Mediation effect of stroke recurrence in the association between post‐stroke interleukin‐6 and functional disability

AIM: Post‐stroke inflammation increases the risk of functional disability through enlarged cerebral infarct size directly and follow‐up stroke event indirectly. We aimed to use post‐stroke proinflammatory cytokine interleukin‐6 (IL‐6) as a marker of inflammatory burden and quantify post‐stroke inflammation's direct and indirect effect on functional disability. METHODS: We analyzed patients with acute ischemic stroke admitted to 169 hospitals in the Third China National Stroke Registry. Blood samples were collected within 24 h of admission. Stroke recurrence and functional outcome measured by the modified Rankin scale (mRS) were assessed via face‐to‐face interviews at 3 months. Functional disability was defined as an mRS score ≥2. Mediation analyses under the counterfactual framework were performed to examine the potential causal chain in which stroke recurrence may mediate the relationship between IL‐6 and functional outcome. RESULTS: Among the 7053 analyzed patients, the median (interquartile range [IQR]) NIHSS score was 3 (1–5), and the median (IQR) level of IL‐6 was 2.61 (1.60–4.73) pg/mL. Stroke recurrence was observed in 458 (6.5%) patients, and functional disability was seen in 1708 (24.2%) patients at the 90‐day follow‐up. Per stand deviation (4.26 pg/mL) increase in the concentration of IL‐6 was associated with an increased risk of stroke recurrence (adjusted odds ratio [aOR], 1.19; 95% CI, 1.09–1.29) and disability (aOR, 1.22; 95% CI, 1.15–1.30) within 90 days. Mediation analyses revealed that 18.72% (95% CI, 9.26%–28.18%) of the relationship between IL‐6 and functional disability was mediated by stroke recurrence. CONCLUSIONS: Stroke recurrence mediates less than 20% of the association between IL‐6 and functional outcome at 90 days among patients with acute ischemic stroke. In addition to typical secondary prevention strategies for preventing stroke recurrence, more attention should be paid to novel anti‐inflammatory therapy to improve functional outcomes directly.