Metabolic regulation of myocardial perfusion in the aging heart

PROJECT SUMMARY Advanced age is the leading risk factor for all chronic diseases. It is associated with a host of genetic, immunologic, and physiologic changes that contribute to progressive tissue dysfunction and an increased risk of mortality. Although many hallmarks of aging have been identified, a key physiological feature of aging is

decreased tissue perfusion and an inability to match perfusion to the metabolic requirements of organ function. The impacts of such deficits in perfusion are more pronounced in tissues with high oxygen demand; hence, due to its high energy demand, the heart is particularly vulnerable to perfusion deficits. Acute increases in myocardial

demand, such as those due to increased physical activity, are met by an increase in perfusion (i.e., hyperemia). This increase in myocardial perfusion is triggered by metabolic signals that evoke coronary vasodilation. Our recent work shows that increases in O2 demand in cardiomyocytes modify the pyridine nucleotide redox potential

(i.e. elevates NADH:NAD) in coronary arterial smooth muscle cells, which stimulates voltage-gated K+ (Kv) channel activity to promote vasodilation. Inhibition of this heterocellular signaling results in hypoperfusion and acute pump failure during stress. We propose that disruption to this signaling is the key mechanism underlying

the progressive age-dependent loss of coupling between myocardial metabolism and coronary vascular tone. Moreover, because cardiac output is essential for adequate perfusion and function of all peripheral tissues, diminished cardiac function at high workloads (e.g., during exercise) likely contributes to widespread dysfunction

and could explain the pervasive deleterious effects of aging. Our preliminary data show that aged mice have reduced myocardial perfusion, impaired diastolic and systolic function, and lower exercise capacity compared with sex-matched young mice. Consistent with cardiac metabolic remodeling as an underlying cause of these

changes, recapitulating the metabolic profile of the aged significantly blunts work-dependent paracrine redox signals to the vasculature, and suppresses the hyperemic response, consistent with a loss of redox-dependent Kv channel stimulation. Furthermore, acute interventions that decrease cardiomyocyte carbohydrate metabolism

(ketone body infusion) rescue myocardial perfusion in aged mice. Based on these preliminary data, we hypothesize that age-dependent changes in myocardial metabolism suppress pyridine nucleotide redox- dependent K+ efflux in vascular smooth muscle, leading to progressive uncoupling of coronary perfusion from

myocardial workload. Accordingly, our specific aims are to: (1) delineate age-dependent changes in cardiac metabolism, myocardial perfusion, and left ventricular function; (2) assess the impact of changes in myocardial glucose metabolism on redox-dependent myocardial hyperemia; and (3) determine the efficacy of myocardial

metabolic interventions to prevent age-dependent exercise intolerance and cardiac remodeling. This project will elucidate the mechanism underlying a key physiological defect associated with aging and provide new insights into how this defect could be attenuated to prolong cardiovascular health and function over the lifespan.