Heart failure: 20 years of progress

There have been remarkable advances in the diagnosis and treatment of heart failure during the past 20 years. The diagnosis of this condition has been impacted by the wide-scale adoption of 2-dimensional echocardiography and the recognition of B-type natriuretic peptide as a

biomarker. Heart failure treatment has also been revolutionized, from the mere management of congestive symptoms to the alteration of adverse neurohormonal activation and, more recently, to the development of biventricular pacing, implantable cardioverter-defibrillators, and left ventricular assist devices.

Diagnosis

In the past, the diagnosis of heart failure was made in patients with characteristic signs and symptoms predominantly resulting from fluid overload. A chest radiograph showing cardiomegaly and pulmonary congestion confirmed this clinical diagnosis. In the 1980s, the widespread availability of 2-dimensional echocardiography allowed for the evaluation of left ventricular size and systolic function, quantitated as the left ventricular ejection fraction. In patients with clinical heart failure, a reduced ejection fraction confirms the presence of a cardiac abnormality. This has become an important criterion for the diagnosis of heart failure. A reduced ejection fraction has served as an entry requirement for almost all of the pivotal clinical trials that provide the evidence that guides heart failure therapy. In the past decade, however, it has become clear that many patients with the typical syndrome of heart failure (40% or more) have a normal ejection fraction above 50%.1 These patients are often elderly and predominantly women. Understanding the pathophysiology and cause of heart failure in these patients and determining the optimal management technique is one of the current challenges.

Plasma B-type natriuretic peptide and its inactive cleavage product,

NT-B-type natriuretic peptide, recently have emerged as useful biomarkers.2 B-type natriuretic peptide and NT-B-type natriuretic peptide are elevated in most patients with decompensated heart failure. These biomarkers decrease in response to effective therapy and provide important prognostic information; thus, they appear to play an important role in the diagnosis and treatment of patients with heart failure. The full value and role of these and other potential biomarkers continue to be an important area of investigation.

Neurohormonal therapy

Twenty years ago, heart failure management focused on relieving symptoms of congestion with diuretics and improving cardiac output with digitalis and inotropic agents. Since then, there has been tremendous progress that has completely changed the way this condition is managed. The adverse consequences of neurohormonal activation in heart failure were first shown in animal studies and subsequently proved in many large randomized clinical trials. The neurohormonal pathways include the renin-angiotensin-aldosterone system and the beta-adrenergic system. Angiotensin-converting enzyme (ACE) inhibitors are now a mainstay for the treatment of heart failure. These drugs reduce mortality and hospitalizations, improve the quality of life, and delay the development of heart failure in patients with asymptomatic left ventricular dysfunction evidenced by a reduced ejection fraction.3 Treatment with ACE inhibitors is now indicated for patients with heart failure of all New York Heart Association (NYHA) functional classes and for those who are asymptomatic and have reduced ejection fractions.4

During treatment with an ACE inhibitor, angiotensin II may be produced by alternate pathways. The cardiovascular effects of angiotensin II—however it is produced—can be blocked with angiotensin II receptor blockers (ARBs). Despite the potential theoretical advantages of ARBs compared with ACE inhibitors, initial studies have not shown ARBs to be superior in patients with symptomatic heart failure or in those who have had a myocardial infarction (MI). Thus, ACE inhibitors remain the cornerstone of treatment for heart failure and for those who have had a large MI. ARBs are, however, an attractive alternative in those who cannot tolerate ACE inhibitors.5 Adding an ARB to an adequate dose of an ACE inhibitor may provide an additional benefit.6,7 Angiotensin stimulates the production of aldo-sterone, which stimulates sodium retention and potassium wasting, and is a powerful mediator of cardiac fibrosis. A substantial portion of aldosterone production occurs independent of angiotensin II and is not blocked by ACE inhibitors or ARBs.8 Adding aldosterone antagonists to ACE inhibitors has been found to be beneficial in patients with NYHA functional class III or IV heart failure and in those with heart failure after a large MI.9,10

One of the greatest advances in heart failure treatment during the past 20 years has been the use of beta blocking agents. Initially, it was thought that beta blockers were

contraindicated in these patients.

In fact, the infusion of beta-adrenergic agents was used to treat this condition. The beta1-specific beta blocker (sustained-release metoprolol)11 and the beta1, beta2, and alpha1 blocker (carvedilol), however, have been shown to improve survival

and left ventricular ejection frac-

tion and reduce hospitalizations.12-15 Thus, these beta-adrenergic blocking agents are indicated in all patients with NYHA functional class II to IV heart failure.4 The recently published Carvedilol Or Metoprolol European Trial (COMET) showed improved survival with carvedilol compared with short-acting metoprolol.16 Whether this observation applies to higher doses of long-acting metoprolol is not known.

Treating diastolic heart failure

Many patients with the typical syndrome of heart failure have a preserved left ventricular ejection fraction (> 50%).1 It has been assumed that heart failure is caused by a problem with filling, or diastolic heart failure, in these patients. The pathophysiology and mechanism of heart failure in these patients remain an area of active investigation. The recently completed Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved study is the only large, randomized, multicenter study of patients with diastolic heart failure.17 The results of this study suggest that treatment with the ARB candesartan may reduce hospitalizations, but not mortality, in these patients. Several other studies are currently evaluating ARBs, ACE inhibitors, and beta blockers in this population.

Other treatment methods

Twenty years ago, cardiac transplantation was becoming established as a viable treatment alternative for patients with end-stage heart failure. The number of transplants performed in the United States has plateaued at about 2,500 per year and is limited by the number of donors. Therefore, most patients

with end-stage heart disease cannot be treated with cardiac transplantation. As a result, attention has been focused on other mechanical and surgical interventions.

Many patients with heart failure have conduction disturbances that lead to dyssynchronous activation of the left ventricle. This produces an uncoordinated and inefficient contraction pattern, contributing to impaired cardiac performance. Bi-ventricular pacing or pacing of the left ventricle alone improves the synchronicity of left ventricular contraction, resulting in improved ejection fraction, exercise time, and quality of life.18 The recently completed Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial demonstrated that biventricular pacing with or without defibrillation reduces mortality and hospitalizations compared with medical therapy in patients with end-stage heart failure and conduction abnormalities.18

Other surgical therapies for advanced heart failure have also been developed. Left ventricular assist devices can be used in end-stage patients who are not candidates for transplantation. The Food and Drug Administration recently approved the limited use of these devices for patients with end-stage congestive heart failure. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial found a significant 2-year mortality benefit for the group treated with left ventricular assist devices compared with the medically treated group.19 However, the survival rate was only 23% in the device-treated arm and 8% in the medically treated group. Survival with left ventricular assist devices is limited by infection, stroke, and mechanical failure.

Conclusion

There have been substantial advances in the diagnosis and treatment of heart failure during the past 20 years. Echocardiography has provided a convenient means of evaluating left ventricular size and function, quantitated as the ejection fraction. This has also led to the recognition that many patients with heart failure have a normal ejection fraction. An understanding of the importance of neurohormonal activation in the development and progression of heart failure has led to the use of effective therapies centered

on blocking the renin-angiotensin-aldosterone system and the beta-adrenergic system. There have also been important developments with biventricular pacing, implantable cardioverter-defibrillators, and left ventricular assist devices.