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(Circulation. 1996;94:2285-2296.)
© 1996 American Heart Association, Inc.

Articles

Medical Therapy Can Improve the Biological Properties of the Chronically Failing Heart

A New Era in the Treatment of Heart Failure

Eric J. Eichhorn, MD; Michael R. Bristow, MD, PhD

the Department of Internal Medicine (Cardiology Division) (E.J.E.), The University of Texas Southwestern and Dallas VA Medical Centers; and the Division of Cardiology (M.R.B.), University of Colorado Health Science Center (Denver).

	Abstract

Top Abstract Introduction Overview of Heart Failure... Adverse Effects of Long-term... Evidence That Medical Therapy... Attenuation of Remodeling and... Clinical Implications References

 
Abstract Myocardial failure has been considered to be an irreversible and progressive process characterized by ventricular enlargement, chamber geometric alterations, and diminished pump performance. However, more recent evidence has suggested that certain types of medical therapy may lead to retardation and even reversal of the cardiomyopathic process. In the failing heart, long-term neurohormonal/autocrine-paracrine activation results in abnormalities in myocyte growth, energy production and utilization, calcium flux, and receptor regulation that produce a progressively dysfunctional, mechanically inefficient heart. Interventions such as ACE inhibition and ß-blockade result in a reduction in the harmful long-term consequences of neurohormonal/autocrine-paracrine effects and retard the progression of left ventricular dysfunction or ventricular remodeling. Furthermore, in subjects with idiopathic dilated or ischemic cardiomyopathy, antiadrenergic therapy with ß-blocking agents appears to be able to partially reverse systolic dysfunction and ventricular remodeling. Although the precise mechanisms underlying this latter effect have not yet been elucidated, the general mechanism appears to be via improvement in the biological function of the cardiac myocyte. Such an improvement in the intrinsic defect(s) responsible for myocardial failure will likely translate into important clinical benefits.

Key Words: heart failure • remodeling • myocardial contraction

	Introduction

Top Abstract Introduction Overview of Heart Failure... Adverse Effects of Long-term... Evidence That Medical Therapy... Attenuation of Remodeling and... Clinical Implications References

 
Cardiac failure due to a cardiomyopathy (myocardial failure) is generally regarded as an irreversible and progressive process characterized by ventricular enlargement, geometric chamber alterations, eccentric hypertrophy, mechanical insufficiency, and depressed pump performance. One widely used definition of myocardial failure is the mechanical failure of the heart to maintain systemic perfusion commensurate with the requirements of metabolizing tissues.¹ This definition and view of myocardial failure dominated the development of medical treatment strategies for the clinical syndrome of heart failure between the mid-1960s and mid-1980s, and the subsequent pharmacological approaches were designed to acutely increase the performance of weakened heart muscle. As described by Ross and Braunwald,² myocardial systolic dysfunction is best demonstrated as a downward and rightward shift in the Frank-Starling relation or a plot of preload or resting length versus myocardial performance. It was largely because positive inotropic or vasodilator agents can acutely shift the cardiac output/preload relation upward and to the left that these types of pharmacological therapies constituted the initial attempts to improve the natural history of chronic heart failure.

Between 1986 and 1993, multiple clinical trials were conducted with vasodilators, positive inotropic agents, or "inodilators" as strategies for enhancing systolic performance, and with one exception,³ all resulted in worsening of the natural history of chronic heart failure.^{3 4 5 6} Furthermore, the disappointing clinical outcome of these trials appears to have been due to long-term adverse effects on the heart, inasmuch as many or most aspects of the clinical syndrome of heart failure—such as exercise tolerance, symptoms, and hemodynamics—were initially improved by these agents.^{7 8} Although the precise nature of the adverse cardiac effects of these agents is not known, an acceleration of the processes leading to arrhythmic/sudden death was observed in some studies.⁹ In addition, a common feature of agents that pharmacologically increase myocardial performance is that they use components of ß-adrenergic pathways to increase contractility¹⁰ or they indirectly activate neurohormonal/autocrine-paracrine compensatory mechanisms in response to vasodilation.^{11 12} Thus, despite beneficial pharmacological properties, these medications all carried the potential to produce adverse effects on the biology of the heart.

In the latter part of the 1980s and early 1990s, evidence began to appear that certain other types of medical therapy might have a beneficial effect on the natural history of left ventricular dysfunction or myocardial failure, despite having initial hemodynamic effects that were either unimpressive^{13 14 15} or even adverse.^{16 17 18 19 20} These two types of therapies, ACE inhibitors and ß-adrenergic–blocking agents, have changed our thinking about the potential of medical treatment of heart failure. Data generated from both clinical trials and model systems indicate that both types of therapy may prevent the progression of pump dysfunction that characterizes the natural history of heart failure and, unexpectedly and remarkably, that ß-blockade may substantially improve pump function in the long term. It is important to emphasize that the beneficial effects of these treatments are not pharmacological but rather are due to favorable effects on the biology of the failing heart. Thus, myocardial failure and the heart failure clinical syndrome no longer need to be viewed as inexorably progressive processes.

