Congestive Heart Failure: Fifty Years of Progress
2000; Lippincott Williams & Wilkins; Volume: 102; Issue: suppl_4 Linguagem: Inglês
10.1161/circ.102.suppl_4.iv-14
ISSN1524-4539
AutoresEugene Braunwald, Michael R. Bristow,
Tópico(s)Cardiomyopathy and Myosin Studies
ResumoHomeCirculationVol. 102, No. suppl_4Congestive Heart Failure: Fifty Years of Progress Free AccessOtherDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessOtherDownload EPUBCongestive Heart Failure: Fifty Years of Progress Eugene Braunwald and Michael R. Bristow Eugene BraunwaldEugene Braunwald From the Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Mass, and the Division of Cardiology, Department of Medicine, University of Colorado Health Sciences Center, Denver. and Michael R. BristowMichael R. Bristow From the Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Mass, and the Division of Cardiology, Department of Medicine, University of Colorado Health Sciences Center, Denver. Originally published14 Nov 2000https://doi.org/10.1161/circ.102.suppl_4.IV-14Circulation. 2000;102:Iv-14–Iv-23Volume 1 of Circulation provides an excellent snapshot of the understanding of the mechanisms and treatment of heart failure a half century ago. During that era, circulatory pathophysiology was at the center of investigative attention. For example, Tinsley Harrison and his group divided heart failure into "primary disorders of filling and primary disorders of emptying,"1 a forerunner of our current terms diastolic and systolic heart failure. The great Swedish clinical physiologist Gustav Nylin used 32P-labeled red blood cells for measuring cardiac output and cardiothoracic blood volume by the indicator-dilution method in normal subjects and in patients with heart failure.2 Andre Cournand's group defined the pathophysiology of heart failure secondary to cor pulmonale, distinguished it from left ventricular failure, and compared the acute hemodynamic effects of digoxin in these 2 conditions.3 In a seminal paper, Raab and Lepeschkin extracted sympathin from the heart and established norepinephrine as the cardiac adrenergic neurotransmitter.4 In one of the earliest efforts to manage patients with chronic congestive heart failure on an outpatient basis, Vander Veer and colleagues demonstrated the effectiveness and tolerability of an oral form of the widely used parenteral diuretic mercuhydrin.5Myocardial FunctionIn the 1950s, the role of hypertrophy in the heart's adaptation to hemodynamic overload was examined. After Laplace's law was applied to the heart and permitted the calculation of wall stress in the human heart,6 it became clear that myocardial hypertrophy prevents excessive elevation of wall stress consequent to hemodynamic overload.78 In the 1960s, there was a lively debate about the mechanism of heart failure secondary to pressure overload. The question was framed as follows: "Does failure of the ventricle as a pump occur in the presence of (an) inadequate contractile mass while the contractile function of each unit (of myocardium) is normal or even supernormal, or does failure result as a consequence of a depression of contractility of the myocardium that is not compensated for by the increase in muscle mass?"9 The latter position was supported by the demonstration of contractile dysfunction in papillary muscles isolated from cats with heart failure secondary to pressure overload.9Subsequently, the contractile process in failing heart muscle has undergone ever closer scrutiny. A defect in sarcomere shortening has been found in myocytes isolated from multiple animal models,10 as well as from patients with advanced heart failure.1011 Moreover, reversibility of this defect through "unloading" the failing heart by placing the patient on a ventricular assist device for several months has been demonstrated.11 This intriguing observation suggests that it may be possible, as a therapeutic strategy, to reverse a process that had long been considered to be irreversible and amenable only to palliative therapy. As a consequence, left ventricular assist devices currently used as "bridges to heart transplantation" may become "bridges to recovery."12 Perhaps even more exciting is the recent realization that the intrinsic defects in myocardial contractile function present in some patients with chronic heart failure may be partially reversed by medical therapy.1314 That is, treatment of patients with chronic systolic heart failure with β-adrenergic blocking agents added to background therapy with ACE inhibitors improves systolic function and may reverse remodeling,13 leading to improved clinical outcomes, including prolonged survival and reduced hospitalizations.14 Thus, the view of chronic myocardial failure as an irreversible, end-stage process is being supplanted by the idea that it is possible to effect true biologically based improvement in the intrinsic defects of function and structure that afflict the chronically failing heart.Abnormalities