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.

Keywords: IL-6; TNF-alpha; biomarkers; crp; fibrinogen; inflammation; outcome; stroke.

Conflict of interest statement

MEn reports grants from Bayer and fees paid to the Charité from AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Amgen, GSK, Sanofi, Covidien, Novartis, Pfizer, all outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Kirzinger, Stroux, Rackoll, Endres, Flöel, Ebinger and Nave.

Figures

Figure 1

Dynamics of inflammatory biomarkers in the PHYS-Stroke study cohort; hs-CRP (A), IL-6 (B), TNF-alpha (C), fibrinogen (D). Levels of markers are expressed as means, 95% CIs as error bars; horizontal dashed lines depict cut-off for normal ranges.

Figure 2

MANOVA-Models, Dynamics of inflammatory biomarkers separated into the two treatment groups; hs-CRP (A), IL-6 (B), TNF-alpha (C), fibrinogen (D); Levels of markers are expressed as Estimated Marginal Means, 95% CIs as error bars; horizontal dashed lines depict cut-off for normal ranges.