Systemic Inflammation Mediates the Association Between Atrial Fibrillation and Functional Outcomes After Ischemic Stroke

Background: Atrial fibrillation (AF) is a major risk factor for ischemic stroke and is associated with worse neurological outcomes. The mechanisms underlying this relationship, particularly the role of systemic inflammation as a mediator linking AF to post-stroke functional outcomes, remain insufficiently understood. Methods: We conducted a retrospective cohort study of 463 patients with acute ischemic stroke (median age 67.0 years [IQR 56.0-74.0]; 27.0% female), including 96 with AF. Candidate mediators were identified using least absolute shrinkage and selection operator (LASSO) regression and single-mediator causal mediation models were applied adjusting for established confounders. Robustness was evaluated using E-values. Results: Patients with AF had more severe neurological deficits and had poorer 90-day functional outcomes. The multivariable model incorporating LASSO-selected variables demonstrated better predictive performance (AUC 0.829) compared to a confounder-only model (AUC 0.757). Mediation analysis demonstrated that neutrophil-to-lymphocyte ratio (NLR) and systemic inflammation response index (SIRI) significantly mediated 22.3% and 17.0% of the association between AF and poor functional outcome, suggesting that systemic inflammation contributes meaningfully to AF-related post-stroke disability. Conclusion: NLR and SIRI partially mediate the association between AF and poor functional outcomes after ischemic stroke, suggesting that systemic inflammation may serve as a potential prognostic marker and that these indices could aid early risk stratification.