Substantial evidence exists regarding the favorable influence of estrogen on cardiovascular outcomes in women. These favorable effects extend beyond those explained by estrogen effects on lipid profile and other recognized risk factors. Accumulating evidence strongly supports these favorable outcome are in part due to direct effects of estrogen on estrogen receptors expressed in cardiovascular tissues, including both the vascular and myocardium. Attenuating the untoward effects of current hormone replacement strategies on non-cardiovascular tissues such as uterus and breast by development of tissue selective estrogen modulators (SERMS) will likely provide novel strategies for the treatment of bone, neurologic, and cardiovascular diseases. Raloxifene, the first SERM approved, was released recently for prevention of osteoporosis, but data, including new data presented in the SCOR (Project 3) support that raloxifene also directly activates the estrogen receptors now know to be expressed in the cardiovascular system. This project will examine the effects of raloxifene on parameters of cardiovascular structure and function in a population of post-menopausal women who have had a myocardial infarction (MI). We will test the hypothesis that raloxifene directly and favorable influences cardiovascular function following MI, in four Specific Aims that examine indices of: (1) left ventricular remodeling, (2) endothelial function, (3) autonomic tone and neurohormonal activation and (4) vulnerability to ventricular arrhythmias. The influence of raloxifene on these four parameters will be studied in a randomized, placebo-controlled, among post-menopausal women with MI and left ventricular dysfunction. We will also examine, through serial blood samples, specific estrogen receptor-related biochemical and genetic markers with the potential to influence these cardiovascular endpoints. Genetic data collected will directly complement the studies proposed in the Framingham population in SCOR Project 1 and may provide a starting point for pharmacogenic selection of therapies in future patients. This study directly and prospectively tests the overall SCOR hypothesis in a human population and will further our understanding of the underlying mechanisms by which estrogen receptor modulation may diminish the burden of cardiovascular diseases and their sequelae in women. Moreover, this study initiates an area of clinical investigation with potential implications for the therapy of ischemic cardiovascular disease sin both women and men.
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