Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF; Group 2) is the most common cause of PH worldwide, but has no proven drug therapy at present. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable and long-lasting prostacyclin analog, treprostinil, is an effective and widely used FDA-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF.
Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet (HFD) and to SU5416/Obese ZSF1 rats, a model which is created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In HFD-exposed mice, chronic treatment with treprostinil prevented hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin - the first-line drug for type 2 diabetes; the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio (PAAT/ET) and tricuspid annular plane systolic excursion (TAPSE) with robust activation of skeletal muscle LKB1/SIRT3-AMPK-GLUT4 signaling.
Our data suggest a potential role of treprostinil as a preventative treatment for mild metabolic syndrome-associated PH-HFpEF. Our data also suggest that combined treatment with treprostinil and metformin may be a potential effective therapy for a more severe disease.