Proinflammatory protein signatures in cryptogenic and large artery atherosclerosis stroke

Objectives: The cause of ischemic stroke remains unknown, cryptogenic, in 25% of young and middle-aged patients. We hypothesized that if atherosclerosis is prominent in cryptogenic stroke, it would have a similar proinflammatory protein signature as large artery atherosclerosis (LAA) stroke.

Materials & methods: Blood was collected in the acute phase and after 3 months from cryptogenic (n = 162) and LAA (n = 73) stroke patients aged 18-69 years and once from age-matched controls (n = 235). Cryptogenic stroke was divided into Framingham Risk Score (FRS) quartiles to compare low and high risk of atherosclerosis. Plasma concentrations of 25 proteins were analyzed using a Luminex multiplex assay. The discriminating properties were assessed with discriminant analysis and C-statistics.

Results: We identified proteins that separated cryptogenic and LAA stroke from controls (area under the curves, AUCs ≥ 0.85). For both subtypes, RANTES, IL-4, and IFN-γ contributed the most at both time points. These associations were independent of risk factors of atherosclerosis. We also identified proteins that separated cryptogenic strokes in the lowest quartile of FRS from those in the highest, and from LAA stroke (AUCs ≥ 0.76), and here eotaxin and MCP-1 contributed the most.

Conclusions: The protein signature separating cases from controls was different from the signature separating cryptogenic stroke with low risk of atherosclerosis from those with high risk and from LAA stroke. This suggests that increased RANTES, IL-4, and IFN-γ in stroke may not be primarily related to atherosclerosis, whereas increased eotaxin and MCP-1 in cryptogenic stroke may be markers of occult atherosclerosis as the underlying cause.