Arnold M. Katz

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 engines 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 Oslers 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 bodys 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

Cellular calcium and cardiac cell death

Claude Bernard recognized over a century ago that an extracellular environment of constant chemical composition was prerequisite for life outside of the stable aquatic environment of the sea. This concept of constancy of composition extends also to the intracellular environment, which can vary only within rather narrow limits that are set by the conditions essential for cell viability. A major role for the sarcolemma, which separates the intracellular and extracellular environment, is to maintain the intracellular environment within these limits. Nevertheless, it is important to note that small variations in this intracellular composition have important implications for cell function. For example, small fluctuations of intracellular free ionized calcium (Ca2+) concentration determine both the contractile and the energetic state of the heart.

DISEASE OF THE HEART IN THE WORKS OF HIPPOCRATES

He who would make accurate forecasts as to those who will recover, and those who will die, and whether the disease will last a greater or less number of days, must understand all the symptoms thoroughly and be able to appreciate them, estimating their powers when they are compared with one another, as I have set forth. Hippocrates, Prognostic XXV (Jones, 1923-31)

Angiotensin II : hemodynamic regulator or growth factor ?

The evolution of our understanding of the actions of ANG II can be described in terms of 3 paradigms that also characterize the development of our knowledge of cardiovascular regulation. The first paradigm, organ physiology, described the variable performance of the heart in terms of length-dependent changes in myocardial contractile function (Starlings Law), and Ang II as a pressor factor that elevated blood pressure. With the shift to the second paradigm, cell biochemistry and biophysics, regulation of cardiac performance came to be explained by altered calcium fluxes and changing myocardial contractility, while the clinical effects of Ang II were understood in terms of changes in the calcium fluxes that control smooth muscle contraction. The third paradigm, gene expression (molecular biology), probably describes the most primitive--and complex--of these regulatory mechanisms. Altered gene expression in response to a variety of chemical and physical forces can explain several aspects of the long-term regulation of cardiac performance in terms of adaptative changes in the architecture and composition of a heterogeneous population of myocardial cells. This third paradigm also describes important effects of Ang II to increase protein synthesis and promote cell growth that appear able both to ameliorate and exacerbate human disease. It is, therefore, probably inappropriate to view Ang II mainly as a vasoconstrictor with secondary effects to induce cell hypertrophy. Instead, Ang II may have been derived from a primitive growth factor that, because it utilized Ca2+ to mediate its effects on gene expression, later in evolution acquired the ability to increase smooth muscle tone and myocardial contractility.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium channel diversity in the cardiovascular system

The flux of calcium ions (Ca2+) into the cytosol, where they serve as intracellular messengers, is regulated by two distinct families of Ca2+ channel proteins. These are the intracellular Ca2+ release channels, which allow Ca2+ to enter the cytosol from intracellular stores, and the plasma membrane Ca2+ channels, which control Ca2+ entry from the extracellular space. Each of these two families of channel proteins contains several subgroups. The intracellular channels include the large Ca2+ channels (ryanodine receptors) that participate in cardiac and skeletal muscle excitation-contraction coupling, and smaller inositol trisphosphate (InsP3)-activated Ca2+ channels. The latter serve several functions, including the pharmacomechanical coupling that activates smooth muscle contraction, and possibly regulation of diastolic tone in the heart. The InsP3-activated Ca2+ channels may also participate in signal transduction systems that regulate cell growth. The family of plasma membrane Ca2+ channels includes L-type channels, which respond to membrane depolarization by generating a signal that opens the intracellular Ca2+ release channels. Calcium ion entry through L-type Ca2+ channels in the sinoatrial (SA) node contributes to pacemaker activity, whereas L-type Ca2+ channels in the atrioventricular (AV) node are essential for AV conduction. The T-type Ca2+ channels, another member of the family of plasma membrane Ca2+ channels, participate in pharmacomechanical coupling in smooth muscle. Opening of these channels in response to membrane depolarization participates in SA node pacemaker currents, but their role in the working cells of the atria and ventricle is less clear. Like the InsP3-activated intracellular Ca2+ release channels, T-type plasma membrane channels may regulate cell growth. Because most of the familiar Ca2+ channel blocking agents currently used in cardiology, such as nifedipine, verapamil and diltiazem, are selective for L-type Ca2+ channels, the recent development of drugs that selectively block T-type Ca2+ channels offers promise of new approaches to cardiovascular therapy.

Cellular mechanisms in congestive heart failure

There is substantial, although not yet conclusive, evidence that the failing heart is in an energy-depleted state. Such an imbalance between energy production and energy utilization would have important implications for the management of patients with congestive heart failure (CHF), most important of which is that therapeutic measures that increase myocardial energy demand could have long-term detrimental effects on the heart. By increasing energy expenditure, vasoconstrictors and positive inotropic agents could worsen cell damage, exacerbate relaxation abnormalities and promote arrhythmias. Conversely, therapy that improved the balance between energy delivery and energy expenditure might be expected to improve prognosis in CHF. For this reason, vasodilators and reduced inotropic drive to the failing heart could prolong survival in these patients. Further understanding of the energetics of the failing heart will be of considerable importance in the formulation of hypotheses regarding long-term therapy that could be evaluated in controlled clinical trials.

