Quantifying the Contribution of Cardiomyocyte Metabolic Dysfunction to the Heart Mechanical Function

Abstract

Hydrolysis of ATP provides the chemical free energy to drive the molecular processes underlying cardiac pumping. Under normal conditions the heart hydrolyzes and resynthesizes the entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the chemical potential (free energy of ATP hydrolysis) at which ATP is synthesized and is made available to drive cellular processes. We hypothesize that this metabolic/energetic dysfunction causes contractile dysfunction of the myocardium in heart failure, contributing to the whole‐body phenotype (venous congestion, exercise intolerance) of heart failure in humans. To test this hypothesis, we used a rat transverse aortic constriction (TAC) model of cardiac decompensation/heart failure to measure the relationships between functional parameters (cardiac output, ejection fraction, etc.) and myocardial energetic state, determined based on measurements of myocardial metabolite pools and mitochondrial oxidative capacity. Cardiac function was measured by echocardiography and hearts were harvested for mitochondrial isolation and phosphate metabolite measurements at the end‐point, either 15 weeks post‐surgery, or 18 weeks post‐surgery. Cardiac phosphate metabolites levels were measured using NADH dependent enzymatic assays and mitochondrial oxidative capacity was measured using an Oroboros O2k Oxygraph. In both cohorts of rats, there was an overall reduction in fatty acid and carbohydrate oxidative capacity, with an increase in the ratio of maximal carbohydrate to fatty acid oxidative capacity in the 18‐week TAC rats compared to sham controls. In addition, we also observed differences in phosphate metabolite levels in both 15‐week TAC and 18‐week TAC rats compared to controls and correlations between metabolite mechanical functional changes. Furthermore, we used multi‐scale computational models of myocardial metabolism and metabolic state‐dependent contractile dynamics to quantify the contribution of reductions in oxidative capacity and metabolite pools levels to heart mechanical function. Our results suggest that there is a causal link between a reduction in free energy of ATP hydrolysis and kinetic impairment of the myosin ATPase cross‐bridge cycle in decompensated hypertrophy/heart failure.Support or Funding InformationFunded by NIH Grants 5T32GM008322‐28 and U01HL122199This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.