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Slowed relaxation was noted in early studies of experimental cardiac hypertrophy, but it was not until the past decade that the importance of lusitropic (relaxation) abnormalities was clearly demonstrated in patients with congestive heart failure. Although an impairment of the ion pumps that cause the myocardium to relax could be due in part to a chronic energy deficiency in the overloaded cells of the hypertrophied and failing heart (as described earlier), recent studies indicate that more complex molecular mechanisms contribute to the diastolic abnormalities. For example, relaxation is slowed in papillary muscles from cardiac-transplant recipients with dilated and hypertrophic cardiomyopathy, even after the tissue is isolated and studied in vitro.

Slowing of the active transport of calcium has been shown in several studies of sarcoplasmic-reticulum vesicles obtained from hypertrophied hearts. In keeping with the earlier emphasis on depressed contractility, this abnormality was initially interpreted as explaining the inotropic rather than the lusitropic abnormalities in heart failure. However, these observations have assumed new importance with the recognition of the clinical importance of relaxation abnormalities in the failing heart.

Impaired relaxation in the failing heart could be explained in part if the uptake of calcium by the sarcoplasmic reticulum was slowed by a chemical-energy deficit or altered membrane assembly. There are, however, other plausible explanations for this lusitropic abnormality; for example, diastolic stiffness may be increased by the spontaneous recycling of calcium in the sarcoplasmic reticulum during diastole. In addition, the energy-dependent reactions that cause the hypertrophied heart to relax appear to be abnormally sensitive to a fall in high-energy phosphate levels, such as occurs in hypoxia. This finding could be explained in part by the attenuation of an allosteric effect of ATP that accelerates the rate of the calcium pump of the sarcoplasmic reticulum. Reports that the calcium sensitivity of the sodium—calcium exchanger is reduced in hypertrophied rat hearts and that the activity of this important mechanism for the extrusion of calcium from the myocardial cell is depressed late in the course of heart failure in hamsters with cardiomyopathy suggest yet other causes for the lusitropic abnormalities in heart failure.

Clinical experience tells us that there is a wide spectrum in the individual hypertrophic response to overload. Most striking are the adolescents in whom massive ventricular hypertrophy develops in the absence of apparent hemodynamic overload; this is, of course, the condition recognized as hypertrophic cardiomyopathy. At the other end of the spectrum are the elderly patients with substantial overloading caused by severe and long-standing systemic hypertension who have relatively less severe left ventricular hypertrophy. In the middle of the spectrum are the hypertensive patients in whom there is no clear relation between the hypertrophic response of the ventricle and the severity and duration of overloading; however, there are reports that the prevalence of hypertensive heart disease for any given level of blood pressure is higher in men than women and in blacks than whites. A suggestion that the attenuation of the hypertrophic response to overload with advancing age may contribute to the high incidence of heart failure in the elderly has recently found support in studies showing a diminished capacity for left ventricular hypertrophy after experimentally induced aortic stenosis94 and insufficiency in aged rats.

Functional Abnormalities in the Hypertrophied and Failing Heart

The protein-isoform changes that have been described thus far probably represent but a small fraction of the molecular abnormalities that develop in chronically overloaded myocardial cells. Additional but as yet incompletely characterized changes in composition are suggested by important functional abnormalities in the hypertrophied and failing heart that may contribute to the arrhythmias and progressive pump dysfunction that lead to death in patients with congestive heart failure.

Electrophysiologic Abnormalities

Arrhythmias are among the most important determinants of prognosis in patients with congestive heart failure. Although these disorders arise in part from conduction inhomogeneities caused by the enlargement and fibrosis of the hypertrophied heart, there is growing evidence that abnormal isoforms of the ion channels responsible for the heart’s electrical activity may also be synthesized in the failing heart.

Prolongation of the action potential, among the most prominent electrophysiologic abnormalities in hypertrophied myocardial cells, may be due in part to an increase in the slow inward calcium current that maintains depolarization during the plateau of the cardiac action potential. Recent evidence suggests that such prolongation may be due in part to the delayed inactivation of L-type calcium channels. This abnormality may also be due to the attenuation of one or more of the outward potassium currents that cause repolarization, including the transient outward potassium current, the ATP-sensitive potassium current, and both inward and delayed rectifier currents.

A role for these molecular abnormalities in the pathogenesis of arrhythmias in patients with heart failure remains unproved; however, this is a rapidly developing field, and specific peptide regions in the large ion-channel proteins that regulate the opening, closing, and inactivation of the channel have recently been identified. The molecular mechanisms responsible for some of the electrophysiologic abnormalities in the failing heart may be elucidated by studies of single ion-channel molecules, which may uncover a molecular basis for some of the arrhythmias commonly seen in congestive heart failure.

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

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.

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.

The systemic responses to impaired cardiac performance that generally predominate in this condition include salt and water retention, vasoconstriction, and sympathetic stimulation.

These responses probably represent the long-term effects of adaptive mechanisms, which by augmenting preload, maintaining blood pressure, and increasing the heart rate compensate for short-term reductions in cardiac output. When sustained in heart failure, however, these responses become deleterious.

Because these compensatory responses to low cardiac output lead to the most prominent symptoms of heart failure, until recently the major goal of therapy for this condition has been to rid the body of excess salt and water and to correct vasomotor abnormalities in the peripheral circulation. The use of diuretics to manage salt and water retention and vasodilators to overcome inappropriate vasoconstriction, however, fails to address directly the primary cardiac abnormalities in these patients. The cardiac glycosides have been the traditional agents used for inotropic therapy. Although Osler recognized almost a century ago that “degeneration and weakening” of the overloaded heart contribute to the clinical deterioration in congestive heart failure, only recently have clinical strategies for the care of these patients begun to address important and progressive abnormalities in the structure and function of the cells of the failing heart.

