Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.

Autor:	Wang L; 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.; The Third Xiangya Hospital, Central South University, Changsha, Hunan, China (L.W.)., Halliday G; 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., Huot JR; Department of Surgery (J.R.H., A.B.), Indiana University School of Medicine, Indianapolis., Satoh T; 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.; Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S.)., Baust JJ; 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., Fisher A; 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., Cook T; 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., Hu J; 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., Avolio T; 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., Goncharov DA; 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., Bai Y; 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., Vanderpool RR; Division of Translational and Regenerative Medicine, University of Arizona, Tucson (R.R.V.)., Considine RV; Division of Endocrinology (R.V.C.), Indiana University School of Medicine, Indianapolis., Bonetto A; Department of Surgery (J.R.H., A.B.), Indiana University School of Medicine, Indianapolis., Tan J; Division of Pulmonary, Allergy and Critical Care Medicine (J.T., A.L.M., E.A.G., M.T.G.), University of Pittsburgh, PA., Bachman TN; 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., Sebastiani A; 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., McTiernan CF; 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., Mora AL; 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.; Division of Pulmonary, Allergy and Critical Care Medicine (J.T., A.L.M., E.A.G., M.T.G.), University of Pittsburgh, PA., Machado RF; 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., Goncharova EA; 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.; Division of Pulmonary, Allergy and Critical Care Medicine (J.T., A.L.M., E.A.G., M.T.G.), University of Pittsburgh, PA., Gladwin MT; 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.; Division of Pulmonary, Allergy and Critical Care Medicine (J.T., A.L.M., E.A.G., M.T.G.), University of Pittsburgh, PA., Lai YC; 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.; Department of Anatomy, Cell Biology & Physiology (Y.-C.L.), Indiana University School of Medicine, Indianapolis.
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2020 Jun; Vol. 40 (6), pp. 1543-1558. Date of Electronic Publication: 2020 Apr 09.
DOI:	10.1161/ATVBAHA.119.313883
Abstrakt:	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.
Databáze:	MEDLINE
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