SCOR IN ISCHEMIC HEART DISEASE IN BLACKS

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The Ischemic Heart Disease in Blacks Specialized Center of Research at Boston University School of Medicine will provide a multidisciplinary approach to the study of microvascular function and dysfunction relevant to the pathogenesis of cardiovascular disease in blacks. We postulate that the principal cardiovascular disorders common among blacks-- hypertension, left ventricular hypertrophy, and myocardial ischemia without epicardial coronary disease--result from a specific microvascular diathesis that is a direct consequence of nitric oxide insufficiency. This unifying theme for our proposal is based on the growing body of evidence that many of the features of the cardiovascular disorders that plague blacks derive from inadequate bioactive nitric oxide. The fundamental mechanism(s) underlying this nitric oxide insufficiency is a major focus of this program, and we propose to address this issue using a combination of approaches, including molecular and cellular studies, animal studies, and clinical patient studies. We make no a priori assumptions about whether inadequate nitric oxide in blacks is a primary or secondary event: evidence exists in support of a primary endothelial abnormality in nitric oxide production that precedes the development of vascular disease, and evidence exists to suggest that abnormalities in nitric oxide bioactivity also accompany the progression of vascular disease. The projects presented in this program will provide a means to assess the mechanisms for decreased elaboration of bioactive nitric oxide both prior to and following the development of a clinical vascular phenotype in man and in relevant animal models. Project 1 will test the hypothesis that microvascular endothelial cells generate insufficient nitric oxide in blacks, and will approach this problem by addressing potential abnormalities of synthesis or inactivation. Project 2 poses as its central hypothesis that impaired nitric oxide bioactivity can explain altered intracellular calcium homeostasis which accompanies the salt- sensitive state. Vascular function and ion channel studies in smooth muscle cells and platelets will be performed to address this question. In Project 3 the role of nitric oxide in modulating the potentially harmful effects of angiotensin II on the heart will be studied, with its principal hypothesis that angiotensin II can induce cardiac fibrosis in the absence of nitric oxide. Project 4 will focus on the responses of hypertrophic myocardium and coronary vasculature from salt-sensitive and/or nitric oxide-deficient rats to ischemia-reperfusion, and will attempt to reduce the extent of ischemia-reperfusion injury by selected pharmacologic and metabolic means. Clinical studies of vascular function in blacks and whites will be conducted in Project 5 to test the hypothesis that abnormal nitric oxide-mediated responses exist in blacks. Using in vivo approaches, these investigators will attempt to dissect the mechanism(s) underlying blunted nitric oxide action in the peripheral and coronary circulations of normotensive salt-sensitive individuals and hypertensive patients. Thus, with this broad spectrum of approaches centered around a well-developed vascular theme, this SCOR in Ischemic Heart Disease in Blacks should provide important new knowledge on the causes and consequences of vascular disease in blacks, and should lead to new approaches for its prevention and treatment.