Significance of a Multiple Biomarkers Strategy Including Endothelial Dysfunction to Improve Risk Stratification for Cardiovascular Events in Patients at High Risk for Coronary Heart Disease

OBJECTIVES: We investigated whether a multiple biomarkers strategy that includes plasma levels of endothelium-derived microparticles (EMP), reflecting endothelial dysfunction, can improve prediction of future cardiovascular events in patients at high risk for coronary heart disease (CHD). BACKGROUND: Detailed risk stratification using multiple biomarkers can provide clinical benefits in high-risk patients. Endothelial dysfunction has been described as a predictor of cardiovascular complications. METHODS: We measured 3 biomarkers in 488 consecutive patients with various CHD risks: B-type natriuretic peptide (BNP), high-sensitivity C-reactive protein (hsCRP), and EMP. We followed 387 stable patients at high risk for CHD and examined future cardiovascular events. RESULTS: During a mean follow-up of 36 months, 55 patients developed cardiovascular events. Multivariate Cox proportional hazards analysis adjusted for established risk factors identified age, BNP, hsCRP, and EMP as significant and independent predictors of future cardiovascular events (age: hazard ratio [HR]: 1.042, 95% confidence interval [CI]: 1.007 to 1.080, p = 0.02; BNP: HR: 1.242, 95% CI: 1.004 to 1.536, p = 0.046; hsCRP: HR: 1.468, 95% CI: 1.150 to 1.875, p = 0.002; EMP: HR: 1.345, 95% CI: 1.094 to 1.652, p = 0.005). The C statistics for cardiovascular events increased when each biomarker or combinations of biomarkers were added to the Framingham risk model (C statistics: Framingham risk model alone 0.636, Framingham risk + BNP 0.695, Framingham risk + hsCRP 0.696, Framingham risk + EMP 0.682, and Framingham risk + BNP + hsCRP + EMP 0.763). CONCLUSIONS: The assessment of endothelial dysfunction by plasma levels of EMP can independently predict future cardiovascular events in patients at high risk for CHD. A multiple biomarkers strategy that includes endothelial dysfunction assessed by EMP can identify patients vulnerable to cardiovascular disease. (University Hospital Medical Information Network number: UMIN000000876).