	Overview of Heart Failure Compensatory Mechanisms

Top Abstract Introduction Overview of Heart Failure... Adverse Effects of Long-term... Evidence That Medical Therapy... Attenuation of Remodeling and... Clinical Implications References

 
Myocardial failure begins with an insult to pump function, such as a myocardial infarction, inflammation, severe hemodynamic overload from hypertensive or valvular disease, genetic causes, or idiopathic myocardial dysfunction. In response to as-yet-undefined signals that probably include arterial underfilling, tissue hypoperfusion, and central venous congestion, compensatory mechanisms are activated to support the failing heart.^{21 22} There are four such physiological adjustments available to stabilize or increase myocardial performance; in the order of their activation kinetics, they are (1) increase in heart rate,²³ (2) increase in contractility,²⁰ (3) increase in preload,²⁴ and (4) increase in the number of contractile elements^{25 26} (Table). As shown in Fig 1, these four adjustments are largely accomplished by an increase in activity of two interrelated neurohormonal/autocrine-paracrine systems, the adrenergic and renin-angiotensin systems.^{21 22} These two neurohormonal systems cross-regulate each other such that activation of one results in increased activity of the other. Renin release from the kidney is a ß₁-adrenergic receptor–mediated response,²⁷ whereas angiotensin II facilitates presynaptic norepinephrine release.^{28 29} Increase in heart rate and contractility is largely due to ß-adrenergic mechanisms mediated by increased cardiac neurotransmitter activity.^{30 31} An increase in preload, which increases cardiac output via the Frank-Starling mechanism,^{2 24} occurs by activation of both the renin-angiotensin and adrenergic systems. Angiotensin II is a major mediator of aldosterone secretion, which causes salt and water retention through effects on the kidney.^{21 32} Nonosmotic release of arginine vasopressin is accomplished by both ß-adrenergic³³ and angiotensin II³⁴ receptor mechanisms in the neurohypophysis. Finally, both norepinephrine (via both - and ß-adrenergic receptor mechanisms) and angiotensin II are powerful mediators of cardiac myocyte cell hypertrophy.^{26 35 36 37 38 39 40} In addition, activation of both the adrenergic and renin-angiotensin systems causes vasoconstriction, which serves to stabilize central blood pressure and redistribute cardiac output to the brain and the heart, which in large part have autoregulatory control of flow. Although redistribution of fluid to these vital organs is obviously advantageous in the short term, the increase in peripheral resistance and left ventricular wall stress actually decreases myocardial performance, particularly in the presence of any degree of pump dysfunction. For this reason, as the adrenergic and renin-angiotensin systems are activated, there is coactivation of several counterregulatory mechanisms—such as atrial natriuretic peptides⁴¹ and vasodilator prostaglandins⁴² —that serve to minimize the effect of -adrenergic and angiotensin II vasoconstriction.

View this table: [in this window] [in a new window]   Table 1. Compensatory Mechanisms Regulating Pump Performance With and Without Heart Failure

View larger version (13K): [in this window] [in a new window]   Figure 1. Heart failure compensatory mechanisms that are activated to support the failing heart. Gray areas indicate physiological mechanisms that stabilize pump function.

	Adverse Effects of Long-term Activation of the Adrenergic and Renin-Angiotensin Systems

Top Abstract Introduction Overview of Heart Failure... Adverse Effects of Long-term... Evidence That Medical Therapy... Attenuation of Remodeling and... Clinical Implications References

 
In the failing heart, progressive left ventricular systolic dysfunction generally occurs due to (1) progressive myocyte dysfunction and (2) cell loss. The progressive impairment in global systolic function and histology is associated with left ventricular remodeling, a series of events that appear to be mediated at least in part by compensatory neurohormonal activation.

Mechanisms Responsible for Progressive Cardiac Myocyte Dysfunction
As shown in Fig 1, although activation of the adrenergic and renin-angiotensin systems is quite effective for short-term compensation, there are long-term adverse consequences of chronic activation of these systems that may override any initial benefit. Because heart rate, contractile state, and wall stress are the three major determinants of myocardial oxygen consumption,^{43 44} the failing dilated ventricle has a much greater metabolic need than smaller ventricles operating at a lower heart rate. The production of fibrosis^{36 37} and alterations in coronary perfusion due to structural changes in the properties of the capillary network and intramural branches of the coronary circulation in the damaged ventricle^{45 46 47 48} results in increased diffusion distance for oxygenated blood, resulting in a relative limitation of oxygen delivery and ischemia. High-energy phosphate reserves may be compromised,^{49 50 51} and substrate utilization may be altered in the failing heart in an unfavorable way.^{52 53 54 55} Thus, as pointed out by Katz,⁴⁹ the failing heart may become an "energy-starved heart." The state of energy deprivation would be expected to damage subcellular processes in the long term and contribute to progressive cardiac myocytic dysfunction.

