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Crossovers Between Functional and Proliferative
Signaling in the Pathogenesis of Heart Failure*
Arnold M. Katz, MD
Professor of Medicine Emeritus,
University of Connecticut School of Medicine Visiting
Professor of Medicine, Dartmouth Medical School, VT, USA
*Modified from an article that appeared in "Cardiology at the Limits" Ed. LH Opie and DM Yellon
New concepts regarding the pathophysiology and treatment of heart failure are appearing at an accelerating rate. Driven by a remarkable collaboration between the basic and clinical sciences, the pace of discovery has increased to the extent that concepts almost universally accepted only a decade ago are now viewed as obsolete, and in some cases, wrong. This article, which uses an historical approach to describe the trajectory of discovery in this field, asks whether the current pace of discovery might be approaching a limit.THOMAS KUHN AND THE PARADIGM SHIFT
A classical paradigm shift occurred in the 17th Century, when Harvey's discovery of the circulation, along with autopsy studies of patients who died of heart failure caused by rheumatic valvular disease, revealed anomalies that overthrew the normal science based on ancient Greek cosmology. Our current understanding of heart failure is in the midst of another paradigm shift that is as remarkable as that which occurred almost 400 years ago.
FFROM EXCESS PHLEGM TO IMPAIRED CARDIAC PUMPING
The works attributed to Hippocrates, most of which were written from the 5th - 3rd Century BC, describe patients with shortness of breath, edema, and anasarca, many of whom suffered from heart failure (2). Hippocrates, who provides explicit instructions as to how to drain pleural effusions, attributed this fluid to an excess of "phlegm" (the cold humor) moving from the brain to the chest. This explanation, along with Galen's view that the heart is the source of heat that it distributes through the body, was part of a paradigm that dominated medical thinking in the West for almost 2000 years (). It was not until 1628, when Harvey described the circulation, that it became possible to understand the hemodynamics of heart failure (for descriptions written before the 20th Century, see references 3-5).
|Figure 1: According to Hippocrates, pleural effusions are caused when an excess of the cold humor (phlegm) moves form the brain to the chest. This paradigm, which was supported by Galen, lasted almost 2000 years, until Harvey's description of the circulation in 1628 stimulated a paradigm shift that overthrew this explanation of heart failure.|
Harvey's discovery of the Circulation made it possible for Mayow, in 1674, to recognize how mitral stenosis causes right ventricular dilatation. Vieussens, in a text published posthumously in 1715, proposed that the pleural effusions seen in this syndrome are caused when serum separates from the blood that backs up behind the narrowed mitral valve. These views, by invalidating the concepts based on Hippocrates and Galen, stimulated a classical paradigm shift.
THE HYPERTROPHIC RESPONSE: EARLY OBSERVATIONS
In 1707, shortly after Mayow's observation that obstruction to blood leaving the heart causes ventricular dilation, Lancisi distinguished between increased cavity size (dilatation) and increased wall thickness (hypertrophy) in enlarged hearts. Morgagni, in 1761, recognized the causal link between chronic overload and hypertrophy. These observations set the stage for a remarkable, and now generally overlooked, century of discovery that focused on the different patterns of growth in failing hearts (). This began in 1801 when Corvisart distinguished between clinical manifestations associated with eccentric hypertrophy (dilatation) and concentric hypertrophy, and continued throughout the 19th Century with the recognition that cardiac enlargement is progressive, and eventually kills the patient. Flint, in the 1850s, suggested that hypertrophy protects the patient from the adverse effects of dilatation, but by the 1880s, Paul and Osler had noted that the hypertrophy itself is also associated with progression. This focus on the hypertrophic response of the failing heart ended around 1920, when publication of Starling's Law of the Heart returned attention to the abnormal hemodynamics in heart disease.
Figure 2: Throughout the 19th Century, emphasis on the mechanisms responsible for heart failure focused on changes in the size and shape of diseased hearts. The progressive nature of dilatation (remodeling) was well understood by the middle of this century, which ended with a clear understanding that hypertrophy too was progressive. This emphasis on changes in the size and shape of the failing heart ended after publication of Starling's Law of the Heart returned attention to the hemodynamics of this syndrome.
SALT AND WATER RETENTION
The clinical picture in heart failure had, since the time of Hippocrates, been dominated by the signs and symptoms of fluid overload. Although a role for the kidney in casing fluid retention had been proposed in the 16th Century, this mechanism did not assume practical importance until 1920, when Saxl and Heilig discovered the diuretic properties of an organic mercurial that was being used to treat syphilitic heart disease (6). Although this demonstrated that drugs affecting renal function could effectively treat heart failure (), mercurial diuretics are of limited value as they have to be given by injection, and more importantly, if used more than twice weekly, they lose their effectiveness. For the next 40 years, therefore, heart failure research emphasized the kidneys in the effort to develop more powerful diuretics that could be given orally. This ended successfully in the 1950s and 1960s with the discovery first of the thiazides, and then of the loop diuretics. The availability of these drugs, which made it possible to cause a diuresis so effective as to exchange congestion for a low output state, returned the focus in heart failure research to the heart.
