AUTHOR=Ferrannini Ele , Manca Maria Laura , Ferrannini Giulia , Andreotti Felicita , Andreini Daniele , Latini Roberto , Magnoni Marco , Williams Stephen A. , Maseri Attilio , Maggioni Aldo P. 

TITLE=Differential Proteomics of Cardiovascular Risk and Coronary Artery Disease in Humans

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 8 - 2021

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.790289

DOI=10.3389/fcvm.2021.790289

ISSN=2297-055X

ABSTRACT=Abstract
Background Proteomics of atypical phenotypes may help unravel cardiovascular disease mechanisms. 
Aim 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. 
Materials and Methods The CAPIRE study (ClinicalTrials.gov 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 ≤1 risk factor (RF+) or ≥3 risk factors (RF–) (based on history, blood pressure, glycemia, lipids, and smoking). 
Results 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 AUCROC’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 HbA1c, and smoking. 
Conclusions In a CCTA-based cohort, four proteins, involved in opposing vascular processes (healing vs adverse remodelling), 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 HbA1c. These findings could contribute to a deeper understanding of the atherosclerotic process beyond traditional risk profile assessment and potentially constitute new treatment targets.