Elevated systemic vascular resistance in
heart failure causes further depression of cardiac function. Decreased systemic vascular resistance, on the other hand, is associated with an improvement in cardiac performance. Thus, peripheral
vasodilators, irrespective of their mechanism of action, have the potential to improve cardiac function in
heart failure. Increased peripheral vascular tone appears to result from a number of interrelated neuroendocrine dysfunctions--an activated renin-angiotensin-aldosterone system, inappropriate release of
arginine vasopressin, and enhanced systemic and cardiac sympathetic activity (indicated by increased levels of circulating
norepinephrine and markedly increased cardiac
norepinephrine release). Augmented sympathetic activity may not only increase systemic vascular resistance but can also induce myocardial cellular dysfunction. Furthermore, downregulation of cardiac beta-
adrenoceptors may contribute to inadequate cardiac performance. Reduction of sympathetic tone and upregulation of the beta-
adrenoceptors is the rationale for beta-blocker
therapy in
heart failure and, indeed, cardioselective beta-blockers improve cardiac function in some patients with
dilated cardiomyopathy. Third-generation beta-blockers, such as
celiprolol, possess both cardioselective and peripheral vasodilatory properties and are therefore potentially beneficial in
heart failure.