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Pathophysiology of heart failure: identifying targets for pharmacotherapy
Med Clin N Am 87 (2003) 303–316
Pathophysiology of heart failure: identifying targets for pharmacotherapy Arnold M. Katz* University of Connecticut Health Center, Farmington, CT, USA Dartmouth Medical School, Hanover, NH, USA
William Withering, who discovered the benefits of digitalis, provided several clinical histories that described the terrible suffering seen in end stage heart failure. His description of a woman ‘‘between forty and fifty years of age’’, who almost certainly had rheumatic heart disease, provided remarkable insights into the pathophysiology that operates in these patients: I found her nearly in a state of suffocation; her pulse extremely weak and irregular, her breath very short and laborious, her countenance sunk, her arms of a leaden colour, clammy and cold. She could not lye down in bed, and had neither strength nor appetite but was extremely thirsty. Her stomach, legs and thighs were greatly swollen; her urine very small in quantity, not more than a spoonful at a time, and that very seldom [1].
This description, which resembles many others in the meticulously recorded case reports that were published before the middle of the twentieth century [2–4], documented the direct consequences of the impaired pump performance and abnormalities that are caused by the neurohumoral response to decreased cardiac output. These functional disorders, until recently, provided the major focus of therapy in patients with heart failure. Additional abnormalities that are caused by molecular changes in the cells of the failing heart that could not have been appreciated by Withering, are known to be associated with deleterious features of the growth response of the heart to overload and damage [5]. These consequences of maladaptive proliferative signaling provide clues to new targets for pharmacotherapy.
* P.O. Box 1048, Norwich, VT 05055-1048. E-mail address: [email protected] 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0025-7125(02)00188-8
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Functional consequences of impaired pump function Several of the clinical manifestations in Withering’s patient can be attributed directly to the pump dysfunction. These include the irregular pulse, which is almost certainly due to atrial fibrillation, and the weak pulse and peripheral cyanosis, which tell us that she had a low cardiac output. Her dyspnea and orthopnea are attributable to pulmonary congestion, which was most likely caused when rheumatic mitral stenosis impeded blood flow from her lungs into the left ventricle. Other clinical findings, however, are not direct consequences of the defective cardiac pump, but instead reflect a more subtle etiology. Her sunken countenance and anorexia are characteristic of cardiac cachexia, which is caused, in part, by elevated cytokine levels, whereas her lack of strength probably results from the skeletal muscle myopathy that is commonly seen in patients with heart failure. Additional features that were noted by Withering can be attributed to the neurohumoral response to low cardiac output; these include the cold damp extremities, the result of peripheral vasoconstriction and sympathetic activation of her sweat glands, fluid retention and oliguria, due in part to renal vasoconstriction and aldosterone release, and thirst, which reflects a central action of vasopressin. The impaired ability of the heart to pump and the neurohumoral response to the low cardiac output in Withering’s patient represent changes in the function of existing structures, and represent functional abnormalities.
Architectural changes in the failing heart: proliferative abnormalities A different type of abnormality became apparent when autopsy examinations revealed changes in the size and shape of the hearts in patients with heart failure [3,4]. These structural alterations were initially interpreted according to the Galenic paradigm, which viewed the heart as the source of heat that it distributed throughout the body. This old paradigm provided the rationale for treatments that included ointments and infusions made from roses, violets, flax, cinnamon, clove-gilly flowers, cubeb, aloe wood, anise, violets, and the bone of stag’s heart, as well as phlebotomy from the left hand [6]. Our modern understanding of heart failure became possible in 1628, when Harvey discovered that blood flows in a circle. This led to a paradigm shift that attributed the clinical picture described by Withering to reduced cardiac output and accumulation of blood behind a diseased heart. Harvey’s description of the circulation also provided a basis for understanding the architectural changes that are commonly found in failing hearts. Mayow, in 1674, seems to have been the first to recognize that obstruction to the flow of blood out of the heart leads to ventricular dilatation [4]. A more important insight was published in the mid-eighteenth century by Morgagni, who described the autopsy findings in a patient with mitral stenosis and noted the
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causal link between chronic hemodynamic overloading and cardiac hypertrophy: [as the result of narrowing of] the orifice by which blood goes into the left ventricle. . .the columnae, and fibres, of the [right] ventricle, were become very thick. . .because a greater thickness of the muscles is the consequence of their more frequent and stronger actions. Without doubt, these parts of the heart must have been constantly and vehemently contracted, and exercis’d, in their effort to thrust on so great a quantity of stagnating blood in the pulmonary vessels, which, by reason of the very difficult entrance into the left ventricle, did not readily admit it. . . [7]
This new understanding of the relationship between hemodynamic overload and changes in the size and shape of diseased hearts initiated more than a century of discovery that related clinical manifestations of heart failure to various architectural patterns of ventricular hypertrophy. By the first decade of the nineteenth century it became apparent that patients with eccentric hypertrophy (dilatation) of the left ventricle have a poorer prognosis than patients with concentric hypertrophy. Dilatation was also noted to have a marked tendency to progress [4], a process that is now referred to as remodeling. Conversely, concentric hypertrophy was initially viewed as an adaptive response that protected patients from the adverse effects of dilatation. By the end of the nineteenth century, however, it became clear that hypertrophy, like dilatation, is associated with progression and contributes to disability and death in patients with heart failure. Emphasis on the architectural changes in diseased hearts dominated clinical studies of heart failure until the early decades of the twentieth century, when advances in hemodynamic physiology refocused attention on the valve abnormalities that, at the time, represented the most common causes of heart failure. Emphasis on the pressure and blood flow abnormalities in this syndrome was highlighted by the introduction of cardiac catheterization in the 1940s, and by rapid progress in cardiac surgery during the 1960s. The importance of altered size and shape of the failing heart faded further into the background in the 1960s and 1970s, when details of the neurohumoral response to low cardiac output began to emerge [8,9] and therapy was directed to alleviating the maladaptive functional effects of neurohumoral mediators, notably vasoconstriction. It was not until 1990s that counterintuitive results of clinical trials redirected attention to the architectural abnormalities that were described by the great clinician-pathologists of the nineteenth century. The renewed interest in the maladaptive features of cardiac hypertrophy took place against the background of the rapid growth of molecular biology. The result has been a series of major advances in our understanding of heart failure, one of the most important of which was the recognition of the importance of abnormal proliferative signaling in pathophysiology and therapy.