Another adverse biological effect of activation of these two systems is direct cardiac toxicity, which appears to be primarily mediated by ß-adrenergic mechanisms for both norepinephrine^{56 57} and angiotensin II.⁵⁸ In the failing heart, angiotensin II appears to be a powerful facilitator of norepinephrine release,^{28 29} and norepinephrine is very toxic to isolated cardiac myocytes.^{56 57} In the intact human heart, interstitial concentrations of norepinephrine exceed those that cause creatine kinase release into the media in isolated cardiac myocytes (W.T. Abraham, C. Rose, and M.R. Bristow, unpublished observations), and it is likely that chronically elevated cardiac norepinephrine level in the failing heart is cytotoxic to cardiac myocytes and possibly other cells. However, even in the presence of nonselective ß-blockade, exogenous angiotensin II may by itself exert some direct toxic effects on the myocyte.^{59 60}

Finally, although the process of hypertrophy increases the number of functioning contractile elements, alterations in gene expression involving calcium handling by the sarcoplasmic reticulum and changes in contractile proteins or their regulatory elements may produce an inefficient contractile apparatus.^{61 62 63 64 65 66} Some or all of these changes ultimately lead to progressive left ventricular dysfunction, best understood as a continued decline in systolic function.

Systolic dysfunction of individual cardiac myocytes is by definition due to a change in gene expression. In rodent systems, the constellation of alterations in gene expression that accompanies cardiac hypertrophy and its transition to myocardial dysfunction has been termed activation of a "fetal" program because the changes recapitulate embryonic or neonatal patterns.^{26 63} Because humans do not exhibit major changes in gene expression during development, they do not exhibit the dramatic fetal program activation that characterizes hypertrophy or failure in rodent hearts.⁶³ However, there are certain changes in human hearts that resemble fetal activation; these include an upregulation in gene expression of atrial natriuretic peptide^{67 68} and perhaps downregulation in the expression of sarcoplasmic reticulum calcium ATPase^{61 62 63} and -myosin heavy chain.^{64 65} Angiotensin II,^{35 36 37 38} endothelins,^{35 66} and adrenergic stimulation^{39 40} have been shown to be potent inducers of the fetal/hypertrophy gene program in model systems. In chronic heart failure, additional changes occur in gene expression that are not typically considered to be part of the fetal program, such as downregulation in ß₁-adrenergic receptors^{69 70} and mRNA.⁷¹ Taken together, these adjustments may decrease systolic performance and compromise myocardial reserve in times of stress, such as during exercise.⁷²

It appears that ß-adrenergic stimulation may play a major role in the development of myocyte dysfunction. In isolated cardiac myocytes, exposure to norepinephrine causes myocyte toxicity, abnormal calcium handling, decreased macromolecular synthesis, and contractile dysfunction.⁵⁷ In humans, markedly elevated catecholamine levels accompanying brain injury⁷³ or pheochromocytoma⁷⁴ cause intrinsic systolic dysfunction. Finally, the use of positive inotropic agents that act on the cAMP contractility–stimulating pathway appears to lead to depressed contractile function after they are withdrawn.^{75 76} Therefore, changes in gene expression, which contribute to the slowing of contraction and disordered calcium handling, may be effected by both the adrenergic and renin-angiotensin systems.

Mechanisms Leading to Loss of Cardiac Myocytes
It is becoming clear from work performed by Anversa and colleagues^{77 78} that cardiac myocyte loss is a common feature of cardiomyopathic processes. Although the degree of cell loss is difficult to quantify, attrition of myocytes within viable portions of ventricles afflicted with ischemic or nonischemic cardiomyopathy probably contributes to progressive myocardial dysfunction. Cardiac myocyte loss may occur via two general mechanisms: necrosis⁷⁷ and apoptosis (Fig 2).^{26 79} Necrosis occurs via cytotoxic mechanisms and may be observed in situations of both acute and chronic myocardial dysfunction. ß-Adrenergic stimulation, including cardiac norepinephrine release⁵⁷ and exposure to angiotensin II,⁶⁰ can readily produce necrosis of cardiac myocytes in model systems.

View larger version (11K): [in this window] [in a new window]   Figure 2. Relationship of neurohormonal activation and production of cardiac myocyte loss due to apoptosis and necrosis and altered gene expression. Cell loss and altered gene expression result in more myocardial dysfunction, and a vicious cycle is established.

Apoptosis, considered to be a product of cell cycle dysregulation in response to stimuli that ordinarily promote growth, may also occur in end-stage failing hearts.^{26 80} Apoptosis most likely occurs as a response to prolonged growth stimulation in the adult terminally differentiated myocyte. The adult myocyte, unable to divide,⁸¹ shifts from a program of cell maintenance to production of muscle-specific gene products. Myogenesis during fetal growth is regulated by the myogenic determination genes (eg, MyoD and myogenin)^{81 82} and the tumor suppressor genes p53 and p107.^{83 84 85} Although the data are limited in adult human hearts, the intermediates responsible for apoptosis (including p53⁸⁵ ) appear to be upregulated in the failing heart and may be further upregulated by angiotensin II.⁸⁶ Additionally, the cytokine tumor necrosis factor- (TNF-), which is increased in chronic heart failure⁸⁷ and mediates biological effects in the failing human heart,⁸⁸ is a potent stimulus for growth^{89 90 91} and induction of apoptosis^{89 92} in model systems. Thus, neurohormonal/autocrine-paracrine signals that are activated or induced in the failing human heart can predispose to both necrosis and apoptosis.