|Figure 3: Discovery of the diuretic properties of organic mercurials in 1920 stimulated research in renal physiology that led to the development of thiazide and loop diuretics. At the same time, basic research in cardiac hemodynamics , followed by the introduction of cardiac catheterization, provided the basis for modern cardiac surgery. The increasing pace of discovery continued with the description of myocardial contractility in 1955, recognition that myocardial contractility is depressed in the failing heart in 1967, and the identification of the first molecular abnormality in the failing heart in 1962.|
Discovery of the renal abnormalities responsible for salt and water retention, and the subsequent recognition of the importance of peripheral vasoconstriction in patients with heart failure, highlighted the role of the neurohumoral response in this syndrome (7). As noted below, unexpected effects of drugs that block this response are providing a major impetus for the paradigm shift that is currently dominating heart failure today.
RETURN TO HEMODYNAMICS
During the era when renal physiology dominated research in heart failure, knowledge of the hemodynamic abnormalities in heart disease continued to advance (). Between World War I and World War II, research in this field was dominated by Wiggers, who characterized the hemodynamics of valvular, congenital, and ischemic heart disease. These studies, which could only be pursued in animal models, were incorporated into clinical medicine following the introduction of cardiac catheterization in the late 1940s. At the same time, advances in the treatment of cardiac injury during World War II provided surgeons the experience that led to the successful operative treatment of rheumatic mitral stenosis. By the 1960s, open heart surgery and the development of prosthetic valves made it possible to palliate most forms of structural heart disease (see 8 for review). At the same time, the causes of heart failure in the industrialized world were changing; rheumatic fever, which had been a scourge through the early years of the 20th Century, virtually disappeared, and most children with congenital heart disease could be cured, or at least palliated, by surgery performed during infancy. At the same time, new causes of heart failure emerged in developed countries. Ischemic heart disease and idiopathic dilated cardiomyopathy are now the major causes of systolic dysfunction, while diastolic dysfunction, which has reached epidemic status in the elderly, is due most commonly to increased afterload on the left ventricle caused by hypertensive heart disease and the reduced aortic compliance that accompanies normal aging.
Renewed emphasis on the hemodynamic causes of heart failure, along with evidence that myocardial contractility is depressed in this syndrome () had a major impact on therapy, and led to the clinical testing of two new classes of drugs. These were vasodilators, which by reducing afterload improve energetics and increase cardiac output, and newly developed inotropic agents, such as amrinone and milrinone, which were initially believed to hold the key to reversing the depressed contractility. Short term clinical trials showed that both vasodilators and inotropic drugs improve hemodynamics and symptoms in heart failure, and two survival trials reported in the late 1980s, V-Heft I (9) and Consensus I (10), demonstrated that the combination of isosorbide dinitrate and hydrazine (V-Heft I ) and an ACE inhibitor (CONSENSUS I) improved survival. As a result, in 1990 it was generally believed that the judicious use of diuretics, vasodilators and inotropes could solve most of the problems in these patients.
|Figure 4: During the 1970s and 1980s, the short-term benefits of new inotropic agents stimulated efforts to increase contractility in the failing heart. The importance of hemodynamics was highlighted by short-term improvement following administration of several classes of vasodilators, and a survival benefit for a vasodilators reported in V-Heft I, and CONSENSUS I. The end of this era was heralded by evidence that inotropic therapy worsened prognosis. The maladaptive features of hypertrophy attracted little attention until 1990, when evidence began to emerge that heart failure was exacerbated by the growth response in overloaded hearts, that angiotensin II evoked a proliferative response, and that myosin mutations caused hypertrophic cardiomyopathy.|
The finding that ACE inhibitors significantly prolong survival in heart failure (9-12) was initially interpreted within the established paradigm that heart failure is a hemodynamic disorder that can be helped by afterload reduction, while the initial short-term benefits of inotropes supported the view that the best way to treat this syndrome is to increase contractility in the failing heart. However, the latter view received a major setback when a trial using milrinone had to be stopped prematurely because this inotrope significantly reduced survival (13). This adverse effect, which was confirmed in subsequent trials (14), provided solid evidence that there is much more to heart failure that decreased contractility, and drew attention to the need to slow progression, as well as to relieve symptoms.
The hypertrophic response, which had dominated thinking about heart failure in the 19th Century, attracted little notice throughout the 20th Century. It was not until 1990 that evidence began to emerge that the prognosis in heart failure is worsened when overload causes hypertrophy (15), that angiotensin II can stimulate a proliferative response (16), and that myosin mutations cause hypertrophic cardiomyopathy (17). Together, these findings heralded the paradigm shift that has now come to dominate thinking about heart failure; that the major problem in this syndrome is a maladaptive growth response that accelerates myocardial cell death in damaged and overloaded hearts.
