Biologic rationale for the use of beta-blockers in the treatment of heart failure.

Enhanced and sustained cardiac adrenergic drive occurs in heart failure and contributes, in part, to the progression of left ventricular (LV) dysfunction and remodeling that are characteristic features of this disease state. Enhanced sympathetic drive in heart failure can lead to down-regulation and desensitization of cardiac beta-adrenergic 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 cycling within the sarcoplasmic reticulum, by defects in myocardial energetics and by ongoing loss of cardiomyocytes through necrosis or apoptosis. Sympathoadrenergic overdrive in heart failure can also trigger the induction of the fetal gene program, a maladaptation that can lead to further compromise of the contractile state. Chronic treatment with beta-blockers in patients with heart failure and in animals with experimentally-induced heart failure has been shown to reverse, prevent, or at the very 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 positively impact 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 heart failure possibly through a desirable shift in substrate utilization. Recent studies from our laboratories have also shown that chronic therapy with beta-blockers in heart failure can attenuate cardiomyocyte apoptosis. Finally, chronic therapy with beta-blockers has been shown to abrogate induction of the fetal gene program. These benefits provide strong reinforcement to the clinical findings that beta-blockers are highly beneficial in the management of patients with chronic heart failure and, when properly used, afford unequivocal reductions in mortality and morbidity in this patient population.