Abstract 2362: Dichloroacetate Reverses the Impaired Cardiac Function and the Electrical Remodeling in Right Ventricular Hypertrophy by Inhibiting Pyruvate Dehydrogenase Kinase
Background: Right ventricular hypertrophy (RVH) and subsequent dysfunction is commonly caused by right ventricular outflow obstruction or pulmonary artery hypertension. In this study, we explore a link between depressed RV function, delayed cardiac repolarization and impaired metabolism in RVH induced by monocrotaline or pulmonary artery banding (PAB). We hypothesize that a glycolytic shift in RVH causes RV dysfunction and electrical remodeling through the activation of pyruvate dehydrogenase kinase (PDK). The therapeutic efficacy of the PDK inhibitor, dichloroacetate, is also assessed.
Methods and Results: In monocrrotaline model, a single injection of monocrotaline (60mg/Kg) was performed in order to produce RVH 4-weeks later in Sprague-Dawley rat (200~240g). In PAB model, 1.6 mm constrictor was placed at main pulmonary artery of the rat. Dichloroacetate (70mg/Kg) was added into drinking water 10 days after monocrotaline injection or the same day after PAB. Monocrotaline caused pulmonary hypertension and RVH. RV O2-consumption was reduced while glycolysis, measured by dual isotope technique in a working heart model, was enhanced. Positron emission tomography (PET) showed increased RV 2-fluoro-2-deoxy-glucose uptake. RV Glut-1 expression and pyruvate dehydrogenase phosphorylation increased. MAPD and QTc-interval were prolonged due to decreased expression of repolarizing voltage-gated K+ channels (Kv1.5 & Kv4.2). Dichloroacetate increased glucose oxidation, resulting in regression of RVH, increased cardiac output (CO) and reversal of electrical remodeling. Likewise, after 8 weeks of PAB, PAB caused RVH, decreased CO and induced the same metabolic changes. In PAB, dichloroacetate decreased RVH, restored cardiac function, and improved metabolism.
Conclusion Although increased afterload initiates RVH, reduction in RV function and MAPD prolongation result, in part, from a PDK-mediated glycolytic shift. PDK inhibition improves RV function, regresses RVH and restores repolarization by enhancing glucose oxidation. Recognition that the RV dysfunction in RVH is a form of hibernating myocardium offers pathophysiologic clarity and suggests new therapeutic targets.