THE CARDIOMYOPATHY OF OVERLOAD: MALADAPTIVE GROWTH
AND ACCELERATED CARDIAC CELL DEATH
Throughout the 1990s, clinical trials with vasodilators yielded anomalous results in terms of the "normal science" that viewed heart failure largely as a hemodynamic disorder . These trials demonstrated that, in spite of providing short-term clinical improvement, most vasodilators worsen prognosis in heart failure (for review see 18-19). The latter include a-adrenergic blockers, short-acting L-type calcium channel blockers, minoxidil, prostacyclin, ibopamine, moxonidine, flosequinan, and phosphodiesterase inhibitors. Among the vasodilators, only the combination of isosorbide dinitrate and hydralazine, ACE inhibitors, and angiotensin II receptor blockers, have a survival benefit. An even more striking anomaly that challenged the traditional view that heart failure is simply a hemodynamic disorder caused by weakened heart muscle is the recent demonstration that b blockers, in spite of a negative inotropic action that initially worsens heart failure, improve long-term prognosis (20-23).
Figure 5: Evidence that proliferative signaling caused by mediators of the neurohumoral response is a major cause of the poor prognosis in heart failure came from clinical trials which showed that most vasodilators worsen prognosis, and that b blockers, in spite of their negative inotropic effects, improve survival.
One explanation for the anomalous findings of the clinical trials reviewed above is that the neurohumoral response, which increases circulating levels of such mediators as norepinephrine and angiotensin II, has a deleterious long-term effect on the failing heart. Many of these harmful effects occur because when vasodilators stimulate the neurohumoral response by lowering blood pressure. The significance of this response lies in the fact that most neurohumoral mediators not only stimulate fluid retention, vasoconstriction and myocardial contractility, but also activate a deleterious long-term response in which stimuli that cause cardiac myocytes to enlarge (hypertrophy) also damage the failing heart. The latter occurs because the proliferative stimuli that initially normalize wall stress by causing hypertrophy also accelerate cell death and cause progressive dilatation (for reviews see 19, 24-25). The latter is especially harmful in the adult heart because the myocytes are terminally differentiated cells that cannot divide, so that cells which die cannot be replaced. For these reasons, overload and neurohumoral mediators such as norepinephrine and angiotensin II establish a vicious cycle of cell death, increased overload, maladaptive proliferative signaling, and further cell death. Other causes of this vicious cycle include cell deformation, which stimulates cell adhesion molecules and cytoskeletal proteins that activate proliferative signal transduction cascades, and intracellular messengers, such as calcium and cyclic AMP. These and other mechanisms operate in heart failure to activate proliferative signaling by such transcriptional regulators as protein kinase-C, the heterotrimeric G proteins, the cytokine-activated JAK/STAT pathway, and mitogenic and stress-activated MAP kinase pathways. These concepts represent a new paradigm which states that the major problem in heart failure is not the hemodynamic abnormalities, but instead is the poor prognosis that results from growth stimuli which accelerate deterioration and cell death in the failing heart.
Key to understanding the mechanism by which the neurohumoral response accelerates progression in heart failure is that many mediators of this response activate proliferative as well as functional responses. The latter, which include chronotropic, inotropic and lusitropic stimulation of the heart, are part of the response that allows organisms to survive attack by "fight and flight" (). Proliferative responses, on the other hand, represent a more primitive means of defense seen in prokaryotes, which literally grow their way out of trouble. This occurs in bacteria, where rapid proliferation generates individuals able to survive a change in the external environment, such as the appearance of an antibiotic. In eukaryotes, where proliferative responses evolve much more slowly than functional responses, the former increase the number of cells in proliferating tissue, such as the bone marrow where this response replaces erythrocytes lost after hemorrhage and provide leukocytes needed to fight infection. In the heart, whose terminally cardiac myocytes have little or no capacity to divide, proliferative signaling is responsible for the hypertrophic response. However, features of this response, such as apoptosis and the cell elongation that causes remodeling, accelerate progression in heart failure. This explains both the ability of angiotensin II and norepinephrine to shorten survival in this syndrome, and the beneficial effects of neurohumoral blockade on prognosis.
Figure 6. Functional signaling, which modifies the behavior of preexisting structures by post-translational modifications, enables an organism to survive using such responses as fight or flight. In the case of proliferative signaling, transcriptional changes make it possible for an organism to grow its way out of trouble. From Katz, Physiology of the Heart (3rd Ed), Philadelphia, Lippincott/Williams & Wilkins, 2001.
IS THERE A LIMIT?
A scientist living at the time of the paradigm shift that followed Harvey's discovery of the circulation would have had no basis for predicting today's paradigm shift. For this reason, it is presumptuous to try to predict future advances in our understanding of heart failure. The complexity of the current paradigm of molecular biology makes it unlikely that understanding of maladaptive proliferative signal transduction will soon be complete, although the pace of discovery is now so rapid that even this limit may be reached more quickly than now seems possible. After all, the understanding of cardiac function that began in the 20th Century with studies of organ physiology, expanded in the 1960s to include cell biochemistry, and over the past decade has incorporated molecular biology (26). What then could be the next step in this process? If scientific progress continues to develop at its current pace, by the end of the 21st Century we may well pass the limits set by molecular biology to enter a new era, one where principles based on quantum mechanics will be used in the search for new understanding and new means to treat heart failure.
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