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.