Heart Failure and Its Management With β‐Blockade: Potential Applications of Once‐Daily Therapy

Heart failure (HF) due to left ventricular (LV) systolic dysfunction is a progressive disease beginning with a primary injury that activates compensatory cardiovascular mechanisms including varying degrees of neurohormonal activation. Within the neurohormonal cascade, activation of the sympathetic nervous system is in part responsible for ongoing myocardial injury, progressive LV remodeling, and functional deterioration eventually leading to symptomatic HF. Large randomized clinical trials of certain β‐blockers added to standard therapies have shown unequivocal benefits in patients with chronic systolic HF resulting in reduced remodeling, fewer total and cardiovascular deaths, and less risk of hospitalization for worsening HF. Evidence‐based clinical guidelines recommend β‐blockers as part of the regimen for patients with systolic HF as well as LV dysfunction following myocardial infarction. Based on published clinical trial results, bisoprolol, carvedilol, and sustained‐release metoprolol succinate are recommended for systolic HF. Carvedilol, propranolol, and timolol are recommended for post‐myocardial infarction LV dysfunction. Unfortunately, these evidence‐based therapies are often underused in actual practice. Various strategies to increase β‐blocker use in HF have been attempted, including in‐hospital initiation of β‐blocker therapy. Simplifying dosing regimens may also improve adherence to prescribed medications. Use of controlled‐release carvedilol may encourage better adherence in patients with LV dysfunction and help overcome at least one barrier to optimal evidence‐based care.     

When to initiate beta-blockers in heart failure: Is it ever too early?

Overwhelming clinical trial evidence confirms the efficacy and safety of β-blockers in patients with heart failure (HF) caused by systolic dysfunction. β-Blockers are recommended in national HF guidelines as standard of care therapy. Yet there is also a large body of evidence demonstrating that the use of β-blockers for HF is seriously inadequate under conventional care. This HF treatment gap is due, in part, to the persistence of perceptions—despite recent evidence to the contrary—that β-blocker therapy should be delayed until HF patients have been titrated to target doses of angiotensin-converting enzyme inhibitors and have been stable for at least 2 to 4 weeks after hospital discharge, and that early β-blocker initiation results in a substantial risk of worsening HF. Conversely, recent clinical trial evidence substantiates that β-blockers significantly reduce the risk of mortality and morbidity, including hospitalization for worsening HF, and have produced early survival benefits in patients with HF. It has also become evident that in-hospital initiation of lifeprolonging cardiovascular therapies, including β-blockers, has a positive impact on clinical outcomes and on longterm patient compliance. Overwhelming clinical evidence suggests that β-blockers should be administered to all stable HF patients without contraindication and that this therapy should be initiated as soon as possible to ensure that patients derive early and long-term improvements in clinical outcomes.     

β-blockers in stage B: a precursor of heart failure

β-blockers are an important treatment of heart failure (HF) and are useful in reducing the progression of the syndrome. They should be considered for patients with asymptomatic left ventricular (LV) dysfunction. Evidence-based β-blocker therapy (bisoprolol, carvedilol, or metoprolol succinate) in combination with standard therapy is a mainstay of treatment of all symptomatic patients with LV systolic dysfunction. Patients in stage B also benefit from the early introduction of β-blockers, but there are no large randomized clinical trials to support this strategy. Whether there is a role for ivabradine in the treatment of HF is not clear.     

Beta-blockers to prevent symptomatic heart failure in patients with stage A and B heart failure

β-blockers have been well-studied in the treatment of the symptomatic stages of chronic heart failure. Frequently physicians treat patients with asymptomatic left ventricular (LV) dysfunction and patients with hypertension on β-blockers without clear evidence that there is value in doing so. Chronic heart failure poses an extraordinary economic burden; any effective therapy that limits the progression to symptomatic heart failure can probably reduce monetary expenditures in addition to potentially reducing morbidity and mortality. In this article, we review the available literature on using β-blockers in stage A and B heart failure to prevent progression to the symptomatic stages. The literature reveals that there is no benefit in using β-blockers to treat essential hypertension. In patients who experience LV dysfunction post-myocardial infarction, even if asymptomatic, there is improved mortality and a trend toward a reduction in progression to symptomatic heart failure. In patients with asymptomatic chronic LV dysfunction there are data that β-blockers reduce LV dimensions and improve ejection fraction. Patients with hypertension should not be given β-blockers as primary treatment. All patients with asymptomatic LV dysfunction should be treated with a β-blocker, regardless of whether they experienced myocardial infarction.     

Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF): rationale and design

Heart failure (HF) affects >5 million patients in the United States, and its prevalence is increasing every year. Despite the compelling scientific evidence that angiotensin-converting enzyme inhibitors and β-blockers reduce hospitalizations and mortality rates in patients with HF, these lifesaving therapies continue to be underused. Several studies in a variety of clinical settings have documented that a significant proportion of eligible patients with HF are not receiving treatment with these guideline-recommended, evidence-based therapies. In patients hospitalized with HF, who are at particularly high risk for re-hospitalization and death, the initiation of β-blockers is often delayed because of concern that early initiation of these agents may exacerbate HF. Recent studies suggest that β-blockers can be safely and effectively initiated in patients with HF before hospital discharge and that clinical outcomes are improved. The Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial demonstrated that pre-discharge initiation of carvedilol was associated with a higher rate of β-blocker use after hospital discharge, with no increase in hospital length of stay. In addition, there was no increase in the risk of worsening of HF. Studies of hospital-based management systems that rely on early (pre-discharge) initiation of evidence-based therapies for patients with cardiovascular disease have also found increases in post-discharge use of therapy and a reduction in the rates of mortality and hospitalization. On the basis of these pivotal studies, the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) program is designed to improve medical care and education of hospitalized patients with HF and accelerate the initiation of evidence-based HF guideline recommended therapies by administering them before hospital discharge. A registry component, planned as the most comprehensive database of the hospitalized HF population focusing on admission to discharge and 60- to 90-day follow-up, is designed to evaluate the demographic, pathophysiologic, clinical, treatment, and outcome characteristics of patients hospitalized with HF. The ultimate aim of this program is to improve the standard of HF care in the hospital and outpatient settings and increase the use of evidence-based therapeutic strategies to save lives.     

Prevention and reversal of LV remodeling with neurohormonal inhibitors

Opinion statement Left ventricular (LV) remodeling refers to alterations in ventricular mass, chamber size, and shape that result from myocardial injury, pressure, or volume overload. Numerous studies have demonstrated that LV remodeling correlates with the incidence of heart failure and death, supporting a causative role for remodeling in heart failure progression. Heart failure trials have shown that neurohormonal antagonists, including angiotensin-converting enzyme (ACE) inhibitors and β-adrenergic receptor blockers (β blockers), reduce remodeling in parallel with improved clinical outcomes. Existing data favor using angiotensin II type 1 (AT1) receptor antagonists (or “ARBs”), although their anti-remodeling effects are less well established. Recently, mineralocorticoid receptor antagonists have gained substantial interest based on favorable clinical trial results, although data regarding their effects on remodeling are limited. Thus, an optimal medical regimen to prevent or limit LV remodeling in patients with LV dysfunction should include both an ACE inhibitor and β-adrenergic receptor antagonist, irrespective of the degree of LV dysfunction and symptom status. For patients intolerant to ACE inhibitors, an AT1 receptor antagonist should be substituted. An aldosterone antagonist should be administered to patients with severe, New York Heart Association class III to IV heart failure who have normal or only mildly impaired renal function, or to those patients with depressed LV function following an acute myocardial infarction. Through the aggressive pharmacologic inhibition of both the renin-angiotensin-aldosterone and sympathetic nervous systems, progressive LV remodeling can be prevented or hindered, thereby favorably altering the natural history of the heart failure syndrome.     

Realities of Newer β-Blockers for the Management of Hypertension

β-blockers are prescribed for a variety of cardiovascular conditions including hypertension, heart failure, primary treatment of myocardial infarction (MI), and secondary prevention of ischemic cardiac events. Yet they remain underprescribed in populations at increased risk for cardiovascular disease because of tolerability and safety concerns. β-Blockers are heterogeneous with respect to pharmacokinetic and pharmacodynamic effects. "Original" agents were nonselective, blocking both β₁-adrenoceptors and β₂-adrenoceptors. Later, new agents were developed with selectivity for β₁-adrenoceptors, and were subsequently followed by β-blockers, which exhibit additional effects, such as vasodilation. Among newer agents, labetalol, carvedilol, and nebivolol have been approved for use in the United States. Nebivolol possesses both β₁-selectivity and nitric oxide–mediated vasodilatory effects, while carvedilol has attractive effects on insulin resistance and exhibits antioxidant effects. Newer β-blockers may overcome concerns about efficacy, adverse effects, and tolerability, while delivering cardiovascular protection.     

