Longfei Wang1,2, Gunner Halliday3, Joshua R Huot4, Taijyu Satoh1,5, Jeffrey J Baust1, Amanda Fisher3, Todd Cook3, Jian Hu1, Theodore Avolio1, Dmitry A Goncharov1, Yang Bai3, Rebecca R Vanderpool6, Robert V Considine7, Andrea Bonetto4, Jiangning Tan8, Timothy N Bachman1, Andrea Sebastiani1, Charles F McTiernan1, Ana L Mora1,8, Roberto F Machado3, Elena A Goncharova1,8, Mark T Gladwin1,8, Yen-Chun Lai3,9. 1. From the Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute (L.W., T.S., J.J.B., J.H., T.A., D.A.G., T.N.B., A.S., C.F.M., A.L.M., E.A.G., M.T.G.), University of Pittsburgh, PA. 2. The Third Xiangya Hospital, Central South University, Changsha, Hunan, China (L.W.). 3. Division of Pulmonary, Critical Care, Sleep and Occupational Medicine (G.H., A.F., T.C., Y.B., R.F.M., Y.-C.L.), Indiana University School of Medicine, Indianapolis. 4. Department of Surgery (J.R.H., A.B.), Indiana University School of Medicine, Indianapolis. 5. Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S.). 6. Division of Translational and Regenerative Medicine, University of Arizona, Tucson (R.R.V.). 7. Division of Endocrinology (R.V.C.), Indiana University School of Medicine, Indianapolis. 8. Division of Pulmonary, Allergy and Critical Care Medicine (J.T., A.L.M., E.A.G., M.T.G.), University of Pittsburgh, PA. 9. Department of Anatomy, Cell Biology & Physiology (Y.-C.L.), Indiana University School of Medicine, Indianapolis.
Abstract
OBJECTIVE: Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the 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. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model 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 high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); 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 and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle. CONCLUSIONS: Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.
OBJECTIVE: Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the 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. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model 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 high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); 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 and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle. CONCLUSIONS: Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.
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