TAMOXIFEN AND CORONARY HEART DISEASE

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DESCRIPTION (Adapted from Applicant's Abstract): Coronary heart disease (CHD) is the leading cause of death among women, although knowledge about interventions that increase or decrease CHD risk among postmenopausal women is limited. Tamoxifen is used widely for the treatment of breast cancer. There is epidemiologic evidence that tamoxifen reduces CHD risk in postmenopausal women with breast cancer, however, supporting data are sparse and the mechanisms by which tamoxifen affects CHD risk remain undetermined. Knowledge of the effects of tamoxifen on CHD risk becomes important in postmenopausal women who are at increased risk for CHD, but do not take estrogen replacement therapy because of concerns about the increased risk of breast cancer associated with unopposed estrogen replacement therapy. This is a randomized trial comparing 5 treatment groups (control, tamoxifen, Premarin, Provera, Premarin + Provera) of surgically postmenopausal female monkeys fed an atherogenic diet designed to mimic the average total plasma cholesterol concentration of women in the United States. The primary objective of the studies proposed is to examine the effects of tamoxifen on mechanisms of CHD (coronary artery atherosclerosis [CAA], arterial thrombosis, and vasospasm). The second objective of these studies is to determine the potential of tamoxifen to replace conventional estrogen replacement therapy with respect to CHD risk. The goal of each specific aim is to determine the effects of tamoxifen on one mechanism of CHD and then compare these effects with those of conventional estrogen treatment. The specific aims are: 1) to determine if, and to what extent, treatment inhibits progression of CAA; 2) to determine the effects of treatment on expression of certain cytokines and growth factors in arteries; 3) to quantify and characterize the effects of treatment on plasma lipoprotein distribution; 4) to determine the effects of treatment on vascular responsiveness of coronary arteries and the mechanisms by which treatment modulates vascular responsiveness; 5) to determine the effects of treatment on arterial thrombosis and growth factor production in injured arteries of high risk female monkeys.