title: A Novel Lipid Biomarker Panel for the Detection of Heart Failure with Reduced Ejection Fraction.
abstract: OBJECTIVE
  In this study we aimed to identify novel metabolomic biomarkers suitable for improved diagnosis of heart failure with reduced ejection fraction (HFrEF).
  
  
  METHODS
  We prospectively recruited 887 individuals consisting of HFrEF patients with either ischemic (ICMP, n = 257) or nonischemic cardiomyopathy (NICMP, n = 269), healthy controls (n = 327), and patients with pulmonary diseases (n = 34). A single-center identification (n = 238) was followed by a multicenter confirmation study (n = 649). Plasma samples from the single-center study were subjected to metabolite profiling analysis to identify metabolomic features with potential as HFrEF biomarkers. A dedicated analytical protocol was developed for the routine analysis of selected metabolic features in the multicenter cohort.
  
  
  RESULTS
  In the single-center study, 92 of 181 metabolomic features with known chemical identity (51%) were significantly changed in HFrEF patients compared to healthy controls (P <0.05). Three specific metabolomic features belonging to the lipid classes of sphingomyelins, triglycerides, and phosphatidylcholines were selected as the cardiac lipid panel (CLP) and analyzed in the multicenter study using the dedicated analytical protocol. The combination of the CLP with N-terminal pro-B-type natriuretic peptide (NT-proBNP) distinguished HFrEF patients from healthy controls with an area under the curve (AUC) of 0.97 (sensitivity 80.2%, specificity 97.6%) and was significantly superior compared to NT-proBNP alone (AUC = 0.93, sensitivity 81.7%, specificity 88.1%, P <0.001), even in the subgroups with mildly reduced left ventricular EF (0.94 vs 0.87; P <0.001) and asymptomatic patients (0.95 vs 0.91; P <0.05).
  
  
  CONCLUSIONS
  The new metabolomic biomarker panel has the potential to improve HFrEF detection, even in mild and asymptomatic stages. The observed changes further indicate lipid alterations in the setting of HFrEF.
authors.affiliation: Department of Internal Medicine III, Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mueller-Hennessen
authors.affiliation: Department of Cardiology, Charité, Campus Virchow-Klinikum, Berlin, Germany.|DZHK, Berlin, Germany.
authors.forename: Hans-Dirk
authors.initials: HD
authors.lastname: Düngen
authors.affiliation: Department of Cardiology and Angiology, University Hospital of Schleswig-Holstein, Kiel, Germany.|DZHK, Hamburg/Kiel/Lübeck, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lutz
authors.affiliation: Department of Cardiology, Charité, Campus Virchow-Klinikum, Berlin, Germany.|DZHK, Berlin, Germany.
authors.forename: Tobias Daniel
authors.initials: TD
authors.lastname: Trippel
authors.affiliation: Department of Pneumology and Respiratory Critical Care Medicine, Thoraxklinik, University of Heidelberg, and Translational Lung Research Center, Member of the German Center for Lung Research, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kreuter
authors.affiliation: Department of Internal Medicine III, Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Sigl
authors.affiliation: Department of Internal Medicine III, Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Müller
authors.affiliation: Department of Cardiology, Charité, Campus Virchow-Klinikum, Berlin, Germany.|DZHK, Berlin, Germany.
authors.forename: Elvis
authors.initials: E
authors.lastname: Tahirovic
authors.affiliation: metanomics GmbH, Berlin, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Witt
authors.affiliation: metanomics GmbH, Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ternes
authors.affiliation: metanomics GmbH, Berlin, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Carvalho
authors.affiliation: metanomics GmbH, Berlin, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Peter
authors.affiliation: Metanomics Health GmbH, Berlin, Germany.
authors.forename: Dietrich
authors.initials: D
authors.lastname: Rein
authors.affiliation: Metanomics Health GmbH, Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Schatz
authors.affiliation: Department of Pneumology and Respiratory Critical Care Medicine, Thoraxklinik, University of Heidelberg, and Translational Lung Research Center, Member of the German Center for Lung Research, Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Herth
authors.affiliation: Department of Internal Medicine III, Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Giannitsis
authors.affiliation: Department of Internal Medicine III, Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Weis
authors.affiliation: Department of Cardiology and Angiology, University Hospital of Schleswig-Holstein, Kiel, Germany.|DZHK, Hamburg/Kiel/Lübeck, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.affiliation: Department of Internal Medicine III, Cardiology, Angiology & Pulmonology, Heidelberg University Hospital, Heidelberg, Germany; hugo.katus@med.uni-heidelberg.de.|DZHK (German Centre for Cardiovascular Research), Heidelberg/Mannheim, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood* / Q000378:metabolism; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000175:diagnosis* / Q000503:physiopathology*; D006801:Humans; D008055:Lipids; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D015415:Biomarkers; D008055:Lipids