The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle

Abstract

Background Right ventricular hypertrophy (RVH) and RV failure contribute to morbidity and mortality in pulmonary arterial hypertension (PAH). The cause of RV dysfunction and the feasibility of therapeutically targeting the RV are uncertain. We hypothesized that RV dysfunction and electrical remodeling in RVH result, in part, from a glycolytic-shift in the myocyte, caused by activation of pyruvate dehydrogenase kinase (PDK). Methods and Results We studied 2 complementary rat models: RVH+PAH (induced by monocrotaline) and RVH+without PAH (induced by pulmonary artery banding, PAB). Monocrotaline-RVH reduced RV O2-consumption and enhanced glycolysis. RV 2-fluoro-2-deoxy-glucose uptake, Glut-1 expression and pyruvate dehydrogenase phosphorylation increased in monocrotaline-RVH. The RV monophasic action potential duration and QTc-interval were prolonged due to decreased expression of repolarizing voltage-gated K+ channels (Kv1.5, Kv4.2). In the RV working-heart model, the PDK inhibitor, dichloroacetate, acutely increased glucose oxidation and cardiac work in monocrotaline-RVH. Chronic dichloroacetate therapy improved RV repolarization and RV function in vivo and in the RV Langendorff model. In PAB-induced RVH, a similar reduction in cardiac output and glycolytic shift occurred and it too improved with dichloroacetate. In PAB-RVH the benefit of dichloroacetate on cardiac output was ~1/3 that in monocrotaline-RVH. The larger effects in monocrotaline-RVH likely reflect dichloroacetate’s dual metabolic benefits in that model: regression of vascular disease and direct effects on the RV. Conclusion Reduction in RV function and electrical remodeling in 2 models of RVH relevant to human disease (PAH and pulmonic stenosis) result, in part, from a PDK-mediated glycolytic shift in the RV. PDK inhibition partially restores RV function and regresses RVH by restoring RV repolarization and enhancing glucose oxidation. Recognition that a PDK-mediated metabolic shift contributes to contractile and ionic dysfunction in RVH offers insight into the pathophysiology and treatment of RVH.

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

“…In a monocrotaline-induced model of RVH and failure, DCA, a PDK inhibitor, reduced cardiac hypertrophy and improved cardiac output as measured in vivo. 88 In a working heart model, DCA acutely improved cardiac function and increased glucose oxidation rates. DCA induced a threefold increase in glucose oxidation rates, whereas glycolysis increased by a mere 25%.…”

Cyclophilin D controls mitochondrial pore–dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice

“…We hypothesize that the mitochondrial calcium-mediated increase in PDH activity may account for the observed elevation in glucose oxidation. For example, inhibition of PDH kinase, which increases PDH activity, enhances glucose oxidation in rat heart (30).…”

Clinical and histopathological relationship of sildenafil and bosentan treatments in rats with monocrotaline induced pulmonary hypertension

“…Cisternaes of sarcoplasmic reticulum are regions, where calcium is deposited. Intracelular calcium levels are increased in PAH, as the result of a decrease in voltage gates Kv channels (Kv1.5 and Kv4.2), which are responsible for repolarization in right ventricular myocytes (24,25). Broadening of cisternaes of rough sarcoplasmic reticulum is observed in rats, in which PAH is developed, and this may be due to the increase in calcium depositions in order to increase cardiac contractility.…”