Background: Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF or CpcPH; WHO Group 2) is the most common cause of PH worldwide, and at present, it has no proven effective therapies. The stable and long-lasting prostacyclin analog, Remodulin (treprostinil), is one of the most effective and widely used drugs for the treatment of pulmonary arterial hypertension via attenuation of pulmonary vascular remodeling. While the effect of Remodulin on metabolic syndrome is unknown, a recent study suggests that prostacyclin analog beraprost sodium can improve glucose intolerance and insulin sensitivity. Here, we sought to evaluate the effectiveness and safety of Remodulin in the treatment of metabolic syndrome-associated PH-HFpEF.
Methods and Results: Obese ZSF1/SU5416 rats, a preclinical model of PH-HFpEF recently developed by our group, were treated with Remodulin (40, 300, and 900 ng/kg/min, osmotic pumps) at the time of SU5416 injection for 14 weeks. No mortality was observed during this 14-week period. Although Remodulin-treated obese ZSF1/SU5416 rats had increased body weights, Remodulin reduced hyperglycemia and glycated hemoglobin levels in a dose-dependent manner compared with untreated animals. In the oral glucose tolerance test, chronic Remodulin supplementation (300 ng/kg/min) significantly improved glucose intolerance in obese ZSF1/SU5416 rats. The glucose-lowering effect of Remodulin was similar to that of metformin (300 mg/kg, drinking water), the first-line drug for modulating metabolic syndrome. Remodulin (300 and 900 ng/kg/min) treatments resulted in lower RV systolic pressure compared to untreated obese ZSF1/SU5416 rats, although no significant differences were observed. In addition, Remodulin had no effect on RV hypertrophy, but significantly increased LV hypertrophy in a dose-dependent manner compared to untreated obese ZSF1/SU5416 rats.
Conclusions: Despite the lack of substantial reduction of pulmonary pressures, our findings indicate that Remodulin-treated obese ZSF1/SU5416 rats exhibit a “healthy obesity” phenotype, and Remodulin has beneficial effects on glucose metabolism with comparable efficacy to metformin.