Circulating total bilirubin and risk of incident cardiovascular disease in the general population

OBJECTIVE: To assess the association of circulating total bilirubin and cardiovascular disease (CVD) risk in a new prospective study and to determine whether adding information on total bilirubin values to established cardiovascular risk factors is associated with improvement in prediction of CVD risk.

APPROACH AND RESULTS: Circulating total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End-stage Disease) prospective study of 7222 participants and 773 incident CVD events. Total bilirubin was log-linearly associated with CVD risk. Age- and sex-adjusted hazard ratio (95% confidence interval) for CVD per 1-SD increase in loge total bilirubin was 0.82 (0.76 to 0.88; P<0.001), which was minimally attenuated to 0.89 (0.82 to 0.96; P=0.003) after further adjustment for established risk factors. In a meta-analysis of 12 population-based prospective studies involving 9378 incident CVD cases, the pooled multivariate-adjusted relative risk (95% confidence interval) for CVD was 0.93 (0.90 to 0.97; P<0.001) per 1-SD increase in total bilirubin levels. The corresponding pooled risks for coronary heart disease and stroke were 0.95 (0.92 to 0.99; P=0.018) and 0.93 (0.88 to 0.98; P=0.006), respectively. Addition of information on total bilirubin to a CVD risk prediction model containing established risk factors was associated with a C-index change of 0.0013 (-0.0004 to 0.0029; P=0.13).

CONCLUSIONS: There is a log-linear inverse association between circulating total bilirubin level and CVD risk, which is independent of established risk factors. Nonetheless, inclusion of total bilirubin in the standard established risk factors panel provides no significant improvement in CVD risk prediction.