Title: Multi-Scale Systems Analysis of Metabolic and Mechanical Determinants of Reserve Cardiac Power Output Abstract: Exercise capacity, a central factor in determining quality of life in healthy aging as well as cardiovascular disease, is determined by a systems-level interaction of factors that are intrinsic to the heart and myocardium and factors that are extrinsic to the heart. Cardiac intrinsic factors include the metabolic power supply and mechanical pumping power of the myocardium. Extrinsic factors include the capacity of the peripheral vasculature to vasodilate in response to increasing demands of exercising musculature and the autonomic chemo- and baroreflexes. The overarching goals of this proposal are to capture and test hypotheses on the mechanisms that determine physiological limitations to cardiac power and output reserve and contribute to diminished left-ventricular power output (LVPO) and exercise intolerance in heart failure (HF). The research plan uses a computational modeling approach to simulate whole-body cardiovascular function, driven by a multi-scale model of myocardial metabolism and mechanics, to analyze data from a battery of phenotyping assessments applied to healthy control subjects and heart failure patients. The first aim of this proposal is to develop and refine the multi-scale framework for simulating whole-body exercise and cardiac energetics and mechanics in humans. This platform will be applied to integrate individual-specific data for testing and refinement of hypotheses in Aims 2 and 3. Subject-specific model parameterization will be used to: (1.) assess the relative contributions of cardiac intrinsic versus peripheral factors in limiting exercise capacity in heart healthy control and failure subjects; (2.) test the hypothesis that the capacity of the myocardium to do mechanical work is limited by its capacity to maintain ATP and its hydrolysis products ADP and Pi at concentrations needed to support contraction and relaxation; and (3.) test the hypothesis that in patients with impaired capacity to maintain these concentrations at physiological levels, this impairment is causally linked to a diminished capacity of the myocardium to do mechanical work.