Ventricular Remodeling
As shown in Fig 3, in response to some combination of neurohormonal/autocrine-paracrine signaling, mechanical deterioration, progressive myocyte dysfunction, and myocyte loss, the failing ventricle undergoes a process termed "remodeling."⁹³ There is an obvious short-term benefit to this strategy in that stroke volume will be larger in the presence of a larger end-diastolic volume by the Frank-Starling mechanism.²⁴ However, this will result in increased systolic and diastolic stresses and over the long term the biological adjustments that lead to remodeling appear to be harmful to myocardial function.

View larger version (18K): [in this window] [in a new window]   Figure 3. Relationship of myocyte dysfunction to development and reversal of remodeling and effects of activation of the cardiac adrenergic and renin-angiotensin systems, as well as antiadrenergic therapy.

The remodeling process in both animal models and humans is associated with the development of eccentric hypertrophy, as first described by Grossman et al.²⁵ Eccentric hypertrophy means an increase in myocardial mass with only minimal or no increase in wall thickness, and this is accomplished by an elongation in cardiac myocytes.^{36 77} Myocyte cell volume may be increased by 100% in the remodeled human ventricle⁷⁷ due to individual cell hypertrophy. Nonmyocytes, particularly fibroblasts, also are major contributors to remodeling.^{36 37} Interstitial fibrosis is increased in patients with eccentric myocyte hypertrophy, including subjects with ischemic and nonischemic dilated cardiomyopathies. Both the production and degradation of the collagen network are controlled by fibroblasts, which in the presence of remodeling and eccentric hypertrophy must produce additional extracellular matrix to maintain structural integrity of the ventricular wall.^{36 37} However, the presence of increased interstitial collagen may account for reduced capillary density and increased oxygen diffusion distance,^{45 46 47 48} which may contribute to metabolic stress or even overt ischemia.^{45 46} In addition, the increase in structural rigidity may impair the ability of myocytes to fully contract, thus reducing contractility.^{36 37}

In addition to hypertrophy and fibrosis, as shown in Fig 3, the left ventricle assumes a larger, more spherical (globular) shape after injury such as myocardial infarction.^{19 93 94} Noninfarcted failing myocardium undergoes similar time-dependent changes that have been attributed to side-to-side slippage, increased myocyte length, and left ventricular hypertrophy.^{19 94 95 96} The result is a shift in left ventricular geometry from a prolate ellipse to a more spherical shape. This in turn causes increased meridianal wall stress,^{94 95} abnormal distribution of fiber shortening,^{94 95 96} functional mitral regurgitation,⁹⁷ worsened exercise tolerance,⁹⁸ and poorer long-term survival.⁹⁶ Data exist in both animal and human systems to suggest that a potent stimulus for the remodeling process is activation of the renin-angiotensin system.^{26 35 36 37} Stretch of myocytes due to the altered load of heart failure results in paracrine-autocrine release of angiotensin II and activation of protein kinase C, resulting in immediate/early (I/E) gene expression (especially c-fos, c-jun, junB, and c-myc), which promotes growth.^{38 99 100 101} Angiotensin II can induce protein synthesis¹⁰² and produce cardiac myocytic hypertrophy in cultured cells⁹⁹ or overt hypertrophy at the organ level.^{37 103 104 105} It is also mitogenic for cardiac fibroblasts and stimulates collagen formation.^{36 37}

Angiotensin may also provide a positive feedback regulation of the hypertrophic response by inducing the angiotensinogen gene and transforming growth factor-ß₁ (TGF-ß) gene.³⁸ TGF-ß also has mitogenic potential and may induce hypertrophy.^{106 107} Finally, ACE inhibitors may inhibit growth not only by inhibiting angiotensin II but also by increasing bradykinin production. Bradykinin produces vasodilation and releases nitric oxide, endothelium-derived growth factor, and prostacyclin, all of which are growth inhibitors.²⁶

There is also evidence that adrenergic stimulation contributes to the remodeling process. Administration of ß-blocking agents may prevent or reverse ventricular dilatation in animal models,^{108 109} and both -³⁹ and ß-adrenergic¹¹⁰ receptors mediate cardiac myocyte hypertrophy, with the ß-adrenergic response being particularly prominent in adult myocytes.¹¹⁰ There are numerous other powerful signals for the remodeling process, including endothelins³⁵ and cytokines such as TNF-^{35 111 112} and cardiotrophin, a newly discovered cytokine that is powerfully hypertrophic.¹¹³

