Details

Autor(en) / Beteiligte

• Wang, Longfei
• Halliday, Gunner
• Huot, Joshua R
• Satoh, Taijyu
• Baust, Jeffrey J
• Fisher, Amanda
• Cook, Todd
• Hu, Jian
• Avolio, Theodore
• Goncharov, Dmitry A
• Bai, Yang
• Vanderpool, Rebecca R
• Considine, Robert V
• Bonetto, Andrea
• Tan, Jiangning
• Bachman, Timothy N
• Sebastiani, Andrea
• McTiernan, Charles F
• Mora, Ana L
• Machado, Roberto F
• Goncharova, Elena A
• Gladwin, Mark T
• Lai, Yen-Chun

Titel

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

Ist Teil von

• Arteriosclerosis, thrombosis, and vascular biology, 2020-06, Vol.40 (6), p.1543

Ort / Verlag

United States

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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.