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(Stroke. 2008;39:2226.)
© 2008 American Heart Association, Inc.

Original Contributions

Associations of Proinflammatory Cytokines With the Risk of Recurrent Stroke

Paul Welsh, BSc; Gordon D.O. Lowe, DSc; John Chalmers, MD, PhD; Duncan J. Campbell, MD, PhD; Ann Rumley, PhD; Bruce C. Neal, PhD; Stephen W. MacMahon, PhD Mark Woodward, PhD

From the Division of Cardiovascular and Medical Sciences (P.W., G.D.O.L., A.R., M.W.), University of Glasgow, Royal Infirmary, Glasgow, Scotland; The George Institute for International Health (J.C., B.C.N., S.W.M., M.W.), University of Sydney, Sydney, Australia; St. Vincent’s Institute of Medical Research and the Department of Medicine (D.J.C.), University of Melbourne, St. Vincent’s Hospital, Melbourne, Australia; and Mount Sinai Medical School (M.W.), New York, NY.

Correspondence to Prof Gordon D.O. Lowe, Division of Cardiovascular and Medical Sciences, University of Glasgow, Queen Elizabeth Building, Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, UK. E-mail g.d.lowe{at}clinmed.gla.ac.uk

Background and Purpose— There are few reports on proinflammatory cytokines and risk of primary or recurrent stroke. We studied the association of interleukin (IL)-6, IL-18, and tumor necrosis factor- (TNF-) with recurrent stroke in a nested case-control study derived from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS).

Methods— We performed a nested case-control study of 591 strokes (472 ischemic, 83 hemorrhagic, 36 unknown subtype) occurring during a randomized, placebo-controlled multicenter trial of perindopril-based therapy in 6105 patients with a history of stroke or transient ischemic attack. Controls were matched for age, treatment group, sex, region, and most recent qualifying event at entry to the parent trial.

Results— IL-6 and TNF-, but not IL-18, were associated with risk of recurrent ischemic stroke independently of conventional risk markers. Adjusted odds ratios comparing the highest to lowest third of their distributions were 1.33 (95% CI, 1.00 to 1.78) for IL-6 and 1.46 (1.02 to 2.10) for TNF-. No inflammatory marker was associated with hemorrhagic stroke risk. In multivariable models, IL-6 and TNF- fully explained observed associations of C-reactive protein and fibrinogen with risk of ischemic stroke, but TNF- retained borderline significance after full adjustment.

Conclusions— Inflammatory markers associated with the acute-phase response (IL-6, TNF-, C-reactive protein, and fibrinogen, but not IL-18) are associated with risk of recurrent stroke. These markers are dependent on each other in multivariable models, and once all were included, only TNF- retained a borderline association. Markers of generalized inflammation of the acute-phase response are associated with recurrent stroke, rather than IL-6, C-reactive protein, or fibrinogen in particular.

Key Words: stroke • inflammation • acute-phase response • epidemiology

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