Endothelium as a therapeutic target in heart failure.

Patients with chronic heart failure are characterized by systemic vasoconstriction and reduced peripheral perfusion, which are thought to contribute to the impaired exercise capacity in this disorder. Whereas an increased sympathetic tone and an activated renin-angiotensin system have been proposed to be involved in the reduced vasodilator capacity in heart failure, the important role of the endothelium in coordinating tissue perfusion has not been recognized until recently. Recent clinical studies have documented impaired endothelium-dependent relaxations of peripheral resistance and conduit arteries in patients with chronic heart failure, most likely due to impaired availability of nitric oxide (NO). On the other hand, the endothelial production of vasoconstricting factors1 such as angiotensin II or endothelin appears to be increased in severe heart failure. Whereas numerous important functions of the endothelium have been recognized in the past, many recent experimental and clinical studies have focused on endothelium-derived NO, probably because one of its main functions, vascular relaxation, can easily be assessed in humans in vivo. NO is a potent endogenous vasodilator and appears to be responsible for the maintenance of basal vascular tone; it is also thought to exert other important effects, such as inhibition/modulation of platelet aggregation, leukocyte adhesion, cell respiration, and apoptosis. The mechanisms of the actions of NO include activation of second messengers such as cGMP, direct effects on redox-sensitive regulatory proteins, and interactions with reactive oxygen species. Impaired endothelium-dependent vascular relaxation has been documented in virtually all cardiovascular disorders and appears to occur early in the course of cardiovascular disorders such as arteriosclerosis, diabetes mellitus, hypercholesterolemia, or hypertension. Impaired endothelium-dependent relaxation may be associated with alterations of other endothelial functions, such as adhesion of leukocytes or altered balance of profibrinolytic to prothrombotic activity; however, whether or not impaired endothelium-dependent relaxation always reflects a more general “endothelium dysfunction” remains …