in Energy MetabolismThe cellular and molecular bases of heart failure have received considerable attention during the past half century and are under continuing active study. Although there is no single unifying pathogenetic theory, a number of biochemical abnormalities have been described in heart failure. There is agreement that the efficiency of the heart as a pump is reduced in the low-output, systolic heart failure that occurs in ischemic heart disease and dilated cardiomyopathy. The "external work" performed by the left ventricle is depressed, whereas its energy consumption is normal or almost so.15 Thus, the dilated, failing heart is energy-inefficient. Second, alterations in cardiac energy metabolism are frequently observed in systolic heart failure. Relative ischemia of the subendocardium occurs in ventricular hypertrophy and dilatation.16 High-energy phosphate stores, especially creatine phosphate (CrP), are reduced, not only in heart failure secondary to acute ischemia but in other forms as well.171819CrP serves as a buffer maintaining high ATP concentrations and a high ATP/ADP ratio. It may also facilitate the transfer of high-energy phosphates from their source in the mitochondria to their principal sites of consumption at the myofibrils and in the sarcoplasmic reticulum. Mitochondrial abnormalities may reduce the availability of high-energy phosphate stores in failing myocardium, perhaps related to mitochondrial damage that is mediated by oxygen radicals or autoantibodies.20 Reductions in the activity of creatine kinase, the enzyme that catalyzes the transfer of high-energy phosphate stores from CrP to ADP to generate ATP, have been reported in many forms of heart failure.21 Reduced activity of this enzyme intensifies the energy deficit in heart failure. If severe enough, the resulting reduction in the free energy of ATP both slows the pump responsible for Ca2+ uptake by the sarcoplasmic reticulum required for myocardial relaxation22 and impairs myofilament cross-bridge cycling, which is the basis of cardiac contraction. These observations, first obtained in experimental models, have been extended to patients with dilated cardiomyopathy by use of 31P magnetic resonance spectroscopy. Importantly, a depressed CrP/ATP ratio in these patients has been found to be an independent, powerful predictor of early death.23Altered Expression or Function of Contractile ProteinsThere is considerable evidence for changes in sarcomeric proteins in the failing human heart242526272829 (Table 1). The data include changes in the gene2425 and protein26 expression of myosin heavy chain isoforms and alterations in the expression of troponin T27 and in the isoform expression of myosin light chain-1.2829 In each case, the altered gene and protein expression most likely represents an induction of a "fetal" pattern of gene expression, whereby certain contractile, calcium-handling, and counterregulatory proteins revert to the mRNA and protein expression pattern that characterizes the fetal stage of development. Although this paradigm was first observed in rodent myocardium,3031 it is now abundantly clear that the same type of gene reprogramming also occurs in the failing, hypertrophied human heart.242526 In the case of fetal expression patterns of thick- and thin-filament contractile proteins, some of the alterations (myosin heavy chain, troponin T) reduce, while at least one (myosin light chain-1) increases, myofibrillar ATPase activity and/or contractile function. The net effect appears to be a reduction in myofibrillar ATPase activity32 and contraction velocity, perhaps because the dominant changes are in myosin heavy chain isoforms. Although in animal models this reduction in velocity of shortening was originally interpreted as being an adaptive, energetically favorable change,33 the end result is an increase in wall stress and maladaptive neurohormonal/cytokine activation (see below) secondary to the reduction in stroke volume and increase in ventricular volume. Thus, activation of harmful hypertrophy signaling pathways may be the biggest outcome of a reversion to fetal gene expression.A number of inherited cardiomyopathies may be related to mutations of genes encoding sarcomeric proteins. Familial hypertrophic cardiomyopathy, which causes impaired filling and diastolic heart failure (and less commonly and in late cases, a dilated phenotype with systolic heart failure), is caused by mutations in the genes encoding sarcomeric proteins. These include components of the thick filaments (cardiac β-myosin heavy chain and myosin light chains), components of the thin filaments (cardiac troponin T, troponin I, and α-tropomyosin), and cardiac myosin-binding protein C.34 All of these mutations probably produce abnormalities of force generation, which then incite a hypertrophic response.35 Dilated cardiomyopathy causing systolic heart failure may result from mutations in genes encoding actin,36 which appear to produce