Elevated Serum Inflammatory Markers in Subacute Stroke Are Associated With Clinical Outcome but Not Modified by Aerobic Fitness Training: Results of the Randomized Controlled PHYS-STROKE Trial

Abstract

Background: Inflammatory markers, such as C-reactive Protein (CRP), Interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha and fibrinogen, are upregulated following acute stroke. Studies have shown associations of these biomarkers with increased mortality, recurrent vascular risk, and poor functional outcome. It is suggested that physical fitness training may play a role in decreasing long-term inflammatory activity and supports tissue recovery.Aim: We investigated the dynamics of selected inflammatory markers in the subacute phase following stroke and determined if fluctuations are associated with functional recovery up to 6 months. Further, we examined whether exposure to aerobic physical fitness training in the subacute phase influenced serum inflammatory markers over time.Methods: This is an exploratory analysis of patients enrolled in the multicenter randomized-controlled PHYS-STROKE trial. Patients within 45 days of stroke onset were randomized to receive either four weeks of aerobic physical fitness training or relaxation sessions. Generalized estimating equation models were used to investigate the dynamics of inflammatory markers and the associations of exposure to fitness training with serum inflammatory markers over time. Multiple logistic regression models were used to explore associations between inflammatory marker levels at baseline and three months after stroke and outcome at 3- or 6-months.Results: Irrespective of the intervention group, high sensitive CRP (hs-CRP), IL-6, and fibrinogen (but not TNF-alpha) were significantly lower at follow-up visits when compared to baseline (p all ≤ 0.01). In our cohort, exposure to aerobic physical fitness training did not influence levels of inflammatory markers over time. In multivariate logistic regression analyses, increased baseline IL-6 and fibrinogen levels were inversely associated with worse outcome at 3 and 6 months. Increased levels of hs-CRP at 3 months after stroke were associated with impaired outcome at 6 months. We found no independent associations of TNF-alpha levels with investigated outcome parameters.Conclusion: Serum markers of inflammation were elevated after stroke and decreased within 6 months. In our cohort, exposure to aerobic physical fitness training did not modify the dynamics of inflammatory markers over time. Elevated IL-6 and fibrinogen levels in early subacute stroke were associated with worse outcome up to 6-months after stroke.Clinical Trial Registration:ClinicalTrials.gov, NCT01953549.

Elevated Serum Uric Acid Increases the Risk of Ischemic Stroke Recurrence and Its Inflammatory Mechanism in Older Adults

“…Inflammatory markers, such as C-reactive protein, interleukin-6, tumor necrosis factor, and fibrinogen, are up-regulated following acute stroke. The associations of these biomarkers with increased mortality, recurrent vascular risk, and poor functional outcome of stroke have been reported ( Whiteley et al, 2011 ; Mobarra et al, 2019 ; Kirzinger et al, 2021 ). Therefore, we speculate that UA may cause recurrence of ischemic stroke through inflammation.…”

Correlation of Serum IL-1β, IL-6, and hs-CRP levels with Infarct Core and Ischemic Penumbra Volume in Acute Ischemic Stroke

“…In ammatory markers such as IL-1, IL-6, CRP, TNF-α, and brinogen are upregulated in AIS. [17] Studies have also associated these in ammatory markers with increased mortality, recurrent vascular risk, and poor functional outcome. [15] They have been suggested to cause injury to vascular endothelial cells, promote the release of in ammatory factors, and activate the coagulation cascade that can lead to further expansion of the infarct core after stroke.…”

“…[3,[20][21][22][23] The most studied in ammatory cytokines in AIS are the pro-in ammatory cytokines IL-1β, Il-6, and TNF-α. [9,17] In this study, we did not include TNF-α because the increasing trend of TNF-α, IL-1β, and IL-6 was consistent; for example, a previous study showed within 72 h of neurological sign onset, in a 1month follow-up period, they assessed NIHSS as primary and plasma levels of TNF-α, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IFN-γ, IP-10, MCP-1, 8-isoprostane were increased. The levels of plasma in ammatory markers TNF-α, IL-1β, IL-6, IL-8, and prostaglandin E2 P were signi cantly decreased in a therapy group after 7 days of intervention, [24] but the in ammatory factors IL-1β and IL-6 were increased signi cantly in cerebral ischemia.…”

“…[10] Several studies have shown that elevated high-sensitive CRP (hs-CRP) after stroke is associated with unfavorable outcomes. [17] Several population-based investigations have demonstrated a correlation between in ammatory biomarkers (such as CRP, brinogen, D-dimer, and white blood cell count) and the risk of incident and recurrent stroke. There have been few studies on the relationship between serum levels of in ammatory factors and ischemic penumbra and their impact on the prognosis of patients with AIS.…”

Contemplating IL‐6, a double‐edged sword cytokine: Which side to use for stroke pathology?

“…Interestingly, those predisposed to lower IL‐6 production also showed greater sIL6R levels 52 . Some research shows higher IL‐6 serum levels at study enrollment correlate to worse outcomes at 3 and 6 months (NCT01953549) 53 . Elevations in IL‐6 at least 3 weeks after initial lacunar stroke predict recurrent vascular events, such as stroke, vascular death, and myocardial infarction 54 .…”