Novel Biomarkers for Aortic Stenosis Identified

The analysis included 11,430 participants (mean age 60 years, 46% male, and 21% Black) from the community-based Atherosclerosis Risk in Communities (ARIC) study who attended study visit 3 (mid-life) and 4899 participants (mean age 76 years, 43% male, and 18% Black) who attended study visit 5 (late-life).
Researchers accessed hospital discharge codes to identify AV events; carried out detailed cardiac phenotyping; assessed changes in AV peak velocity (AVmax), AV area, and dimensionless index (DI); and analyzed more than 4800 plasma proteins.
Mendelian randomization (MR) identified proteins with potential causal effects of aortic stenosis (AS) to prioritize as potential targets to prevent AS or slow its progression.
Researchers assessed the generalizability of their findings in a replication cohort of 3413 participants in the community-based observational Cardiovascular Health Study (CHS).
Over a median follow-up of 22 years, 912 ARIC participants were hospitalized with an AV diagnosis or intervention.

Researchers identified 52 circulating proteins associated with both AV hemodynamics and AS severity according to echocardiography (AVmax and DI) when assessed cross-sectionally in late-life (visit 5) and with incident AV-related hospitalization when ascertained in mid-life (visit 3).
Of the 52 candidate proteins, six were significantly associated with moderate or severe AS, one of which was matrix metalloproteinase (MMP12); higher MMP12 levels were robustly associated with incident AV hospitalizations, worse AV hemodynamics, greater increase in AVmax over 6 years in late-life, greater degree of AV calcification in late-life, and greater expression in calcific than normal or fibrotic AV tissue.
Another candidate marker was complement C1q tumor necrosis factor–related protein 1 (C1QTNF1), which was also robustly associated with AV hemodynamics and the risk for incident AV events. MR analysis identified a consistent potential causal effect of C1QTNF1 on both AS and higher AVmax.
The analysis also confirmed the AS prognostic relevance of growth differentiation factor 15 and found higher circulating leptin levels were associated with less hemodynamic AS and a lower risk for AV hospitalization.
In the external replication analysis, magnitudes of association of the 52 proteins with incident moderate or severe AS were generally similar to those for incident AV-related hospitalization in ARIC.

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