Abstract 341: Estrogen Prevents Sudden Death and Spontaneous Ventricular Fibrillation Associated with Pulmonary Hypertension via Estrogen Receptor Beta Mediated Mechanism
Introduction: Previously we showed that right ventricular failure (RVF) secondary to pulmonary hypertension (PH) is associated with spontaneous ventricular fibrillation (VF) and sudden death in rats. We also discovered that estrogen (E2) therapy rescues severe PH and RVF. Estrogen receptor b (ERb) has been shown to play a protective role both in heart and lung. Here we hypothesize that E2 prevents sudden death and abolishes spontaneous VF associated with RVF through ERb.
Methods: Male rats were treated with monocrotaline (MCT 60 mg/kg, s.c.) or PBS (CTRL, n=9). At day 21, MCT rats were left untreated to develop RVF by day 30 (n=9), or treated with E2 (42.5 ug/kg/day, s.c., n=9) with or without ERb antagonist PHTPP (850 ug/kg/day, s.c., n=8) from day 21 to day 30. RV ejection fraction (RVEF) was serially monitord with echocardiography. Direct RV catheterisation was performed terminally to record RV pressure (RVP). At ~day 30, hearts were studied in isolated-perfused Langendorff setting and microelectrode recordings were made. RV-epicardial activation pattern was optically mapped using fluorescent voltage-sensitive dye (RH-237). Trichrome staining was performed to assess cardiac fibrosis. Values are expressed as Mean±SEM.
Results: By day 30, MCT rats developed severe PH (RVP=72±4 vs. 30±2 mmHg in CTRL, p<0.05) and RV failure (RVEF=33±3% vs. 65±1 in CTRL, p<0.05) with moderate RV fibrosis and ∼30% of RVF rats died suddenly. Early after depolarization (EADs) and spontaneous VF were observed in RVF group during normal Tyrode perfusion with wave front dynamics supported by both focal and multiple wavelet patterns. E2 therapy resulted in complete rescue of PH (RVP=38±3 mmHg, p<0.05 vs. RVF; RVEF=60±2%, p<0.05 vs. RVF; no signs of fibrosis) and none of the rats died in E2-groups. No VF was initiated in any of the control or E2 treated rat hearts. In the presence of ERb antagonist PHTPP, E2 could not rescue PH (RVP=60±4 vs. 38±3 in E2; RVEF=42±2 vs. 60±2 % in E2; p<0.05 vs. E2); moderate RV fibrosis was present and spontaneous EADs and VF were observed in all the hearts similar to RVF group.
Conclusions: In conclusion, E2-therapy rescues PH-induced RVF and prevents VF by reversing PH-induced RV-dysfunction and fibrosis most likely through ERb-mediated mechanism.
- © 2012 by American Heart Association, Inc.