Objective: Adipocytokines are hormones secreted from adipose tissue that possibly link adiposity and the risk of cardiovascular disease, but limited prospective data exist on plasma adipocytokines and ischemic stroke risk. We investigated associations and predictive properties of 4 plasma adipocytokines, namely resistin, adipsin, leptin, and total adiponectin, with regard to incident ischemic stroke in the PRIME Study. Methods: A cohort of 9,771 healthy men 50 to 59 years of age at baseline was followed up over a period of 10 years. In a nested case–control study, 95 ischemic stroke cases were matched with 190 controls on age, study center, and date of examination. Hazard ratios (HRs) per standard deviation increase in plasma adipocytokine levels were estimated using conditional logistic regression analysis. The additive value of adipocytokines in stroke risk prediction was evaluated by discrimination and reclassification metrics. Results: Resistin (HR, 1.88; 95% confidence interval [CI], 1.16–3.03), adipsin (HR, 2.01; 95% CI, 1.33–3.04), and total adiponectin (HR, 1.53; 95% CI, 1.01–2.34), but not leptin, were independent predictors of ischemic stroke. The performance of a traditional risk factor model predicting ischemic stroke was significantly improved by the simultaneous inclusion of resistin, adipsin, and total adiponectin (c‐statistic: 0.673 [95% CI, 0.631–0.766] vs 0.826 [95% CI, 0.792–0.892], p < 0.001; net reclassification improvement: 38.1%, p < 0.001). Interpretation: Higher plasma levels of resistin, adipsin, and total adiponectin were associated with an increased 10‐year risk of ischemic stroke among healthy middle‐aged men. Resistin, adipsin, and total adiponectin provided incremental value over traditional risk factors for the prediction of ischemic stroke risk. ANN NEUROL 2012;

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.

Background: Adipokines play an important role in glucose, lipid and lipoprotein metabolisms, as well as in coagulation and inflammatory processes. So far, studies have evaluated the association of individual adipokines with future coronary heart disease (CHD) event and provided mixed results. Objectives: We sought to investigate the association of a set of adipocytokines, including total adiponectin, adipsin, resistin, leptin and plasminogen activator inihibitor-1 (PAI-1), with future CHD events in apparently healthy men. Methods: We built a nested case-control study within the PRIME Study, a multicenter prospective cohort of 9779 healthy European middle-aged men. Total adiponectin, adipsin, resistin, leptin and PAI-1 were measured in the baseline plasma sample of 617 men who developed a first CHD event (coronary death, myocardial infarction, stable or unstable angina) during 10 years of follow-up and in 1215 study-matched controls, by multiplex assays using commercial kits. HRs for CHD were estimated by conditional logistic regression analysis. Results: Median concentrations of total adiponectin, adipsin and resistin were similar in cases and in controls, whereas those of leptin and PAI-1 were higher in cases than in controls, 6.30 vs 5.40 ng ml À1 , and 10.09 vs 8.48 IU ml À1 , respectively. The risk of future CHD event increased with increasing quintiles of baseline leptin and PAI-1 concentrations only in unadjusted analysis (P-value for trend o0.003 and o0.0001, respectively). However, these associations were no longer significant after adjustment for usual CHD risk factors including hypertension, diabetes, smoking, total cholesterol, triglycerides and HDL cholesterol. Conversely, baseline CRP and IL-6 levels remained associated with CHD risk in multivariate analysis. Conclusions: In apparently healthy men, circulating total adiponectin, adipsin, resistin, leptin and PAI-1 were not independent predictors of future CHD event.