an abnormality of force generation or transmission similar to genetic defects in cytoskeletal proteins, which are also associated with dilated cardiomyopathy (see below).Abnormalities of Excitation-Contraction Coupling: Diastolic Heart FailureAbnormalities of excitation-contraction coupling occur in many forms of heart failure. Calcium ions (Ca2+) play a central role in both cardiac contraction and relaxation, and a number of abnormalities of receptors, pumps, and proteins responsible for the transsarcolemmal and intracellular movements of Ca2+ have been described in the failing human heart. In end-stage human myocardial failure, the result of these changes appears to be a prolongation of the Ca2+ transient37 and an increase in diastolic Ca2+ concentration.38 These changes, probably caused by an impairment in the protein expression39 or function40 of sarcoplasmic reticular ATPase (SERCA-2a), would be expected to impair both diastolic and systolic function.Diastolic dysfunction secondary to impaired myocardial relaxation and/or ventricular filling is associated with many cases of systolic dysfunction, but it is the primary cause of the clinical syndrome of heart failure in as many as one third of all cases. Impaired cardiac filling may be caused by structural abnormalities, eg, pericardial constriction or increased interstitial fibrosis; by physiological abnormalities, eg, abbreviation of diastole, as occurs in tachycardia; and by abnormalities in myocyte relaxation, such as decreased activity or protein expression of the SERCA-2a. Relatively low levels of expression of the transsarcolemmal Na+-Ca2+ transporter can have a similar effect by reducing Ca2+ elimination from myocytes.41 In addition, the aforementioned reduction of myofibrillar ATPase activity resulting from isoform shifts of contractile or regulatory proteins may prolong cross-bridge attachment between actin and myosin and thereby impair myocardial relaxation.Cytoskeletal AbnormalitiesThe cardiac myocyte cytoskeleton is now known to be able to influence myocardial function dynamically, particularly in the setting of pressure overload, in which excessive microtubular polymerization has been shown to adversely affect systolic function.42 In addition, the concentrations of a number of cytoskeletal proteins, such as desmin, tubulin, vinculin, dystrophin, talin, and spectrin, appear to be increased in end-stage failing human hearts.43 Conversely, the sarcomeric skeletal proteins α-actinin, titin, and myomesin may be decreased in end-stage failing human hearts,43 and in a single patient with an idiopathic dilated cardiomyopathy, a complete absence of metavinculin has been reported.44 These changes may interfere with normal myocyte function and cause or contribute to cell and chamber remodeling.An impressively increasing number of cytoskeletal gene mutations have been shown to be the basis for dilated cardiomyopathy phenotypes.45 At the moment, the list in humans includes dystrophin,45 desmin,46 sarcoglycans,47 and the nuclear-envelope proteins lamin A and C.4849 The strain-specific model of heart failure/cardiomyopathy in the Syrian golden hamster has been shown to be due to a mutation in the δ-sarcoglycan gene.50 In animals, genetic ablation of the cytoskeleton-associated muscle LIM protein (MLP) produces a useful model of dilated cardiomyopathy.51 It has been reported that MLP expression is reduced in the failing left ventricular myocardium of patients with dilated and ischemic cardiomyopathy.52 Because MLP is important for the regulation of the cytoarchitecture of cardiac myocytes, reduced MLP content could be responsible for the impaired systolic function in ischemic or idiopathic dilated cardiomyopathy.53 Thus, mutations in various genes encoding cytoskeletal proteins appear to lead to the idiopathic dilated cardiomyopathy phenotype, suggesting that altered expression of this class of proteins might have a role in the development of acquired (secondary) dilated cardiomyopathies as well.Alterations in β-Adrenergic Receptor Signal TransductionAn alteration in β-receptor signal transduction, downregulation of β1-adrenergic receptors, was one of the first candidates proposed for a molecular defect in the failing human heart.5455 Multiple alterations in β-receptor signal transduction have been described in the failing human heart, and there is little doubt that they reduce cardiac reserve and contribute to decreased exercise responses in patients with chronic heart failure.55 As originally conceived, changes in β-receptor signal transduction were viewed as partially adaptive changes, serving the useful purpose of withdrawing the cardiac myocyte from harmful adrenergic stimulation.55 With the recent recognition that β-adrenergic receptors may possess intrinsic activity and exist in an activated state even in the absence of agonists, the idea has emerged that the loss of β-receptor signal transduction can directly reduce intrinsic myocardial