BACKGROUND: Many studies have explored whether individual plasma protein biomarkers improve cardiovascular disease risk prediction. We sought to investigate the use of a plasma proteomics-based approach in predicting different cardiovascular outcomes. METHODS: Among 51 859 UK Biobank participants (mean age, 56.7 years
45.5% male) without cardiovascular disease and with proteomics measurements, we examined the primary composite outcome of fatal and nonfatal coronary heart disease, stroke, or heart failure (major adverse cardiovascular events), as well as additional secondary cardiovascular outcomes. An exposome-wide association study was conducted using relative protein concentrations, adjusted for a range of classic, demographic, and lifestyle risk factors. A prediction model using only age, sex, and protein markers (protein model) was developed using a least absolute shrinkage and selection operator-regularized approach (derivation: 80% of cohort) and validated using split-sample testing (20% of cohort). Their performance was assessed by comparing calibration, net reclassification index, and RESULTS: Over a median 13.6 years of follow-up, 4857 participants experienced first major adverse cardiovascular events. After adjustment, the proteins most strongly associated with major adverse cardiovascular events included NT-proBNP (N-terminal pro B-type natriuretic peptide
hazard ratio [HR], 1.68 per SD increase), proADM (pro-adrenomedullin
HR, 1.60), GDF-15 (growth differentiation factor-15
HR, 1.47), WFDC2 (WAP four-disulfide core domain protein 2
HR, 1.46), and IGFBP4 (insulin-like growth factor-binding protein 4
HR, 1.41). In total, 222 separate proteins were predictors of all outcomes of interest in the protein model, and 86 were selected for the primary outcome specifically. In the validation cohort, compared with the PREVENT risk factor model, the protein model improved net reclassification (net reclassification index +0.09), and CONCLUSIONS: Measurement of targeted protein biomarkers produced superior prediction of aggregated and disaggregated cardiovascular events. This study represents proof of concept for the application of targeted proteomics in predicting a range of cardiovascular outcomes.