Abstract 5906: In Nonischemic Dilated Cardiomyopathy Glutamate Uptake is Associated with a Decrease in Maximal ATP Synthesis Flux
Myocardial glutamate uptake and alanine release have been reported to be increased in patients with coronary artery disease. However, in patients with nonischemic dilated cardiomyopathy (NIDCM) myocardial glutamate flux has not been well described. We employ Flux Balance Analysis (FBA), a systems based approach, to evaluate the role of glutamate and other metabolites in patients with NIDCM. We hypothesize that glutamtate is taken up by the myocardium in NICDM patients, but its uptake does not result in an increase in the maximal ATP synthesis flux. Blood was drawn from the radial artery and the coronary sinus from 16 male patients (mean age 57 +/− 17) with NIDCM (NYHA Class III and IV) undergoing biventricular ICD implantation, and plasma concentrations of oxygen, glucose, lactate, pyruvate, free fatty acids (FFA) and 22 amino acids were obtained. Metabolite fluxes, expressed as ratios to oxygen flux, were calculated. FBA, optimizing for ATP production and using measured fluxes as constraints, was performed with MetaFluxNet 1.8 on a metabolic network of the human cardiac mitochondria (189 reactions, 230 metabolites) which was previously reconstructed from published mitochondrial proteomic data (615 proteins) from human heart tissue. There was net myocardial uptake of glucose, free fatty acids, lactate, glutamate, aspartate (p < 0.05) and net myocardial secretion of alanine (p < 0.02) in NIDCM patients. FFA uptake correlated with glutamate uptake (R = 0.78, p < 0.0005). FBA demonstrated that glutamate uptake in NIDCM patients correlated with a decrease in maximal ATP synthesis flux (p < 0.035, mean −0.27% +/− 3.27%). Furthermore, contribution of FFA uptake to maximal ATP synthesis flux (mean 29.75% +/− 33.1%) correlated negatively with glucose uptake flux (R = −0.73, p < 0.002). In conclusion, NIDCM patients exhibit a net myocardial uptake of glucose, FFA, lactate, glutamate, and aspartate. In NIDCM patients with lower glucose uptake rates, the contribution of FFA uptake to maximal ATP synthesis flux is greater. Furthermore, in NIDCM patients, glutamate uptake correlates with a decrease in maximal ATP synthesis flux, which may represent a maladaptive metabolic state.