Right ventricular maladaptive functional and electrical remodeling in male Fischer rats during progressive pulmonary...

Cardiac arrhythmias are suspected as a major cause of sudden cardiac death (SCD) in pulmonary arterial hypertension (PAH); however, the mechanisms underlying right ventricle (RV) electrical remodeling, arrhythmias, and SCD in PAH remain unclear. We investigated the mechanisms of increased susceptibility to SCD during progressive PAH in the Fischer CDF rat monocrotaline (MCT) model. Echocardiography, electrocardiogram, and cardiac catheterization were performed at 4 and 5 wk post MCT injection (MCT-4 and MCT-5 groups, respectively). Hearts were isolated and Langendorff-perfused, and changes in action potential (AP) duration (APD) were evaluated by voltage optical mapping. A progressive increase in RV systolic pressure was observed in MCT-4 and MCT-5 compared to control. In MCT-4, we observed RV hypertrophy with preserved cardiac function and chamber size, indicating adaptive RV remodeling. Conversely, maladaptive RV remodeling was seen in MCT-5, indicated by reduced cardiac function, along with increased RV internal diameter. Electrically, we observed delayed repolarization and prolongation of RV AP and QT interval in the MCT-5 compared to control and MCT-4. Electrical changes were consistent with decreased Kcnh2, Kcnk2, and Scn7a expression in the RV. Reduced RV vascular density together with upregulation of hypoxia-regulated genes were noted in MCT-5 compared to control, which along with the observed ST elevation suggests RV ischemia. In summary, Fischer CDF rats develop maladaptive RV functional and electrical remodeling at 5 wk post MCT that is associated with reduced RV potassium and sodium channel expression and elevated markers of RV ischemia. These changes may contribute to increased susceptibility to arrhythmias and SCD in PAH.NEW & NOTEWORTHY This study shows maladaptive right ventricle (RV) functional and electrical remodeling in pulmonary arterial hypertension (PAH) in Fischer CDF rats, a rat strain that is susceptible to sudden cardiac death in PAH. The electrical changes in the RV were associated with reduced expression of potassium and sodium channels in the RV, reduced RV vascular density, and elevated markers of RV ischemia. Combination of these changes may increase the risk of sudden cardiac death in PAH.