What Is Heart Failure?

Since this article focuses on the state of the failing myocardium, rather than on alterations elsewhere in the body that result from impaired cardiac performance, heart failure is defined in terms of myocardial abnormalities. Thus, no effort is made to define this condition in terms of the clinical syndromes of heart failure, which — as already pointed out — are dominated by the circulatory consequences rather than the myocardial causes of the condition.

MacKenzie’s definition of heart failure as “exhaustion of the reserve force of the heart muscle” highlights the importance of myocardial abnormalities in patients with this condition. Of course, MacKenzie’s “reserve force” and the mechanism by which it might be “exhausted” in the failing heart could not be understood in terms of the knowledge of cardiac muscle that existed at the beginning of the century. It was not until the late 1960s, when myocardial contractility came to be appreciated as a manifestation of complex biochemical and biophysical processes in the myocardium, that our modern understanding of the pathophysiology of heart failure in terms of disordered myocardial-cell function became possible.

MORE than 80 years ago, Sir James MacKenzie noted: “The more I study the symptoms of heart failure, and the more I reflect on the part played by the heart muscle, the more convinced I am that… heart failure is due to the exhaustion of the reserve force of the heart muscle.” Except for the cardiac glycosides, however, therapy for congestive heart failure generally has focused on the systemic signs and symptoms that appear when the failing heart becomes unable to meet the hemodynamic demands of the body, rather than on abnormalities in the heart muscle itself, which both cause and exacerbate the clinical disability.

A new understanding of the pathophysiology of congestive heart failure has led to the identification of important cellular and molecular alterations in the failing heart. Although often masked by prominent systemic compensations for depressed cardiac performance, notably salt and water retention and vasoconstriction, the heart-muscle disorders play a major part in determining the poor prognosis in this condition, which a few years ago had a five-year mortality of approximately 50 percent. Stimulated by a growing realization that medical therapy can alter this grim outlook, applications of new knowledge of the pathophysiology of the heart in congestive heart failure are increasingly affecting strategies for the clinical care of patients with the condition.

Although myocardial hypertrophy, one of the most important responses of the failing heart, is an adaptive process that enables the heart to compensate for overloading, the cells of the hypertrophied, failing heart are not normal. This review of the cellular abnormalities in the failing myocardium describes a cardiomyopathy of overload that appears to be among the chief causes of deterioration and death in patients with congestive heart failure.

Clinical Syndromes in Heart Failure

The hemodynamic abnormalities that result from heart failure are conceptually simple because, as a pump, the heart has but two ways to fail: through inadequate emptying of the venous reservoirs (backward failure) and through reduced ejection of blood under pressure into the aorta and pulmonary artery (forward failure). However, the response of the body to these abnormalities is complex and varies from person to person. Furthermore, because blood flows in a circle, forward failure and backward failure generally coexist, although the highly variable circulatory adjustments in response to impaired pump performance may cause one or the other to dominate the clinical picture in any given patient.

In patients with left ventricular dysfunction, by far the most common cause of heart failure, an increase in left atrial pressure (backward failure) leads to dyspnea, to pulmonary congestion, and when severe, to pulmonary edema. Reduced cardiac output (forward failure) causes poor tissue perfusion and fatigue; since the body tends to protect blood pressure at the expense of cardiac output (because of vasoconstriction), hypotension is uncommon in chronic heart failure, usually appearing only in the very late stages when pump function has become severely impaired.

Molecular changes in the proteins synthesized by the myocardium play a major part in the adaptation of the hypertrophied heart to chronic overload and may influence the long-term prognosis in patients with congestive heart failure. However, as noted more than a decade ago, the extent to which most changes induced by chronic overload contribute to or compensate for the deterioration of the heart is still poorly-understood.

Alterations in Myosin

The synthesis of the myosin heavy chains, which determine myosin ATPase activity (a measure of the rate of energy liberation by myosin in vitro) and muscle-shortening velocity (a measure of the rate of energy use by myosin in vivo), is altered by chronic hemodynamic overloading and heart failure. The functional consequences of the expression of different members of the family of genes that encode the myosin heavy chain have been studied in depth in the rat ventricle: the expression of a VI (α) myosin heavy chain leads to high myosin ATPase activity and rapid shortening velocity, and the expression of a V3 (β) myosin heavy chain leads to low myosin ATPase activity and slow shortening velocity. In response to overload, the preferential synthesis of the V3 heavy chain causes “slow” myosin to replace “fast” myosin, which by decreasing the rate of cross-bridge cycling reduces myocardial contractility. At the same time, however, the tension generated during each systole is increased, which facilitates ejection by the overloaded heart. Furthermore, although the slowing of cross-bridge cycling has a negative inotropic effect, it also improves mechanical efficiency and so is sparing of energy.

A change in the myosin-gene expression has also been observed in overloaded human hearts. Although the human ventricle synthesizes only a slow-myosin isoform, changes similar to those just described for the rat ventricle have been seen in human atria, in which a decrease in the proportion of fast (α) atrial myosin heavy chains parallels the pathologic elevation of left atrial pressure and the extent of left atrial enlargement. Overload has also been found to alter the expression of myosin light chains in the human heart; however, in this case the new gene product is a ventricular isoform of the myosin subunit.

A recent report that the abnormal gene responsible for hypertrophic cardiomyopathy is located on chromosome 14, where both α and β cardiac myosin heavy chains also map, may provide a clue about the pathogenesis of this abnormal hypertrophic response of the myocardium.