Cellular Actions and Pharmacology of the Calcium Channel Blocking Drugs

The calcium channel blockers represent a group of diverse chemical structures that block calcium-selective channels in the plasma membranes of a variety of excitable cells. As the calcium fluxes carried by these channels allow the calcium ion (Ca2+) to gain access to the cell interior, where calcium serves as an activator messenger, calcium channel blockers generally act to inhibit cell function. By reducing the depolarizing currents caused by the entry of positively charged Ca2+ into the negatively charged interior of resting cells, the calcium channel blockers also inhibit excitatory processes that depend on calcium entry across the plasma membrane. These principles account for most of the effects of calcium channel blockers on the cardiovascular system. The calcium channel blockers inhibit contractile function in the heart and vascular smooth muscle and, because the initial depolarizing currents in the sinoatrial and atrioventricular nodes are carried by calcium channels, slow the heart rate and prolong atrioventricular conduction. The negative inotropic and vasodilatory effects of the calcium channel blockers, both of which can reduce systemic blood pressure, offer a theoretic basis for their potential use in the treatment of hypertension. The tissue specificity exhibited by some of the calcium channel blockers may enhance their therapeutic value in selected hypertensive patients. Of the three calcium channel blockers now available for use in the United States (diltiazem, nifedipine, and verapamil), diltiazem and verapamil are approximately equipotent in inhibiting calcium channel function in the heart and vascular smooth muscle, whereas nifedipine is more potent in smooth muscle. This tissue specificity can be used to advantage in the management of hypertension. These pharmacologic principles underlie the growing appreciation of the potential value of the calcium channel blockers in the treatment of hypertension.

The “Modern” View of Heart Failure How Did We Get Here?

The inauguration of a new journal provides a unique opportunity to look back on the way that we arrived at our present state of understanding. In the case of heart failure, it is possible to trace a remarkable history that, for Western medicine, extends back to clinical descriptions collected in works attributed to Hippocrates in ancient Greece. Since the fifth century BCE, physicians and scientists have approached this clinical syndrome in at least 9 different ways (Table). The increasing rapidity with which these views have changed illustrates how new knowledge has narrowed the gap between clinical medicine and basic science.1 nnView this table:nnTable. Changing Views of Heart Failure nnnnThe present article describes how our understanding of heart failure has evolved over the past 2500 years. Having been active in this area since the 1950s and having shared many reminiscences with my father, Louis N. Katz, who played an active role in academic cardiology between the 1920s and 1970s, I have included several personal insights about progress since the beginning of the 20th century.nnPatients with what may have been heart failure are described in ancient Greek and Roman texts, but edema, anasarca, and dyspnea, the most common clinical manifestations mentioned in early writings, have other causes. Difficulties in evaluating these clinical descriptions are due partly to lack of pathophysiological understanding of disease, which was then viewed as an imbalance between opposing humors (Figure 1). nnnnFigure 1. Two views of the circulation. A, Galen’s view. Pneuma derived from air (blue) reaches the heart from the lungs via the venous artery (pulmonary artery) and arterial vein (pulmonary veins). Natural spirits that enter the heart from the liver (green), along with vital spirits (heat) generated in the left ventricle, are distributed throughout the body by an ebb and flow in the arteries (red). Animal …

Clinical and electrocardiographic features of cardiac rupture following acute myocardial infarction

Abstract Characteristic clinical and electrocardiographic findings are reported in six autopsy cases of cardiac rupture following acute myocardial infarction. These patients were generally elderly with an acute, transmural myocardial infarction uncomplicated by pump failure. They had hypertension and/or a stressful episode prior to cardiac rupture. Delay in diagnosis of myocardial infarction, absence of previous history of coronary artery disease and new or protracted chest pain were frequent accompanying findings. At the time of cardiac rupture the electrocardiogram showed persistent electrical activity when apparent mechanical activity was absent (electromechanical dissociation), preceded or accompanied by S-T segment elevation or depression.

Maladaptive Growth in the Failing Heart: The Cardiomyopathy of Overload

The hypertrophic response to overload plays an important role in the progressive deterioration of the failing heart—the “Cardiomyopathy of Overload”—and so contributes to the poor prognosis in patients with heart failure. Although increased myocyte size reduces the load on individual sarcomeres, hypertrophy also has maladaptive features. The latter include molecular changes that weaken and impair relaxation in the overloaded heart, and accelerate cardiac myocyte death. Different types of overload lead to concentric and eccentric hypertrophy; as the latter tends to progress (“remodeling”), dilatation is associated with an especially poor prognosis. Concentric hypertrophy is due largely to cardiac myocyte thickening, while eccentric hypertrophy is caused by cell elongation. These differences, along with evidence that concentric hypertrophy is initiated by increased diastolic stretch while eccentric hypertrophyresults from increased systolic stress, indicate that these growth responses are mediated by different signal transudation pathways. The beneficial effects of neurohumoral blockers in patients with heart failure are due partly to their ability to inhibit maladaptive features of overload-induced proliferative signaling. The molecular complexity of the hypertrophic response now being uncovered offers opportunities for the development of new therapy to inhibit remodeling and cell death in the failing heart.