Blood N1-methyladenosine (m¹A) RNA modification and outcome after cardiac arrest

Background: Cardiac arrest (CA) is a leading cause of mortality and neurological disability. Prediction of post-CA outcomes is challenging. Epitranscriptomic (RNA) modifications are emerging as potential biomarkers due to their regulatory roles in RNA metabolism and disease progression. However, their relevance in CA remains unexplored. Objective: This study aimed to investigate the association between N1-methyladenosine (m¹A) RNA modification and outcome after CA. Methods: Total RNA was extracted from whole blood samples of 211 patients collected 48 h after return of spontaneous circulation (ROSC). M¹A and adenosine (A) blood levels were quantified using liquid chromatography coupled to mass spectrometry (LC-MS), and the ratio m¹A/A was calculated. Neurological outcome assessed using the cerebral performance category (CPC) score and survival at 6 months were used as end-points. Results: Patients with moderate to severe neurological outcome or death within 6 months after CA (CPC 2–5) exhibited elevated m¹A/A ratio compared to survivors without neurological sequelae (CPC 1) (p = 0.03). In multivariable logistic regression, higher m¹A/A levels were associated with an increased risk of moderate to severe neurological outcome or death at 6 months compared to survivors without neurological sequelae (odds ratio [95% confidence interval] 1.50 [1.04–2.19]), after adjustment for age, time between CA and return of spontaneous circulation, lactate and neuron-specific enolase levels. In Kaplan-Meier survival analysis, patients with elevated m¹A/A levels showed a lower probability of survival at 6 months (p = 0.003). Conclusion: This study provides the first evidence that m¹A RNA methylation, reflected by the m¹A/A ratio, is associated with neurological outcome and death at 6 months after CA. Although these findings require validation, they raise the possibility that m¹A RNA methylation could help to improve prognostication after CA.