Abstract 3557: Mitochondrial Dysfunction Outweighs Beneficial Effects of Altered Substrate Selection in Heart Failure
During the development of heart failure, a switch from fatty acid to glucose oxidation has been considered beneficial for contractile function. However, such a mechanism would require intact mitochondrial function. We hypothesized that impairment in mitochondrial oxidative capacity may limit beneficial effects of altered myocardial substrate preference in the setting of overt heart failure. Male rats were subjected to pressure overload for 20 weeks using transverse aortic constriction. Following pressure overload, rats developed dyspnoea and pleural effusions, ventricular dysfunction (EF: 53±8 vs. 75±6% sham; p<0,05) and left ventricular dilatation (LVEDD 9,9±0,6 vs. 7,6±0,3; p<0,05), indicating decompensated heart failure. Cardiac power of isolated working hearts was markedly reduced in heart failure rats (2,9±0,5 vs. 9,0±0,8mW). Despite a relative shift towards increased glucose oxidation (glucose/fatty acid oxidation 0,72±0,26 vs. 0,43±0,12), absolute oxidation rates were reduced in isolated working failing hearts both for glucose (μmol/min/gdw: 0,16±0,03 vs. 0,38±0,08; p<0,05) and fatty acids (μmol/min/gdw: 0,28±0,04 vs. 1,02±0,04). Failing hearts were also unable to increase glucose oxidation in the presence of insulin (+0,25±0,04 vs. +0,88±0,16μmol;p<0,05). The reduction in oxidation rates was accompanied by marked impairment in maximal ADP-stimulated O2 consumption of isolated mitochondria from failing hearts (natomsO/min/mg protein: glutamate 200±16 vs. 585±92, palmitoyl-carnitine193±15 vs. 802±75, pyruvate 198±29 vs. 549±87, succinate 405±39 vs. 720±80; all p<0,05). Expression of PGC-1α, OXPHOS and fatty acid oxidation genes was reduced, and mitochondrial citrate synthase activity was decreased (U/g wet weight: 5,1±0,8 vs. 24,6±2,1). Thus, mitochondrial dysfunction may outweigh beneficial effects of preferential glucose oxidation by limiting overall oxidative capacity. This limited capacity may contribute to cardiac decompensation in late stage heart failure. Reduced abundance of mitochondrial substrate oxidative enzymes may underlie decreased oxidative capacity for any respiratory substrate, potentially resulting from PGC-1α mediated transcriptional downregulation.