Combined Elevated Levels of the Proinflammatory Cytokines IL-18 and IL-12 Are Associated with Clinical Events in Patients with Coronary Artery Disease: An Observational Study

摘要

Background: Interleukin (IL)-18 in synergy with IL-12 is critical in the initiation and progression of Th-1-type responses. IL-18 and IL12 elevation has been associated with atherosclerosis, and their interaction is hypothesized to partly be driven by glucose. We aimed to explore if simultaneous elevation of IL-18 and IL-12, as related to glucose levels, would influence the prognosis in coronary artery disease (CAD). Method: Patients (n=1001) with angiographically verified stable CAD were investigated (78% men, mean age 62 years, 20% current smokers). IL-18 and IL-12 were measured by conventional ELISA methods. High fasting glucose (FG) was defined as the 75 percentile, that is, >6.2mmol/L. Results: After 2-year follow-up, 100 cardiovascular endpoints (fatal and nonfatal acute myocardial infarction, unstable angina, and stroke) were recorded. Subjects with simultaneous (not separate) levels in upper tertiles of both markers were at higher risk of cardiovascular events, compared to subjects in lowest tertile of both (odds ratio=1.70, 95% confidence interval 1.11-2.61, adjusted P=0.016), with no influence of high FG. Hyperglycemia associated with higher IL-18 levels (adjusted P=0.009) and IL-12 levels was considerably lower in current smokers (adjusted P<0.001). Conclusion: Simultaneous elevated circulating levels of IL-18 and IL-12 increased the event rate after 2 years in CAD patients, independent of hyperglycemia.