A Modern Perspective on β-Blocker Use in Hypertension: Clinical Trials and Their Influence on Clinical Practice

National guidelines recommend β-blockers as second step agents after diuretic therapy in patients without compelling indications despite little clinical trial evidence of cardiovascular outcome benefits in uncomplicated essential hypertension. In high-risk patients with hypertension, such as those with a previous myocardial infarction or diabetes, heart failure, or coronary artery disease, β-blockers have been shown to reduce the risk of cardiovascular mortality and to reduce events beyond those ascribed to blood pressure (BP) lowering. The use of a β-blocker-based regimen in patients with diabetes has been shown to reduce cardiovascular mortality, progression of diabetic nephropathy, and stroke. Lowering BP in hypertensive patients is a primary goal, but it is also essential that goal BP be achieved with the fewest adverse consequences (ie, by choosing agents that do not worsen concomitant conditions or cause unacceptable side effects). Physicians must consider issues of possible worsening insulin resistance and dyslipidemia associated with some β-blockers. These metabolic concerns, however, are not an issue for the combined β-/αblocker carvedilol. This review highlights historical data and important clinical trials that underscore the importance of β-blockade in specific patients and delineates situations where β-blockers benefit patients with hypertension and/or cardiovascular disease.     

Aldosterone receptor blockers in the treatment of heart failure

Opinion statement Heart failure is associated with neurohormonal activation, including activation of the renin-angiotensin-aldosterone system. Plasma aldosterone levels are elevated in patients with heart failure in spite of the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers because of angiotensin-independent stimuli for aldosterone production. In addition to its long recognized role in sodium retention, aldosterone has a number of other deleterious effects, including the increase in myocardial and vascular fibrosis and myocardial remodeling in patients with heart failure. Based on strong clinical trial data, low-dose aldosterone receptor blockers are recommended to improve morbidity and mortality in patients with severe chronic heart failure due to left ventricular systolic dysfunction and in patients with heart failure associated with left ventricular systolic dysfunction after acute myocardial infarction, and in patients already on standard therapy including ACE inhibitors (or angiotensin receptor blockers) and β blockers. In view of the potential for serious hyperkalemia with the use of aldosterone receptor blockers, it is essential to monitor serum potassium closely and to adjust the dose of aldosterone antagonists based on serum potassium levels. Close adherence to the dosing regimens used in the clinical trials (RALES [Randomized Aldactone Evaluation Study] and EPHESUS [Eplerenone Post-AMI Heart Failure Efficacy and Survival Study]) is recommended. These agents should not be initiated in patients with severe renal insufficiency and closer monitoring is warranted in those with mild to moderate renal insufficiency or diabetes.     

Use of beta blockers in patients with post-MI left ventricular dysfunction

Opinion statement β Blockers have been shown to reduce mortality after myocardial infarction (MI) in several large trials. Despite strong evidence supporting the role of β blockers in treating patients after MI, less than half are prescribed these drugs. The majority of studies demonstrating efficacy of β blockers in the treatment of the post-MI patients were conducted at a point in time when left ventricular (LV) dysfunction was considered a strong contraindication to their use. In addition, when these studies were carried out a variety of therapies that are known to improve survival were not yet available. In the present era, β blockers are routinely used to treat patients with heart failure due to systolic dysfunction. Until recently, however, there was uncertainty about their role in the management of patients with LV dysfunction after MI. The recent CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) study demonstrated a significant mortality benefit when carvedilol was added to standard therapy in patients with LV dysfunction after MI. This article reviews information regarding the initiation and maintenance of β blockers in patients with post-MI LV dysfunction.     

