Plasma levels of soluble receptor for advanced glycation end products are associated with endothelial function and predict cardiovascular events in nondiabetic patients

Abstract

We sought to test the hypothesis that decreased plasma soluble receptor for advanced glycation end products (sRAGE) levels were associated with endothelial dysfunction in nondiabetic patients. sRAGE, a C-truncated secretary isoform of the receptor protein, has been shown to neutralize vascular damage mediated by advanced glycation end products, and has been implicated in atherogenesis. However, the relation between plasma sRAGE level and endothelial function remains unclear. Plasma levels of sRAGE were examined in 180 nondiabetic participants with suspected coronary artery disease. Endothelial function was evaluated by endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery. The primary end point was the combined occurrence of major adverse cardiovascular events, including nonfatal myocardial infarction, revascularization with percutaneous coronary intervention or coronary artery bypass grafting, ischemic stroke, and cardiovascular death. All participants were divided into three groups according to the magnitude of FMD: group 1 (FMD <3%), group 2 (FMD >or=3 and <6%), group 3 (FMD >or=6%). The plasma levels of sRAGE were significantly decreased in group 1 compared with groups 2 and 3 (676+/-270, 820+/-357, and 1140+/-451 pg/ml; P<0.001). By multivariate analysis, it was shown that the plasma sRAGE level was an independent predictor of endothelium-dependent FMD (R = 0.46; P<0.001). After a 48-month follow-up period, there were 23 events (26%) in the lower sRAGE group(<or=median, 809 pg/ml) and 11 events (12%) in the higher sRAGE group (>809 pg/ml; P<0.05). By the Kaplan-Meier analysis, it was shown that enhanced plasma levels of sRAGE were associated with better major adverse cardiovascular event-free survival (P = 0.032). The results indicate that plasma sRAGE levels are positively associated with endothelial function and predict cardiovascular events in nondiabetic participants with suspected coronary artery disease, suggesting its pivotal role in atherothrombosis.