title: The vascular marker soluble fms-like tyrosine kinase 1 is associated with disease severity and adverse outcomes in chronic heart failure.
abstract: OBJECTIVE
  We sought to evaluate placental growth factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) as clinical biomarkers in chronic heart failure (HF).
  
  
  BACKGROUND
  Vascular remodeling is a crucial compensatory mechanism in chronic HF. The angiogenic ligand PlGF and its target receptor fms-like tyrosine kinase 1 modulate vascular growth and function, but their relevance in human HF is undefined.
  
  
  METHODS
  We measured plasma PlGF and sFlt-1 in 1,403 patients from the Penn Heart Failure Study, a multicenter cohort of chronic systolic HF. Subjects were followed for death, cardiac transplantation, or ventricular assist device placement over a median follow-up of 2 years.
  
  
  RESULTS
  The sFlt-1 was independently associated with measures of HF severity, including New York Heart Association functional class (p < 0.01) and B-type natriuretic peptide (p < 0.01). Patients in the 4th quartile of sFlt-1 (>379 pg/ml) had a 6.17-fold increased risk of adverse outcomes (p < 0.01). This association was robust, even after adjustment for the Seattle Failure Model (hazard ratio: 2.54, 95% confidence interval [CI]: 1.76 to 2.27, p < 0.01) and clinical confounders including HF etiology (hazard ratio: 1.67, 95% CI: 1.06 to 2.63, p = 0.03). Combined assessment of sFlt-1 and B-type natriuretic peptide exhibited high predictive accuracy at 1 year (area under the receiver-operator characteristic curve: 0.791, 95% CI: 0.752 to 0.831) that was greater than either marker alone (p < 0.01 and p = 0.03, respectively). In contrast, PlGF was not an independent marker of disease severity or outcomes.
  
  
  CONCLUSIONS
  Our findings support a role for sFlt-1 in the biology of human HF. With additional study, circulating sFlt-1 might emerge as a clinically useful biomarker to assess the influence of vascular remodeling on clinical outcomes.
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. bonnie.ky@uphs.upenn.edu
authors.forename: Bonnie
authors.initials: B
authors.lastname: Ky
authors.forename: Benjamin
authors.initials: B
authors.lastname: French
authors.forename: Kosha
authors.initials: K
authors.lastname: Ruparel
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Sweitzer
authors.forename: James C
authors.initials: JC
authors.lastname: Fang
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Levy
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000150:complications; D006801:Humans; D008297:Male; D008875:Middle Aged; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000097:blood*; D012720:Severity of Illness Index; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*
chemical_list: D015415:Biomarkers; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1