Proteomic Signatures of High-Risk Coronary Plaque Features and Incident Events

Patients with and without obstructive coronary artery disease (oCAD) experience heterogeneous cardiovascular risk, and coronary computed tomography angiography (CCTA) high-risk plaque features are not universally available. This study evaluated whether circulating proteomic profiles clarify plaque biology and improve risk assessment. Proteomic profiling of 572 proteins was performed in PROMISE (N = 1,724), with validation in Dan-NICAD (N = 2,743) and UK Biobank (N = 53,018). A high-risk composite phenotype (HRCP) combined oCAD, high stenosis or plaque burden, high coronary calcium, and high-risk plaque features. Thirty-seven proteins were independently associated with HRCP and were mapped to inflammatory, metabolic, and proteolytic pathways; 7 were also associated with major adverse cardiovascular events, including lipoprotein lipase and cathepsin D. While the 37-protein score added little discrimination beyond clinical factors, it improved reclassification (net reclassification index = 0.13, P < 0.001), suggesting proteomic profiles may complement clinical models while elucidating disease biology and highlighting cathepsin D as a potential therapeutic target.