Pathophysiology of heart failure: identifying targets for pharmacotherapy.

Recent advances in our understanding of the pathophysiology of heart failure have greatly increased the number of potential targets for therapy. The most important of these advances was the recognition that a major goal of therapy should be to modify long-term proliferative responses, as well as to achieve short-term functional improvement. This conclusion emerged from several clinical trials which showed that correction of functional abnormalities in these patients, although often of immediate clinical value, can worsen long-term prognosis. Although vasodilators alleviate the disability that is caused by excessive afterload, most increase long-term mortality: similarly, although inotropic drugs provide immediate relief of symptoms and are useful as temporary support in patients with damaged hearts, most inotropes also shorten long-term survival. Treatment of chronic heart failure should not be targeted simply at the signs and symptoms noted by Withering. Instead, a major goal of therapy should be to slow progression by modifying maladaptive growth responses in the failing heart, which were unknown when Withering discovered that digitalis can alleviate the signs and symptoms of heart failure. New targets for treatment, therefore, include the maladaptive proliferative signaling cascades that cause progressive ventricular dilatation (remodeling) and hastens cardiac cell death. The ability to inhibit maladaptive proliferative signaling in patients with heart failure was greatly enhanced by the rapid pace of discovery in molecular biology. New understanding of the ability of neurohumoral mediators, such as norepinephrine and angiotensin II, to stimulate remodeling, apoptosis, and other deleterious features of the hypertrophic response has opened important areas for research into the causes and therapy of heart failure. Similarly, potential roles for cell adhesion molecules, cytokines, and peptide growth factors in activating maladaptive proliferative responses suggests additional targets for therapy. This and other new information regarding signal transduction pathways, notably the many crossovers between functional and proliferative signaling, provide promising opportunities in this rapidly advancing area of study.