Interleukin-6, C-Reactive Protein, and Vascular Recurrence After Stroke With and Without Atherosclerosis

John J McCabe^#^{1

2

3}, Katie Harris^#⁴, Cathal Walsh^{1

5}, Sarah Gorey^{1

2

3}, Markus Arnold⁶, Gian Marco De Marchis^{7

8}, Pablo Hervella⁹, Ramon Iglesias-Rey⁹, Christina Jern^{10

11}, Mira Katan^{5

6}, Linxin Li¹², Nobukazu Miyamoto¹³, Joan Montaner^{14

15

16

17}, Francisco Purroy^{18

19}, Peter M Rothwell¹², Tara M Stanne^{10

11}, Cathie Sudlow^{20

21}, Yuji Ueno¹³, Mikel Vicente-Pascual^{18

19}, William Whiteley^{22

21}, Mark Woodward^{4

23}, Peter J Kelly^{1

2

3}

Affiliations

¹ Health Research Board (HRB) Stroke Clinical Trials Network Ireland (SCTNI) (J.J.M., C.W., S.G., P.J.K.).
² School of Medicine, University College Dublin (UCD), Ireland (J.J.M., S.G., P.J.K.).
³ Stroke Service, Mater Misericordiae University Hospital, Dublin, Ireland (J.J.M., S.G., P.J.K.).
⁴ The George Institute for Global Health, University of New South Wales, Sydney, Australia (K.H., M.W.).
⁵ Department of Biostatistics, Trinity College Dublin, Ireland (C.W., M.K.).
⁶ Neurology Department, University Hospital of Zurich, Switzerland (M.A., M.K.).
⁷ Neurology Department, University Hospital Basel, Switzerland (G.M.D.M.).
⁸ Neurology Clinic and Stroke Center, University Teaching and Research Hospital St. Gallen, Switzerland (G.M.D.M.).
⁹ Neuroimaging and Biotechnology Laboratory (NOBEL), Health Research Institute of Santiago de Compostela, Spain (P.H., R.I.-R.).
¹⁰ Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden (C.J., T.M.S.).
¹¹ Department of Clinical Genetics and Genomics, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden (C.J., T.M.S.).
¹² Wolfson Centre for the Prevention of Stroke and Dementia (L.L., P.M.R.), University of Oxford, United Kingdom.
¹³ Neurology Department, Juntendo University School of Medicine, Tokyo, Japan (N.M., Y.U.).
¹⁴ Neurology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain (J.M.).
¹⁵ Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Spain (J.M.).
¹⁶ Neurology, Virgen Macarena Hospital, Sevilla, Spain (J.M.).
¹⁷ Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Spain (J.M.).
¹⁸ Department of Neurology, Hospital Universitari Arnau de Vilanova, Lleida, Spain (F.P., M.V.-P.).
¹⁹ Department of Clinical Neurosciences, University of Lleida, Spain (F.P., M.V.-P.).
²⁰ Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics (C.S.), University of Edinburgh, United Kingdom.
²¹ Centre for Clinical Brain Sciences (C.S., W.W.), University of Edinburgh, United Kingdom.
²² Nuffield Department of Population Health (W.W.), University of Oxford, United Kingdom.
²³ The George Institute for Global Health, School of Public Health, Imperial College London, United Kingdom (M.W.).

^# Contributed equally.

PMID: 40677223
DOI: 10.1161/STROKEAHA.125.052091

Meta-Analysis

Interleukin-6, C-Reactive Protein, and Vascular Recurrence After Stroke With and Without Atherosclerosis

John J McCabe et al. Stroke. 2025 Sep.

. 2025 Sep;56(9):2588-2596.

doi: 10.1161/STROKEAHA.125.052091. Epub 2025 Jul 18.

Authors

Affiliations

¹ Health Research Board (HRB) Stroke Clinical Trials Network Ireland (SCTNI) (J.J.M., C.W., S.G., P.J.K.).
² School of Medicine, University College Dublin (UCD), Ireland (J.J.M., S.G., P.J.K.).
³ Stroke Service, Mater Misericordiae University Hospital, Dublin, Ireland (J.J.M., S.G., P.J.K.).
⁴ The George Institute for Global Health, University of New South Wales, Sydney, Australia (K.H., M.W.).
⁵ Department of Biostatistics, Trinity College Dublin, Ireland (C.W., M.K.).
⁶ Neurology Department, University Hospital of Zurich, Switzerland (M.A., M.K.).
⁷ Neurology Department, University Hospital Basel, Switzerland (G.M.D.M.).
⁸ Neurology Clinic and Stroke Center, University Teaching and Research Hospital St. Gallen, Switzerland (G.M.D.M.).
⁹ Neuroimaging and Biotechnology Laboratory (NOBEL), Health Research Institute of Santiago de Compostela, Spain (P.H., R.I.-R.).
¹⁰ Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden (C.J., T.M.S.).
¹¹ Department of Clinical Genetics and Genomics, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden (C.J., T.M.S.).
¹² Wolfson Centre for the Prevention of Stroke and Dementia (L.L., P.M.R.), University of Oxford, United Kingdom.
¹³ Neurology Department, Juntendo University School of Medicine, Tokyo, Japan (N.M., Y.U.).
¹⁴ Neurology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain (J.M.).
¹⁵ Institute de Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Spain (J.M.).
¹⁶ Neurology, Virgen Macarena Hospital, Sevilla, Spain (J.M.).
¹⁷ Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Spain (J.M.).
¹⁸ Department of Neurology, Hospital Universitari Arnau de Vilanova, Lleida, Spain (F.P., M.V.-P.).
¹⁹ Department of Clinical Neurosciences, University of Lleida, Spain (F.P., M.V.-P.).
²⁰ Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics (C.S.), University of Edinburgh, United Kingdom.
²¹ Centre for Clinical Brain Sciences (C.S., W.W.), University of Edinburgh, United Kingdom.
²² Nuffield Department of Population Health (W.W.), University of Oxford, United Kingdom.
²³ The George Institute for Global Health, School of Public Health, Imperial College London, United Kingdom (M.W.).