function, that is, function in the absence of catecholamine agonists.56 However, at this point there is no evidence that this can occur in the failing human heart, inasmuch as dynamic changes in myocardial function can be dissociated from changes in intrinsic β-receptor signal transduction.57Ventricular Hypertrophy and RemodelingCardiac Myocyte HypertrophyMost types of myocardial failure are preceded by cell and chamber hypertrophy. The development of myocardial hypertrophy initially represents an important adaptive mechanism to hemodynamic stresses.9 The initial functional benefits of the hypertrophic response include an increase in the number of contractile elements, a lowering of wall stress through increased wall thickness in concentric hypertrophy, and increasing stroke volume by increasing end-diastolic volume in eccentric hypertrophy.8 The hypertrophic process is characterized by structural changes at the cardiac myocyte level that are translated into alterations in chamber size and geometry,58 collectively called remodeling. In addition to cardiac myocytes, other myocardial cells, such as fibroblasts, and increased production of extracellular matrix participate in the remodeling process. In pressure-overload hypertrophy, additional sarcomeres are assembled in parallel, leading to thicker myocytes, to a concentric pattern of ventricular hypertrophy, and initially to well-maintained systolic function. In contrast, in volume overload, additional sarcomeres are assembled in series, leading to longer myocytes, ventricular dilatation, and earlier dysfunction.As listed in Table 1, numerous signaling pathways have been shown to induce cardiac myocyte and myocardial chamber hypertrophy. Most, if not all, the signaling pathways listed in Table 1 produce pathological hypertrophy, that is, hypertrophy accompanied by contractile dysfunction and poor clinical outcomes. Increased hemodynamic stress (either pressure or volume overload) appears to be sensed by myocytes, leading to changes in myocardial gene expression. It has been proposed that mechanical deformation activates sarcolemmal ion channels and is also transmitted to the nuclear membrane by the cytoskeleton.59 Intracellular [Ca2+] is a regulator of myocyte hypertrophy, in part through a pathway involving calcineurin, a Ca2+-sensitive phosphatase,60 which can be blocked by cyclosporin A.6061 This pathway and the calmodulin kinase pathway are both activated by increases in intracellular [Ca2+], and both may be involved in hypertrophic responses resulting from abnormalities in Ca2+ handling mechanisms or in response to neurohormonal-cytokine signaling.62Neurohormonal and autocrine/paracrine mediators of hypertrophy include norepinephrine (via α- or β-receptor pathways), angiotensin II, endothelin 1, fibroblast growth factor, transforming growth factor-β1, the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and G protein 130–signaling cytokines. These agonists transmit their signals through signal transduction proteins (such as ras, Gαq, and Gαs) to activate a family of enzymes (such as protein kinase C [PKC], mitogen-activated protein kinases, and Raf-1 kinases) that induce the fetal gene program. Activation of G-coupled isoforms of PKC stimulates hypertrophy, which can lead to a fibrotic cardiomyopathy,6364 and PKC-β isoforms are upregulated in the failing human heart.65The molecular signature of pathological hypertrophy is fetal gene induction, including changes in gene expression of contractile proteins and calcium handling that interfere with contractile function. Thus, hypertrophy is not simply a matter of a quantitative increase in contractile proteins and other key elements that initiate and regulate contraction, but rather, it is also associated with qualitative changes in gene expression that lead to an impairment of contractile function. A list of genes considered to be part of the human fetal program that is reinduced in hypertrophy is given in Table 2.The precise mechanism(s) responsible for the transition from adaptive hypertrophy to maladaptive heart failure are elusive, but there are several candidate mechanisms. In addition to deficiencies in high-energy phosphate stores and defects in excitation-contraction coupling, excess formation of myocyte microtubules, which impairs sarcomere shortening, may be involved.42 On the basis of work done in animal models3031 and humans,242526 induction of the contractile protein fetal gene program to the point where contractile function is severely impaired is a viable candidate, as is the development of Ca2+-handling abnormalities that are part of6667 or separate from39 fetal gene induction. Attenuation, or in some cases even total loss, of β-adrenergic signal transduction as the major means of supporting decreased myocardial performance probably contributes to the transition as well.68 Other possibilities include ultrastructural disorganization of cytoskeletal proteins and the development