Differential Proteomics of Cardiovascular Risk and Coronary Artery Disease in Humans

Background:& nbsp;Proteomics of atypical phenotypes may help unravel cardiovascular disease mechanisms.& nbsp;Aim:& nbsp;We aimed to prospectively screen the proteome of four types of individuals: with or without coronary artery disease (CAD), each with or without multiple risk factors. Associations with individual risk factors and circulating biomarkers were also tested to provide a functional context to the protein hits.& nbsp;Materials and Methods:& nbsp;The CAPIRE study ( Identifier: NCT02157662) is a cross-sectional study aimed at identifying possible new mechanisms promoting or protecting against atherothrombosis. Quantification (by aptamer technology), ranking (using partial least squares), and correlations (by multivariate regression) of ~5000 plasma proteins were performed in consecutive individuals aged 45-75 years, without previous cardiovascular disease, undergoing computed tomography angiography for suspected CAD, showing either > 5/16 atherosclerotic segments (CAD(+)) or completely clean arteries (CAD(-)) and either & LE; 1 risk factor (RF+) or & GE;3 risk factors (RF-) (based on history, blood pressure, glycemia, lipids, and smoking).& nbsp;Results:& nbsp;Of 544 individuals, 39% were atypical (93 CAD(+)/RF-; 120 CAD(-)/RF+) and 61% typical (102 CAD(+)/RF+; 229 CAD(-)/RF-). In the comparison with CAD(+)/RF- adjusted for sex and age, CAD(-)/RF+ was associated with increased atrial myosin regulatory light chain 2 (MYO) and C-C motif chemokine-22 (C-C-22), and reduced protein shisa-3 homolog (PS-3) and platelet-activating factor acetylhydrolase (PAF-AH). Extending the analysis to the entire cohort, an additional 8 proteins were independently associated with CAD or RF; by logistic regression, the 12-protein panel alone discriminated the four groups with AUC(ROC)'s of 0.72-0.81 (overall p = 1.0e(-38)). Among them, insulin-like growth factor binding protein-3 is positively associated with RF, lower BMI, and HDL-cholesterol, renin with CAD higher glycated hemoglobin HbA(1c), and smoking.& nbsp;Conclusions:& nbsp;In a CCTA-based cohort, four proteins, involved in opposing vascular processes (healing vs. adverse remodeling), are specifically associated with low CAD burden in high CV-risk individuals (high MYO and C-C-22) and high CAD burden in low-risk subjects (high PS-3 and PAF-AH), in interaction with BMI, smoking, diabetes, HDL-cholesterol, and HbA(1c). These findings could contribute to a deeper understanding of the atherosclerotic process beyond traditional risk profile assessment and potentially constitute new treatment targets.