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Functional and proliferative response in heart failure Hemodynamic abnormalities in patients with heart failure, along with altered renal and pulmonary function and many features of the neurohumoral response, represent functional responses in which the behavior of existing structures is altered. Conversely, cardiac dilatation and hypertrophy represent changes in the size, shape, and molecular composition of cardiac myocytes and nonmyocytes. These structural changes, which differ fundamentally from the functional responses that explain most of the clinical features described by Withering, represent responses to abnormal proliferative (transcriptional) signaling. Functional and proliferative responses occur over different time courses (Fig. 1) [10]. Functional changes appear rapidly; for example, increased chronotropy, inotropy, and lusitropy can appear within seconds to facilitate short-term ‘‘fight and flight’’ responses. Proliferative responses occur much more slowly because they depend on changes in cell size, shape, and composition; the latter can be viewed as allowing an overloaded heart literally to ‘‘grow its way out of trouble’’. In heart failure, the clinical consequences of functional and proliferative signaling can differ markedly, and often have opposite effects on patient well-being and survival. The immediate functional responses initiated by b1-adrenergic stimulation, which increases heart rate, contractility, and
Fig. 1. Functional signaling, which modifies the behavior of pre-existing structures by posttranslational modifications, provides for rapid responses that enable organisms to survive by ‘‘fight or flight’’ responses. Proliferative signaling, uses more slowly evolving responses that allow organisms to grow their way out of trouble. (Modified from Katz AM. Physiology of the heart. 3rd edition. Philadelphia: Lippincott/Williams & Wilkins; 2001; with permission.)
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relaxation, are beneficial because they increase cardiac output; however, when sustained, adrenergic drive activates deleterious proliferative responses that worsen long-term prognosis in patients with heart failure (see later discussion). Proliferative signaling, whose consequences can be beneficial and deleterious, exhibits a similar dichotomy. For example, the hypertrophic response to overload initially normalizes wall stress (see later discussion), and so is beneficial, whereas over the long-term, several features of overloadinduced cardiac hypertrophy shorten myocyte survival. The deleterious consequences of proliferative signaling play an important role in the poor prognosis of patients with chronic hemodynamic overloading of the heart; these responses can be viewed as initiating a ‘‘cardiomyopathy of overload’’ [11]. According to this interpretation, overload initiates a vicious cycle in which overload-induced hypertrophy accelerates myocardial cell death, which increases the load on surviving myocytes, which stimulates further proliferative signaling, which causes more cell death. The deleterious features of overload-induced hypertrophy came as a surprise to many modern investigators, even though this fact was clearly understood by the great clinical pathologists of the nineteenth century [4]. The cardiomyopathy of overload The maladaptive consequences of cardiac hypertrophy attracted little notice by modern cardiologists until the role of ventricular architecture in determining wall tension (the Law of Laplace, which had been understood in the late nineteenth century but then forgotten) was rediscovered in the 1950s [12]. This stimulated measurements of systolic wall stress in patients with left ventricular overload caused by valvular heart disease. Estimates in the late 1960s and early 1970s showed that overload-induced hypertrophy could normalize wall stress [13–15], evidence that seemed to support the then prevalent (and early nineteenth century) view that this proliferative response is largely beneficial. Meerson’s confirmation of the late nineteenth century view that overload-induced hypertrophy shortens survival [16], however, re-emphasized the fact that this proliferative response can also be maladaptive. Counterintuitive results of several clinical trials, along with discoveries in molecular biology, provided further evidence for the clinical importance of the cardiomyopathy of overload. An important clue to the maladaptive consequences of proliferative signaling that contribute to the cardiomyopathy of overload was provided by the finding of low myofibrillar ATPase activity in failing human hearts [17], a change that would be expected to reduce myocardial contractility. By 1990, a growing body of evidence indicated that the same signaling processes which stimulated the heart to hypertrophy might also accelerate myocardial cell death; this suggested several potential mechanisms for the vicious cycle of overload-induced hypertrophy and myocardial damage in the failing heart [11]. Among the most important is cell deformation which is
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caused by increased stretch and wall stress. As discussed later, the abnormal mechanical stresses can stimulate proliferative signal transduction cascades that stimulate hypertrophy and can cause progressive dilatation (remodeling) and apoptosis (for review see [5]). Progression of the cardiomyopathy of overload can also be accelerated by most mediators of the neurohumoral response, which stimulate functional responses and activate proliferative responses. Other extracellular messengers, such as the cytokines, initiate functional and proliferative responses that can contribute to the vicious cycles that cause cell death in the failing heart. The maladaptive consequences of proliferative signaling include architectural changes that exacerbate energy starvation, cell elongation which accelerates remodeling, and induction of apoptosis. Exploration of the many molecular responses to proliferative signal transduction cascades can be expected to uncover new mechanisms that will allow the development of novel approaches to pharmacotherapy for inhibiting the maladaptive growth responses involved in the cardiomyopathy of overload. Crossovers between functional and proliferative signaling in the failing heart As recently as the early 1990s, functional and proliferative responses were thought to be affected by entirely different signaling pathways (Fig. 2) [18]. A familiar example of functional signaling is the mechanism by which b-adrenergic stimulation causes phosphorylation of plasma membrane L-type calcium channels to increase myocardial contractility (Fig. 3); the resulting increase in stroke volume is a typical functional response.
Fig. 2. Functional and proliferative signaling were thought to be mediated by two entirely different mechanisms as shown in this figure; it is now clear, however, that there are many ‘‘crossovers’’ between these signal transduction cascades. (Modified from Katz AM. Physiology of the heart. 3rd edition. Philadelphia: Lippincott/Williams & Wilkins; 2001; with permission.)
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Fig. 3. Depiction of the signal cascade by which exercise evokes an inotropic response that increases ejection. This cartoon shows fourteen of these steps as a series of buckets where, in each step, the incoming signal causes the bucket to pour its contents into the next bucket, thereby transmitting the signal down the cascade. In cellular signal transduction different ‘‘substances’’ pass from one bucket to the next. (From Katz AM. Physiology of the heart. 3rd edition. Philadelphia: Lippincott/Williams & Wilkins; 2001; with permission.)