of extensive interstitial myocardial fibrosis. Finally, apoptosis (see below) could be a key component of myocardial decompensation in certain settings.Relationship Between Myocardial Contractile Dysfunction and Hypertrophy/RemodelingAn extremely important concept that has emerged in recent years is the close connection between remodeling and contractile dysfunction. These are the 2 most important pathophysiological processes in the failing heart, and as depicted in Figure 1, they are intimately interrelated. That is, if cardiac myocyte or myocardial contractile dysfunction is initially present, numerous hypertrophy signaling pathways that ultimately lead to remodeling will be activated. Conversely, if remodeling without contractile dysfunction is initially present, as has been demonstrated in some animal models,69 contractile dysfunction will follow. This may be due to any of several processes that include energetic stress,70 altered Ca2+ handling,71 and induction of the fetal gene program. Conversely, any type of therapy that interrupts this positive feedback cycle will attenuate or reverse the progression of myocardial function and remodeling.13Extracellular MatrixHypertrophied and failing hearts usually exhibit considerable interstitial fibrosis, which stiffens the ventricles and impedes both contraction and relaxation. An increased expression of a number of extracellular matrix proteins, including several forms of collagen and fibronectin, has been described. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are intimately involved in the remodeling of the cardiac matrix. Enhanced expression of MMPs and reduced expression of TIMPs have been described in heart failure, and the application of an inhibitor has been shown to retard experimentally produced heart failure.72Cardiac Myocyte ApoptosisA recently emphasized and probably important component of the remodeling process and of the transition from adaptive hypertrophy to heart failure is cardiac myocyte apoptosis, or programmed cell death.7374 This precisely orchestrated genetic program is stimulated by a variety of factors, including hypoxia; enhanced activity of G-coupled proteins through activation of β- and α-adrenergic receptors, angiotensin II, and TNF-α (see below); mitochondrial injury; myocyte Ca2+ overload; cell injury of diverse causes, including O2-derived free radicals; activation of certain sarcolemmal receptors (Fas receptors); and the action of a class of specific proteases, the caspases. The latter degrade target proteins in the nucleus, cytoskeleton, and mitochondria. Stretching of sarcomeres in vitro results in the release of angiotensin II from cardiac cells, which triggers myocyte apoptosis. ACE inhibition can prevent this form of cell death in vivo.75Pacing-induced heart failure has served as a useful experimental model for the study of idiopathic dilated cardiomyopathy.18 This form of heart failure has been found to be associated with enhanced expression of Bax, a gene that stimulates apoptosis, and with attenuation of the expression of a proto-oncogene, Bal-2, which protects against apoptosis. These changes in gene expression may be caused by the activation of the tumor suppressor gene p53.75 The myocardial apoptosis that occurs during aging and that is accelerated in overloaded cells increases the burden on surviving myocytes and hastens their death, thereby setting up a vicious circle. In experimental preparations, marked reductions in apoptosis have been found with β-adrenergic blockade, ACE inhibition, and blockade of the angiotensin II type I receptor.74 Although its role in less advanced forms of human myocardial failure is uncertain, cardiac myocyte apoptosis has been clearly demonstrated in end-stage failing human hearts.76 Thus, as shown in Figure 2, cell loss via apoptosis or necrosis joins altered expression of genes regulating contractility as 2 fundamental processes that can produce progressive myocardial dysfunction in the failing human heart.Neurohormonal-Cytokine ChangesStudies in the early 1960s demonstrated the presence of increased concentrations of circulating norepinephrine77 and reduced cardiac content of norepinephrine in patients with heart failure.78 A large number of investigations on neurohormonal changes in heart failure followed. It is now clear that in conditions characterized by a reduction of cardiac output and/or an increase in wall stress, a number of neurohormonal systems, notably the adrenergic system, the renin-angiotensin-aldosterone system (RAAS), and the hypothalamic-neurohypophyseal system are activated. Also, there is release of endothelin from the vascular bed. The activation of these systems initially serves to maintain arterial pressure and thereby coronary and cerebral perfusion pressures. Blood volume is conserved in the presence of hypovolemia or is expanded in the case of heart failure; the latter enhances contraction of the acutely failing ventricle by allowing it to