title: Association of Circulating MicroRNA-124-3p Levels With Outcomes After Out-of-Hospital Cardiac Arrest: A Substudy of a Randomized Clinical Trial.
abstract: The value of microRNAs (miRNAs) as biomarkers has been investigated in various clinical contexts. Initial small-scale studies suggested that miRNAs might be useful indicators of outcome after cardiac arrest.
  
  
  
  To address the prognostic value of circulating miRNAs in a large cohort of comatose patients with out-of-hospital cardiac arrest.
  
  
  
  This substudy of the Target Temperature Management After Cardiac Arrest (TTM) trial, a multicenter randomized, parallel-group, assessor-blinded clinical trial, compared the 6-month neurologic outcomes and survival of patients with cardiac arrest after targeted temperature management at 33°C or 36°C. Five hundred seventy-nine patients who survived the first 24 hours after the return of spontaneous circulation and who had blood samples available for miRNA assessment were enrolled from 29 intensive care units in 9 countries from November 11, 2010, to January 10, 2013. Final follow-up was completed on July 3, 2013, and data were assessed from February 1, 2014, to February 1, 2016.
  
  
  
  Blood sampling at 48 hours after the return of spontaneous circulation.
  
  
  
  The primary end point was poor neurologic outcome at 6 months (cerebral performance category score, 3 [severe neurologic sequelae], 4 [coma], or 5 [death]). The secondary end point was survival until the end of the trial. Circulating levels of miRNAs were measured by sequencing and polymerase chain reaction.
  
  
  
  Of the 579 patients (265 men [80.3%]; mean [SD] age, 63 [12] years), 304 patients (52.5%) had a poor neurologic outcome at 6 months. In the discovery phase with short RNA sequencing in 50 patients, the brain-enriched miR-124-3p level was identified as a candidate prognostic variable for neurologic outcomes. In the validation cohort of 529 patients, mean (SD) levels of miR-124-3p were higher in patients with a poor outcome (8408 [12 465] copies/µL) compared with patients with a good outcome (1842 [3025] copies/μL; P < .001). The miR-124-3p level was significantly associated with neurologic outcomes in the univariable analysis (odds ratio, 6.72; 95% CI, 4.53-9.97). In multivariable analyses using logistic regression, miR-124-3p levels were independently associated with neurologic outcomes (odds ratio, 1.62; 95% CI, 1.13-2.32). In Cox proportional hazards models, higher levels of miR-124-3p were significantly associated with lower survival (hazard ratio, 1.63; 95% CI, 1.37-1.93).
  
  
  
  Levels of miR-124-3p can be used as prognostication tools for neurologic outcome and survival after out-of-hospital cardiac arrest. Thus, miRNA levels may aid in tailoring health care for patients with cardiac arrest.
  
  
  
  clinicaltrials.gov Identifier: NCT01020916.
authors.affiliation: Cardiovascular Research Unit, Luxembourg Institute of Health (LIH), Luxembourg.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Devaux
authors.affiliation: Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Josef
authors.initials: J
authors.lastname: Dankiewicz
authors.affiliation: Cardiovascular Research Unit, Luxembourg Institute of Health (LIH), Luxembourg.
authors.forename: Antonio
authors.initials: A
authors.lastname: Salgado-Somoza
authors.affiliation: Department of Anaesthesia and Intensive Care Medicine, Centre Hospitalier de Luxembourg, Luxembourg.
authors.forename: Pascal
authors.initials: P
authors.lastname: Stammet
authors.affiliation: Competence Centre for Methodology and Statistics, LIH, Luxembourg.
authors.forename: Olivier
authors.initials: O
authors.lastname: Collignon
authors.affiliation: Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Gilje
authors.affiliation: Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Gidlöf
authors.affiliation: Cardiovascular Research Unit, Luxembourg Institute of Health (LIH), Luxembourg.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Unit, Luxembourg Institute of Health (LIH), Luxembourg.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Vausort
authors.affiliation: Department of Cardiology B, The Heart Centre, Rigshospitalet University Hospital, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Hassager
authors.affiliation: Department of Intensive Care, University Hospital of Wales, Cardiff.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Wise
authors.affiliation: Department of Intensive Care, Leeuwarden Medical Centrum, Leeuwarden, the Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Kuiper
authors.affiliation: Department of Anesthesia and Intensive Care, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Friberg
authors.affiliation: Division of Neurology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Cronberg
authors.affiliation: Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Erlinge
authors.affiliation: Department of Anesthesia and Intensive Care, Clinical Sciences, Lund University and Helsingborg Hospital, Helsingborg, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Nielsen
mesh_terms: D015415:Biomarkers / Q000097:blood; D003128:Coma; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D058687:Out-of-Hospital Cardiac Arrest / Q000097:blood* / Q000401:mortality; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D015415:Biomarkers; C000621032:MIRN1243 microRNA, human; D035683:MicroRNAs