Circulating cytokine levels and 5-year vascular recurrence after stroke: A multicenter prospective cohort study

Abstract Background and objectives Anti-inflammatory therapies are tested in randomized trials for secondary stroke prevention. Detecting inflammatory biomarkers that predict vascular recurrence could optimize patient selection for these trials. Methods In a multicenter prospective cohort study, we measured plasma levels of 22 inflammatory cytokines in 486 acute stroke patients (474 ischemic strokes and 12 intracerebral hemorrhages; median age 68 years, 34% female, median 3 days post-stroke onset). Patients were followed for over 5 years through telephone and in-person interviews to record the occurrence of the following outcomes: (1) recurrent stroke or transient ischemic attack (TIA; primary outcome); (2) a composite of recurrent vascular events (stroke, TIA, acute coronary syndrome, hospital admission due to heart failure, and death; secondary outcome). Associations between cytokine levels and these outcomes were analyzed using Cox proportional hazards models adjusted for demographic and vascular risk factors. Results During the 5-year follow-up period, 59 patients (12.1%) experienced recurrent stroke or TIA, and 118 (24.3%) experienced recurrent vascular events. After adjustments for demographic and vascular risk factors, and correction for multiple comparisons, higher plasma levels of CD62E (adjusted Hazard Ratio (aHR)/SD increment: 1.63, 95%CI 1.22–2.20) and MIF (aHR: 1.56, 95%CI 1.18–2.06) in the acute phase after stroke were statistically significantly associated with increased risk of recurrent stroke or TIA. The associations followed a dose-response pattern across quartiles of CD62E and MIF levels. Adding baseline CD62E and MIF levels to models including age, sex, vascular risk factors, and baseline C-reactive protein (CRP) levels led to significant improvements in the prediction of 5-year risk of recurrent stroke or TIA (ΔC-index 0.030–0.050). Conclusion Among stroke patients, higher baseline levels of CD62E and MIF improved prediction of 5-year risk of recurrent stroke or TIA on top of vascular risk factors and CRP levels. Whether assessment of these cytokines could improve patient selection for secondary prevention trials of anti-inflammatory treatments, should be explored in future studies.