Muhammad Hammadah1, Vasiliki V Georgiopoulou1, Andreas P Kalogeropoulos1, Malory Weber1, Xi Wang1, Michael A Samara1, Yuping Wu1, Javed Butler1, W H Wilson Tang2. 1. From the Department of Cardiovascular Medicine, Heart and Vascular Institute (M.H., W.H.W.T.), Department of Cellular and Molecular Medicine, Lerner Research Institute (M.W., X.W., W.H.W.T.), Cleveland Clinic, OH; Department of Cardiology, Emory University, Atlanta, GA (M.H., V.V.G., A.P.K.); Department of Cardiology, Minneapolis Heart Institute, MN (M.A.S); Department of Mathematics, Cleveland State University, OH (Y.W.); Cardiovascular Division, Stony Brook University, NY (J.B.). 2. From the Department of Cardiovascular Medicine, Heart and Vascular Institute (M.H., W.H.W.T.), Department of Cellular and Molecular Medicine, Lerner Research Institute (M.W., X.W., W.H.W.T.), Cleveland Clinic, OH; Department of Cardiology, Emory University, Atlanta, GA (M.H., V.V.G., A.P.K.); Department of Cardiology, Minneapolis Heart Institute, MN (M.A.S); Department of Mathematics, Cleveland State University, OH (Y.W.); Cardiovascular Division, Stony Brook University, NY (J.B.). tangw@ccf.org.
Abstract
BACKGROUND: Vascular endothelial dysfunction may play an important role in the progression of heart failure (HF). We hypothesize that elevated levels of vascular markers, placental-like growth factor, and soluble Fms-like tyrosine kinase-1 (sFlt-1) are associated with adverse outcomes in patients with HF. We also assessed possible triggers of sFlt-1 elevation in animal HF models. METHODS AND RESULTS: We measured plasma placental-like growth factor and sFlt-1 in 791 HF patients undergoing elective coronary angiogram. Median (interquartile range) placental-like growth factor and sFlt-1 levels were 24 (20-29) and 382 (277-953) pg/mL, respectively. After 5 years of follow-up, and after using receiver operator characteristic curves to determine optimal cutoffs, high levels of sFlt-1 (≥ 280 pg/mL; adjusted hazard ratio, 1.47; 95% confidence interval, 1.03-2.09; P=0.035) but not placental-like growth factor (≥ 25 pg/mL; adjusted hazard ratio, 1.26; 95% confidence interval, 0.94-1.71, P=0.12) were associated with adverse cardiovascular outcomes. In addition, significant elevation of sFlt-1 levels was observed in left anterior descending artery ligation and transverse aortic constriction HF mouse models after 4 and 8 weeks of follow-up, suggesting vascular stress and ischemia as triggers for sFlt-1 elevation in HF. CONCLUSIONS: Circulating sFlt-1 is generated as a result of myocardial injury and subsequent HF development. Elevated levels of sFlt-1 are associated with adverse outcomes in stable patients with HF.
BACKGROUND: Vascular endothelial dysfunction may play an important role in the progression of heart failure (HF). We hypothesize that elevated levels of vascular markers, placental-like growth factor, and soluble Fms-like tyrosine kinase-1 (sFlt-1) are associated with adverse outcomes in patients with HF. We also assessed possible triggers of sFlt-1 elevation in animal HF models. METHODS AND RESULTS: We measured plasma placental-like growth factor and sFlt-1 in 791 HF patients undergoing elective coronary angiogram. Median (interquartile range) placental-like growth factor and sFlt-1 levels were 24 (20-29) and 382 (277-953) pg/mL, respectively. After 5 years of follow-up, and after using receiver operator characteristic curves to determine optimal cutoffs, high levels of sFlt-1 (≥ 280 pg/mL; adjusted hazard ratio, 1.47; 95% confidence interval, 1.03-2.09; P=0.035) but not placental-like growth factor (≥ 25 pg/mL; adjusted hazard ratio, 1.26; 95% confidence interval, 0.94-1.71, P=0.12) were associated with adverse cardiovascular outcomes. In addition, significant elevation of sFlt-1 levels was observed in left anterior descending artery ligation and transverse aortic constriction HFmouse models after 4 and 8 weeks of follow-up, suggesting vascular stress and ischemia as triggers for sFlt-1 elevation in HF. CONCLUSIONS: Circulating sFlt-1 is generated as a result of myocardial injury and subsequent HF development. Elevated levels of sFlt-1 are associated with adverse outcomes in stable patients with HF.
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