Carvedilol's antiarrhythmic properties: therapeutic implications in patients with left ventricular dysfunction

Carvedilol is a beta- and alpha-adrenergic-blocking drug with clinically important antiarrhythmic properties. It possesses anti-ischemic and antioxidant activity and inhibits a number of cationic channels in the cardiomyocyte, including the HERG-associated potassium channel, the L-type calcium channel, and the rapid-depolarizing sodium channel. The electrophysiologic properties of carvedilol include moderate prolongation of action potential duration and effective refractory period; slowing of atrioventricular conduction; and reducing the dispersion of refractoriness. Experimentally, carvedilol reduces complex and repetitive ventricular ectopy induced by ischemia and reperfusion. In patients, carvedilol is effective in controlling the ventricular rate response in atrial fibrillation (AF), with and without digitalis, and is useful in maintaining sinus rhythm after cardioversion, with and without amiodarone. In patients with AF and heart failure (HF), carvedilol reduces mortality risk and improves left ventricular (LV) function. Large-scale clinical trials have demonstrated that combined carvedilol and angiotensin-converting enzyme inhibitor therapy significantly reduces sudden cardiac death, mortality, and ventricular arrhythmia in patients with LV dysfunction (LVD) due to chronic HF or following myocardial infarction (MI). Despite intensive neurohormonal blockade, mortality rates remain relatively high in patients with post-MI and nonischemic LVD. Recent trials of implantable cardioverter-defibrillators added to pharmacologic therapy, especially beta blockers, have shown a further reduction in arrhythmic deaths in these patients.     

Beta-adrenergic blocking agents in heart failure

Cardiac dysfunction in heart failure is widely recognized as a progressive process, regardless of the clinical signs and symptoms. An increase in cardiac sympathetic drive is one of the earliest neurohormonal responses occurring in patients with heart failure and may be one of the major causes of the progressive remodeling leading to the decline in myocardial function, and responsible for the poor prognosis of patients with heart failure. Therefore, recent data provided by several appropriately designed clinical trials clearly indicate the benefits of beta-adrenoceptor blocking agents, combined with diuretics, ACE inhibitors, and digoxin in chronic heart failure class II to IV due to systolic ventricular dysfunction. The benefits are related to symptoms, functional capacity, remodeling, and improvement in left ventricular function, reduction in cardiovascular hospitalization, a decrease in the overall and sudden cardiac death rate, and are similar in patients with ischemic or nonischemic cardiomyopathy, independent of age, gender, or functional class. In this review we describe the cardiovascular effects of the increase in sympathetic drive, the pharmacological properties of the beta-blockers most evaluated in heart failure therapy (metoprolol, bisoprolol, and carvedilol), the major clinical trials related to these agents in heart failure, the recommendations for their appropriate use in clinical practice, the precautions to be adopted, and how to handle the more common adverse reactions.     

Long-term effect of β-blocker in ST-segment elevation myocardial infarction in patients with preserved left ventricular systolic function: a propensity analysis

The current guidelines for acute myocardial infarction (AMI) recommended that β-blocker should be used in patients with decreased left ventricular (LV) systolic function for long-term period. However, the effect of β-blocker in AMI patients with preserved LV systolic function is uncertain. We sought to assess the long-term effect of β-blocker in AMI patients with preserved LV systolic function. During the follow-up period (1997–2011), total 3508 patients were performed percutaneous coronary intervention (PCI). Of these patients, 424 AMI patients with preserved LV systolic function [ejection fraction (EF) > 40 %] were analyzed. Median follow-up period was 4.7 years. Then, patients were divided into two groups (β-blocker group 197 patients and no-β-blocker group 227 patients). However, there are substantial differences in baseline characteristics between two groups. Therefore, we calculated propensity score to match the patients in β-blocker and no-β-blocker groups. After post-match patients (N = 206, 103 matched pair), β-blocker therapy significantly reduced cardiac death compared with no-β-blocker [hazard ratio (HR) 0.40, p = 0.04], whereas β-blocker therapy was not associated with major adverse cardiac events (MACE) and all-cause death. β-Blocker is an effective treatment for AMI patients who underwent PCI with preserved LV systolic function.     

