Plasma protein profiling identified 52 proteins associated with aortic valve peak velocity and incident hospitalization, with 6 proteins including MMP12 and C1QTNF1 linked to moderate or severe AS.
Observational (n=11,430)
Yes
Do specific plasma proteins associate with the development and progression of aortic stenosis?
Large-scale proteomics identified MMP12 as a novel circulating biomarker for aortic stenosis risk and C1QTNF1 as a potential causal target for preventing progression.
BACKGROUND Limited data exist regarding risk factors for aortic stenosis (AS). The plasma proteome is a promising phenotype for discovery of novel biomarkers and potentially causative mechanisms. OBJECTIVES The aim of this study was to discover novel biomarkers with potentially causal associations with AS. METHODS We measured 4,877 plasma proteins (SomaScan aptamer-affinity assay) among ARIC (Atherosclerosis Risk In Communities) study participants in mid-life (visit 3 V3; n = 11,430; age 60 ± 6 years) and in late-life (V5; n = 4,899; age 76 ± 5 years). We identified proteins cross-sectionally associated with aortic valve (AV) peak velocity (AVmax) and dimensionless index by echocardiography at V5 and with incident AV-related hospitalization after V3 with the use of multivariable linear and Cox proportional hazard regression. We assessed associations of candidate proteins with changes in AVmax over 6 years and with AV calcification with the use of cardiac computed tomography, replicated analysis in an independent sample, performed Mendelian randomization, and evaluated gene expression in explanted human AV tissue. RESULTS Fifty-two proteins cross-sectionally were associated with AVmax and dimensionless index at V5 and with risk of incident AV-related hospitalization after V3. Among 3,413 participants in the Cardiovascular Health Study, 6 of those proteins were significantly associated with adjudicated moderate or severe AS, including matrix metalloproteinase 12 (MMP12), complement C1q tumor necrosis factor–related protein 1 (C1QTNF1), and growth differentiation factor-15. MMP12 was also associated with greater increase in AVmax over 6 years, greater degree of AV calcification, and greater expression in calcific compared with normal or fibrotic AV tissue. C1QTNF1 had consistent potential causal effects on both AS and AVmax according to Mendelian randomization analysis. CONCLUSIONS These findings identify MMP12 as a potential novel circulating biomarker of AS risk and C1QTNF1 as a new putative target to prevent AS progression.
“Commentary by Dr. Valentin Fuster.”
Shelbaya et al. (2024) conducted an observational in Aortic stenosis (n=11,430). Plasma proteins was evaluated on Aortic valve peak velocity (AVmax), dimensionless index, and incident AV-related hospitalization. Plasma protein profiling identified 52 proteins associated with aortic valve peak velocity and incident hospitalization, with 6 proteins including MMP12 and C1QTNF1 linked to moderate or severe AS.