Quantification of Coronary Atherosclerosis and Inflammation to Predict Coronary Events and All-Cause Mortality

OBJECTIVES: This study sought to determine whether the evaluation of the combined presence of coronary artery calcium (CAC) and high-sensitivity C-reactive protein (hsCRP) improves discrimination and stratification of hard coronary events and all-cause mortality in the general population. BACKGROUND: Coronary atherosclerosis is a chronic inflammatory disease. Both hsCRP as a measure of inflammation and CAC as a measure of coronary plaque burden have been shown to improve risk appraisal. METHODS: Framingham risk variables, hsCRP, and CAC were measured in 3,966 subjects without known coronary artery disease or acute inflammation. After 5 years, incident coronary deaths, nonfatal myocardial infarction, and all-cause mortality were determined. RESULTS: CAC and hsCRP independently predicted 91 coronary events (adjusted hazard ratios [HRs]: log(2)(CAC+1) = 1.25 [95% confidence interval (CI): 1.16 to 1.34], p < 0.0001; hsCRP = 1.11 [95% CI: 1.02 to 1.21], p = 0.019) and 130 deaths (adjusted HRs: log(2)(CAC+1) = 1.12 [95% CI: 1.06 to 1.19], p < 0.0001; hsCRP = 1.11 [95% CI: 1.04 to 1.19], p = 0.004). For coronary events, net reclassification improvement (NRI) was 23.8% (p = 0.0007) for CAC and 10.5% (p = 0.026) for hsCRP. Adding CAC to Framingham risk variables and hsCRP further improved discrimination of coronary risk but not vice versa. Among persons without CAC, those with hsCRP >3 mg/l versus <3 mg/l had a significantly higher coronary risk (p = 0.006). For all-cause mortality, integrated discrimination improvement (IDI) was positive when CAC or hsCRP were added to age and sex (+0.51%, p < 0.001 and +0.43%, p = 0.012, respectively). Adjusted HRs in the highest versus lowest category of a risk index derived from established CAC and hsCRP thresholds (i.e., CAC = 100 and hsCRP = 3 mg/l) were 5.92 (95% CI: 3.14 to 11.16) for coronary events and 3.02 (95% CI: 1.82 to 5.01) for all-cause mortality (p < 0.0001 each). The adjusted HR for coronary events in intermediate risk subjects was 6.98 (95% CI: 2.47 to 19.73), p < 0.001. CONCLUSIONS: The risk of coronary events and all-cause mortality that is mediated by the presence of coronary atherosclerosis and systemic inflammation can be estimated by CAC and hsCRP. An improvement in coronary risk prediction and discrimination was predominantly driven by CAC, whereas hsCRP appears to have a role especially in persons with very low CAC scores.