title: Use of biomarkers to establish potential role and function of circulating microRNAs in acute heart failure.
abstract: BACKGROUND
  Circulating microRNAs (miRNAs) emerge as potential heart failure biomarkers. We aimed to identify associations between acute heart failure (AHF)-specific circulating miRNAs and well-known heart failure biomarkers.
  
  
  METHODS
  Associations between 16 biomarkers predictive for 180day mortality and the levels of 12 AHF-specific miRNAs were determined in 100 hospitalized AHF patients, at baseline and 48hours. Patients were divided in 4 pre-defined groups, based on clinical parameters during hospitalization. Correlation analyses between miRNAs and biomarkers were performed and complemented by miRNA target prediction and pathway analysis.
  
  
  RESULTS
  No significant correlations were found at hospital admission. However, after 48hours, 7 miRNAs were significantly negatively correlated to biomarkers indicative for a worse clinical outcome in the patient group with the most unfavorable in-hospital course (n=21); miR-16-5p was correlated to C-reactive protein (R=-0.66, p-value=0.0027), miR-106a-5p to creatinine (R=-0.68, p-value=0.002), miR-223-3p to growth differentiation factor 15 (R=-0.69, p-value=0.0015), miR-652-3p to soluble ST-2 (R=-0.77, p-value<0.001), miR-199a-3p to procalcitonin (R=-0.72, p-value<0.001) and galectin-3 (R=-0.73, p-value<0.001) and miR-18a-5p to procalcitonin (R=-0.68, p-value=0.002). MiRNA target prediction and pathway analysis identified several pathways related to cardiac diseases, which could be linked to some of the miRNA-biomarker correlations.
  
  
  CONCLUSIONS
  The majority of correlations between circulating AHF-specific miRNAs were related to biomarkers predictive for a worse clinical outcome in a subgroup of worsening heart failure patients at 48hours of hospitalization. The selective findings suggest a time-dependent effect of circulating miRNAs and highlight the susceptibility to individual patient characteristics influencing potential relations between miRNAs and biomarkers.
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Eline L
authors.initials: EL
authors.lastname: Vegter
authors.affiliation: Momentum Research, Inc., Hagmattstrasse 17, CH-4123 Allschwil, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schmitter
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Yanick
authors.initials: Y
authors.lastname: Hagemeijer
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands; European Research Institute for the Biology of Ageing and University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Ovchinnikova
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.affiliation: University of California at San Francisco, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Teerlink
authors.affiliation: Inova Heart and Vascular Institute, Falls Church, VA, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: O'Connor
authors.affiliation: Cardiology, The Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Metra
authors.affiliation: Momentum Research, Durham, NC, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Davison
authors.affiliation: Merck Research Laboratories, Rahway, NY, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bloomfield
authors.affiliation: Momentum Research, Durham, NC, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Cotter
authors.affiliation: National Heart & Lung Institute, Royal Brompton & Harefield Hospitals, Imperial College, London, UK.
authors.forename: John G
authors.initials: JG
authors.lastname: Cleland
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Givertz
authors.affiliation: Medical University, Clinical Military Hospital, Wroclaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van der Meer
authors.affiliation: European Research Institute for the Biology of Ageing and University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Eugene
authors.initials: E
authors.lastname: Berezikov
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. Electronic address: a.a.voors@umcg.nl.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Mohsin A F
authors.initials: MA
authors.lastname: Khan
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D016208:Databases, Factual / Q000639:trends; D004232:Diuretics / Q000627:therapeutic use; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000175:diagnosis* / Q000188:drug therapy; D006760:Hospitalization / Q000639:trends; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood* / Q000502:physiology; D008875:Middle Aged; D014970:Xanthines / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D004232:Diuretics; D035683:MicroRNAs; D014970:Xanthines; C073525:rolofylline
keywords: Acute heart failure; Biomarkers; Circulating microRNAs; Correlation analysis; Pathways