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A different signal transduction cascade, proliferative signaling by MAP kinase (mitogen-activated protein kinase) pathways, is shown in Fig. 4. These complex pathways are activated by several signals, including peptide growth factors and cell deformation, to initiate a variety of proliferative responses. MAP kinase pathways include a series of highly regulated phosphorylations that eventually catalyze the phosphorylation of MAP kinase, a protein kinase that enters the nucleus where it can phosphorylate a variety of transcription factors. The phosphorylated transcription factor can then bind to specific sites on DNA to modify such proliferative responses as protein synthesis, cell cycling, and apoptosis. There are many crossovers between functional and proliferative signal transduction pathways. Among the most important in patients with heart failure are crossovers that are initiated by neurohumoral mediators, like norepinephrine and angiotensin II, which were initially identified as mediators of functional signaling. It is now clear, however, that these extracellular messengers can also stimulate proliferative responses that were once thought to be under the ‘‘exclusive’’ control of enzyme-linked signaling pathways (see Fig. 4; for review see [19]). Several mechanisms by which the signal transduction pathway (see Fig. 3) can stimulate proliferative signaling are shown in Fig. 5. As discussed later, these and other crossovers can explain why b-adrenergic blockers inhibit remodeling in the failing heart. The converse is also true; ligand-binding to tyrosine kinase receptors also has functional effects, such as modification of myocardial contractility. Proliferative signaling initiated by cell deformation: role of the cytoskeleton The cytoskeleton is a major participant in the proliferative signaling that controls hypertrophy of the overloaded heart. This highly organized intracellular protein framework includes several structural proteins that, like the steel girders within a modern building, maintain cellular architecture. In addition to holding key intracellular elements in ordered relationships, the cytoskeleton in cardiac myocytes connects the myofilaments to the extracellular matrix and to adjacent cells; these interactions are essential for tension development and shortening in the walls of the heart. In addition to these mechanical functions, the cytoskeleton participates in communications between cells and their surrounding structures by activating phosphorylation cascades (see Fig. 4). The resulting proliferative signals play a critical role in adapting form to function to optimize contractile performance in the heart [20]. The cytoskeleton, therefore, represents more than a system of ‘‘beams and girders’’ that maintain cell shape; its role in cell signaling is analogous to a building in which the steel framework also serves as the phone system (for review see [21]). Interactions between cells and the extracellular matrix or other cells are made possible by specialized plasma membrane proteins called adhesion molecules. Adhesion molecules include integrins, which connect cells to the
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Fig. 4. Proliferative signaling initiated when a peptide growth factor binds to its enzyme-linked receptor. Binding of the ligand causes the receptor to form an aggregate which activates latent tyrosine kinase activity. Resulting autophosphorylation of the receptor creates a ‘‘docking site’’ that binds, and then phosphorylates Shc to establish another docking site. Grb2 is then added to a multi-protein aggregate which assembles along the inner surface of the plasma membrane. This aggregate then activates Sos, a guanine nucleotide-exchange factor, which stimulates Ras, a guanine nucleotide-binding protein, to exchange bound guanosine diphosphate (GDP) for guanosine triphosphate (GTP). The activated Ras-GTP complex then stimulates Raf-1, a MAP kinase kinase kinase (MAPKKK) to phosphorylate and activate the MAP kinase kinase (MAPKK) MEK-1, which then phosphorylates the MAP kinase (MAPK) ERK-2. Translocation of the phosphorylated ERK-2, the activated MAP kinase, to the nucleus allows the latter to phosphorylate nuclear transcription factors (tc) that interact with specific DNA sequences on nuclear genes. (Modified from Katz AM. Pathophysiology, molecular biology, and clinical management. Philadelphia: Lippincott/Williams & Wilkins; 2001; with permission.)
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Fig. 5. Signal diversification, showing several steps in the functional signal transduction cascade shown in Fig. 3 that allow sustained sympathetic stimulation to activate proliferative signaling. Prolonged b-receptor activation (Step 2) causes the receptors to become internalized, where they can form a ‘‘platform’’ that activates MAP kinase pathways. Activation of Gaq and Gbc by the ligand-bound b-receptors at Step 3 can initiate mitogenic signals, while activated cyclic AMP-dependent protein kinases at Step 6 can directly phosphorylate several transcription factors. Other transcription factors can be activated by increased cytosolic calcium (Step 9). The increase in contractility (Step 13) can itself modify cell structure and composition when altered stresses on the cell surface activate proliferative signaling by cell adhesion molecules. (From Katz AM. Physiology of the heart. 3rd edition. Philadelphia: Lippincott/ Williams & Wilkins; 2001; with permission.)
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surrounding extracellular matrix, and cadherins and desmogleins, which link cells to other cells. In addition to providing physical linkages between cells and the extracellular matrix, adhesion molecules activate proliferative signal transduction cascades within cells. Integrins, which link the cytoskeleton to the extracellular matrix, participate in signal transduction by activating cytosolic protein kinases whose substrates include transcription factors that regulate the cell cycle and apoptosis (for review see [22–26]). Cadherins, found in the fascia adherens of the intercalated disc, attach to cortical actin filaments within myocardial cells (for review see [27,28]), whereas desmogleins, found in desmosomes that are also located in the intercalated discs, link the intermediate (desmin) filaments of adjacent cells to one other. In addition to providing mechanical connections between cells, therefore, these adhesion molecules can activate intracellular protein kinases that participate in proliferative signaling. The ability of adhesion molecules to respond to local changes in the mechanical stresses on cardiac myocytes allows these physical forces to modify the architecture of the heart by inducing specific changes in cardiac myocyte size and shape. It seems likely that the ability of increased systolic stress (pressure overload) to cause cell thickening and concentric hypertrophy, and diastolic stretch (volume overload) to cause cell elongation and eccentric hypertrophy [29], reflects the activation of different proliferative signaling pathways by different types of cytoskeletal deformation [30]. Because remodeling, the tendency of dilatation to progress, is probably due, at least in part, to stimuli mediated by the cytoskeleton which cause cell elongation, signal transduction pathways that are controlled by adhesion molecules may provide important targets for new pharmacological agents. Clinical evidence for abnormal proliferative