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

Area of Science:

• Cardiovascular Medicine
• Proteomics
• Biomarker Discovery

Background:

• Cardiovascular risk is heterogeneous in patients with and without obstructive coronary artery disease (oCAD).
• Coronary computed tomography angiography (CCTA) high-risk plaque features are not universally available for risk stratification.
• Novel biomarkers are needed to clarify plaque biology and enhance cardiovascular risk assessment.

Purpose of the Study:

• To investigate whether circulating proteomic profiles can elucidate coronary artery plaque biology.
• To determine if proteomic signatures improve cardiovascular risk assessment in patients with and without oCAD.
• To identify potential therapeutic targets based on proteomic findings.

Main Methods:

• Proteomic profiling of 572 proteins was conducted in the PROMISE cohort (N=1,724) and validated in Dan-NICAD (N=2,743) and UK Biobank (N=53,018).
• A high-risk composite phenotype (HRCP) was defined, incorporating oCAD, plaque burden, coronary calcium, and CCTA high-risk plaque features.
• Statistical analyses identified proteins associated with HRCP and major adverse cardiovascular events (MACE).

Main Results:

• Thirty-seven proteins were independently associated with the HRCP, mapping to inflammatory, metabolic, and proteolytic pathways.
• Seven proteins, including lipoprotein lipase and cathepsin D, were associated with MACE.
• A 37-protein score demonstrated improved risk reclassification (net reclassification index = 0.13, P < 0.001) beyond clinical factors.

Conclusions:

• Circulating proteomic profiles offer insights into coronary artery disease plaque biology.
• Proteomic signatures can complement clinical models for improved cardiovascular risk assessment.
• Cathepsin D emerges as a potential therapeutic target for cardiovascular disease.