title: Serially measured circulating miR-22-3p is a biomarker for adverse clinical outcome in patients with chronic heart failure: The Bio-SHiFT study.
abstract: BACKGROUND
  Several studies have suggested circulating microRNAs (miRs) are associated with heart failure, but these studies were small, and limited to single miR measurements. We examined 7 miRs which were previously linked to heart failure, and tested whether their temporal expression level predicts prognosis in a prospective cohort of chronic heart failure (CHF) patients.
  
  
  RESULTS
  In 2011-2013, 263 CHF patients were included. At inclusion and subsequently every 3months, we measured 7miRs. The primary endpoint (PE) comprised heart failure hospitalization, cardiovascular mortality, cardiac transplantation and LVAD implantation. Associations between temporal miR patterns and the PE were investigated by joint modelling, which combines mixed models with Cox regression. Mean age was 67±13years, 72% were men and 27% NYHA classes III-IV. We obtained 873 blood samples (median 3 [IQR 2-5] per patient). The PE was reached in 41 patients (16%) during a median follow-up of 0.9 [0.6-1.4] years. The temporal pattern of miR-22-3p was independently associated with the PE (HR [95% CI] per doubling of level: 0.64 [0.47-0.77]). The instantaneous change in level (slope of the temporal miR pattern) of miR-22-3p was also independently associated with the PE (HR [95% CI] per doubling of slope: 0.33 [0.20-0.51]). These associations remained statistically significant after adjustment for temporal patterns of NT-proBNP, Troponin T and CRP.
  
  
  CONCLUSIONS
  The temporal pattern of circulating miR-22-3p contains important prognostic and independent information in CHF patients. This concept warrants further investigation in larger series with extended follow-up.
authors.affiliation: Cardiology, Medical Centre Alkmaar, Alkmaar, The Netherlands.
authors.forename: Nick
authors.initials: N
authors.lastname: van Boven
authors.affiliation: Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: K Martijn
authors.initials: KM
authors.lastname: Akkerhuis
authors.affiliation: Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Sharda S
authors.initials: SS
authors.lastname: Anroedh
authors.affiliation: Biostatistics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Rizopoulos
authors.affiliation: Cardiology, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Yigal
authors.initials: Y
authors.lastname: Pinto
authors.affiliation: Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Battes
authors.affiliation: Cardiology, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Hans L
authors.initials: HL
authors.lastname: Hillege
authors.affiliation: Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Kadir C
authors.initials: KC
authors.lastname: Caliskan
authors.affiliation: Cardiology, Medical Centre Alkmaar, Alkmaar, The Netherlands.
authors.forename: Tjeerd
authors.initials: T
authors.lastname: Germans
authors.affiliation: Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Olivier C
authors.initials: OC
authors.lastname: Manintveld
authors.affiliation: Cardiology, Medical Centre Alkmaar, Alkmaar, The Netherlands.
authors.forename: Jan-Hein
authors.initials: JH
authors.lastname: Cornel
authors.affiliation: Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Alina A
authors.initials: AA
authors.lastname: Constantinescu
authors.affiliation: Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Boersma
authors.affiliation: Cardiology, Medical Centre Alkmaar, Alkmaar, The Netherlands.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Umans
authors.affiliation: Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands. Electronic address: i.kardys@erasmusmc.nl.
authors.forename: Isabella
authors.initials: I
authors.lastname: Kardys
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000032:analysis; D002908:Chronic Disease; D000074166:Circulating MicroRNA / Q000032:analysis; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000175:diagnosis / Q000401:mortality; D016027:Heart Transplantation / Q000706:statistics & numerical data*; D006353:Heart-Assist Devices / Q000706:statistics & numerical data*; D006760:Hospitalization / Q000706:statistics & numerical data*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D017063:Outcome Assessment, Health Care; D062072:Patient Acuity; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D016019:Survival Analysis
chemical_list: D015415:Biomarkers; D000074166:Circulating MicroRNA; C548375:MIRN22 microRNA, human; D035683:MicroRNAs
keywords: Biomarkers; Chronic heart failure; MicroRNAs; Mortality; Prognostication