Impaired Myocardial Energetics Contributes To Mechanical Dysfunction In Decompensated Failing Hearts

Cardiac mechanical function is supported by ATP hydrolysis which provides the chemical free energy to drive the molecular processes underlying cardiac pumping. Physiological rates of myocardial ATP consumption require the heart to resynthesize its entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the chemical potential at which ATP is synthesized is available to drive cellular processes. The objective of this study is to determine how metabolic/energetic dysfunction that occurs during heart failure affects mechanical function of the heart. Specifically, we hypothesize that changes in phosphate metabolite concentrations (ATP, ADP, inorganic phosphate) that are associated with decompensation and failure have direct roles in impeding contractile function of the myocardium in heart failure, contributing to the whole-body phenotype. To test this hypothesis, a transverse aortic construction (TAC) rat model of pressure overload, hypertrophy, and decompensation was used to measure relationships between metrics of whole-organ pump function and myocardial energetic state. At week 18 post-surgery cardiac pump function was measured by echocardiography before hearts were harvested for both mitochondrial purification and phosphate metabolite measurements. Results show an overall reduction in capacity for oxidative ATP synthesis fueled by either fatty acid or carbohydrate substrates in myocardium from TAC animals compared to sham-operated controls. Changes in phosphate metabolite levels in the TAC rats were correlated with impaired mechanical function, consistent with our overall hypothesis. Furthermore, analysis based on a multi-scale computational model of myocardial metabolism and contractile dynamics predicts that these correlations are causal in that buildup of ATP hydrolysis products kinetically impairs the myosin ATPase crossbridge cycle in decompensated hypertrophy/heart failure.