signaling in the failing heart The greater clinical importance of abnormal proliferative signaling than functional signaling in heart failure began to emerge only recently, when long-term trials made it clear that efforts to correct the obvious hemodynamic disorders often worsen prognosis. Although in short-term clinical studies vasodilators were initially found to increase cardiac output and improve energetics by unloading the failing left ventricle, most direct-acting arteriolar dilators were subsequently shown to worsen survival. Vasodilators with adverse long-term effects include a-adrenergic blockers, shortacting L-type calcium channel blockers, minoxidil, prostacyclin, ibopamine, moxonidine, flosequinan, and phosphodiesterase inhibitors (for review see [5,31]). A likely explanation for the adverse effects is that although these drugs cause immediate clinical improvement by unloading the failing left ventricle, the lowered blood pressure also increases the release of neurohumoral mediators, like norepinephrine, angiotensin II, and endothelin, all of which evoke deleterious long-term proliferative responses. Among the vasodilators, only ACE inhibitors, angiotensin II receptor blockers, and
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a drug combination that includes isosorbide dinitrate, have been shown to have a survival benefit [31]. The long-term benefit of these drugs is probably attributable to their antiproliferative effects, rather than their ability to reduce afterload. The finding that b-blockers improve long-term prognosis in heart failure provides additional evidence for the importance of maladaptive proliferative signaling in this syndrome [32–35]. Despite their negative inotropic action, a functional response that initially worsens the hemodynamic abnormality, b blockers were found to slow, and even reverse transiently, the progressive dilatation (remodeling) of the failing heart ([36,37]; for review see [5,38– 40]). Conversely, the deleterious effects of inotropic drugs that increase cyclic AMP levels probably include stimulation of maladaptive proliferative responses, as well as proarrhythmic effects [41,42]. Spironolactone is another neurohumoral inhibitor that was found to prolong survival in patients with heart failure; it had initially been used to treat heart failure because of its short-term diuretic effect [43]. The long-term benefit of this drug now seems to be the result of inhibition of such proliferative responses as aldosterone-induced synthesis of plasma membrane calcium channels in cardiac myocytes [44] and synthesis of the extracellular matrix [45]. Summary Recent advances in our understanding of the pathophysiology of heart failure have greatly increased the number of potential targets for therapy. The most important of these advances was the recognition that a major goal of therapy should be to modify long-term proliferative responses, as well as to achieve short-term functional improvement. This conclusion emerged from several clinical trials which showed that correction of functional abnormalities in these patients, although often of immediate clinical value, can worsen long-term prognosis. Although vasodilators alleviate the disability that is caused by excessive afterload, most increase long-term mortality; similarly, although inotropic drugs provide immediate relief of symptoms and are useful as temporary support in patients with damaged hearts, most inotropes also shorten long-term survival. Treatment of chronic heart failure should not be targeted simply at the signs and symptoms noted by Withering. Instead, a major goal of therapy should be to slow progression by modifying maladaptive growth responses in the failing heart, which were unknown when Withering discovered that digitalis can alleviate the signs and symptoms of heart failure. New targets for treatment, therefore, include the maladaptive proliferative signaling cascades that cause progressive ventricular dilatation (remodeling) and hastens cardiac cell death. The ability to inhibit maladaptive proliferative signaling in patients with heart failure was greatly enhanced by the rapid pace of discovery in molecular biology. New understanding of the ability of neurohumoral mediators, such as norepinephrine and angiotensin II, to stimulate remodeling,
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apoptosis, and other deleterious features of the hypertrophic response has opened important areas for research into the causes and therapy of heart failure. Similarly, potential roles for cell adhesion molecules, cytokines, and peptide growth factors in activating maladaptive proliferative responses suggests additional targets for therapy. This and other new information regarding signal transduction pathways, notably the many crossovers between functional and proliferative signaling, provide promising opportunities in this rapidly advancing area of study.
References [1] Withering W. An account of the foxglove and some of its medical uses. Birmingham: Swinney; 1785. [2] Jarcho S. The concept of heart failure. From Avicenna to Albertini. Cambridge (MA): Harvard University Press; 1980. [3] Katz AM. Evolving concepts of heart failure: cooling furnace, malfunctioning pump, enlarging muscle. Part I. Heart failure as a disorder of the cardiac pump. J Card Fail 1997;3:319–34. [4] Katz AM. Evolving concepts of heart failure: cooling furnace, malfunctioning pump, enlarging muscle. Part II. Hypertrophy and dilatation of the failing heart. J Card Fail 1998;4:67–81. [5] Katz AM. Heart Failure: pathophysiology, molecular biology, and clinical management. Philadelphia: Lippincott/Williams & Wilkins; 2000. [6] Singer C. The fasciculus medicinae of Johannes de Ketham. Birmingham (AL): Classics of Medicine; 1988. [7] Morgagni JB. The seats and causes of diseases. Book II. On diseases of the thorax. Letter XVII, Article 13. Tr. Alexander B. London: Millar and Cadell; 1769. [8] Francis GS, Goldsmith SR, Levine TB, et al. The neurohumoral axis in congestive heart failure. Ann Int Med 1984;101:370–7. [9] Harris P. Evolution and the cardiac patient. Cardiovasc Res 1983;17:313–445. [10] Katz AM. Tonic and phasic mechanisms in the regulation of myocardial contractility. Basic Res Cardiol 1976;71:447–55. [11] Katz AM. Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure. N Engl J Med 1990;322:100–10. [12] Burton AC. Physical principles of circulatory phenomena: the physical equilibria of the heart and blood vessels. In: Hamilton WF, Dow P, editors. Handbook of physiology, vol. 1. Washington, DC: Am Physiol Soc; 1962. p. 85–106. [13] Grossman W, Jones D, McLaurin LP. Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 1975;56:56–64. [14] Hood WP Jr, Rackley CE, Rolett EL. Wall stress in the normal and hypertrophied human left ventricle. Am J Cardiol 1968;22:5550–8. [15] Sandler H, Dodge HT. Left ventricular tension and stress in man. Circ Res 1963;13:91–104. [16] Meerson FZ. On the mechanism of compensatory hyperfunction and insufficiency of the heart. Cor Vasa 1961;3:161–77. [17] Alpert NR, Gordon MS. Myofibrillar adenosine triphosphatase activity in congestive heart failure. Am J Physiol 1962;202:940–6. [18] Bourne HR. Team blue sees red. Nature 1995;376:727–9. [19] van Biesen T, Luttrell LM, Hawes BE, et al. Mitogenic signaling via G protein-coupled receptors. Endoc Rev 1996;17:698–714. [20] Katz AM, Katz PB. Homogeneity out of heterogeneity. Circulation 1989;79:712–7. [21] Katz AM. Physiology of the heart. 3rd edition. Philadelphia: Lippincott; 2001.
