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

Abstract

AimPost‐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.MethodsWe 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.ResultsAmong 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.ConclusionsStroke 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.

Inflammatory marker profiles and in‐hospital neurological deterioration in patients with acute minor ischemic stroke

“…IL‐6 shows a clear dose–response association with the risk of incident AIS 32 . A previous study showed that over 80% of the functional damage after AIS resulted from perturbations to the IL‐6 pathway, rather than stroke recurrence 33 . As ND is considered to be a predictive factor for long‐term poor outcomes, 7 the correlation between ND and poor long‐term outcomes may result from a prolonged post‐stroke inflammatory state.…”

“… 32 A previous study showed that over 80% of the functional damage after AIS resulted from perturbations to the IL‐6 pathway, rather than stroke recurrence. 33 As ND is considered to be a predictive factor for long‐term poor outcomes, 7 the correlation between ND and poor long‐term outcomes may result from a prolonged post‐stroke inflammatory state. IL‐6 signaling mechanisms 34 and levels of hsCRP 35 vary at different phases of an ischemic stroke; therefore, further studies are required to provide clear evidence of inflammatory profiles during admission, hospitalization, and follow‐up to verify this hypothesis.…”

Exploring causal association between circulating inflammatory cytokines and functional outcomes following ischemic stroke: A bidirectional Mendelian randomization study

“…The modified Rankin Scale (mRS) was used to evaluate the functional outcomes in the 3 months after IS. A lower mRS score (0-2) indicates a better functional outcome (n = 3741), and a higher score (3)(4)(5)(6) indicates an adverse functional outcome (n = 2280). This study used the results adjusted for age, gender, ancestry, and baseline stroke severity for the primary MR analysis.…”

“…Aside from traditional risk factors such as blood pressure, smoking, and sleep [3][4][5], as an indispensable part of the pathophysiology of stroke, inflammation assumes a pivotal role in the pathogenesis and prognosis of the disease [6]. Several cytokines and growth factors are involved in the regulation of inflammatory responses [7].…”