Abstract 20289: Impaired Ventricular Function and Glucose Oxidation in Right Ventricular Hypertrophy Reflect Reduced Pyruvate Dehydrogenase and are Improved by Dichloroacetate, an Inhibitor of Pyruvate Dehydrogenase Kinase
Introduction: Right ventricular failure (RVF) is the major cause of death in patients with pulmonary hypertension. There are no approved therapies to specifically treat RVF 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. Here we studied the relative effects of DCA on glucose and fatty acid oxidation in the Fawn-Hooded rat, a strain that spontaneously develops PH and RVH.
Methods and Results: Two groups of rats were used: control (age-matched Sprague-Dawley rats, CTR), and Fawn-Hooded rats (FHR). PH was confirmed by decreased pulmonary artery acceleration time corrected by heart rate on Pulse Doppler (FHR, 0.08±0.01; CTR, 0.11±0.00 ms*min/beats, P<0.05) and increased RV/LV+septum ratio (FHR, 0.30±0.02; CTR, 0.22±0.01, P<0.001). The expression of pyruvate dehydrogenase beta subunit was reduced 35% in FHR (P<0.05) and there was a trend toward increased PDK4 expression in the RV. Cardiac metabolism and the effects of DCA were evaluated in isolated working hearts. Glucose oxidation was decreased in FHR vs CTR [FHR, 432±73; CTR, 1030±175 nmol/(g*min), P<0.01] and glycolysis was increased [FHR, 3219±226; CTR, 2468±198 nmol/(g*min), P<0.05]. Fatty acid oxidation was slightly decreased in FHR. DCA (1 mM), added to the perfusate, caused a 3.6-fold increase in glucose oxidation (P<0.001) and decreased glycolysis in FHR hearts. This was accompanied by a 2.6-fold reduction in proton production (P<0.01). DCA also significantly decreased fatty acid oxidation by 44% (P<0.05). Acetyl-CoA production and ATP production were reduced in FHR vs Control (P<0.01 and P<0.05, respectively). DCA increased both acetyl CoA and ATP production in FHR (P<0.05). Due to the improvement of glucose oxidation in FHR, cardiac work increased in a time-dependent manner towards the end of 40 min perfusion with DCA.
Conclusions: RVH is associated with reduced PDH and increased PDK expression. The PDKi, DCA improves glucose oxidation and reduces glycolysis and fatty acid oxidation in FHR RVH, suggesting that PDKi may be a promising therapy for RVF.
- © 2010 by American Heart Association, Inc.