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

John J. McCabe; Katie Harris; Cathal Walsh; Sarah Gorey; Markus Arnold; Gian Marco De Marchis; Pablo Hervella; Ramon Iglesias-Rey; Christina Jern; Mira Katan; Linxin Li; Nobukazu Miyamoto; Joan Montaner; Francisco Purroy; Peter M. Rothwell; Tara M. Stanne; Cathie Sudlow; Yuji Ueno; Mikel Vicente-Pascual; William Whiteley; Mark Woodward; Peter J. Kelly

doi:10.1161/STROKEAHA.125.052091

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

John J. McCabe
, Katie Harris
, Cathal Walsh
, Sarah Gorey
, Markus Arnold
, Gian Marco De Marchis
, Pablo Hervella
, Ramon Iglesias-Rey
, Christina Jern
, Mira Katan
, Linxin Li
, Nobukazu Miyamoto
, Joan Montaner
, Francisco Purroy
, Peter M. Rothwell
, Tara M. Stanne
, Cathie Sudlow
, Yuji Ueno
, Mikel Vicente-Pascual
, William Whiteley

Mark Woodward, Peter J. Kelly

Health Research Board (HRB) Stroke Clinical Trials Network Ireland (SCTNI)
University College Dublin
University of New South Wales
Trinity College Dublin
University of Zurich
University of Basel
University Teaching and Research Hospital
Health Research Institute of Santiago de Compostela
University of Gothenburg
Sahlgrenska University Hospital
Wolfson Centre for the Prevention of Stroke and Dementia
University of Oxford
Juntendo University
Vall d'Hebron University Hospital
Hospital Universitario Virgen del Rocio
Hospital Universitario Virgen Macarena
Autonomous University of Barcelona
University of Lleida
Usher Institute of Population Health Sciences and Informatics
Centre for Clinical Brain Sciences
Hospitalt Universitari Arnau de Vilanova de Lleida
University of Edinburgh
Imperial College London

Research output: Contribution to journal › Article › peer-review

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 10148 patients (3448 [34.0%] had atherosclerosis) with 21177 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.

Original language	English
Pages (from-to)	2588-2596
Number of pages	9
Journal	Stroke
Volume	56
Issue number	9
DOIs	https://doi.org/10.1161/STROKEAHA.125.052091
Publication status	Published - 1 Sep 2025
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

atherosclerosis
atrial fibrillation
coronary disease
inflammation
interleukins

Access to Document

10.1161/STROKEAHA.125.052091

Cite this

McCabe, J. J., Harris, K., Walsh, C., Gorey, S., Arnold, M., De Marchis, G. M., Hervella, P., Iglesias-Rey, R., Jern, C., Katan, M., Li, L., Miyamoto, N., Montaner, J., Purroy, F., Rothwell, P. M., Stanne, T. M., Sudlow, C., Ueno, Y., Vicente-Pascual, M., ... Kelly, P. J. (2025). Interleukin-6, C-Reactive Protein, and Vascular Recurrence After Stroke With and Without Atherosclerosis. Stroke, 56(9), 2588-2596. https://doi.org/10.1161/STROKEAHA.125.052091

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

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 10148 patients (3448 [34.0\%] had atherosclerosis) with 21177 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 logeunit 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 logeunit) in patients without atherosclerosis. However, there was no evidence of statistical interaction between IL-6 levels and atherosclerosis status for either outcome (Pinteraction=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 logeunit) and without atherosclerosis (RR, 1.07 [95\% CI, 1.01–1.14]; Pinteraction=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]; Pinteraction=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",

author = "McCabe, \{John J.\} and Katie Harris and Cathal Walsh and Sarah Gorey and Markus Arnold and \{De Marchis\}, \{Gian Marco\} and Pablo Hervella and Ramon Iglesias-Rey and Christina Jern and Mira Katan and Linxin Li and Nobukazu Miyamoto and Joan Montaner and Francisco Purroy and Rothwell, \{Peter M.\} and Stanne, \{Tara M.\} and Cathie Sudlow and Yuji Ueno and Mikel Vicente-Pascual and William Whiteley and Mark Woodward and Kelly, \{Peter J.\}",

note = "Publisher Copyright: {\textcopyright} 2025 American Heart Association, Inc.",

year = "2025",

month = sep,

day = "1",

doi = "10.1161/STROKEAHA.125.052091",

language = "English",

volume = "56",

pages = "2588--2596",

journal = "Stroke",

issn = "0039-2499",

number = "9",

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McCabe, JJ, Harris, K, Walsh, C, Gorey, S, Arnold, M, De Marchis, GM, Hervella, P, Iglesias-Rey, R, Jern, C, Katan, M, Li, L, Miyamoto, N, Montaner, J, Purroy, F, Rothwell, PM, Stanne, TM, Sudlow, C, Ueno, Y, Vicente-Pascual, M, Whiteley, W, Woodward, M & Kelly, PJ 2025, 'Interleukin-6, C-Reactive Protein, and Vascular Recurrence After Stroke With and Without Atherosclerosis', Stroke, vol. 56, no. 9, pp. 2588-2596. https://doi.org/10.1161/STROKEAHA.125.052091

TY - JOUR

T1 - Interleukin-6, C-Reactive Protein, and Vascular Recurrence After Stroke With and Without Atherosclerosis

AU - McCabe, John J.

AU - Harris, Katie

AU - Walsh, Cathal

AU - Gorey, Sarah

AU - Arnold, Markus

AU - De Marchis, Gian Marco

AU - Hervella, Pablo

AU - Iglesias-Rey, Ramon

AU - Jern, Christina

AU - Katan, Mira

AU - Li, Linxin

AU - Miyamoto, Nobukazu

AU - Montaner, Joan

AU - Purroy, Francisco

AU - Rothwell, Peter M.

AU - Stanne, Tara M.

AU - Sudlow, Cathie

AU - Ueno, Yuji

AU - Vicente-Pascual, Mikel

AU - Whiteley, William

AU - Woodward, Mark

AU - Kelly, Peter J.

PY - 2025/9/1

Y1 - 2025/9/1

N2 - 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 10148 patients (3448 [34.0%] had atherosclerosis) with 21177 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 logeunit 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 logeunit) in patients without atherosclerosis. However, there was no evidence of statistical interaction between IL-6 levels and atherosclerosis status for either outcome (Pinteraction=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 logeunit) and without atherosclerosis (RR, 1.07 [95% CI, 1.01–1.14]; Pinteraction=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]; Pinteraction=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.

AB - 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 10148 patients (3448 [34.0%] had atherosclerosis) with 21177 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 logeunit 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 logeunit) in patients without atherosclerosis. However, there was no evidence of statistical interaction between IL-6 levels and atherosclerosis status for either outcome (Pinteraction=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 logeunit) and without atherosclerosis (RR, 1.07 [95% CI, 1.01–1.14]; Pinteraction=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]; Pinteraction=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.

KW - atherosclerosis

KW - atrial fibrillation

KW - coronary disease

KW - inflammation

KW - interleukins

UR - https://www.scopus.com/pages/publications/105010861530

U2 - 10.1161/STROKEAHA.125.052091

DO - 10.1161/STROKEAHA.125.052091

M3 - Article

C2 - 40677223

AN - SCOPUS:105010861530

SN - 0039-2499

VL - 56

SP - 2588

EP - 2596

JO - Stroke

JF - Stroke

IS - 9

ER -

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

Abstract

UN SDGs

Keywords

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