneity of Protein Isoforms Synthesized in Response to Overload

It is now evident that the synthesis of new proteins in the overloaded heart is not due simply to the overall stimulation of muscle growth. Instead, the control of protein synthesis is complex, and the rates at which altered isoforms of several myofibrillar proteins appear are dissimilar. For example, new myosin and actin isoforms appear at different times during the initial response to overload. This complexity is highlighted by the recent finding that the localization of newly synthesized isoforms of myosin and actin in the overloaded rat heart also differs. New β-myosin heavy chains appear first in the subendocardial regions of the left ventricle and around blood vessels, whereas the fetal isoform of actin appears more uniformly throughout the myocardium. The heterogeneity in the appearance of the β-myosin may reflect the higher tension in the subendocardium and around blood vessels or, possibly, a local response to growth factors released by endothelial and endocardial cells.

Isoform changes in the hypertrophied heart have also been reported for lactate dehydrogenase,78 creatine kinase,79 , 80 and the sarcolemmal sodium pump.

Biochemical Changes

The pioneering work of Meerson,50 who first characterized the biochemical events that lead to myocardial deterioration and cell death in animals with acute aortic constriction, has provided an understanding of the cellular events in the overloaded heart that corresponds to the clinical observations made 75 years earlier by Osler. Meerson, like Osler, described three stages in the response of the heart to a sudden hemodynamic overload (Table 2). The first stage, which Meerson called transient breakdown, lasts several days and is characterized by acute heart failure with left ventricular dilatation, pulmonary congestion, and low cardiac output. The adaptive effects of cardiac hypertrophy then lead to a stage of stable hyperfunction, in which increased left ventricular mass raises cardiac output and alleviates the pulmonary congestion. However, in accord with Osler’s clinical observations, the compensation does not last but after several months is followed by progressive left ventricular failure. In this final stage, which Meerson called exhaustion and progressive cardiosclerosis, the hypertrophied heart undergoes progressive fibrosis and cell death, the circulatory manifestations of heart failure worsen, and the animals die.

Although the deterioration of the chronically overloaded heart, referred to here as the cardiomyopathy of overload, may be due in part to energy starvation (see above), there is growing evidence that molecular changes in the proteins synthesized in affected hearts also contribute to the downhill course usually seen in chronic congestive heart failure.

Abnormal Gene Expression in the Hypertrophied Myocardium

Since the pioneering work of Alpert and Gordon,53 who demonstrated that myosin ATPase activity is depressed in failing hearts, a growing number of molecular changes have been recognized in overloaded myocardial cells. This ability of the heart to alter its protein composition is a general process that can be viewed as a tonic control mechanism, which also adapts myocardial function to such long-term circulatory changes as aging and endocrine abnormalities.54 , 55 In addition, the remarkable ability of adjacent cells in the myocardium to express different genes gives rise to a “mosaicism” in which molecular heterogeneity in the proteins of the myocardium may help to achieve functional homogeneity, promoting efficient cardiac function.
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The appearance of abnormal isoforms of key myocardial proteins in the hypertrophic response to chronic overloading results from changes in gene expression that can arise from at least two different mechanisms. The first is the expression of different members of the multigene families that encode many important proteins of the heart. This mechanism is clearly seen in the rodent heart, in which the preferential synthesis of altered myosin isoforms adapts ventricular function to chronic abnormalities of the heart and circulation (see the next section). Variability in the proteins synthesized in the myocardium also results from alternative splicing, in which the exons of a single gene are assembled in different patterns as the nuclear RNA is processed to form messenger RNA. This mechanism allows the information contained in a single gene to encode the structures of several protein isoforms through variations in the manner by which the DNA sequence of the gene becomes transcribed into messenger RNA.

The complexity of cardiac hypertrophy was recognized almost a century ago by Osier, who observed that the heart’s first response to sudden hemodynamic overload, such as that caused by aortic-valve rupture, is a phase of “development” in which the myocardium begins to hypertrophy. The resulting augmentation of muscle mass, by distributing the excess load among an increased number of sarcomeres, alleviates the acute heart failure and so is clearly beneficial. Although the initial hypertrophic response leads to Osler’s second phase, compensation, and is thus adaptive, the hypertrophy that initially helped the heart to meet the overload does not end well. Instead, the chronically overloaded heart degenerates and weakens, leading to a final stage that Osier called broken compensation. Thus, like salt and water retention and vasoconstriction, myocardial hypertrophy provides effective compensation for only a limited time. Following a pattern similar to that of the circulatory adjustments to low cardiac output, cardiac hypertrophy appears to become deleterious when it becomes chronic. Unfortunately, in most patients who seek medical care for heart failure, the myocardium has probably already entered Osier’s final phase of broken compensation, the cardiomyopathy of overload.

Changing Composition of the Hypertrophied Heart
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Central to an understanding of the cardiomyopathy of overload is a knowledge of the structural and functional abnormalities that initiate and perpetuate the deterioration of the hypertrophied, failing myocardium (Osler’s broken compensation). These abnormalities have been studied in depth from a morphologic standpoint and are now beginning to be understood at a molecular level in the light of the growing knowledge of changes in gene expression by the cells of the overloaded myocardium.

Morphologic Changes

Using traditional morphologic techniques, Linzbach noted that after initially thickening in response to overload, the walls of the heart become thinned in end-stage heart failure. Myocyte necrosis stimulates the proliferation of fibroblasts, replacing myocardial cells with connective tissue, and causes the late dilatation that increases the tension that must be developed by the muscular walls of the failing heart. The resulting progressive overload on the surviving cells of the hypertrophied heart, together with the relative decrease in capillary density and the number of mitochondria discussed earlier, probably contributes to a chronic energy deficit that sets up a vicious circle in the failing heart. Thus, although hypertrophy increases the number of sarcomeres and so is beneficial at first, this response represents an imperfect compensation because, when overloading is sustained, the hypertrophied myocardial cells ultimately deteriorate and die.

