Associations of proinflammatory cytokines with the risk of recurrent stroke

Stroke. 2008 Aug;39(8):2226-30. doi: 10.1161/STROKEAHA.107.504498. Epub 2008 Jun 19.

Abstract

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-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Reaction / immunology
  • Acute-Phase Reaction / metabolism
  • Aged
  • Biomarkers / blood
  • Brain Ischemia / epidemiology
  • Brain Ischemia / immunology
  • C-Reactive Protein / immunology
  • C-Reactive Protein / metabolism
  • Case-Control Studies
  • Cerebral Hemorrhage / epidemiology
  • Cerebral Hemorrhage / immunology
  • Cytokines / blood*
  • Cytokines / immunology
  • Female
  • Fibrinogen / immunology
  • Fibrinogen / metabolism
  • Humans
  • Interleukin-18 / blood
  • Interleukin-18 / immunology
  • Interleukin-6 / blood
  • Interleukin-6 / immunology
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Recurrence
  • Risk Factors
  • Stroke / epidemiology*
  • Stroke / immunology*
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Biomarkers
  • Cytokines
  • Interleukin-18
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Fibrinogen
  • C-Reactive Protein