title: Elevated Soluble Fms-Like Tyrosine Kinase-1 and Placental-Like Growth Factor Levels Are Associated With Development and Mortality Risk in Heart Failure.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Muhammad
authors.initials: M
authors.lastname: Hammadah
authors.affiliation: 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.).
authors.forename: Vasiliki V
authors.initials: VV
authors.lastname: Georgiopoulou
authors.affiliation: 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.).
authors.forename: Andreas P
authors.initials: AP
authors.lastname: Kalogeropoulos
authors.affiliation: 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.).
authors.forename: Malory
authors.initials: M
authors.lastname: Weber
authors.affiliation: 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.).
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.).
authors.forename: Michael A
authors.initials: MA
authors.lastname: Samara
authors.affiliation: 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.).
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.affiliation: 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.).
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
authors.affiliation: 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.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D017023:Coronary Angiography; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000175:diagnosis / Q000201:enzymology / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D000072483:Placenta Growth Factor; D011237:Predictive Value of Tests; D011257:Pregnancy Proteins / Q000097:blood*; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012372:ROC Curve; D012307:Risk Factors; D013997:Time Factors; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*
chemical_list: D015415:Biomarkers; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: animal; heart failure; ligation; mice; placenta growth factor