Systemic chemokine levels, coronary heart disease, and ischemic stroke events

Abstract

Objectives:To quantify the association between systemic levels of the chemokine regulated on activation normal T-cell expressed and secreted (RANTES/CCL5), interferon-␥-inducible protein-10 (IP-10/CXCL10), monocyte chemoattractant protein-1 (MCP-1/CCL2), and eotaxin-1 (CCL11) with future coronary heart disease (CHD) and ischemic stroke events and to assess their usefulness for CHD and ischemic stroke risk prediction in the PRIME Study. Methods:After 10 years of follow-up of 9,771 men, 2 nested case-control studies were built including 621 first CHD events and 1,242 matched controls and 95 first ischemic stroke events and 190 matched controls. Standardized hazard ratios (HRs) for each log-transformed chemokine were estimated by conditional logistic regression.Results: None of the 4 chemokines were independent predictors of CHD, either with respect to stable angina or to acute coronary syndrome. Conversely, RANTES (HR ϭ 1.70; 95% confidence interval [CI] 1.05-2.74), IP-10 (HR ϭ 1.53; 95% CI 1.06-2.20), and eotaxin-1 (HR ϭ 1.59; 95% CI 1.02-2.46), but not MCP-1 (HR ϭ 0.99; 95% CI 0.68-1.46), were associated with ischemic stroke independently of traditional cardiovascular risk factors, hs-CRP, and fibrinogen. When the first 3 chemokines were included in the same multivariate model, RANTES and IP-10 remained predictive of ischemic stroke. Their addition to a traditional risk factor model predicting ischemic stroke substantially improved the C-statistic from 0.6756 to 0.7425 (p ϭ 0.004). Conclusions:In asymptomatic men, higher systemic levels of RANTES and IP-10 are independent predictors of ischemic stroke but not of CHD events. RANTES and IP-10 may improve the accuracy of ischemic stroke risk prediction over traditional risk factors. Neurology ® 2011;77:1165-1173 GLOSSARY CHD ϭ coronary heart disease; CI ϭ confidence interval; HDL ϭ high-density lipoprotein cholesterol; HR ϭ hazard ratio; hs-CRP ϭ high sensitivity C-reactive protein; IP-10 ϭ interferon-␥-inducible protein-10; MCP-1 ϭ monocyte chemoattractant protein-1; NRI ϭ Net Reclassification Improvement; RANTES ϭ regulated on activation normal T-cell expressed and secreted.

Multiple Biomarkers for the Prediction of Ischemic Stroke

“…Clinical information, computerized tomodensitometry scans (compatible signs), angiographic and autopsy data were used to distinguish between ischemic and hemorrhagic stroke events. 3,4 After 10 years of follow-up, the stroke event status was available for 95.1% of the cohort. Details of an assessment of the quality of data have been published elsewhere.…”

“…In the Prospective Epidemiological Study on Myocardial Infarction (PRIME), we have shown an incremental value of chemokines and adipocytokines in predicting ischemic stroke. 3,4 Biomarkers of hemostasis, inflammation, and endothelial activation represent further candidates for risk prediction, but evidence for their prospective association and prognostic relevance with regard to ischemic stroke is yet to be established. Moreover, simultaneous assessment of multiple biomarkers from distinct biological pathways, the so-called multimarker approach, has been hypothesized to enhance risk prediction in a clinically relevant manner.…”

“…Furthermore, associations between these biomarkers and ischemic stroke were examined, including 5 biomarkers that were previously identified to be associated with ischemic stroke in the PRIME study, namely 2 chemokines (regulated on activation normal T-cell expressed and secreted [RANTES], interferon-γ-inducible-protein-10 [IP-10]) and 3 adipocytokines (resistin, adipsin, total adiponectin). 3,4 This step aimed at identifying from an initial set of 14 biomarkers those most significantly associated with ischemic stroke. Our second objective was to put the results into a clinical perspective by studying the usefulness of the most significant biomarkers for individual risk prediction of ischemic stroke using metrics of discrimination and reclassification.…”

Circulatory Levels of C-X-C Motif Chemokine Ligands 1, 9, and 10 Are Elevated in Patients with Ischemic Stroke

“…As previously mentioned, CXCL10 plays a pleiotropic role in prolonged leukocyte recruitment, astrocyte migration/activation, and neuron attachment/sprouting after focal stroke [14,15]. A previous study demonstrated the focal enhanced serum levels of CXCL10 in rat brains peaking at 1 h, a followed by a second peak at 3-6 h, and a third peak at 15 days after stroke [16]. In recent studies, CCL12, CCL5, and CXCL10 were associated with ischemic stroke independent of traditional cardiovascular risk factors.…”

“…CXCL10 plays a pleiotropic role in prolonged leukocyte recruitment, astrocyte migration/activation, and neural attachment/sprouting following focal stroke [14,15]. In recent studies, CCL11, CCL5, and CXCL10 are associated with ischemic stroke independent of traditional cardiovascular risk factors [16].…”