Long-term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction

OBJECTIVES: This study was designed to evaluate whether in vivo caspase inhibition can prevent myocardial contractile protein degradation, improve myocardial function, and attenuate ventricular remodeling. BACKGROUND: Apoptosis is thought to play an important role in the development and progression of heart failure (HF) after a myocardial infarction (MI). However, it is not known whether inhibiting apoptosis can attenuate left ventricular (LV) remodeling and minimize systolic dysfunction. METHOD: A 28-day infusion of caspase inhibitor (n = 12) or vehicle (n = 9) was administered to rats immediately after an anterior MI. In addition, five sham-operated rats given the caspase inhibitor were compared with 17 untreated sham-operated animals to study effects in non-MI rats. Left ventricular function, remodeling parameters, and hemodynamics were studied four weeks later. Myocardial caspase 3 activation and troponin-I contractile protein cleavage were studied in the non-infarct, remote LV myocardium using Western blots. Apoptosis was assessed using immunohistochemistry for activated caspase-positive cells as well as the TUNEL method. Collagen volume was estimated using morphometry. RESULTS: Caspase inhibition reduced myocardial caspase 3 activation. This was accompanied by less cleavage of troponin-I, an important component of the cardiac contractile apparatus, and fewer apoptotic cardiomyocytes. Furthermore, caspase inhibition reduced LV-weight-to-body-weight ratio, decreased myocardial interstitial collagen deposition, attenuated LV remodeling, and better preserved LV systolic function after MI. CONCLUSIONS: Caspase inhibition, started soon after MI and continued for four weeks, preserves myocardial contractile proteins, reduces systolic dysfunction, and attenuates ventricular remodeling. These findings may have important therapeutic implications in post-MI HF.     

The latest generation of beta-blockers: New pharmacologic properties

β-Blockers have generally demonstrated smaller reductions in cardiovascular events, compared with other antihypertensive classes, despite similar reductions in blood pressure. This may be due to the ineffectiveness of traditional β-blockers, such as atenolol, in reducing central aortic pressure, a strong, independent predictor of cardiovascular outcome. However, the β-blocker class is heterogeneous, and some newer β-blockers, which exhibit vasodilatory effects independent of β-blockade, provide beneficial effects on arterial stiffness and endothelial dysfunction, which may lead to reductions in central aortic pressure and improvements in clinical outcomes. For example, the vasodilating β-blocker nebivolol was shown to improve forearm blood flow and arterial stiffness and, in a large clinical study, to significantly reduce morbidity and mortality, independent of left ventricular ejection fraction, among patients with chronic heart failure. Further research is warranted to investigate any potential differences between traditional and newer vasodilating β-blockers on cardiovascular outcomes.     

Carvedilol administration in acute myocardial infarction results in stronger inhibition of early markers of left ventricular remodeling than metoprolol

Background

The structural secuelae of acute myocardial infarction (AMI) is mostly dictated by left ventricular (LV) remodelling, leading to heart failure. Monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a critical role in LV remodelling.β-blockers are first line therapy for AMI and heart failure; however, the mechanisms responsible for their benefits remain poorly understood. Different β-blocker agents have been shown to exert beneficial activities both in AMI and heart failure, however, their role in early remodelling after ischemia/reperfusion is to be fully elucidated.We sought to compare the effect of 2 of the most prescribed β-blocker agents in early markers of LV remodelling after AMI.

Methods

A reperfused AMI was induced in Yorshire pigs, being randomized to early intravenous carvedilol, metoprolol or placebo. Twenty-four hours after reperfusion markers of early remodelling were addressed in the LV.

Results

The early administration of both β-blockers is able to significantly reduce macrophage infiltration as well as the expression and activity of MCP-1 and MMP-2 compared to placebo. The effects of carvedilol were much stronger than those of metoprolol. Conversely, carvedilol upregulated the expression TIMP-2 to a greater extent than metoprolol.

Conclusions

In an AMI model closely mimicking human pathophysiology, the early administration of carvedilol reduced the expression of markers associated with early LV remodelling to greater extent than metoprolol. These findings may explain the superior clinical benefits exerted by carvedilol in heart failure.     