Relationships Among Cardiac Myocyte Dysfunction, Cardiac Myocyte Loss, and Ventricular Remodeling
As shown in Fig 4, myocyte hypertrophy, intrinsic dysfunction of cardiac myocytes, and myocyte loss and remodeling are likely to be separate but related processes that act in a mutually reinforcing manner; that is, hypertrophy and increased myocyte length, which through changes in gene expression lead to intrinsic myocyte contractile dysfunction, would be expected to lead to ventricular dilatation and further activation of neurohumoral signals for growth, which is part of the remodeling process. Neurohormonal activation and the process of remodeling may compromise myocyte function through adverse effects on metabolism^{52 53 54 55} and capillary blood flow.^{45 46 47 48} Cardiac myocytes or tissue preparations isolated from such "remodeled" chambers exhibit intrinsic systolic dysfunction,^{114 115 116} suggesting that the remodeling process is related to diminished intrinsic function. Conversely, if intrinsic myocyte function could be improved in the long term, this would be expected to lead to a reversal of remodeling as wall stress is diminished and neurohormonal/autocrine-paracrine activation is decreased. Cell loss will also lead to remodeling because the remaining myocytes must hypertrophy to maintain contractile function, and by-products of cell death will induce an inflammatory response that will increase fibrosis.

View larger version (21K): [in this window] [in a new window]   Figure 4. Relationships among cardiac myocyte dysfunction, myocyte loss, and ventricular remodeling.

	Evidence That Medical Therapy Can Improve the Inherent Biological Function of the Failing Heart

Top Abstract Introduction Overview of Heart Failure... Adverse Effects of Long-term... Evidence That Medical Therapy... Attenuation of Remodeling and... Clinical Implications References

 
Because the natural history of heart failure follows the natural history of left ventricular dysfunction,^{117 118} most clinicians view symptomatic heart failure as an inexorably progressive process. However, recent data derived from both model systems and clinical trials indicate that the progression in left ventricular dysfunction can not only be attenuated by medical therapy but also be reversed. In the following, we summarize the data indicating that medical therapy can produce favorable biological effects in the failing heart and emphasize that such an approach has the potential to favorably alter the natural history of heart failure.

Improvement in Intrinsic Myocyte Function and Chamber Characteristics With Antiadrenergic Therapy
Animal Models of Myocardial Failure
Improvement in intrinsic myocardial function
It is clear from both animal and human studies of myocardial failure that cardiac myocyte function may improve with ß-adrenergic blockade. Gwathmey and associates^{119 120 121} examined the effect of ß-blocker therapy in the furazolidone-treated turkey model, which resembles human dilated cardiomyopathy with regard to mechanical dysfunction, morphology, and biochemical alterations. In these studies, administration of the ß-blocking agent carteolol resulted in improvement in ejection fraction, reduction in ventricular volumes, and an increase in developed pressure.¹²¹ In addition, the administration of carteolol resulted in a mortality benefit.¹²⁰ In another set of experiments, Glass et al¹¹⁹ as well as Mulieri et al¹²² found that heart failure results in an abnormal force-frequency relation. In isolated muscle from normal hearts, as the frequency of stimulation increases, the heart produces more force.²³ In the failing heart, increased heart rate produces less force. The administration of nifedipine, a calcium channel antagonist, acutely reversed this phenomenon in the failing heart,¹¹⁹ suggesting that calcium overload and an inability to handle calcium at fast heart rates may be responsible for this phenomenon. These authors also demonstrated that chronic administration of the ß-blocker propranolol to furazolidone-treated turkeys normalized this abnormal force/frequency relation, improved high-energy phosphate production, and normalized abnormalities in calcium handling.¹²¹ They concluded that ß-adrenergic blockade protected the heart against energetic and sarcoplasmic reticulum dysfunction in the failing heart. Thus, in the furazolidone cardiomyopathy model, ß-blockers may improve the biological function of the failing heart muscle.

Tsutsui et al¹¹⁴ examined the effect of ß-adrenergic blockade in a canine model of chronic mitral regurgitation. They found that treatment with atenolol resulted in restoration of ventricular and myocyte contractile function. This improvement in contractile function was demonstrated not only in the intact heart but also in isolated myocytes. Thus, the fundamental improvement in contractility was not a pharmacological effect but rather was the result of biological improvement within the myocyte itself. Finally, Tsutsui et al noted an increase in mass and myofibrillar content in the ß-blocker–treated group compared with failing hearts not given ß-blockers. These data suggest that there were more contractile elements to generate force, helping to explain the improvement in contractile function.

Effect of ß-blockade on chamber characteristics
Sabbah et al¹⁰⁸ produced myocardial dysfunction in dogs with microembolization and randomized the animals to enalapril, metoprolol, or no treatment.

The untreated dogs had progressive increases in ventricular volumes and more spherical ventricles in the ensuing 3 months, whereas the dogs treated with ACE inhibition or ß-blockade had no increase in volumes or significant alteration of shape.

McDonald et al¹⁰⁹ produced localized necrosis by application of DC shock in dogs. Dogs treated with captopril and metoprolol had a significant reduction in left ventricular mass and chamber diameter compared with placebo-treated animals. These data support the ability of ß-blockers to slow or even reverse the process of progressive ventricular enlargement and geometric alterations that occur after injury.

Clinical Investigations
Improved intrinsic systolic function
The effect of ß-adrenergic blockade on ventricular function has been examined in >15 placebo-controlled studies^{52 123 124 125 126 127 128 129 130 131 132 133 134 135} involving >2000 patients with chronic heart failure from systolic dysfunction.

