This Program Project renewal represents a multidisciplinary approach to the problem of myocardial hypertrophy and heart failure. The physiological models will also be utilized for biochemical, molecular biological and pathological studies. Project #1 represents a continuation of studies directed by Dr. S. Vatner on alterations in LV function induced by LV hypertrophy and failure. These studies will be supported by the effort of Dr. I. Mirsky, a mathematical biophysicist. During the last Program Project period, abnormal mechanisms of LV systolic and diastolic function and myocardial perfusion were identified in LV hypertrophy and failure. The current renewal contains experiments designed to assess the mechanisms of these abnormal findings and to determine whether these abnormalities are unique to the aortic banding pressure overload or also exist in other models of hypertrophy and failure, e.g., pacing-induced heart failure. Of particular importance are the joint specific aims between Project 1 and Project 2 examining altered mechanisms of beta-adrenergic receptor signalling in the hypertrophied and failing heart and the extent to which these abnormalities result in altered physiological responsiveness to sympathomimetic amines and exercise. Other major goals of this Program Project are to examine alterations in molecular biology in hypertrophy and heart failure and to pursue molecular mechanisms of the altered beta- adrenergic signalling. This involves a collaborative effort between Projects 2 and 3 utilizing the laboratories of Drs. B. Nadal-Ginard, along with those of Drs. D. Vatner, C. Homcy and T. Wagner. A major additional component of the renewal will be Project 4 led by Dr. R. Shannon, which focuses on the control of the coronary circulation in the hypertrophied and failing heart. The combined effort of this group of physiologists, biochemists and molecular biologists working closely together will provide further understanding of important mechanisms involving altered myocardial and coronary vascular function and gene expression in the hypertrophied and failing myocardium.
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