Association of Circulating MicroRNA-124-3p Levels With Outcomes After Out-of-Hospital Cardiac Arrest: A Substudy of a Randomized Clinical Trial

Yvan Devaux; Josef Dankiewicz; Antonio Salgado-Somoza; Pascal Stammet; Olivier Collignon; Patrik Gilje; Olof Gidlöf; Lu Zhang; Mélanie Vausort; Christian Hassager; Matthew P Wise; Michael Kuiper; Hans Friberg; Tobias Cronberg; David Erlinge; Niklas Nielsen; for Target Temperature Management After Cardiac Arrest Trial Investigators

doi:10.1001/jamacardio.2016.0480

Association of Circulating MicroRNA-124-3p Levels With Outcomes After Out-of-Hospital Cardiac Arrest: A Substudy of a Randomized Clinical Trial

Yvan Devaux, Josef Dankiewicz, Antonio Salgado-Somoza, Pascal Stammet, Olivier Collignon, Patrik Gilje, Olof Gidlöf, Lu Zhang, Mélanie Vausort, Christian Hassager, Matthew P Wise, Michael Kuiper, Hans Friberg, Tobias Cronberg, David Erlinge, Niklas Nielsen, for Target Temperature Management After Cardiac Arrest Trial Investigators

36 Citationer (Scopus)

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 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. MAINOUTCOMES AND MEASURES: The primary end point was poor neurologic outcomeat6 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%) hada poor neurologic outcomeat 6months. Inthe 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.

Originalsprog	Engelsk
Tidsskrift	JAMA Cardiology
Vol/bind	1
Udgave nummer	3
Sider (fra-til)	305-313
Antal sider	9
DOI	https://doi.org/10.1001/jamacardio.2016.0480
Status	Udgivet - 1 jun. 2016
Udgivet eksternt	Ja

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10.1001/jamacardio.2016.0480

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Devaux, Y., Dankiewicz, J., Salgado-Somoza, A., Stammet, P., Collignon, O., Gilje, P., Gidlöf, O., Zhang, L., Vausort, M., Hassager, C., Wise, M. P., Kuiper, M., Friberg, H., Cronberg, T., Erlinge, D., Nielsen, N., & for Target Temperature Management After Cardiac Arrest Trial Investigators (2016). Association of Circulating MicroRNA-124-3p Levels With Outcomes After Out-of-Hospital Cardiac Arrest: A Substudy of a Randomized Clinical Trial. JAMA Cardiology, 1(3), 305-313. https://doi.org/10.1001/jamacardio.2016.0480

Devaux, Y, Dankiewicz, J, Salgado-Somoza, A, Stammet, P, Collignon, O, Gilje, P, Gidlöf, O, Zhang, L, Vausort, M, Hassager, C, Wise, MP, Kuiper, M, Friberg, H, Cronberg, T, Erlinge, D, Nielsen, N & for Target Temperature Management After Cardiac Arrest Trial Investigators 2016, 'Association of Circulating MicroRNA-124-3p Levels With Outcomes After Out-of-Hospital Cardiac Arrest: A Substudy of a Randomized Clinical Trial', JAMA Cardiology, bind 1, nr. 3, s. 305-313. https://doi.org/10.1001/jamacardio.2016.0480

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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 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. MAINOUTCOMES AND MEASURES: The primary end point was poor neurologic outcomeat6 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%) hada poor neurologic outcomeat 6months. Inthe 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.",

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author = "Yvan Devaux and Josef Dankiewicz and Antonio Salgado-Somoza and Pascal Stammet and Olivier Collignon and Patrik Gilje and Olof Gidl{\"o}f and Lu Zhang and M{\'e}lanie Vausort and Christian Hassager and Wise, {Matthew P} and Michael Kuiper and Hans Friberg and Tobias Cronberg and David Erlinge and Niklas Nielsen and {for Target Temperature Management After Cardiac Arrest Trial Investigators}",

year = "2016",

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day = "1",

doi = "10.1001/jamacardio.2016.0480",

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TY - JOUR

T1 - Association of Circulating MicroRNA-124-3p Levels With Outcomes After Out-of-Hospital Cardiac Arrest

T2 - A Substudy of a Randomized Clinical Trial

AU - Devaux, Yvan

AU - Dankiewicz, Josef

AU - Salgado-Somoza, Antonio

AU - Stammet, Pascal

AU - Collignon, Olivier

AU - Gilje, Patrik

AU - Gidlöf, Olof

AU - Zhang, Lu

AU - Vausort, Mélanie

AU - Hassager, Christian

AU - Wise, Matthew P

AU - Kuiper, Michael

AU - Friberg, Hans

AU - Cronberg, Tobias

AU - Erlinge, David

AU - Nielsen, Niklas

AU - for Target Temperature Management After Cardiac Arrest Trial Investigators

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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 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. MAINOUTCOMES AND MEASURES: The primary end point was poor neurologic outcomeat6 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%) hada poor neurologic outcomeat 6months. Inthe 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.

AB - 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 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. MAINOUTCOMES AND MEASURES: The primary end point was poor neurologic outcomeat6 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%) hada poor neurologic outcomeat 6months. Inthe 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.

KW - Journal Article

U2 - 10.1001/jamacardio.2016.0480

DO - 10.1001/jamacardio.2016.0480

M3 - Journal article

C2 - 27438111

SN - 2380-6583

VL - 1

SP - 305

EP - 313

JO - JAMA Cardiology

JF - JAMA Cardiology

IS - 3

ER -

Association of Circulating MicroRNA-124-3p Levels With Outcomes After Out-of-Hospital Cardiac Arrest: A Substudy of a Randomized Clinical Trial

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