In every study of >1 month's duration, left ventricular ejection fraction has been consistently shown to increase with ß-blocker therapy.^{133 134 135} No negative studies of >1 month's duration exist. Most importantly, three human studies^{52 127 136} and one animal study¹¹⁴ with four different ß-blocking agents have shown that the improvement in ventricular function is due to increased systolic ventricular performance. Improved performance appears to be due to enhanced contractility.¹¹⁴ Examples of ß-blockers producing an improvement in the Frank-Starling relation are shown in Fig 5. The third-generation compound bucindolol was the first ß-blocker shown to shift the Frank-Starling relation up and to the left relative to placebo, as shown in Fig 5a.¹²³ Similar effects have been shown for the structurally related third-generation compound carvedilol^{124 125} (Fig 5a). Because a plot of pulmonary wedge pressure versus stroke volume index may be affected by afterload and heart rate, it was critical to examine the effects of ß-blockers with an accepted load-independent methodology such as peak dP/dt versus end-diastolic volume at a fixed heart rate.^{52 136} This was first reported for bucindolol (Fig 5b), for which it could be unequivocally demonstrated that the improvement in ejection fraction and stroke work index was due to improved intrinsic systolic function, as observed from the upward/leftward shift in the ventricular diastolic volume versus dP/dt relation¹³⁶ (Fig 5b). Subsequently, it was shown that the second-generation compound metoprolol had a similar effect on this relationship, whereas placebo treatment produced no change⁵² (Fig 5b). In addition, all studies that reported measurements have shown a reduction in ventricular volumes by 3 months of therapy.^{19 52 126 127 136} In addition, one study demonstrated an improvement in myocardial relaxation with ß-blockade.¹³⁶

View larger version (46K): [in this window] [in a new window]   Figure 5. Effects of bucindolol (a) and carvedilol (b) on left ventricular function. a, Effects (±SEM) of treatment with bucindolol (n=13) or placebo (n=9) on left ventricular function plots in a group of patients with idiopathic dilated cardiomyopathy. SVI indicates stroke volume index; PCW, pulmonary capillary mean pressure. Plot of data originally presented in Gilbert et al.123 b, Effects of 4 months of treatment with carvedilol (n=23) or placebo (n=18) on left ventricular function in a group of patients with idiopathic dilated cardiomypathy. Plot of data originally presented in Reference 125. (Reprinted from References 123 and 125123 125 with permission.) b, Effect of 12 weeks' treatment with bucindolol (c) or metoprolol (d) on the relationship of dP/dt vs end-diastolic volume in subjects with dilated cardiomyopathy from either ischemic or idiopathic causes. (Reproduced from References 52 and 136 by permission.)

To underscore that the effects of ß-blocking agents are not directly related to their pharmacological properties, as shown in Fig 6, a recent study demonstrated that after 1 day of therapy with metoprolol, left ventricular ejection fraction was depressed compared with baseline, but by 1 month it had returned to baseline.¹⁹ This is in general agreement with the depression of myocardial contractility and hemodynamics²⁰ after the acute administration of second-generation ß-blocking agents in chronic heart failure. Ejection fraction does not improve until after 1 month of metoprolol therapy,¹⁹ and generally it becomes significantly increased at 3 months. In chronic heart failure, the decrease in myocardial function with institution of ß-blockade is due to the pharmacological effect of withdrawal of ß-adrenergic support to the failing heart. Thus, in chronic heart failure, the improved performance and efficiency after ß-blocker treatment cannot be accounted for by a "positive inotropic" effect induced pharmacologically. Indeed, positive inotropes have not been shown to improve ejection fraction on a long-term basis.¹³⁷ In contrast, the delay in improvement in ejection fraction¹⁹ appears to be within the time frame necessary for a secondary biological effect to take place.¹³⁸ The contrast between the short-term pharmacological effects of metoprolol and its long-term biological effects on left ventricular ejection fraction is highlighted in Fig 6.

View larger version (44K): [in this window] [in a new window]   Figure 6. Changes in left ventricular ejection fraction from baseline (BSLN) to day 1, month 1, and month 3 in the metoprolol and standard therapy groups. Ejection fraction decreased at day 1 and increased after only 1 month of metoprolol therapy. In the standard therapy group, ejection fraction did not change significantly. (Reproduced from Reference 19 with permission.)

After 3 to 6 months of treatment, ß-blocking agents reduce both systolic and diastolic volumes,^{19 52 126 127 136} suggesting that improved intrinsic systolic function has occurred. Load-independent measures of systolic function clearly demonstrate that performance is increased in subjects treated with ß-blocking agents for periods of 3 months,^{52 127 136} which is in contrast to the acute pharmacological myocardial depressant effects.^{16 19 20}

Effects on chamber characteristics
Long-term effects of ß-blocker therapy on left ventricular mass and geometry have recently been examined.¹⁹ Over a 3-month period, left ventricular volumes and function improved, but left ventricular mass did not change. However, by 18±5 months of therapy, left ventricular mass had regressed. In addition, as left ventricular mass regressed, the ventricle, which is more spherical or globular in heart failure, became more elliptical. This was the first convincing demonstration in heart failure that reverse remodeling is possible. Similar results have recently been observed with the third-generation ß-blocker carvedilol. When compared with placebo, LV mass was significantly reduced after 4 months of treatments, and the sphericity index was significantly increased (became more elliptical) after 12 months of carvedilol therapy (E.M. Gilbert, B. Lowes, and M.R. Bristow, unpublished observations).

