title: The WAP four-disulfide core domain protein HE4: a novel biomarker for heart failure.
abstract: OBJECTIVE
  This study investigated clinical determinants and added prognostic value of HE4 as a biomarker not previously described in heart failure (HF).
  
  
  BACKGROUND
  Identification of plasma biomarkers that help to risk stratify HF patients may help to improve treatment.
  
  
  METHODS
  Plasma HE4 levels were determined in 567 participants of the COACH (Coordinating study evaluating outcomes of Advising and Counseling in Heart failure). Patients had been hospitalized for HF and were followed for 18 months. The primary endpoint of this study was a composite of all-cause mortality and HF hospitalization.
  
  
  RESULTS
  HE4 showed a strong correlation with HF severity, according to New York Heart Association functional class and brain natriuretic peptide (BNP) levels (p < 0.001). HE4 also showed a positive correlation with GDF15 (p < 0.001) and, in addition, correlated with kidney function (estimated glomerular filtration rate [eGFR]; p < 0.001). Cox regression analysis revealed that a doubling of HE4 levels was associated with a hazard ratio (HR) of 1.73 (95% confidence interval [CI]: 1.53 to 1.95) for the primary outcome (p < 0.001). After correction for age, gender, BNP, and eGFR, the HR was 1.46 (95% CI: 1.23 to 1.72; p < 0.001), and after additional adjustment for GDF15, the HR lowered to 1.30 (95% CI: 1.07 to 1.59; p = 0.009). The area under the curve in the receiver-operating characteristic curve analysis increased from 0.727 to 0.752 when HE4 was included in the clinical evaluation (p = 0.051). The integrated discrimination improvement and net reclassification index for reclassification showed significant improvements when HE4 was added to the clinical model, and this remained significant after BNP inclusion in the model.
  
  
  CONCLUSIONS
  HE4 plasma levels are correlated with markers of HF severity, show prognostic value, and can improve risk assessment in HF.
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands. Electronic address: r.a.de.boer@umcg.nl.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.affiliation: Department of Epidemiology, University Medical Center Groningen, University of Groningen, the Netherlands.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Epidemiology, University Medical Center Groningen, University of Groningen, the Netherlands.
authors.forename: Douwe
authors.initials: D
authors.lastname: Postmus
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands.
authors.forename: Kevin
authors.initials: K
authors.lastname: Damman
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands; Department of Social and Welfare Studies, Faculty of Health Sciences, Linköping University, Norrköping, Sweden.
authors.forename: Tiny
authors.initials: T
authors.lastname: Jaarsma
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.affiliation: Alere San Diego, Inc., San Diego, California.
authors.forename: William D
authors.initials: WD
authors.lastname: Arnold
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands; Department of Epidemiology, University Medical Center Groningen, University of Groningen, the Netherlands.
authors.forename: Hans L
authors.initials: HL
authors.lastname: Hillege
authors.affiliation: Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands.
authors.forename: Herman H W
authors.initials: HH
authors.lastname: Silljé
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000097:blood*; D006801:Humans; D008297:Male; D011506:Proteins / Q000032:analysis*; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D015415:Biomarkers; D011506:Proteins; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human
keywords: HE4; WFDC-2; biomarker; heart failure; prognostic marker