title: Biomarkers for characterization of heart failure - Distinction of heart failure with preserved and reduced ejection fraction.
abstract: BACKGROUND
  Heart failure (HF) incidence is rising worldwide and HF with preserved ejection fraction (HFpEF) represents nearly half of all cases. Treatment options are still limited in HFpEF in comparison to HF with reduced ejection fraction (HFrEF).
  
  
  METHODS
  We analyzed biomarkers in the general population to characterize HFpEF and HFrEF and defined a biomarker index to differentiate HFpEF from HFrEF. Growth differentiation factor-15 (GDF-15), soluble source of tumorigenicity 2 (sST2), C-reactive protein (CRP) and NT-proBNP were measured in 5000 individuals of the population-based Gutenberg Health Study (GHS). The median follow-up time for all-cause mortality was 7.3years with 213 events.
  
  
  RESULTS
  Identification of subjects with HF was improved by GDF-15 (p<0.001) in addition to NT-proBNP with an odds ratio (OR) of 1.4 (95% confidence interval [CI]:1.1-1.7). Discrimination of subjects with and without HF was slightly higher for GDF-15 (area under the ROC curve [AUC]:0.79 [95%CI:0.75-0.83]) compared to NT-proBNP (AUC:0.77 [95% CI:0.72-0.82]). For subjects with HF, differentiating HFpEF from HFrEF was feasible with the index ((CRP+GDF-15+sST2)/NT-proBNP) with an OR of 3.7 (95% CI:1.9-8.5) (p<0.001). The best biomarkers predicting all-cause mortality were NT-proBNP and GDF-15 with a hazard ratio (HR) of 1.9 (95% CI:1.6-2.2) and 1.7 (95%CI:1.6-1.9) (both p<0.001), respectively.
  
  
  CONCLUSIONS
  GDF-15 was useful to detect prevalent HF in addition to NT-proBNP and was elevated in HFrEF and HFpEF, whereas NT-proBNP was higher in HFrEF than in HFpEF. All biomarkers were useful to predict mortality in the general population. The index of ((CRP+GDF-15s+sST2)/NT-proBNP) was able to discriminate HFpEF from HFrEF.
authors.affiliation: University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sinning
authors.affiliation: University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg, Germany.
authors.forename: Tibor
authors.initials: T
authors.lastname: Kempf
authors.affiliation: University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarzl
authors.affiliation: University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Lanfermann
authors.affiliation: University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg, Germany.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ojeda
authors.affiliation: University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors.forename: Renate B
authors.initials: RB
authors.lastname: Schnabel
authors.affiliation: University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg, Germany.
authors.forename: Elvin
authors.initials: E
authors.lastname: Zengin
authors.affiliation: German Center for Cardiovascular Research (DZHK), Partner Site Rhine Main, Germany; University Medical Center of the Johannes Gutenberg-University Mainz, Department of Medicine 2, Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Wild
authors.affiliation: Institute of Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Karl-J
authors.initials: KJ
authors.lastname: Lackner
authors.affiliation: German Center for Cardiovascular Research (DZHK), Partner Site Rhine Main, Germany; University Medical Center of the Johannes Gutenberg-University Mainz, Department of Medicine 2, Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Munzel
authors.affiliation: University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.affiliation: Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
authors.affiliation: University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.affiliation: University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany. Electronic address: d.westermann@uke.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism*; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D006333:Heart Failure / Q000097:blood* / Q000175:diagnosis* / Q000401:mortality; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D011237:Predictive Value of Tests; D011379:Prognosis; D013318:Stroke Volume
chemical_list: D015415:Biomarkers; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D002097:C-Reactive Protein
keywords: C-reactive protein; Growth-differentiation factor-15; Heart failure; Heart failure with reduced and preserved ejection fraction; Soluble source of tumorigenicity 2