C64-04 Right Ventricular Electrical Remodeling in Two Models of Severe Pulmonary Arterial Hypertension

Abstract Background Pulmonary arterial hypertension (PAH) is a progressive and incurable disease of the pulmonary circulation, with right heart failure being the leading cause of death, accounting for approximately 50% of deaths in PAH. However, the remaining half of the patients die due to other causes. Sudden cardiac death, responsible for an additional 20-30% of deaths, is often attributed to cardiac arrhythmias, although the underlying mechanisms remain unclear. Indeed, several clinical studies have reported progressive electrical changes in the right ventricle (RV) of PAH patients. However, the mechanisms underlying RV electrical remodeling, arrhythmias and sudden death in PAH remains unclear. In this study, we characterized the hemodynamic, structural, and electrical changes in the monocrotaline (MCT) and SU5416-hypoxia (SuHx) models using Fischer CDF rats. Method Fischer CDF rats were used to establish two experimental models of severe PAH. In MCT model, rats received a single injection of MCT (60mg/kg, s.c.) or vehicle. In SuHx model, rats were administered SU5416 (20mg/kg in DMSO, s.c.) and exposed to hypoxia (10% O2) for three weeks, followed by one week of normoxia. Hemodynamic assessment via RV catheterization and echocardiography was performed at the experimental endpoints — 5 weeks post-MCT and 4 weeks post-SU5416 in SuHx group. Electrocardiograms (ECG) were recorded following echocardiography to assess electrical abnormalities and a PCR array was performed to assess the changes in expression of ion channel in the RV. Results Both MCT and SuHx rats exhibited a marked increase in RV systolic pressure compared to their respective controls. Consistent with hemodynamic changes, both MCT and SuHx rats demonstrated pronounced RV hypertrophy, reduced RV fractional shortening and cardiac index, and an increased RV internal diameter, indicative of maladaptive RV remodeling in these models. ECG analysis revealed a significant prolongation of QT interval and shortening of QRS interval in both models relative to controls. Moreover, we observed reduction in the expression of potassium and sodium channel genes that were associated with QT prolongation in these models. Conclusion Both the MCT and SuHx models successfully reproduced severe PAH and associated electrical remodeling. Importantly, down-regulation of potassium channels was associated with the QT prolongation, which may underly the susceptibility to cardiac arrhythmias and sudden death in these models. This abstract is funded by: Canadian Institute of Health Research