The research proposed in this application employs measurements of myocardial blood flow (MBF) with 13N ammonia and PET in patients with coronary risk factors but without coronary artery disease in order to detect noninvasive alterations in coronary vasoreactivity as likely events early in the evolution of coronary atherosclerosis. Specifically, it will test with adenosine the total integrated coronary vasomotor function and, more specifically, through responses of MBF to cold pressor testing the predominantly endothelial dependent coronary vasoreactivity. The past and preliminary observations support the feasibility of this approach for exploring coronary vasomotion. PET based measurements are unique to this study because MBF measurements in absolute units are required which are not possible with more conventional approaches in two types of patients, one with insulin resistance and Type-II-Diabetes and a second one of postmenopausal women with coronary risk factors. In the diabetic patients the applicants will also determine coronary artery calcium scores with EBCT in order to compare alterations in vasomotor function and structural changes as well as their time dependent progression and whether the possible progression of insulin resistance to Type-II-Diabetes can be demonstrated and whether rigorous anti-diabetic control possibly in conjunction with lipid lowering can retard this progression. In the postmenopausal women, the applicants will explore protective effects of estrogens and examine whether this effect is negated or modified by progestins and its different forms and further, whether adequate protection requires addition of statins and anti-oxidants. If successful, the observation could lay the foundation for larger prospective clinical trials and, most importantly, provide new insights into the early atherogenic process as well as possibilities to beneficially influence its progression.
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