(Adapted from the applicant's abstract) This application describes a 5-year career development training program for Dr. Kim Brownley. The program includes extensive research and pedagogical training designed to facilitate her growth as an independent researcher investigating combination modality therapies in high-risk cardiac patient populations. The plan is structured around a randomized placebo-controlled study of raloxifene and aerobic exercise training in hypertensive postmenopausal women. Dr. Kathleen Light, whose expertise is in cardiovascular stress responses, hypertension, and hormone (estrogen) replacement therapy (HRT), will serve as mentor. A collaborative support team is also in place, including: 1) Dr. James Blumenthal, who specializes in exercise training interventions in coronary heart disease (CHD); and 2) Alan Hinderliter, M.D. (Cardiology consultant), who will provide training in ultrasound measurement of cardiovascular function, and oversee data interpretation from a clinical perspective. The proposed study will investigate cardiovascular, neuroendocrine, and metabolic functioning in borderline and stage I hypertensive postmenopausal women. This patient group is at increased CHD risk due to elevations in blood pressure (BP), insulin resistance, and low-density lipoproteins. HRT and exercise training can offset these harmful effects by enhancing vasodilatory processes, and their effects may be additive when combined. HRT improves cardiovascular and neuroendocrine function; yet despite these benefits, HRT use and compliance are low because of added cancer risks in some women. Raloxifene, a second-generation nonsteroidal selective anti-estrogen, has beneficial lipid and osteogenic effects but does not confer added cancer risks. However, the cardiovascular effects of raloxifene are unspecified. Also, HRT has only modest BP-reducing effects and is thus insufficient antihypertensive therapy for hypertensive postmenopausal women. In contrast, exercise training has robust BP-reducing potential, especially in hypertensive individuals. Therefore, after all subjects complete a 3-month intervention with raloxifene alone, they will be randomized to either an additional 3-month treatment with raloxifene alone or treatment with raloxifene plus exercise training. Pre- and post-treatment assessments will include: 1) impedance cardiography measures of hemodynamic responses to laboratory challenge, 2) 24-hour ambulatory BP and impedance cardiography monitoring, 3) echocardiography assessment of left-ventricular geometry and function, 4) B-mode ultrasound assessment of flow-mediated brachial artery dilatation, 5) assay of neuroendocrine and lipid levels at rest and in response to laboratory stress, and 6) euglycemic insulin clamp to assess insulin sensitivity. Implementation of this training will provide a unique and highly advantageous opportunity for Dr. Brownley to work with this team of senior scientist- practitioners within the collaborative environments of the University of North Carolina and Duke University. This investigation, coupled with the didactic experiences outlined in this plan, will lay the foundation for her future endeavors as a scientific advocate for the systematic investigation of underlying mechanisms of hypertensive heart disease, and for the delivery of effective combination behavioral and pharmacological interventions for stress- related cardiovascular disorders in patients at increased risk for CHD.
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