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[22] Assoian RK, Zhu X. Cell anchorage and the cytoskeleton as partners in growth factor dependent cell cycle progression. Curr Opin Cell Biol 1997;9:93–8. [23] Giancotti FG. Integrin signaling: specificity and control of cell survival and cell cycle progression. Curr Opin Cell Biol 1997;9:691–700. [24] Hsueh WA, Law RE, Do YS. Integrins, adhesion, and cardiac remodeling. Hypertension 1997;31:176–80. [25] Lafrenie RM, Yamada KM. Integrin-dependent signal transduction. J Cell Develop Biol 1997;61:543–53. [26] Meredith JE Jr, Winitz S, Lewis JM, et al. The regulation of growth and intracellular signaling by integrins. Endoc Rev 1996;17:207–20. [27] Aberle H, Schwartz H, Kemler R. Cadherin-catenin complex: protein interactions and their implications for cadherin function. J Cell Biochem 1996;61:514–23. [28] Yap AS, Brieher WM, Gumbiner BM. Molecular and functional analysis of cadherinbased adherens junction. Annu Rev Cell Dev Biol 1997;13:119–46. [29] Gerdes AM, Capasso JM. Editorial review: structural remodeling and mechanical dysfunction of cardiac myocytes in heart failure. J Mol Cell Cardiol 1995;27:849–56. [30] Yamamoto K, Dang QN, Maeda Y, et al. Regulation of cardiac myocyte mechanotransduction by the cardiac cycle. Circulation 2001;103:1459–64. [31] Packer M, Cohn JN. Consensus recommendations for the management of heart failure. Am J Cardiol 1999;83(Suppl 2A);1A–38A. [32] CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study II. (CIBIS-II): a randomised trial. Lancet 1999;353:9–13. [33] LeChat P, Packer M, Chalon S, et al. Clinical effects of b-adrenergic blockade in chronic heart failure. Circulation 1998;98:1184–91. [34] Merit-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001–7. [35] Packer M, Bristow MR, Cohn JN, et al, for the US Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with heart failure. N Engl J Med 1996;334:1349–55. [36] Hall SA, Cigarroa CG, Marcoux L, et al. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with betaadrenergic blockade. J Am Coll Cardiol 1995;25:1154–61. [37] Lowes BD, Gill EA, Abraham WT, et al. Effects of carvedilol on left ventricular mass, chamber geometry, and mitral regurgitation in chronic heart failure. Am J Cardiol 1999;83:1201–5. [38] Chien KR. Stress pathways and heart failure. Cell 1999;98:555–8. [39] Eichhorn EJ, Bristow MR. Medical therapy can improve the biological properties of the chronically failing heart. Circulation 1996;94:2285–96. [40] Mann DL. Mechanisms and models in heart failure. A combinatorial approach. Circulation 1999;100:999–1008. [41] Cohn JN, Goldstein SO, Greenberg BH, et al. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. N Engl J Med 1998;339:1810–6. [42] Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe heart failure. N Engl J Med 1991;325:1468–75. [43] Pitt B, Zannad F, Remme WJ, et al, for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–17. [44] Be´nitah J-P, Vassort G. Aldosterone upregulated Ca2þ current in adult rat cardiomyocytes. Circ Res 1999;95:1139–45. [45] Zannad F, Alla F, Douset B, et al, on behalf of the RALES Investigators. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure. Insights from the Randomized Aldactone Evaluation Study (RALES). Circulation 2000;102:2700–6.
Pathophysiology of heart failure: identifying targets for pharmacotherapy Arnold M. Katz* University of Connecticut Health Center, Farmington, CT, USA Dartmouth Medical School, Hanover, NH, USA
William Withering, who discovered the benefits of digitalis, provided several clinical histories that described the terrible suffering seen in end stage heart failure. His description of a woman ‘‘between forty and fifty years of age’’, who almost certainly had rheumatic heart disease, provided remarkable insights into the pathophysiology that operates in these patients: I found her nearly in a state of suffocation; her pulse extremely weak and irregular, her breath very short and laborious, her countenance sunk, her arms of a leaden colour, clammy and cold. She could not lye down in bed, and had neither strength nor appetite but was extremely thirsty. Her stomach, legs and thighs were greatly swollen; her urine very small in quantity, not more than a spoonful at a time, and that very seldom [1].
This description, which resembles many others in the meticulously recorded case reports that were published before the middle of the twentieth century [2–4], documented the direct consequences of the impaired pump performance and abnormalities that are caused by the neurohumoral response to decreased cardiac output. These functional disorders, until recently, provided the major focus of therapy in patients with heart failure. Additional abnormalities that are caused by molecular changes in the cells of the failing heart that could not have been appreciated by Withering, are known to be associated with deleterious features of the growth response of the heart to overload and damage [5]. These consequences of maladaptive proliferative signaling provide clues to new targets for pharmacotherapy.
* P.O. Box 1048, Norwich, VT 05055-1048. E-mail address: [email protected] 0025-7125/03/$ - see front matter Ó 2003, Elsevier Science (USA). All rights reserved. doi:10.1016/S0025-7125(02)00188-8
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Functional consequences of impaired pump function Several of the clinical manifestations in Withering’s patient can be attributed directly to the pump dysfunction. These include the irregular pulse, which is almost certainly due to atrial fibrillation, and the weak pulse and peripheral cyanosis, which tell us that she had a low cardiac output. Her dyspnea and orthopnea are attributable to pulmonary congestion, which was most likely caused when rheumatic mitral stenosis impeded blood flow from her lungs into the left ventricle. Other clinical findings, however, are not direct consequences of the defective cardiac pump, but instead reflect a more subtle etiology. Her sunken countenance and anorexia are characteristic of cardiac cachexia, which is caused, in part, by elevated cytokine levels, whereas her lack of strength probably results from the skeletal muscle myopathy that is commonly seen in patients with heart failure. Additional features that were noted by Withering can be attributed to the neurohumoral response to low cardiac output; these include the cold damp extremities, the result of peripheral vasoconstriction and sympathetic activation of her sweat glands, fluid retention and oliguria, due in part to renal vasoconstriction and aldosterone release, and thirst, which reflects a central action of vasopressin. The impaired ability of the heart to pump and the neurohumoral response to the low cardiac output in Withering’s patient represent changes in the function of existing structures, and represent functional abnormalities.