It is unclear whether the regression of left ventricular hypertrophy observed in these studies is a primary effect of blockade of adrenergic activity or rather an indirect effect. The response to ß-blockade in patients with left ventricular hypertrophy due to hypertension has been variable despite reductions in blood pressure.⁴⁰ Thus, indirect effects such as inhibition of renin-angiotensin, inhibition of endothelin release, or reduction in left ventricular wall stress may have played a role in reducing left ventricular mass.

	Attenuation of Remodeling and Myopathic Processes by Inhibition of Renin-Angiotensin System

Top Abstract Introduction Overview of Heart Failure... Adverse Effects of Long-term... Evidence That Medical Therapy... Attenuation of Remodeling and... Clinical Implications References

 
Animal Models of Myocardial Failure
Hypertrophy and Growth
Several investigators have demonstrated that the use of an ACE inhibitor can result in regression of hypertrophy in animal models. Linz et al¹⁰³ showed in a genetic rat model of hypertension that normalization of blood pressure by sympatholytic agents or direct vasodilators did not result in regression of hypertrophy but that ACE inhibitors did.

Baker et al¹⁰⁴ banded rat aortas above the renal arteries, which resulted in left ventricular hypertrophy 7 to 15 days after banding. One group of rats received ACE inhibitors, which prevented the development of hypertrophy despite a lack of difference in blood pressure from rats not receiving ACE inhibitors. In addition, angiotensinogen mRNA was increased in the hypertrophied ventricles. Although plasma renin activity was increased for 1 to 3 days after the banding, the development of hypertrophy occurred 7 to 15 days after banding. These data suggest a localized paracrine-autocrine/angiotensin II effect on production of hypertrophy.

Treatment of newborn pigs with an ACE inhibitor has been shown to interfere with normal postnatal growth of the left ventricle.¹⁰⁵ Thus, angiotensin II appears to play a critical role in the development of left ventricular hypertrophy, and ACE inhibitors are able to regress or prevent the development of hypertrophy in several animal models.

Myocyte Function
Recent work in a pacing-tachycardia dog model of heart failure has shown that an ACE inhibitor can attenuate the myocyte lengthening, reduction in velocity of shortening, and reduction in left ventricular ejection fraction that are associated with ventricular remodeling in this model.¹³⁹ These observations emphasize the relatedness of the processes that lead to cell hypertrophy, myocyte dysfunction, and remodeling, and they emphasize the point (outlined in Fig 3) that a favorable effect on any one of these may result in improvement in the others.

Left Ventricular Geometric Alterations
In 1985, Pfeffer and Pfeffer^{140 141} demonstrated in rats that the larger the myocardial infarction, the greater the remodeling and ventricular enlargement in the ensuing days and the worse the prognosis. Captopril-treated rats had significant attenuation of this ventricular enlargement and maintained a more normal end-diastolic pressure.¹⁴⁰

Sabbah et al¹⁰⁸ produced myocardial dysfunction in dogs with microembolization and randomized the animals to enalapril, metoprolol, or no treatment. The untreated dogs had progressive increases in ventricular volumes and more spherical ventricles in the ensuing 3 months, whereas the dogs treated with ACE inhibition or ß-blockade had no increase in volumes or significant alteration of shape.

McDonald et al¹⁰⁹ performed a similar study in dogs with chamber dilation due to localized necrosis produced by DC shock. Dogs treated with captopril and metoprolol had a significant reduction in left ventricular mass and chamber diameter compared with placebo-treated animals. These data support the ability of ACE inhibitors and ß-blockers to slow or even reverse the process of progressive ventricular enlargement and geometric alterations that occurs after injury.

Clinical Investigations
It is clear that in the presence of systolic dysfunction, ACE inhibitors reduce mortality and retard the progression of the heart failure clinical syndrome.^{142 143 144} However, ACE inhibitors also attenuate the process of ventricular enlargement/maladaptive remodeling after myocardial infarction and in patients with chronic heart failure.^{145 146 147} Pfeffer et al¹⁴⁵ and Mitchell et al¹⁴⁶ have shown that after an anterior wall myocardial infarction, there is a progressive increase in end-diastolic and end-systolic volumes and an increase in the sphericity of the left ventricle between 3 weeks and 1 year. This change in geometry occurs at a time when infarct expansion has already occurred and thus represents ventricular remodeling. These late geometric changes were prevented or retarded by ACE inhibitor therapy. In addition, those who received an ACE inhibitor had reduced pulmonary capillary wedge pressure and better exercise tolerance. Sharpe et al¹⁴⁷ found a similar result in patients with inferior as well as anterior infarction.

