Individuals with high levels of inflammatory biomarkers, including C-reactive protein (CRP), total homocysteine (tHcy), tumor necrosis factor receptor 2 (TNFR2), and vascular endothelial growth factor (VEGF), face a greater risk of incident ischemic stroke. The findings from a study examining this relationship were published in Neurology.1
Inflammation has been previously implicated2 in ischemic stroke pathogenesis, and patients with systemic inflammation have been shown to have poor stroke outcomes.3 Research efforts have therefore been focused on better determining individuals at greatest risk of stroke and possible therapeutic targets.
To determine the predictive utility of specific inflammatory blood biomarkers, Ashkan Shoamanesh, MD, of the Population Health Research Institute at McMaster University in Hamilton, Ontario, Canada, and colleagues conducted an observational study of the Framingham Offspring Cohort (N=3224). Participants had no prior history of transient ischemic attack or stroke, had a mean age of 61 years, and were followed for a mean of 9.3 years. During that time, 98 participants experienced an incident ischemic stroke.
The investigators measured a panel of 15 inflammatory biomarkers, including those involved in systemic inflammation, vascular inflammation, endothelial dysfunction, and oxidative stress.
After adjusting for age and sex, CRP (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.04-1.56), TNFR2 (HR 1.33, 95% CI 1.09- 1.63), tHcy (HR 1.32, 95% CI 1.11-1.58), and VEGF (HR 1.25, 95% CI 1.07-1.46) were all found to be associated with incident ischemic stroke. After adjusting for variables of the Framingham Stroke Risk Profile (systolic blood pressure, hypertension treatment, current smoking, diabetes, cardiovascular disease, and atrial fibrillation), only CRP did not remain statistically significant (TNFR2: HR 1.24, 95% CI 1.02-1.51; tHcy: HR 1.20, 95% CI 1.01-1.43; and VEGF: HR 1.21, 95% CI 1.04-1.42).
When all 4 biomarkers were added to the criteria for the Framingham Stroke Risk Profile, the result was the greatest improvement in prediction of ischemic stroke compared to adding individual biomarkers (net reclassification improvement [
NRI]: 0.34 [0.12- 0.57], P < .05). Notably, the addition of VEGF to the risk profile alone produced the greatest discriminatory ability (NRI: 0.27 [0.03-0.50], P < .05). This association between VEGF and ischemic stroke has been previously noted, with evidence suggesting a more indirect rather than causal relationship between VEGF and future stroke. 4,5
“Identifying people who are at risk for stroke can help us determine who would benefit most from existing or new therapies to prevent stroke,” Dr Shoamanesh said in a statement. “Future research could also investigate whether lowering the levels of these biomarkers or blocking their action could be a way to prevent strokes. However, our study does not provide evidence that these markers are validated well enough to be implemented in clinical practice.”
The authors noted several limitations to their research, including the fact that the study was observational and that infections, chronic diseases, and other conditions that could affect outcomes were not accounted for.
Further studies to evaluate these biomarkers as possible therapeutic targets for stroke prevention are warranted, they concluded.
Disclosures: Dr Shoamanesh reported receiving support as the Marta and Boris Chair in Stroke Research and Care. The study was funded by the Framingham Heart Study’s National Heart, Lung, and Blood Institute; National Institute of Neurologic Disorders and Stroke; the National Institute on Aging; and the National Institutes of Health.
- Shoamanesh A, Preis SR, Beiser AS, et al. Circulating biomarkers and incident ischemic stroke in the Framingham Offspring Study. Neurology. 2016 Aug 24; doi:10.1212/WNL.0000000000003115. [Epub ahead of print]
- Jin R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol. 2010;87(5):779-89.
- Whiteley W, Jackson C, Lewis S, et al. Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6. PLoS Med. 2009;6(9):e1000145.
- Pikula A, Beiser AS, Chen TC, et al. Serum brain-derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury: Framingham Study. Stroke. 2013;44:2768-2775.
- Campbell RJ, Bell CM, Paterson JM, et al. Stroke rates after introduction of vascular endothelial growth factor inhibitors for macular degeneration: a time series analysis. Ophthalmology. 2012;119:1604-1608.