Abstract 385: D-2-hydroxyglutaric acid Acutely Impairs Oxidative Decarboxylation in the Heart
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) have been described in low-grade glioma and in acute myeloid leukemia. Accumulation of the oncometabolite D-2-hydroxyglutaric acid (2HG) and its release into the blood is associated with dilated cardiomyopathy. The mechanisms leading to changes in cardiac metabolism and contractile function are unknown. We studied in the isolated working rat heart preparation metabolic consequences of increased 2HG supply and its impact on cardiac energy provision. In combination with physiological levels of glucose (5mM) and lactate (0.5mM), hearts were perfused at different concentrations with 2HG (0.5mM, 1.0mM). We confirmed the uptake and enrichment of 2HG in the tissue through liquid chromatography followed by mass spectrometry (LC/MS). 2HG markedly decreased cardiac power and cardiac efficiency in a concentration dependent manner. At the same time glucose oxidation increased significantly (1.4±0.1 μmol/min/g dry wt, p<0.05) at higher workloads. The alpha-Ketoglutarate Dehydrogenase activity was reduced by two-fold (2.84±0.56 μmol/min/g dry wt, p<0.01) and production of reactive oxygen species (e.g. H2O2) increased by three-fold (1.06±0.07 μmol/min/g dry wt, p<0.01) in presence of 2HG. Consistent with this reduction in oxidative decarboxylation, the cytosolic NAD+/NADH redox state increased (3.1±0.1, p<0.001), while the cellular energy charge declined (AMP:ATP ratio, 0.15±0.1, p<0.001). Together, our results demonstrate a direct impairment of cardiac energy substrate metabolism with a resulting decline in contractile function. The data suggests that 2HG directly suppresses cardiac function by specific metabolic alterations in a range of pathologies.
Author Disclosures: A. Karlstaedt: None. X. Zhang: None. H. Vasquez: None. M.A. Goodell: None. H. Taegtmeyer: None.
- © 2015 by American Heart Association, Inc.