The long-term objective of this application is to identify the structural and functional pathogenetic mechanisms responsible for the onset, development, and progression of the congestive dilated cardiomyopathy of the aged heart. Aging is assumed to occur when the growth reserve capacity of the coronary vasculature is reduced or exhausted resulting initially in a decreased oxygenation potential of the tissue and subsequently in cell loss, scar formation, increased deposition of collagen in the interstitial space and finally impairment of cardiac function. Experiments will be performed to answer the following questions: (a) What is the sequence of structural events in the entire coronary vasculature that leads to local ischemia with myocyte loss in the ventricle? (b) Are the changes in the quantitative parameters of the coronary circulation accompanied by similar changes in the distribution of coronary blood flow (CBF) in the myocardium? (c) How do myocardial damage and repair affect cardiac function? Since coronary atherosclerosis is a major risk factor in the old population, a slowly progressive constriction of the left coronary artery will be performed to establish whether: (d) the growing heart, during maturation, is capable of compensating a mild coronary artery constriction by duplicating intramural vessels in order to reduce coronary resistance and maintain adequate flow and function; and (e) coronary narrowing in adult aging rats potentiates the aging process by inducing more severe tissue damage, impairment of CBF and ventricular dysfunction. A third set of experiments will evaluate the influence of hypertension on the aging myocardium to demonstrate whether: (f) hypertension-induced hypertrophy consumes at an early stage of life the vascular reserve of the coronary bed with a precocious appearance of the injurious events of the aging process. A fourth group of experiments will examine the protective action of captopril on aging alone, and in combination with coronary artery narrowing or hypertension to establish whether: (g) drugs which reduce the workload on the heart and limit myocyte hypertrophy can maintain a more frequently efficient proportion between the muscle mass and the coronary vasculature so that the cardiovascular adaptation to the aging process can be altered favorably and chronically.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Pulmonary Research A Study Section (CVA)
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New York University
Schools of Medicine
New York
United States
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Leri, Annarosa; Rota, Marcello; Pasqualini, Francesco S et al. (2015) Origin of cardiomyocytes in the adult heart. Circ Res 116:150-66
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Leri, Annarosa; Anversa, Piero (2013) Stem cells and myocardial regeneration: cooperation wins over competition. Circulation 127:165-8

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