EXCEED THE 8PAC6 PROVIDED. Cocaine use and HIV infection independently communicateincreased cardiovascular disease risk. Selenium deficiency has been observed in cocaine abusers and in HIV infected persons and is associated with risk for cardiovascular disease and cardiomyopathy. Selenium is a cofactor required in a biochemical pathway that decreases oxidative stress and facilitates vascular endothelial-dependent dilation. Oxidative stress is linked to atherogenesis and alterations in cardiac and vascular structure and function. Selenium also promotes insulin- glucose metabolism, enhancing insulin sensitivity, which is a critical substrate of the insulin metabolic syndrome. The insulinmetabolic syndrome is associated with alterations in cardiac structure/function and vascular endothelial function central to the pathogenesis of cardiovascular disease. Therefore, because selenium reduces oxidative stress and enhances insulin-glucose metabolism and cardiovascular function, the proposed study will examine the effect of selenium supplementation on cardiovascular disease risk in a randomized, double-blindtrial of HIV infected persons who are cocaine abusers. To control for the effect of substance abuse, these subjects will be compared with HIV infected persons with no history of illicit drug use. Selenium-treated compared with placebo-treated subjects are hypothesized to display diminished oxidative stress [8-epi-prostaglandin Fan] and improved insulin sensitivity, cardiac function [cardiac output, contractility, compliance, and wall stress], and vascular function [vascular endothelial-dependent and independent vasodilation,total peripheral resistance]. Consequently, diminished evidence ofcardiovascular disease risk as reflected by decreased abnormalities in the insulin metabolic syndrome is predicted. This project will examine 280 (of 400 randomized) HIV infected cocaine-abusing and non-drug using men and women. Measures of insulin metabolic syndrome [insulin sensitivity using the euglycemia-insulin clamp, central fat deposition, lipid metabolism, fibrinolytic function, blood pressure, sympathetic function, and cardiac structure] will be obtained pre-treatment, and 9 months and 18months post-treatment. We postulate that the unique impact of selenium on oxidative metabolic, vascular endothelial, and insulin-signaling mechanisms will decrease cardiovascular risk and provide critical insight into the mechanisms of cardiovascular pathogenesis in these at-risk populations.