Substudies from the SOLVD study examined the effect of enalapril on left ventricular size and mass in patients with left ventricular dysfunction (ejection fraction 0.35) and mild-to-moderate heart failure (primarily NYHA class II/III).^{148 149} In both of these substudies, enalapril prevented increases in end-diastolic and end-systolic volumes. In addition, enalapril prevented an increase over 1 year in left ventricular mass, and diastolic function was better in the enalapril group. In an uncontrolled investigation with the ACE inhibitor benazepril, Doherty et al¹⁵⁰ reported a small (6%) decrease in left ventricular mass measured by magnetic resonance imaging over a 12-week period in 17 subjects. In these studies, there also were small decreases in ventricular volume, a decrease in an index of contractility, and an improvement in ejection fraction that was due to afterload reduction. Because magnetic resonance imaging is a more accurate method of measuring mass and volume, it is possible that in the chronically failing, hypertrophied, and remodeled ventricle, ACE inhibitors effect small decreases in left ventricular mass that cannot be determined with echocardiography. However, there is no evidence from clinical investigations that ACE inhibitor therapy can lead to substantial reversal of the remodeling process or to improved intrinsic myocyte function. Rather, the available data indicate that in established dilated cardiomyopathies, the administration of ACE inhibitors retards progression to increased left ventricular mass and a more spherical geometry, but that they do not actually regress hypertrophy or reverse the remodeling process. Although ACE inhibitors partially block the formation of angiotensin II, thereby diminishing the effects of the renin-angiotensin system on the myocyte, and although ACE inhibitors initially reduce adrenergic activity,^{28 151} plasma norepinephrine increases over time.¹⁵² These data suggest that progressive sympathetic nervous system activation occurs even in the presence of ACE inhibitors and enforce the need for a concomitant adjunctive antiadrenergic strategy to block the long-term sequelae of norepinephrine on the heart. The use of a ß-blocking agent will also result in further deactivation of the renin-angiotensin system, even in the presence of an ACE inhibitor.¹⁵³

	Clinical Implications

Top Abstract Introduction Overview of Heart Failure... Adverse Effects of Long-term... Evidence That Medical Therapy... Attenuation of Remodeling and... Clinical Implications References

 
A combination of myocyte hypertrophy, myocyte loss, and intrinsic cardiac myocytic dysfunction leads to ventricular remodeling and a decrease in systolic function and left ventricular ejection fraction. Decreased left ventricular ejection fraction is a powerful predictor of adverse outcome in subjects with chronic heart failure.^{117 118} Thus, improved clinical outcome should result from strategies that reduce the biological signals responsible for myocyte growth, dysfunction, and loss and chamber remodeling. In the case of ACE inhibitors, their relatively minor effects, consisting of an attenuation of the remodeling process, translate into modest reduction (15% to 30%) in mortality. As shown in Fig 3, in the case of antiadrenergic therapy with the third-generation compounds carvedilol and bucindolol, which are capable of blocking all ß-adrenergic input to the failing heart,^{154 155} inhibiting the renin-angiotensin system,¹⁵³ and markedly improving intrinsic myocardial function,^{125 136} the potential to improve the natural history of heart failure may be even greater. The US clinical trials for carvedilol were recently stopped because of the marked (65%) reduction in mortality that was achieved in both ischemic and nonischemic groups.^{130 131} Indeed, although the number of end points was small, this was the largest reduction in mortality ever associated with medical therapy of chronic heart failure. Furthermore, because carvedilol produced a dose-related improvement in left ventricular function and a dose-related reduction in mortality,¹³¹ it is likely that the mortality reduction was related to improvement in myocardial biological function. Because of the therapeutic potential of biological modification of the failing heart by third-generation ß-blocking agents, the National Institutes of Health and Veterans Administration Cooperative Clinical Trials Programs are jointly sponsoring a large mortality trial with bucindolol (the BEST trial),¹⁵⁶ which also is examining specific mechanisms by which this type of treatment alters myocardial gene expression. It is likely that additional treatments to inhibit the renin-angiotensin and adrenergic systems will be developed, and other critical pathways involved in adverse biological processes in the failing heart will be identified and lead to additional therapeutic strategy.

Consequently, left ventricular systolic dysfunction and clinical heart failure can now be considered to be at least partially reversible. Furthermore, the ability to alter the biology of the failing heart in a favorable way by antiadrenergic therapy is "proof of concept" that the future of heart failure treatment lies in identifying adverse biological processes and developing treatments that can normalize them. Thus, the clinician may eventually view the treatment of heart failure solely in the context of improving the biological function of the myocardium.

	Footnotes

 
Reprint requests to Eric J. Eichhorn, MD, Cardiac Catheterization Laboratory (IIIA2), University of Texas Southwestern and Dallas Veterans Administration Medical Centers, 4500 S. Lancaster, Dallas, TX 75216. E-mail Eichhorn@Ryburn.SWMED.EDU; or Michael R. Bristow, MD, PhD, University of Colorado Health Sciences Center, Division of Cardiology, B139, 4200 E Ninth Ave, Denver, CO 80262. E-mail Michael.Bristow@UCHSC.edu.

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