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Elevated pro-inflammatory CD4⁺CD28^– lymphocytes and stroke recurrence and death

From the Stroke Branch (Drs. Hadareishvili, Li, Wright, Warach, Hallenbeck, and Baird), Stroke Neuroscience Unit (Drs. Li, Wright, and Baird), Laboratory of Neurophysiology (Drs. Maric and Barker), and Biostatistics Branch (Dr. Dambrosia), National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD.

Address correspondence and reprint requests to Dr. A.E. Baird, Stroke Neuroscience Unit, National Institute of Neurologic Disorders and Stroke, NIH, 10 Center Dr., MSC 1294, Rm. 3N258, Bethesda, MD 20892-1294; e-mail: bairda{at}ninds.nih.gov

Objective: To determine if the CD4⁺CD28^– T-cell subset is expanded in patients with recurrent stroke or death after acute ischemic stroke. This subset of the peripheral blood T-cell lymphocyte population has a strong pro-inflammatory and tissue-damaging potential.

Methods: Consecutive patients within the first 48 hours of ischemic stroke were prospectively studied. Peripheral blood CD4⁺CD28^– cells were quantified by flow cytometry. The study endpoint was recurrent stroke or death from any cause during 1 year of follow-up.

Results: One hundred six patients (mean age 75.0 ± 13.5 years; 50 women) were studied. The median CD4⁺CD28^– cell count was 4.5% (range 0.2 to 72.2%). Twenty-seven endpoints (10 recurrent strokes and 17 deaths) occurred during follow-up. Stroke recurrence/death rates were significantly associated with increasing CD4⁺CD28^– counts, rising from 14.2% in patients with CD4⁺CD28^– levels of <1.0 to 48.1% for those with CD4⁺CD28^– counts of >8.0% (p = 0.003, Cochran linear test of trend). Higher CD4⁺CD28^– counts were also present in patients with a history of prior stroke (p = 0.03). After adjustment for age, admission NIH Stroke Scale score, prior stroke, and atrial fibrillation, CD4⁺CD28^– counts of >8.0% were associated with a cumulative hazard ratio of 5.81 (95% CI: 1.58 to 21.32) for stroke recurrence or death.

Conclusions: Rising counts of circulating CD4⁺CD28^– cells are associated with an increasing risk of stroke recurrence and death, in addition to an observed association with prior stroke. Expansion of this T-cell subset presumably represents a biomarker and possibly a contributory pathogenic mechanism of recurrent stroke and death after ischemic stroke.

Received February 25, 2004. Accepted in final form June 15, 2004.

*Drs. Nadareishvili and Li contributed equally to this project.

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