Architectural changes in the failing heart: proliferative abnormalities A different type of abnormality became apparent when autopsy examinations revealed changes in the size and shape of the hearts in patients with heart failure [3,4]. These structural alterations were initially interpreted according to the Galenic paradigm, which viewed the heart as the source of heat that it distributed throughout the body. This old paradigm provided the rationale for treatments that included ointments and infusions made from roses, violets, flax, cinnamon, clove-gilly flowers, cubeb, aloe wood, anise, violets, and the bone of stag’s heart, as well as phlebotomy from the left hand [6]. Our modern understanding of heart failure became possible in 1628, when Harvey discovered that blood flows in a circle. This led to a paradigm shift that attributed the clinical picture described by Withering to reduced cardiac output and accumulation of blood behind a diseased heart. Harvey’s description of the circulation also provided a basis for understanding the architectural changes that are commonly found in failing hearts. Mayow, in 1674, seems to have been the first to recognize that obstruction to the flow of blood out of the heart leads to ventricular dilatation [4]. A more important insight was published in the mid-eighteenth century by Morgagni, who described the autopsy findings in a patient with mitral stenosis and noted the
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causal link between chronic hemodynamic overloading and cardiac hypertrophy: [as the result of narrowing of] the orifice by which blood goes into the left ventricle. . .the columnae, and fibres, of the [right] ventricle, were become very thick. . .because a greater thickness of the muscles is the consequence of their more frequent and stronger actions. Without doubt, these parts of the heart must have been constantly and vehemently contracted, and exercis’d, in their effort to thrust on so great a quantity of stagnating blood in the pulmonary vessels, which, by reason of the very difficult entrance into the left ventricle, did not readily admit it. . . [7]
This new understanding of the relationship between hemodynamic overload and changes in the size and shape of diseased hearts initiated more than a century of discovery that related clinical manifestations of heart failure to various architectural patterns of ventricular hypertrophy. By the first decade of the nineteenth century it became apparent that patients with eccentric hypertrophy (dilatation) of the left ventricle have a poorer prognosis than patients with concentric hypertrophy. Dilatation was also noted to have a marked tendency to progress [4], a process that is now referred to as remodeling. Conversely, concentric hypertrophy was initially viewed as an adaptive response that protected patients from the adverse effects of dilatation. By the end of the nineteenth century, however, it became clear that hypertrophy, like dilatation, is associated with progression and contributes to disability and death in patients with heart failure. Emphasis on the architectural changes in diseased hearts dominated clinical studies of heart failure until the early decades of the twentieth century, when advances in hemodynamic physiology refocused attention on the valve abnormalities that, at the time, represented the most common causes of heart failure. Emphasis on the pressure and blood flow abnormalities in this syndrome was highlighted by the introduction of cardiac catheterization in the 1940s, and by rapid progress in cardiac surgery during the 1960s. The importance of altered size and shape of the failing heart faded further into the background in the 1960s and 1970s, when details of the neurohumoral response to low cardiac output began to emerge [8,9] and therapy was directed to alleviating the maladaptive functional effects of neurohumoral mediators, notably vasoconstriction. It was not until 1990s that counterintuitive results of clinical trials redirected attention to the architectural abnormalities that were described by the great clinician-pathologists of the nineteenth century. The renewed interest in the maladaptive features of cardiac hypertrophy took place against the background of the rapid growth of molecular biology. The result has been a series of major advances in our understanding of heart failure, one of the most important of which was the recognition of the importance of abnormal proliferative signaling in pathophysiology and therapy.
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Functional and proliferative response in heart failure Hemodynamic abnormalities in patients with heart failure, along with altered renal and pulmonary function and many features of the neurohumoral response, represent functional responses in which the behavior of existing structures is altered. Conversely, cardiac dilatation and hypertrophy represent changes in the size, shape, and molecular composition of cardiac myocytes and nonmyocytes. These structural changes, which differ fundamentally from the functional responses that explain most of the clinical features described by Withering, represent responses to abnormal proliferative (transcriptional) signaling. Functional and proliferative responses occur over different time courses (Fig. 1) [10]. Functional changes appear rapidly; for example, increased chronotropy, inotropy, and lusitropy can appear within seconds to facilitate short-term ‘‘fight and flight’’ responses. Proliferative responses occur much more slowly because they depend on changes in cell size, shape, and composition; the latter can be viewed as allowing an overloaded heart literally to ‘‘grow its way out of trouble’’. In heart failure, the clinical consequences of functional and proliferative signaling can differ markedly, and often have opposite effects on patient well-being and survival. The immediate functional responses initiated by b1-adrenergic stimulation, which increases heart rate, contractility, and
Fig. 1. Functional signaling, which modifies the behavior of pre-existing structures by posttranslational modifications, provides for rapid responses that enable organisms to survive by ‘‘fight or flight’’ responses. Proliferative signaling, uses more slowly evolving responses that allow organisms to grow their way out of trouble. (Modified from Katz AM. Physiology of the heart. 3rd edition. Philadelphia: Lippincott/Williams & Wilkins; 2001; with permission.)
