Abstract 13260: Large Scale Plasma Proteomics Identifies MMP-12 As a Novel Biomarker of Aortic Stenosis Progression

Background: Aortic stenosis (AS) is associated with significant morbidity and mortality and is increasing in prevalence. Limited data exist regarding circulating biomarkers of AS risk. Methods: Among Atherosclerosis Risk in Communities study participants with available proteomics (Somascan v4) at study Visit 5 (2011-13; n=4,899; age 76 ± 5 years, 57% women), we used multivariable linear regression to evaluate the association of 4,877 plasma proteins with peak aortic valve (AV) velocity and AV dimensionless index. We then tested their association, when assessed at study Visit 3 (1993-95; n=11,430; age 60 ± 6, 54% women), with incident AV-related hospitalization post-Visit 3 (median follow-up 22, IQR 14 - 25 years) using multivariable Cox PH regression models. For the resulting candidate proteins, we assessed the association of Visit 5 protein levels with change in AV peak velocity over 6 years from Visit 5 to 7 (2018-19; n=2,314) and with quantitative AV calcification by cardiac CT at Visit 7 (n=1,804); associations with incident adjudicated AS in the Cardiovascular Health Study (CHS; n=3,413); and differences in AV tissue expression in normal, fibrotic, and calcific segments of explanted stenotic human AVs (n=3). Results: We identified 52 plasma proteins with consistent associations with AV peak velocity, AV dimensionless index, and incident AV hospitalization. Of these 52 proteins, MMP12 was also associated with magnitude of increase in AV peak velocity between Visits 5 and 7 (Figure), and with magnitude of AV calcification by CT at Visit 7 (adjusted OR 1.25 [95% CI 1.19-1.32], p=1.7x10 -17 ). Higher MMP12 was also associated with incident moderate or severe AS in CHS, an independent cohort. MMP12 expression was greater in calcific compared to fibrotic or normal AV tissue segments. Conclusions: Plasma MM12 is a potential novel circulating biomarker of AS risk.