CHRONIC INHIBITION OF PYRUVATE DEHYDROGENASE KINASE WITH DICHLOROACETATE, IMPROVES CARDIAC METABOLISM AND FUNCTION IN RIGHT VENTRICULAR HYPERTROPHY IN FAWN-HOODED RATS

Abstract

Background: Right ventricular failure (RVF) is the leading cause of death in patients with pulmonary hypertension (PH). We previously showed that chronic administration of the pyruvate dehydrogenase kinase inhibitor (PDKi), dichloroacetate (DCA), increases glucose oxidation and improves cardiac output and contractility in monocrotaline-induced PH/RVH. We also showed that acute treatment with DCA (for 40 minutes) improves glucose oxidation and cardiac work in monocrotaline-induced RVH. We hypothesize that chronic treatment of DCA will also improve glucose oxidation and cardiac function in RV in Fawn-Hooded rats (FHR), a rat that spontaneously develops PH. Methods and Results: Two groups of rats were used: FHR and age-matched FHR with chronic DCA treatment (0.75g/L in drinking water for 6 months). DCA reduced PH (evident by lengthening of the pulmonary artery acceleration time from 12.7±1.2 to 22.4±1.9 ms, P<0.01). DCA increased cardiac output (78.6±12.6 to 114.9±7.6 ml/min; P<0.05), stroke volume (178.3±37.4 to 339.5±23.3 ml; P<0.05), treadmill distance (170.5±22.4 to 239.1±19.5 m; P<0.01). Using a Seahorse Extracelluar Flux Analyzer to measure metabolism in isolated RV cardiomyocytes, DCA tended to increase glucose oxidation from 16.0±3.5 to 21.2±5.3 pM/(min∗μg) (P>0.05) and reduce glycolysis from 3.1±0.9 to 1.5±0.3 mPH/ (min∗μg) (P>0.05) in isolated myocytes in FHR. Using a dual isotope technique however DCA did significantly increase RV glucose oxidation from 170.5±22.4 to 239.1±19.5 nM/(min∗g) (P<0.001). Conclusion: DCA improves PH, cardiac function and exercise capacity in FHR. There is a statistically insignificant trend toward improvement of glucose oxidation and inhibition of glycolysis in isolated myocytes and this is associated with a significant increase in glucose oxidation in the RV working heart. Metabolic function has not been previously measured in the FHR RV. The current study suggests PDKi may be a potential therapeutic strategy for PH and RVF.