OBJECTIVE: We studied the association of plasma albumin with cardiovascular disease (CVD) and explored potential mechanisms behind the association in the CGPS (Copenhagen General Population Study). We also performed a meta-analysis to summarize the association between plasma albumin and CVD in individuals without preexisting CVD. Approach and Results: We included 100 520 individuals without prior CVD with 8247 incident CVD events developed during a median follow-up of 8.5 years. Rates of CVD outcomes were calculated using Cox regression and Fine and Gray competing-risks regression. The association of plasma albumin and CVD was approximately linear and confounder adjustment had little influence on the effect estimates, except for some attenuation after CRP (C-reactive protein) adjustment. In analyses according to subtypes of CVD events, the hazard ratios for each 10 g/L lower plasma albumin were 1.17 (95% CI, 1.08-1.28) for ischemic heart disease, 1.25 (95% CI, 1.09-1.43) for myocardial infarction, 1.37 (95% CI, 1.21-1.54) for any stroke, and 1.46 (95% CI, 1.28-1.68) for ischemic stroke. In the meta-analysis, we combined estimates from prospective and nested case-control studies investigating the association of plasma albumin with CVD. The meta-analysis included 14 studies with 150 652 individuals (12 studies reported events totaling 11 872). The risk ratio for a CVD event per 10 g/L lower plasma albumin was 1.96 (95% CI, 1.43-2.68) in previous studies and 1.85 (95% CI, 1.39-2.47) including our study with 57% weight in the meta-analysis. Exploratory analyses of the mechanism of the association indicated that it was probably not due to fatty acid binding but may be due to the regulation of plasma albumin by inflammation.

CONCLUSIONS: There is a robust, independent association of low plasma albumin with CVD, partly explained by plasma albumin as a negative acute-phase reactant.

CLINICAL TRIAL REGISTRATION: URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=95796. Unique identifier: CRD42018095796.