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relaxation, are beneficial because they increase cardiac output; however, when sustained, adrenergic drive activates deleterious proliferative responses that worsen long-term prognosis in patients with heart failure (see later discussion). Proliferative signaling, whose consequences can be beneficial and deleterious, exhibits a similar dichotomy. For example, the hypertrophic response to overload initially normalizes wall stress (see later discussion), and so is beneficial, whereas over the long-term, several features of overloadinduced cardiac hypertrophy shorten myocyte survival. The deleterious consequences of proliferative signaling play an important role in the poor prognosis of patients with chronic hemodynamic overloading of the heart; these responses can be viewed as initiating a ‘‘cardiomyopathy of overload’’ [11]. According to this interpretation, overload initiates a vicious cycle in which overload-induced hypertrophy accelerates myocardial cell death, which increases the load on surviving myocytes, which stimulates further proliferative signaling, which causes more cell death. The deleterious features of overload-induced hypertrophy came as a surprise to many modern investigators, even though this fact was clearly understood by the great clinical pathologists of the nineteenth century [4]. The cardiomyopathy of overload The maladaptive consequences of cardiac hypertrophy attracted little notice by modern cardiologists until the role of ventricular architecture in determining wall tension (the Law of Laplace, which had been understood in the late nineteenth century but then forgotten) was rediscovered in the 1950s [12]. This stimulated measurements of systolic wall stress in patients with left ventricular overload caused by valvular heart disease. Estimates in the late 1960s and early 1970s showed that overload-induced hypertrophy could normalize wall stress [13–15], evidence that seemed to support the then prevalent (and early nineteenth century) view that this proliferative response is largely beneficial. Meerson’s confirmation of the late nineteenth century view that overload-induced hypertrophy shortens survival [16], however, re-emphasized the fact that this proliferative response can also be maladaptive. Counterintuitive results of several clinical trials, along with discoveries in molecular biology, provided further evidence for the clinical importance of the cardiomyopathy of overload. An important clue to the maladaptive consequences of proliferative signaling that contribute to the cardiomyopathy of overload was provided by the finding of low myofibrillar ATPase activity in failing human hearts [17], a change that would be expected to reduce myocardial contractility. By 1990, a growing body of evidence indicated that the same signaling processes which stimulated the heart to hypertrophy might also accelerate myocardial cell death; this suggested several potential mechanisms for the vicious cycle of overload-induced hypertrophy and myocardial damage in the failing heart [11]. Among the most important is cell deformation which is
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caused by increased stretch and wall stress. As discussed later, the abnormal mechanical stresses can stimulate proliferative signal transduction cascades that stimulate hypertrophy and can cause progressive dilatation (remodeling) and apoptosis (for review see [5]). Progression of the cardiomyopathy of overload can also be accelerated by most mediators of the neurohumoral response, which stimulate functional responses and activate proliferative responses. Other extracellular messengers, such as the cytokines, initiate functional and proliferative responses that can contribute to the vicious cycles that cause cell death in the failing heart. The maladaptive consequences of proliferative signaling include architectural changes that exacerbate energy starvation, cell elongation which accelerates remodeling, and induction of apoptosis. Exploration of the many molecular responses to proliferative signal transduction cascades can be expected to uncover new mechanisms that will allow the development of novel approaches to pharmacotherapy for inhibiting the maladaptive growth responses involved in the cardiomyopathy of overload. Crossovers between functional and proliferative signaling in the failing heart As recently as the early 1990s, functional and proliferative responses were thought to be affected by entirely different signaling pathways (Fig. 2) [18]. A familiar example of functional signaling is the mechanism by which b-adrenergic stimulation causes phosphorylation of plasma membrane L-type calcium channels to increase myocardial contractility (Fig. 3); the resulting increase in stroke volume is a typical functional response.
Fig. 2. Functional and proliferative signaling were thought to be mediated by two entirely different mechanisms as shown in this figure; it is now clear, however, that there are many ‘‘crossovers’’ between these signal transduction cascades. (Modified from Katz AM. Physiology of the heart. 3rd edition. Philadelphia: Lippincott/Williams & Wilkins; 2001; with permission.)
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Fig. 3. Depiction of the signal cascade by which exercise evokes an inotropic response that increases ejection. This cartoon shows fourteen of these steps as a series of buckets where, in each step, the incoming signal causes the bucket to pour its contents into the next bucket, thereby transmitting the signal down the cascade. In cellular signal transduction different ‘‘substances’’ pass from one bucket to the next. (From Katz AM. Physiology of the heart. 3rd edition. Philadelphia: Lippincott/Williams & Wilkins; 2001; with permission.)
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A different signal transduction cascade, proliferative signaling by MAP kinase (mitogen-activated protein kinase) pathways, is shown in Fig. 4. These complex pathways are activated by several signals, including peptide growth factors and cell deformation, to initiate a variety of proliferative responses. MAP kinase pathways include a series of highly regulated phosphorylations that eventually catalyze the phosphorylation of MAP kinase, a protein kinase that enters the nucleus where it can phosphorylate a variety of transcription factors. The phosphorylated transcription factor can then bind to specific sites on DNA to modify such proliferative responses as protein synthesis, cell cycling, and apoptosis. There are many crossovers between functional and proliferative signal transduction pathways. Among the most important in patients with heart failure are crossovers that are initiated by neurohumoral mediators, like norepinephrine and angiotensin II, which were initially identified as mediators of functional signaling. It is now clear, however, that these extracellular messengers can also stimulate proliferative responses that were once thought to be under the ‘‘exclusive’’ control of enzyme-linked signaling pathways (see Fig. 4; for review see [19]). Several mechanisms by which the signal transduction pathway (see Fig. 3) can stimulate proliferative signaling are shown in Fig. 5. As discussed later, these and other crossovers can explain why b-adrenergic blockers inhibit remodeling in the failing heart. The converse is also true; ligand-binding to tyrosine kinase receptors also has functional effects, such as modification of myocardial contractility. Proliferative signaling initiated by cell deformation: role of the cytoskeleton The cytoskeleton is a major participant in the proliferative signaling that controls hypertrophy of the overloaded heart. This highly organized intracellular protein framework includes several structural proteins that, like the steel girders within a modern building, maintain cellular architecture. In addition to holding key intracellular elements in ordered relationships, the cytoskeleton in cardiac myocytes connects the myofilaments to the extracellular matrix and to adjacent cells; these interactions are essential for tension development and shortening in the walls of the heart. In addition to these mechanical functions, the cytoskeleton participates in communications between cells and their surrounding structures by activating phosphorylation cascades (see Fig. 4). The resulting proliferative signals play a critical role in adapting form to function to optimize contractile performance in the heart [20]. The cytoskeleton, therefore, represents more than a system of ‘‘beams and girders’’ that maintain cell shape; its role in cell signaling is analogous to a building in which the steel framework also serves as the phone system (for review see [21]). Interactions between cells and the extracellular matrix or other cells are made possible by specialized plasma membrane proteins called adhesion molecules. Adhesion molecules include integrins, which connect cells to the
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Fig. 4. Proliferative signaling initiated when a peptide growth factor binds to its enzyme-linked receptor. Binding of the ligand causes the receptor to form an aggregate which activates latent tyrosine kinase activity. Resulting autophosphorylation of the receptor creates a ‘‘docking site’’ that binds, and then phosphorylates Shc to establish another docking site. Grb2 is then added to a multi-protein aggregate which assembles along the inner surface of the plasma membrane. This aggregate then activates Sos, a guanine nucleotide-exchange factor, which stimulates Ras, a guanine nucleotide-binding protein, to exchange bound guanosine diphosphate (GDP) for guanosine triphosphate (GTP). The activated Ras-GTP complex then stimulates Raf-1, a MAP kinase kinase kinase (MAPKKK) to phosphorylate and activate the MAP kinase kinase (MAPKK) MEK-1, which then phosphorylates the MAP kinase (MAPK) ERK-2. Translocation of the phosphorylated ERK-2, the activated MAP kinase, to the nucleus allows the latter to phosphorylate nuclear transcription factors (tc) that interact with specific DNA sequences on nuclear genes. (Modified from Katz AM. Pathophysiology, molecular biology, and clinical management. Philadelphia: Lippincott/Williams & Wilkins; 2001; with permission.)
