Abstract 6171: High-dose Epoprostenol Therapy Reverses Pulmonary Hypertension by Inducing Pulmonary Artery Smooth Muscle Cell Apoptosis in Patients with Idiopathic Pulmonary Arterial Hypertension
Background: Intravenous epoprostenol has been shown to improve long-term survival in patients with idiopathic pulmonary arterial hypertension (IPAH). Although most experts believe that the appropriate dose range of epoprostenol is between 25 and 40 ng/kg/min, the optimal dose has not been determined. In the present study, we investigated the hemodynamic change induced by high-dose epoprostenol therapy in IPAH patients, and we determined by experiments the reason why high-dose epoprostenol improves hemodynamics.
Methods: We evaluated hemodynamics in 16 IPAH patients (11 females and 5 males, mean epoprostenol dosage was 100.7±35.4 ng/kg/min) treated with high-dose epoprostenol. Lung tissues obtained from 2 IPAH patients and one non-PAH patient were assessed by terminal dUTP nick end-labeling (TUNEL) assays. We examined the induction of apoptosis by epoprostenol in cultured PAH-pulmonary artery smooth muscle cells (PASMCs) and non-PAH-PASMCs. To assess the apoptosis in cultured PASMCs, we performed TUNEL assay, caspase-3,-7 assays and transmission electron microscopy. We also examined the expression of survivin by immunocytochemical analysis.
Results: Compared with the baseline state, there were significant reductions in mean pulmonary artery pressure (26%) and pulmonary vascular resistance (66%). Hemodynamic improvements in the present study were superior to those in previous studies. Apoptotic cells were detected in lung tissues obtained from IPAH patients treated with high-dose epoprostenol. TUNEL-positive and caspase-3,-7-active cells were observed in cultured PAH-PASMCs treated with epoprostenol at a high concentration. Condensation of chromatin along the nuclear membrane and fragmentation of the nucleus were observed by transmission electron microscopy. Epoprostenol at a high concentration significantly induced apoptosis in cultured PAH-PASMCs compared with that in non-PAH-PASMCs (7.69% versus 1.92%; P<0.01). Immunocytochemical analysis revealed that epoprostenol suppressed expression of survivin in cultured PAH-PASMCs.
Conclusions: The results of the present study showed that high-dose epoprostenol therapy reverses pulmonary hypertension by induction of PASMCs apoptosis.