Associations of proinflammatory cytokines with the risk of recurrent stroke.
OBJECTIVE
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-alpha (TNF-alpha) 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-alpha, 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-alpha. No inflammatory marker was associated with hemorrhagic stroke risk. In multivariable models, IL-6 and TNF-alpha fully explained observed associations of C-reactive protein and fibrinogen with risk of ischemic stroke, but TNF-alpha retained borderline significance after full adjustment.


CONCLUSIONS
Inflammatory markers associated with the acute-phase response (IL-6, TNF-alpha, 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-alpha 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.
Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, UK.
Paul
P
Welsh
Gordon D O
GD
Lowe
John
J
Chalmers
Duncan J
DJ
Campbell
Ann
A
Rumley
Bruce C
BC
Neal
Stephen W
SW
MacMahon
Mark
M
Woodward
D000210:Acute-Phase Reaction / Q000276:immunology / Q000378:metabolism; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002545:Brain Ischemia / Q000453:epidemiology / Q000276:immunology; D002097:C-Reactive Protein / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002543:Cerebral Hemorrhage / Q000453:epidemiology / Q000276:immunology; D016207:Cytokines / Q000097:blood* / Q000276:immunology; D005260:Female; D005340:Fibrinogen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020382:Interleukin-18 / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012008:Recurrence; D012307:Risk Factors; D020521:Stroke / Q000453:epidemiology* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology
D015415:Biomarkers; D016207:Cytokines; D020382:Interleukin-18; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D005340:Fibrinogen; D002097:C-Reactive Protein