Left atrial remodelling contributes to the progression of asymptomatic left ventricular systolic dysfunction to chronic symptomatic heart failure

Systolic heart failure (HF) is a progressive disorder that often begins with asymptomatic left ventricular (LV) systolic dysfunction and culminates in symptoms from fluid overload and poor end-organ perfusion. The progression to symptomatic HF is accompanied by marked activation of neurohormonal and cytokine systems, as well as a series of adaptive LV anatomical and functional changes, collectively referred to as LV remodelling. However, the mechanisms underlying symptom appearance have not been delineated and the weight of experimental and clinical evidence suggests that the development of symptomatic HF occurs independently of the haemodynamic status of the patient. The left atrium is a muscular chamber strategically located between the left ventricle and the pulmonary circulation with important mechanical function (modulation of LV filling), which is closely coupled with its endocrine (atrial natriuretic peptide synthesis and secretion) and regulatory (contribution to the control of sympathetic activity and vasopressin release) functions. In this narrative review we provide evidence supporting the concept that left atrial dilation and systolic dysfunction (left atrial remodelling) contributes to the progression of asymptomatic LV dysfunction to chronic symptomatic systolic HF as it is a prerequisite for the development of the pulmonary congestion and marked neuronhormoral activity that characterize the symptomatic state.     

Glucagon‐like Peptide‐1 and Myocardial Protection: More than Glycemic Control

Pharmacologic intervention for the failing heart has traditionally targeted neurohormonal activation and ventricular remodeling associated with cardiac dysfunction. Despite the multitude of agents available for the treatment of heart failure, it remains a highly prevalent clinical syndrome with substantial morbidity and mortality, necessitating alternative strategies of targeted management. One such area of interest is the ability to modulate myocardial glucose uptake and its impact on cardioprotection. Glucose‐insulin‐potassium (GIK) infusions have been studied for decades, with conflicting results regarding benefit in acute myocardial infarction. Based on the same concepts, glucagon‐like peptide‐1‐[7–36] amide (GLP‐1) has recently been demonstrated to be a more effective alternative in left ventricular (LV) systolic dysfunction. This paper provides a review on the current evidence supporting the use of GLP‐1 in both animal models and humans with ischemic and nonischemic cardiomyopathy. Copyright © 2009 Wiley Periodicals, Inc.     

Heart failure following anterior myocardial infarction: an indication for ventricular restoration, a surgical method to reverse post-infarction remodeling

Anterior myocardial infarction produces abrupt left ventricular (LV) dysynergy and global systolic dysfunction. Rapid intense neurohumoral activation, infarct expansion, and early ventricular chamber dilatation all contribute to restoring a normal stroke volume despite a persistently depressed ejection fraction. Continued neurohumoral activation provokes late remodeling of the remote non-infarcted myocardium, characterized by an abnormal progressively increasing LV volume/mass ratio that leads to further LV remodeling.Heart failure is a progressive disorder of LV remodeling. Heart failure from post-infarction remodeling is unique because of the persistent non-functioning scar that self- perpetuates abnormal loading conditions and neurohumoral activation. Medical therapy attenuates remodeling and improves survival but does not change the size of the scar. Surgical ventricular restoration to exclude the non-functioning infarct from the ventricular cavity decreases ventricular volumes, increases global ejection fraction, attenuates neurohumoral activation and yields an excellent 5-year survival. Combined medical and surgical therapy is recommended in this patient population.     

Heart Failure Following Anterior Myocardial Infarction: An Indication for Ventricular Restoration,a Surgical Method to Reverse Post-Infarction Remodeling

Anterior myocardial infarction produces abrupt left ventricular (LV) dysynergy and global systolic dysfunction. Rapid intense neurohumoral activation, infarct expansion, and early ventricular chamber dilatation all contribute to restoring a normal stroke volume despite a persistently depressed ejection fraction. Continued neurohumoral activation provokes late remodeling of the remote non-infarcted myocardium, characterized by an abnormal progressively increasing LV volume/mass ratio that leads to further LV remodeling.Heart failure is a progressive disorder of LV remodeling. Heart failure from post-infarction remodeling is unique because of the persistent non-functioning scar that self- perpetuates abnormal loading conditions and neurohumoral activation. Medical therapy attenuates remodeling and improves survival but does not change the size of the scar. Surgical ventricular restoration to exclude the non-functioning infarct from the ventricular cavity decreases ventricular volumes, increases global ejection fraction, attenuates neurohumoral activation and yields an excellent 5-year survival. Combined medical and surgical therapy is recommended in this patient population.