Neurohormonal activation, oxygen free radicals, and apoptosis in the pathogenesis of congestive heart failure.

Abstract

A variety of pathophysiologic processes are activated in patients with congestive heart failure (CHF), and some of these have been implicated in the progression of the disease. The most important processes to be activated in CHF are the neurohormonal systems, which include the renin-angiotensin system, the sympathetic nervous system, and the endothelin system. In addition to the neurohormonal systems, the formation of reactive oxygen free radicals is increased in patients with CHF. It has been postulated that stimulation of neurohormonal pathways and the formation of oxygen free radicals ultimately lead to the activation of a family of transcription factors that are involved in cardiac remodeling, which is a hallmark of CHF. In addition, the formation of oxygen free radicals has been implicated in the process of apoptosis or programmed cell death, which may be responsible for a continued loss of myocardial cells, resulting in the progressive decrease in left ventricular function that occurs over time in patients with CHF. Carvedilol is a multiple-action neurohormonal antagonist that is effective in slowing the progression of CHF. In double-blind, placebo-controlled clinical trials, carvedilol decreased mortality by 65% (p <0.001) and significantly reduced hospitalization. Carvedilol is a nonselective beta-blocker and vasodilator, the latter activity resulting from alpha1-adrenoceptor blockade. The hemodynamic responses produced by carvedilol result primarily from the blockade of beta1-, beta2-, and alpha1-adrenoceptors. Carvedilol reduces total peripheral vascular resistance and preload without significantly compromising cardiac output or eliciting reflex tachycardia. Carvedilol is also a potent antioxidant that may protect the myocardium from damage produced by oxygen radicals and, as a consequence of its antioxidant activity, carvedilol also inhibits apoptosis in the myocardium. The ability of carvedilol to inhibit apoptosis in the heart may be responsible, in part, for the ability of the drug to reduce mortality and to inhibit the progression of CHF.