Proinflammatory protein signatures in cryptogenic and large artery atherosclerosis stroke

Abstract

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.

Systemic inflammation after stroke: implications for post‐stroke comorbidities

“…Interestingly, blood CRP levels differ between stroke subtypes, since large‐vessel strokes had higher CRP levels at follow‐up compared with all other stroke subtypes, including small‐vessel strokes, cardioembolic strokes, cryptogenic strokes, and others (Ladenvall et al , 2006). More recent findings also reported a higher frequency of activated human leukocyte antigen (HLA − DR + ) cells in blood 2 months after ischemic stroke (Roth et al , 2018), and found that circulating IL‐4 and IFN‐γ levels persisted elevated up to 3 months poststroke, regardless of stroke etiology (Holmegaard et al , 2021). Hence, whether post‐stroke chronic inflammation could be influenced by the infarct topography and/or the co‐existence of any other comorbidity still needs to be elucidated.…”

Longitudinal Study Reveals Long-Term Proinflammatory Proteomic Signature After Ischemic Stroke Across Subtypes

“…1,6,7 It follows that inflammation has previously been implicated in the main etiological subtypes of ischemic stroke: large artery atherosclerosis (LAA), cardioembolic stroke, small artery occlusion stroke (SAO), and cryptogenic stroke. 1,8,9 Moreover, vessel wall inflammation has been proposed as one of the causes of cervical arterial dissection (CeAD). 10 Although inflammation appears to be relevant for different ischemic stroke subtypes, few studies on circulating inflammatory plasma proteins have performed subtype-specific analyses.…”

Hypoxic postconditioning drives protective microglial responses and ameliorates white matter injury after ischemic stroke

“…It plays an important role in the pathogenesis of IS due to its ability to cross the blood–brain barrier 36 . The level of eotaxin increases with the occurrence of IS, and the increase in eotaxin aggravates IS injury 37 . Macrophage inflammatory protein‐1 gamma (MIP‐1γ) also belongs to the CC‐chemokine family.…”