^# Contributed equally.

PMID: 40677223
DOI: 10.1161/STROKEAHA.125.052091

Abstract

Background: Uncertainty remains whether inflammation is implicated in poststroke recurrence in patients without atherosclerosis. We evaluated the contribution of atherosclerosis status to the association between inflammatory markers and major adverse cardiovascular events (MACE) poststroke.

Methods: We performed an individual-participant data meta-analysis of 11 prospective cohorts (12 countries, 1995-2017). Studies included patients with ischemic stroke/transient ischemic attack and measured IL (interleukin)-6/hsCRP (high-sensitivity C-reactive protein) postevent. We analyzed the association between IL-6/hsCRP and recurrent stroke/MACE using multivariable Cox regression analyses (conditional logistic regression for 1 study). Analyses were stratified by the presence/absence of atherosclerosis (definition: prior history of coronary disease, peripheral artery disease, or large artery atherosclerotic stroke) and adjusted for cardiovascular risk factors/preventative medication.

Results: Overall 10 148 patients (3448 [34.0%] had atherosclerosis) with 21 177 years of follow-up were included (1707 MACE outcomes/1353 recurrent strokes). In patients with atherosclerosis, IL-6 was independently associated with MACE (risk ratio [RR], 1.22 [95% CI, 1.08-1.37]; per log_eunit increase) and recurrent stroke (RR, 1.23 [95% CI, 1.08-1.41]). Compared with patients in the bottom quarter, those in the top quarter of IL-6 levels had double the risk of MACE (RR, 2.05 [95% CI, 1.37-3.08]) and stroke (RR, 1.97 [95% CI, 1.28-3.05]). IL-6 was also associated with MACE (RR, 1.11 [95% CI, 1.01-1.23]) but not stroke (RR, 1.08 [95% CI, 0.98-1.20]; per log_eunit) in patients without atherosclerosis. However, there was no evidence of statistical interaction between IL-6 levels and atherosclerosis status for either outcome (P_interaction=0.25 and 0.13 for MACE/recurrent stroke, respectively). hsCRP was associated with MACE in patients with (RR, 1.12 [95% CI, 1.05-1.21]; per log_eunit) and without atherosclerosis (RR, 1.07 [95% CI, 1.01-1.14]; P_interaction=0.28). No association with recurrent stroke was observed for hsCRP with (RR, 1.06 [95% CI, 0.98-1.14]) or without atherosclerosis (RR, 0.97 [95% CI, 0.91-1.04]; P_interaction=0.18).

Conclusions: IL-6/hsCRP were associated with poststroke recurrence irrespective of atherosclerosis. These data support the inclusion of patients in trials of anti-inflammatory therapies after stroke with elevated IL-6 or hsCRP, including those without prior atherosclerotic events.

Keywords: atherosclerosis; atrial fibrillation; coronary disease; inflammation; interleukins.

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Conflict of interest statement

Dr McCabe is supported by grant funding from the Irish Institute for Clinical Neuroscience. Dr Katan received funding from the Swiss National Science Foundation; grants from the Swiss Heart Foundation and USZ Foundation; participated on advisory boards and speaker honoraria for Medtronic, Bristol-Myers Squibb (BMS), Pfizer/Jansen, and Astra Zeneca; and received in-kind contributions from Roche Diagnostics, Brahms, and Thermo Fisher Scientific. P.M. Rothwell participated in consultancy work for Abbott, and Bayer, Sanofi and data/safety monitoring for BMS. Dr Sudlow received grant support from Asthma Lung UK, British Heart Foundation, Medical Research Council, Kidney Research UK, the Stroke Association, and Diabetes UK. Dr Whiteley participated in consultancy work for Bayer and Viatris; data/safety monitoring for several clinical trials (ICAD-CATIS [Combination Antithrombotic Treatment for Prevention of Recurrent Ischemic Stroke in Intracranial Atherosclerotic Disease], TEMPO-2 [Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion], PROTECT-U [Prospective Randomized Open-Label Trial to Evaluate Risk Factor Management in Patients With Unruptured Intracranial Aneurysms], CHOSEN [Chlorhexidine or Toothpaste, Manual or Powered Brushing to Prevent Pneumonia Complicating Stroke], PAX-D [Pramipexole for Depression], INTERACT-3 [Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial 3]); and received compensation from UK Courts for expert witness services. Dr Kelly is the principal investigator of the CONVINCE trial (Colchicine for Prevention of Vascular Inflammation in Non-Cardioembolic Stroke) and received grant funding from the Health Research Board, Ireland. L. Li reports compensation from Frontiers Neurology for other services, Neurology for other services, European Stroke Organization for other services, European Stroke Journal for other services, and International Journal of Stroke for other services. L. Li reports employment by the University of Oxford and received grants from the National Institute for Health Research. The other authors report no conflicts.

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Interleukin-6, C-Reactive Protein, and Vascular Recurrence After Stroke With and Without Atherosclerosis

Affiliations

Interleukin-6, C-Reactive Protein, and Vascular Recurrence After Stroke With and Without Atherosclerosis

Authors

Affiliations

Abstract

Conflict of interest statement

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LinkOut - more resources

Full Text Sources

Medical

Research Materials