The Cardiomyopathy of Overload: An Unnatural Growth Response in the Hypertrophied Heart

[Overload] excites a more forcible ventricular action which for a time enables the ventricles to expel their contents. Meanwhile, hypernutrition follows, and hypertrophy is produced. The increased muscular growth for a certain period protects against the occurrence of dilatation. At length, the hypertrophy reaches a point beyond which it cannot advance; for the muscles of the heart, like other muscles, cannot increase indefinitely. There is a limit to the hypertrophic enlargement, and this limit varies in different persons just as the voluntary muscles in different persons attain, by the same efforts, to different degrees of development. The causes, however, persist and perhaps become more and more operative after the utmost degree of hypertrophy which is possible has taken place. These causes then can produce only dilatation, and from this period the progressive enlargement is due to augmentation of the cavities. This view is not only rational, but sustained by the facts derived from clinical experience . According to this view, hypertrophy becomes an important conservative provision, first, against over-accumulation of blood, and second, against the more serious form of enlargement, viz., dilatation. Austin Flint, 1870 [1] Heart failure is traditionally viewed as a clinical syndrome in which the impaired ability of the heart to pump blood decreases cardiac output and increases venous pressures. This focus on the paradigm of organ physiology, however, fails to emphasize what I believe is the most important clinical problem in patients with heart failurethat of decreased life expectancy, which averages less than 5 years even in patients with moderate heart failure [2]. Advances in a second paradigm, that of cell biochemistry, have provided a detailed understanding of the calcium cycles responsible for excitation-contraction coupling and relaxation and of how abnormalities in these cycles can impair the performance of the failing heart [3]. Recent evidence that growth abnormalities, which accompany hypertrophy of the overloaded myocardium, may play an important role in the deterioration of patients with heart failure [4, 5] has shifted our focus to a third paradigm, that of gene expression (molecular biology) [6]. One way to view the overloaded, failing heart is by analogy to an automobile that has begun to break down while pulling a heavy trailer. It is becoming apparent that the problem in patients with heart failure is not simply impaired performance of the engine (abnormal organ physiology) or even malfunction of the engine's components (abnormal cell biochemistry). As described below, recent clinical studies have provided surprising and, in some cases, counterintuitive findings that are not readily explained by the organ or cell paradigms. Instead, these results suggest that heart failure is accompanied by abnormalities in gene expression analogous to the replacement of normal engine parts with abnormally brittle components. Accordingly, efforts to understand the progressive deterioration and long-term therapeutic response of the failing heart are shifting from the more obvious organ and cellular abnormalities to as-yet poorly understood disorders of cell growth and proliferation. Response of the Heart to Long-Term Overload The importance of cardiac hypertrophy in the response to overload was noted in the middle of the last century by Austin Flint [1] who postulated that, like skeletal muscle enlargement in athletes, hypertrophy compensates for hemodynamic overloading of the heart. Whereas Flint attributed the eventual failure of this adaptive response to worsening of the primary cause of the overload, such as valvular insufficiency, Osler [7] suggested that weakening and degeneration of the hypertrophied heart muscle caused the progressive failure of the chronically overloaded heart. Direct evidence for Osler's hypothesisthat changes in the hypertrophied myocardium contribute to deterioration of the overloaded heartwas provided by the pioneering studies of Meerson [8], who examined the natural history in experimental animals after surgical coarctation of the aorta. Meerson found that although the acute heart failure that immediately followed aortic constriction was alleviated by left ventricular hypertrophy, premature cell death in the hypertrophied, overloaded heart caused the animals to die of progressive heart failure. This progression is caused partly by a vicious cycle in which cell death in the overloaded heart adds further to the overload on surviving cardiac myocytes. Evidence that this progression from adaptive to maladaptive hypertrophy is not caused simply by the increased load was provided by Grossman and colleagues [9], who found that the hypertrophic response to aortic stenosis and insufficiency initially normalizes left ventricular wall stress. These findings indicate that the maladaptive response that follows a long-standing overload involves