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Fig. 5. Signal diversification, showing several steps in the functional signal transduction cascade shown in Fig. 3 that allow sustained sympathetic stimulation to activate proliferative signaling. Prolonged b-receptor activation (Step 2) causes the receptors to become internalized, where they can form a ‘‘platform’’ that activates MAP kinase pathways. Activation of Gaq and Gbc by the ligand-bound b-receptors at Step 3 can initiate mitogenic signals, while activated cyclic AMP-dependent protein kinases at Step 6 can directly phosphorylate several transcription factors. Other transcription factors can be activated by increased cytosolic calcium (Step 9). The increase in contractility (Step 13) can itself modify cell structure and composition when altered stresses on the cell surface activate proliferative signaling by cell adhesion molecules. (From Katz AM. Physiology of the heart. 3rd edition. Philadelphia: Lippincott/ Williams & Wilkins; 2001; with permission.)
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surrounding extracellular matrix, and cadherins and desmogleins, which link cells to other cells. In addition to providing physical linkages between cells and the extracellular matrix, adhesion molecules activate proliferative signal transduction cascades within cells. Integrins, which link the cytoskeleton to the extracellular matrix, participate in signal transduction by activating cytosolic protein kinases whose substrates include transcription factors that regulate the cell cycle and apoptosis (for review see [22–26]). Cadherins, found in the fascia adherens of the intercalated disc, attach to cortical actin filaments within myocardial cells (for review see [27,28]), whereas desmogleins, found in desmosomes that are also located in the intercalated discs, link the intermediate (desmin) filaments of adjacent cells to one other. In addition to providing mechanical connections between cells, therefore, these adhesion molecules can activate intracellular protein kinases that participate in proliferative signaling. The ability of adhesion molecules to respond to local changes in the mechanical stresses on cardiac myocytes allows these physical forces to modify the architecture of the heart by inducing specific changes in cardiac myocyte size and shape. It seems likely that the ability of increased systolic stress (pressure overload) to cause cell thickening and concentric hypertrophy, and diastolic stretch (volume overload) to cause cell elongation and eccentric hypertrophy [29], reflects the activation of different proliferative signaling pathways by different types of cytoskeletal deformation [30]. Because remodeling, the tendency of dilatation to progress, is probably due, at least in part, to stimuli mediated by the cytoskeleton which cause cell elongation, signal transduction pathways that are controlled by adhesion molecules may provide important targets for new pharmacological agents. Clinical evidence for abnormal proliferative signaling in the failing heart The greater clinical importance of abnormal proliferative signaling than functional signaling in heart failure began to emerge only recently, when long-term trials made it clear that efforts to correct the obvious hemodynamic disorders often worsen prognosis. Although in short-term clinical studies vasodilators were initially found to increase cardiac output and improve energetics by unloading the failing left ventricle, most direct-acting arteriolar dilators were subsequently shown to worsen survival. Vasodilators with adverse long-term effects include a-adrenergic blockers, shortacting L-type calcium channel blockers, minoxidil, prostacyclin, ibopamine, moxonidine, flosequinan, and phosphodiesterase inhibitors (for review see [5,31]). A likely explanation for the adverse effects is that although these drugs cause immediate clinical improvement by unloading the failing left ventricle, the lowered blood pressure also increases the release of neurohumoral mediators, like norepinephrine, angiotensin II, and endothelin, all of which evoke deleterious long-term proliferative responses. Among the vasodilators, only ACE inhibitors, angiotensin II receptor blockers, and
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a drug combination that includes isosorbide dinitrate, have been shown to have a survival benefit [31]. The long-term benefit of these drugs is probably attributable to their antiproliferative effects, rather than their ability to reduce afterload. The finding that b-blockers improve long-term prognosis in heart failure provides additional evidence for the importance of maladaptive proliferative signaling in this syndrome [32–35]. Despite their negative inotropic action, a functional response that initially worsens the hemodynamic abnormality, b blockers were found to slow, and even reverse transiently, the progressive dilatation (remodeling) of the failing heart ([36,37]; for review see [5,38– 40]). Conversely, the deleterious effects of inotropic drugs that increase cyclic AMP levels probably include stimulation of maladaptive proliferative responses, as well as proarrhythmic effects [41,42]. Spironolactone is another neurohumoral inhibitor that was found to prolong survival in patients with heart failure; it had initially been used to treat heart failure because of its short-term diuretic effect [43]. The long-term benefit of this drug now seems to be the result of inhibition of such proliferative responses as aldosterone-induced synthesis of plasma membrane calcium channels in cardiac myocytes [44] and synthesis of the extracellular matrix [45]. Summary Recent advances in our understanding of the pathophysiology of heart failure have greatly increased the number of potential targets for therapy. The most important of these advances was the recognition that a major goal of therapy should be to modify long-term proliferative responses, as well as to achieve short-term functional improvement. This conclusion emerged from several clinical trials which showed that correction of functional abnormalities in these patients, although often of immediate clinical value, can worsen long-term prognosis. Although vasodilators alleviate the disability that is caused by excessive afterload, most increase long-term mortality; similarly, although inotropic drugs provide immediate relief of symptoms and are useful as temporary support in patients with damaged hearts, most inotropes also shorten long-term survival. Treatment of chronic heart failure should not be targeted simply at the signs and symptoms noted by Withering. Instead, a major goal of therapy should be to slow progression by modifying maladaptive growth responses in the failing heart, which were unknown when Withering discovered that digitalis can alleviate the signs and symptoms of heart failure. New targets for treatment, therefore, include the maladaptive proliferative signaling cascades that cause progressive ventricular dilatation (remodeling) and hastens cardiac cell death. The ability to inhibit maladaptive proliferative signaling in patients with heart failure was greatly enhanced by the rapid pace of discovery in molecular biology. New understanding of the ability of neurohumoral mediators, such as norepinephrine and angiotensin II, to stimulate remodeling,
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apoptosis, and other deleterious features of the hypertrophic response has opened important areas for research into the causes and therapy of heart failure. Similarly, potential roles for cell adhesion molecules, cytokines, and peptide growth factors in activating maladaptive proliferative responses suggests additional targets for therapy. This and other new information regarding signal transduction pathways, notably the many crossovers between functional and proliferative signaling, provide promising opportunities in this rapidly advancing area of study.
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