Yvan Devaux1, Josef Dankiewicz2, Antonio Salgado-Somoza1, Pascal Stammet3, Olivier Collignon4, Patrik Gilje2, Olof Gidlöf2, Lu Zhang1, Mélanie Vausort1, Christian Hassager5, Matthew P Wise6, Michael Kuiper7, Hans Friberg8, Tobias Cronberg9, David Erlinge2, Niklas Nielsen10. 1. Cardiovascular Research Unit, Luxembourg Institute of Health (LIH), Luxembourg. 2. Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden. 3. Department of Anaesthesia and Intensive Care Medicine, Centre Hospitalier de Luxembourg, Luxembourg. 4. Competence Centre for Methodology and Statistics, LIH, Luxembourg. 5. Department of Cardiology B, The Heart Centre, Rigshospitalet University Hospital, Copenhagen, Denmark. 6. Department of Intensive Care, University Hospital of Wales, Cardiff. 7. Department of Intensive Care, Leeuwarden Medical Centrum, Leeuwarden, the Netherlands. 8. Department of Anesthesia and Intensive Care, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden. 9. Division of Neurology, Department of Clinical Sciences, Lund University, Lund, Sweden. 10. Department of Anesthesia and Intensive Care, Clinical Sciences, Lund University and Helsingborg Hospital, Helsingborg, Sweden.
Abstract
IMPORTANCE: 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. OBJECTIVE: To address the prognostic value of circulating miRNAs in a large cohort of comatose patients with out-of-hospital cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS: 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 miRNAassessment 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. INTERVENTIONS: Blood sampling at 48 hours after the return of spontaneous circulation. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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). CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01020916.
RCT Entities:
IMPORTANCE: 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. OBJECTIVE: To address the prognostic value of circulating miRNAs in a large cohort of comatosepatients with out-of-hospital cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: Blood sampling at 48 hours after the return of spontaneous circulation. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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). CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01020916.
Authors: Ye Ma; Chan Chen; Shu Zhang; Qiao Wang; Hai Chen; Yuanlin Dong; Zheng Zhang; Yan Li; Zhendong Niu; Tao Zhu; Hai Yu; Bin Liu Journal: Oncotarget Date: 2017-05-23
Authors: Yvan Devaux; Antonio Salgado-Somoza; Josef Dankiewicz; Adeline Boileau; Pascal Stammet; Anna Schritz; Lu Zhang; Mélanie Vausort; Patrik Gilje; David Erlinge; Christian Hassager; Matthew P Wise; Michael Kuiper; Hans Friberg; Niklas Nielsen Journal: Theranostics Date: 2017-06-25 Impact factor: 11.556