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 (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] per SD increment: 1.595, 95%CI, 1.186–2.145) and MIF (aHR: 1.581, 95%CI, 1.186–2.107) 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 0.039 to 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.

JB is a co-inventor of patents covering anti-MIF strategies for inflammatory and cardiovascular diseases. ME reports grants from Bayer and fees paid to the Charite from Amgen, AstraZeneca, Bayer, BMS, Daiichi Sankyo, all outside the submitted work. MKG reports consulting fees from Tourmaline Bio, Inc. and GLG and involvement in the Editorial Board (Methodology and Biostatistics) of Neurology, all outside the scope of the submitted work. The remaining authors have nothing to declare.

https://www.dzne.de/en/research/studies/clinical-studies/demdas/

This work was supported by the FoeFoLe program of LMU Munich (FoeFoLe-Forschungsprojekt Reg.-Nr. 1120 to MKG), the Fritz-Thyssen Foundation (grant ref. 10.22.2.024MN to MKG), the German Research Foundation (DFG; Emmy Noether grant GZ: GE 3461/2-1, ID 512461526 to MKG; Munich Cluster for Systems Neurology EXC 2145 SyNergy, ID 390857198 to MKG and JB; CRC1123 projects A2 and A3 to JB), the Hertie Foundation (Hertie Network of Excellence in Clinical Neuroscience, ID P1230035 to MKG), the German Research Foundation (DFG) as part of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy - ID 390857198, to MDi), and the Vascular Dementia Research Foundation. The DEMDAS study was funded by the German Center for Neurodegenerative Diseases. M.E. received funding from DFG under Germany's Excellence Strategy - EXC-2049 - 390688087 and KFO-5023 project 2.

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Participants were drawn from the DEMDAS study (DZNE [German Center for Neurodegenerative Diseases] - Mechanisms of Dementia After Stroke), a multicenter, prospective cohort study conducted at six tertiary stroke centers in Germany. The study was conducted in accordance with the Declaration of Helsinki and received ethical approval from institutional review boards of the participating sites. Primary ethics approval for the multicenter study was granted by the Ethics Committee of the Medical Faculty at LMU Munich (201-13), and additional approvals were obtained from the Ethics Committee of the Medical Faculty at the University of Bonn (116/13), the Ethics Committee of the University Medical Center Göttingen (21/1/12), and the Ethics Committee of the Technical University of Munich (93/14 S). The Berlin study site (Charité - Universitätsmedizin Berlin) was covered by the ethics approval of the Medical Faculty of LMU Munich, according to Section 15 of the Berlin Medical Association Professional Code of Conduct (September 2009). Written informed consent was obtained from all participants or their legal representatives.

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All data produced in the present study are available upon reasonable request to the authors.