Normal mechanical function of the heart requires that ATP be continuously synthesized at a hydrolysis potential of roughly -60 kJ mol-1. Yet in both the aging and diseased heart the relationships between cardiac work rate and concentrations of ATP, ADP, and inorganic phosphate are altered. Important outstanding questions are: To what extent do changes in metabolite concentrations that occur in aging and heart disease affect metabolic/molecular processes in the myocardium? How are systolic and diastolic functions affected by changes in metabolite concentrations? Does metabolic energy supply represent a limiting factor in determining physiological maximal cardiac power output and exercise capacity? Does the derangement of cardiac energetics that occurs with heart failure cause exercise intolerance?
To answer these questions, we have developed a multi-physics multi-scale model of cardiac energy metabolism and cardiac mechanics that simulates the dependence of myocardial ATP demand on muscle dynamics and the dependence of muscle dynamics on cardiac energetics. Model simulations predict that the maximal rate at which ATP can be synthesized at free energies necessary to drive physiological mechanical function determine maximal heart rate, cardiac output, and cardiac power output in exercise. Furthermore, we find that reductions in cytoplasmic adenine nucleotide, creatine, and phosphate pools that occur with aging impair the myocardial capacity to synthesize ATP at physiological free energy levels, and that the resulting changes to myocardial energetic status play a causal role in contributing to reductions in maximal cardiac power output with aging. Finally, model predictions reveal that reductions in cytoplasmic metabolite pools contribute to energetic dysfunction in heart failure, which in turn contributes to causing systolic dysfunction in heart failure.