These considerations, which may explain reports of detrimental effects when inotropic drugs have been used to treat chronic heart failure, lack conclusive experimental support. Furthermore, they may not apply to the cardiac glycosides, which have only moderate inotropic effects and, by increasing baroreceptor sensitivity, may reduce afterload and slow the heart in patients with heart failure.
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Energetics in the Failing Heart

In heart failure, whether due to abnormal hemodynamic demands, as are produced by aortic stenosis, or to the loss of functional myocardial tissue, as occurs after myocardial infarction, the active myocardial cells become overloaded. The resulting increase in the rate of mechanical-energy expenditure by the overloaded heart not only is sustained from day to day, but persists when activity is curtailed by rest, and even during sleep.

Hypertrophy unloads the cells of the failing heart by adding new sarcomeres and thus has an energy-sparing effect because it decreases the rate of mechanical-energy expenditure by the overloaded sarcomeres. However, several changes in the architecture of the hypertrophied heart can exacerbate the imbalance between energy expenditure and energy production. Such changes include an increase in the distance between capillaries40 and a decrease in the density of transverse capillary profiles, which impair the diffusion of substrates, notably oxygen, essential for the production of energy by the hypertrophied heart. This imbalance is especially marked in the relatively underperfused subendocardial regions of the left ventricle and is reflected in a decrease in the coronary reserve. Cellular abnormalities also appear to contribute to energy starvation in the chronically overloaded failing heart; for example, long-standing hypertrophy increases the cell volume occupied by myofibrils, which increases the number of ATP-consuming myofibrils supplied by each ATP-generating mitochondrion, thus potentially exacerbating an energy deficit. Depressed contractility in the failing heart (see below) lessens energy demands and so may be compensatory in terms of the energetics of the individual myocardial cells. Viewed from the standpoint of the circulation, of course, depressed contractility is detrimental.

Hypertrophic Response of the Heart to Chronic Overload

It is now apparent that hypertrophy of the overloaded heart is a complex process that is both beneficial and detrimental. Like the short-term effects of salt and water retention and vasoconstriction, the effect of the benefit of an increased number of sarcomeres dominates the initial adaptation to overload. It is mainly when the overload is sustained, in chronic heart failure, that the deleterious effects of hypertrophy, referred to here as the cardiomyopathy of overload, become prominent. When hypertrophy is induced by exercise, however, its detrimental effects appear to be minimal or absent, possibly because of the intermittent rather than sustained stimulus to cell growth.

Complex responses of the vasculature, along with remarkable plasticity in the cellular composition of the heart, allow the circulation to adapt to both acute and chronic low-output states. However, the short-term and long-term responses to a fall in cardiac output are quite different. In evolutionary terms, the most important of these responses favor survival after hemorrhage, which is, of course, a short-term challenge to the circulation. This is readily understood, because an ability to recover from an acute blood loss favors the retention in the gene pool of the traits needed to withstand such important causes of hemorrhage as childbirth and the injuries common in those who have the aggressiveness needed to search for food and defend the family. Although essential in meeting these short-term challenges, the responses of the cardiovascular system to low cardiac output can, when sustained, have detrimental long-term effects.

The inotropic response to these second messengers, along with the chronotropic response (not shown), increases cardiac output; however, an increase in the cytosolic calcium concentration may overload the systems that pump calcium out of the cell during diastole and so may also exacerbate the relaxation abnormalities in the failing heart. Cellular calcium overload can also cause transient depolarizations16 that may contribute to the arrhythmias seen in patients with heart failure. Although sympathetic stimulation accelerates the rate of calcium uptake by the sarcoplasmic reticulum, thus promoting relaxation (lusitropy), other abnormalities in the chronically overloaded failing heart depress the rate of calcium uptake (see the next section). Thus, the neurohumoral response to an acute fall in cardiac output initiates adaptive short-term compensatory responses, but when the low-output state becomes chronic, neurohumoral stimulation can have deleterious long-term effects on the heart.
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Depressed Contractility in the Failing Heart

Evidence that contractility is usually depressed in the hypertrophied, failing heart led to the logical corollary that an increase in myocardial contractility would benefit patients with heart failure. Much as the pneumococcus represents the pathogenic organism in lobar pneumonia, depressed contractility was once viewed as the cause of most cases of heart failure. Thus, just as penicillin is the usual treatment for pneumococcal pneumonia, positive inotropic drugs came to be viewed as the specific treatment for heart failure.

The identification of calcium as the key intracellular messenger in cardiac excitation–contraction coupling made possible the development of powerful inotropic drugs. By modifying the myocardial metabolism of calcium, such drugs could alleviate the depressed myocardial contractility then viewed as the chief cardiac abnormality in patients with heart failure. It is possible, however, that powerful inotropic stimulation, although a logical short-term measure to maintain circulatory function in patients with acute heart failure, could have deleterious effects in some patients with chronic congestive heart failure. These effects include cell damage caused by increased energy expenditure, a view that is supported by reports of depressed concentrations of high-energy phosphates in both experimental and clinical heart failure. Since relaxation, like contraction, requires the expenditure of high-energy phosphates, an imbalance between energy production and energy use in the overloaded heart may contribute to the relaxation abnormalities now recognized to have a major pathophysiologic role in heart failure. Inotropic drugs, by increasing cytosolic calcium and cyclic AMP concentrations in the myocardium, may also have arrhythmogenic side effects.