Åke Hjalmarson, M.D., Ph.D., and Sidney Goldstein, M.D., Guest Editors
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From Hypertension to Heart Failure: What Have We Learned? [PDF]
P. W. F. Wilson, M.D.
Hypertension is associated with an increased risk for heart failure, stroke, and end-stage renal disease. The mechanisms involved in progression from hypertension to heart failure have been the focus of many recent studies. In addition, we have learned much from epidemiologic studies that have helped identify risk factors for hypertension and have thus provided insight into mechanisms that are involved in the pathogenesis of this disease. This paper will consider the epidemiology of both hypertension and heart failure and their relationship with left ventricular hypertrophy. In addition, results of recent clinical trials of antihypertensive agents will be reviewed.
Prevention of Sudden Cardiac Death with Beta Blockers [PDF]
Å. Hjalmarson, M.D., Ph.D.
Beta blockers have been shown to reduce the risk of sudden cardiac death in more than 50 randomized trials involving more than 55,000 patients. Relative reductions (vs. placebo) in cardiac death in some of these trials ranged from 30 to 50%. These reductions are substantially gresses including angiotensin-converting enzyme inhibitors. However, not all beta blockers confer equal benefit to patients at risk of sudden cardiac death. Results from various trials suggest that lipophilic beta blockers--such as timolol, metoprolol, propranolol, bisoprolol, and carvedilol--may be more beneficial than hydrophilic beta blockers. Results of animal studies have indicated that sudden cardiac death is mediated, at least in part, by the central nervous system, which may account for why lipophilic agents have more pronounced clinical effects. Based on the results of numerous clinical and mechanistic studies, it is suggested that beta blockers should be given to all patients at risk for sudden cardiac death, including those patients with previous myocardial infarction, hypertension, or congestive heart failure.
The Cellular and Physiologic Effects of Beta Blockers in Heart Failure [PDF]
Hani N. Sabbah, Ph.D.
Enhanced and sustained cardiac adrenergic drive occurs in heart failure (HF) and contributes, in part, to the progression of left ventricular (LV) dysfunction and remodeling that are characteristic of this disease state. Enhanced sympathetic drive in HF can lead to downregulation and desens receptors with a consequent impairment of myocardial reserve and exercise tolerance. This sympathoadrenergic maladaptation can also lead to cellular abnormalities in the failing heart, manifested by defects in calcium handling of the sarcoplasmic reticulum, by defects in myocardial energetics, and by ongoing loss of cardiomyocytes through necrosis or apoptosis. Chronic treatment with beta blockers in patients with HF and in animals with experimentally induced HF has been shown to reverse, prevent, or, at the least, arrest many, if not all, of these adverse processes. Beta blockers improve function of the failing LV, prevent or reverse progressive LV dilation, chamber sphericity, and hypertrophy, and consequently have positive impact on cardiac remodeling. Beta blockers also reduce heart rate and LV wall stress, leading to reduced myocardial oxygen consumption, a clear benefit to the failing heart. Beta blockers can also improve the intrinsic contractile function of cardiomyocytes and have also been shown to improve myocardial energetics in HF, possibly through desirable changes in substrate utilization. Recent studies from our laboratories have also shown that beta blockers can attenuate cardiomyocyte apoptosis in HF. These benefits provide strong reinforcement to the clinical findings that beta blockers are highly beneficial for the management of patients with chronic HF and, when properly used, afford unequivocal reductions in mortality and morbidity in this patient population. At present, there is general agreement that increased cardiac sympathetic drive occurs in HF and may potentially be an important contributor to the progression of LV dysfunction and chamber remodeling that is characteristic of this disease state. Experimental studies in animal models of HF1 as well as clinical studies in patients with HF have suggested that chronic therapy with beta blockade is effective in preventing the progression of LV dysfunction and remodeling, the latter evidenced by reversal and/or prevention of progressive LV dilation and chamber sphericity. Results of recent multicenter clinical trials support these findings and have made it abundantly clear that long-term therapy with beta blockade inhibits clinical progression and has a major impact on mortality and morbidity in patients with HF that is at least as favorable, if not better, than that observed with angiotensin-converting enzyme (ACE) inhibitors. Beta blockers improve mortality and morbidity in HF and also improve LV ejection fraction (EF), a beneficial feature that, until recently, has only been attributed to positive inotropic agents.
Experience with Beta Blockers in Heart Failure Mortality Trials [PDF]
E. J. Eichhorn, M.D.
Recent investigations have indicated that chronic heart failure can be reversed with agents that inhibit the renin-angiotensin-aldosterone or sympathetic nervous system, such as angiontensin-converting enzyme (ACE) inhibitors and beta blockers. A meta-analysis of clinical trials of ACE inhiborted reductions in mortality ranging from 13 to 33%, but as ACE inhibitors do not block chronic noradrenergic stimulation of the heart, mortality remains unacceptably high. Beta blockers have been shown to increase left ventricular ejection fraction, reduce end-systolic and end-diastolic cardiac dimensions, improve quality of life, and reduce mortality. All-cause mortality in the US Carvedilol trial was reduced 65%, and in MERIT-HF there was a 49% reduction in mortality from heart failure among patients receiving metoprolol CR/XL. MERIT-HF was ended early because of evidence of survival benefit. Although certain effects of beta blockers may be considered class effects, it is not yet clear whether there are differences between beta1- selective antagonists and nonselective agents. The benefits conferred across differences in disease severity, race, and age should be answered as large ongoing and planned clinical trials of beta blockers are completed.
The Mortality Effect of Metoprolol CR/XL in Patients with Heart Failure: Results of the MERIT-HF Trial [PDF]
S. Goldstein, M.D., and Å. Hjalmarson, M.D., Ph.D.
The study was undertaken to investigate the effect of metoprolol CR/XL on all-cause mortality in patients with heart failure in New York Heart Association (NYHA) class IIIV. In all, 3,991 patients in NYHA class IIIV who were stable on standard sin-converting enzyme inhibitors, diuretics, and digitalis, were randomized to metoprolol CR/XL or placebo and uptitrated from 12.5 or 25 mg to 200 mg over an 8-week period and were planned to be followed for a period of 2 years. The study was stopped earlier than planned due to the significant benefit achieved with metoprolol CR/XL on all-cause mortality. Treatment with metoprolol CR/XL was associated with a 34% decrease in all-cause mortality, 38% decrease in cardiovascular mortality, 41% decrease in sudden death, and 49% decrease in death due to progressive heart failure. The average dose of metoprolol CR/XL at the end of the study was 159 mg, and 64% of the patients were receiving 200 mg of metoprolol CR/XL. There was no significant difference in the placebo and active treatment group with regard to permanent discontinuation. Treatment of patients in NYHA class IIIV with metoprolol CR/XL is associated with a significant decrease in total mortality.
This supplement is based on the proceedings of the satellite symposium entitled, Back to the Future: A New Era for Beta Blockade in Management of Heart Failure presented at the Annual Meeting of the American College of Cardiology (ACC) on March 6, 1999. The symposium and this publication were supported by an educational grant from AstraZeneca Pharmaceuticals.
The opinions expressed in this presentation are those of the panelists and are not attributable to the sponsor or the publisher, editor, or editorial board of Clinical Cardiology. Clinical judgment must guide each physician in weighing the benefits of treatment against the risk of toxicity. References made in the articles may indicate uses of drugs at dosages, for periods of time, and in combinations not included in the current prescribing information.