more than the progressive increase in the causes, as proposed by Flint [1]. Instead, the ability of long-term overloading to cause myocardial cell death and cardiac fibrosis indicates that long-standing cardiac hypertrophy is accompanied by a progressive, eventually lethal growth abnormality that I have called a cardiomyopathy of overload [4]. Treatment of Heart Failure As recently as a decade ago, when heart failure was viewed largely as a disorder of organ function, the major goal of therapy was to reverse the adverse effects of the body's attempts to compensate for the decreased cardiac output caused by the failing cardiac pump (Table 1). Thus, the mainstays of therapy were diuretics, which act on the kidney to counteract salt and water retention, and vasodilators, which alleviate excessive afterload by relaxing arteriolar resistance vessels. Except for the cardiac glycosides, treatment was not directed to the heart itself. Table 1. Compensatory Mechanisms Initiated by Low Cardiac Output* The significance of prognosis as a major problem in patients with heart failure led, in the 1980s, to several long-term clinical trials, many of which have generated counterintuitive findings that are leading us to reevaluate the pathophysiologic mechanism of heart failure. As noted below, powerful inotropic agents (which intuitively seemed to be logical therapy for patients who have decreased cardiac pumping) actually increased mortality, whereas some negative inotropic drugs (when administered for several months) were found to improve pump function and symptoms. Equally strikingand equally counterintuitiveis recent clinical experience with vasodilators. Because of evidence that the failing heart is in an energy-starved state [10], it was expected that vasodilator drugs, which not only increase cardiac output but also decrease cardiac energy expenditure, would improve survival in patients with heart failure. Yet, only two classes of vasodilatorsthe converting enzyme inhibitors, and the combination of nitrates and a direct-acting arteriolar dilatorhave been found to prolong life in these patients. Unexpectedly, several recent clinical trials have shown that other vasodilators, although they unload the failing heart, accelerate deterioration and worsen prognosis in patients with chronic heart failure. Positive and Negative Inotropic Agents Although drugs that increase myocardial contractility are clearly of value in the short-term treatment of acute cardiac decompensation, long-term inotropic stimulation of the failing heart can be harmful. Adverse effects, notably arrhythmias, have been especially prominent when agents that increase cellular cyclic adenosine monophosphate (AMP) levels, either by inhibiting its breakdown (phosphodiesterase inhibitors) or increasing its production (-adrenergic agonists), were given in inotropic doses on a long-term basis to patients with heart failure [11-18]. Even the intermittent administration of dobutamine, which during the short term improves symptoms, has been reported [19] to decrease long-term survival in these patients. Conversely, -adrenergic blockers, which have negative inotropic effects that can worsen heart failure symptoms acutely, have been found to improve symptoms and left ventricular function after long-term administration to patients with heart failure [20-23]. The ability of digoxin to improve symptoms in patients with heart failure has recently been confirmed in two trials [24, 25] where this drug was withdrawn, but evaluation of the effects of this drug on survival must await the results of a large clinical trial now under way and sponsored by the National Heart, Lung and Blood Institute and the Veteran Affairs Cooperative Studies Center. The cardiac glycosides, which are often viewed simply as positive inotropic agents, have important central actions that increase parasympathetic tone and inhibit sympathetic outflow in patients with heart failure [26, 27]. A role for these central effects is suggested by evidence that the most prominent hemodynamic effect of digoxin withdrawal is an approximately 15% increase in heart rate [24, 25]. These seemingly paradoxical long-term consequences of the administration of positive and negative inotropic agents were not entirely unexpected because of their effects on the energetics of the failing heart [28, 29] and because positive inotropic agents are arrhythmogenic [30]. More surprising, however, is evidence that many vasodilators, despite the fact that when given in the short term they increase cardiac output and decrease cardiac energy expenditure, reduce long-term survival in patients with heart failure. Vasodilators A solid rationale exists for using vasodilators to unload the failing heart. Indeed, it was for this reason that nitrates were introduced more than a century ago to relieve angina [31], and the ability of vasodilators to alleviate acute pulmonary edema has been known for more than 40 years [32]. Although vasodilators were introduced to relieve symptoms of c