Abstract 2623: Right Ventricular Hypertrophy in Monocrotaline-induced Pulmonary Hypertension is Associated with Impaired Oxidative Metabolism and Action Potential Prolongation

Abstract

Introduction: Right ventricular hypertrophy (RVH) and right ventricular failure are major determinants of prognosis and functional state in pulmonary artery hypertension (PAH). We previously found a mitochondrial metabolic shift in the pulmonary circulation in clinical as well as experimental PAH that includes a shift from oxidation to glycolysis, decreased production of reactive oxygen species (ROS) and normoxic activation of HIF-1α and decreased expression of voltage-gated potassium channels. In this study, we hypothesize that during RVH there is a similar metabolic shift in the RV characterized by impaired mitochondrial respiration and that the resulting electrical remodeling causes action potential prolongation. Methods and Results: PAH was induced in Sprague-Dawley rats by single injection of monocrotaline (60mg/Kg). At 3 weeks, PAH was confirmed by a shortened pulmonary artery acceleration time vs controls (13.8±0.7 vs 36.2±0.2 msec, P < 0.001) as determined by Doppler Echo. RVH was also evident, with a thicker right ventricular free wall in monocrotaline vs control hearts (1.3±0.1 vs 0.9±0.0 mm, P < 0.001 vs control) as assessed by two-dimensional and M-mode Echo. Oxygen consumption of right ventricular tissues (140mg samples) was measured using high-resolution respirometry. In an RV Langendorff model, RV systolic pressure (RVSP) and RV monophasic action potential duration (MAP) were measured. The ratio of RV/LV+S weight increased to 2 fold with monocrotaline (P < 0.001). RVSP in MCT group was increased to 50.9±10.6 vs 21.3±2.7 mmHg, P < 0.05). RV O2-consumption in RVH was significantly reduced vs control [144.1±37.6 vs 277.0±27.4 pmol/(sec*ml), P < 0.05]. The duration of 90% and 75% repolarization of MAP (MAPD90 and MAPD75) was markedly prolonged in RVH (145% and 136% vs controls; P < 0.001, P < 0.05, respectively). Importantly, MAPD90 increased in direct proportion to the severity of PAH, as measured by RVSP. Conclusions: RVH was associated with impaired RV metabolism as evidenced by reduced O2 consumption. This metabolic shift was associated with significant action potential prolongation in the RV. The consequences of this ionic remodeling for arrhythmogenisis and contractility remain to be determined.