move up on its Starling curve.Whereas activation of these systems is clearly adaptive over the short term in acute heart failure and hypovolemic shock, it became clear in the 1980s that persistent activation is maladaptive in chronic heart failure. Thus, continued activation of the adrenergic system increases ventricular afterload and therefore the hemodynamic burden placed on the failing ventricle. At the same time, activation of this system contributes to an increase in heart rate and myocardial energy costs; it may cause hypertrophy, ischemia, and tachyarrhythmias and damage myocytes further, perhaps through myocardial Ca2+ overload or apoptosis.74 At the myocardial level, there is ample evidence of overactivity of adrenergic drive. The original observation in failing human hearts was that cardiac content of the adrenergic neurotransmitter norepinephrine was reduced or depleted.78 We now know that this tissue-store depletion is the result of sustained increased release and decreased reuptake of neurotransmitter,7980 resulting in a constant exposure to levels of norepinephrine that are almost certainly cardiotoxic.1455 Chronic β-adrenergic stimulation has been shown to induce expression of the proinflammatory cytokines TNF-α, IL-1, and IL-6,81 which may impair cardiac contraction, promote chamber enlargement, and thus play a significant role in the development of a dilated cardiomyopathy phenotype. The reaction of the heart to this maladaptive signaling is easily measured; in explanted, severely failing human hearts, the density of β1-adrenergic receptors, the G protein coupling of both β1- and β2-receptors, β-adrenergic stimulation of the activity of the enzyme adenylyl cyclase, and in some studies the intracellular concentration of cAMP are all reduced.145568 Phosphorylation of β1-receptors by the β-adrenergic receptor kinase-1, an enzyme that is increased in heart failure, has been shown to be an important mechanism for desensitization of these receptors.82 Activation of β1-receptors through a cAMP-dependent kinase, PKA, causes the phosphorylation of phospholamban, a protein that in its unphosphorylated state inhibits the uptake (and release) of Ca2+ by the SERCA-2a. Phosphorylation of phospholamban enhances the uptake of Ca2+ from the cytoplasm. Loss of the β-adrenergic mechanism in heart failure leaves phospholamban in the unphosphorylated state, thereby impairing Ca2+ movements and interfering with cardiac contraction and relaxation.83 In addition, genetic variants of β-adrenergic receptors may be associated with rapid progression of heart failure.8485In the severely failing heart, acute blockade of β-adrenergic receptors can remove hemodynamically important β-adrenergic support and may thereby intensify heart failure. Gradual escalation of the dose of orally administered β-adrenergic blockers, however, has been shown to be of substantial clinical benefit,868788 and β-blocker therapy is now recommended for all but the most advanced cases of symptomatic chronic systolic heart failure.14 The myocardial functional effects of chronic β-blockade are in fact diametrically opposite to the acute effects, because long-term (≥3 months) blockade is associated with improved intrinsic systolic function and decreased ventricular volumes.13 These salutary effects on myocardial function and structure are most likely responsible for the majority of the clinical benefits produced by β-blocking agents, which include a substantial reduction in mortality and a reduction in heart failure–related hospitalizations in chronic heart failure.14Heart failure is also characterized by elevated circulating and tissue concentrations of angiotensin II, a vasoconstrictor that increases ventricular afterload and causes myocyte hypertrophy, apoptosis, interstitial fibrosis, cardiac and vascular remodeling, and the secretion of aldosterone. The latter also plays an important role in cardiac remodeling, the proliferation of fibroblasts, and the deposition of collagen.89 These changes increase the passive stiffness of the ventricles and the arterial bed, interfere with ventricular filling, and reduce arterial compliance.90 Elevated concentrations of circulating aldosterone are predictive of adverse outcome in heart failure patients.91 Inhibitors of the RAAS, ie, ACE inhibitors, angiotensin receptor blockers, and aldosterone inhibitors, have all been found to exert salutary effects in the treatment of heart failure. Indeed, ACE inhibitors are now considered to be a cornerstone in the management of most forms of heart failure and many forms of cardiac hypertrophy.There is increasing evidence of cross talk between the adrenergic system and the RAAS. Thus, in patients with heart failure, ACE inhibition has been found to reduce the enhanced peripheral sympathetic nerve impulse traffic92 and cardiac adrenergic drive,93 and the beneficial effects of ACE inhibitors appear to be especially prominent in patients with adre
Referência(s)