TOPLINE:
A new analysis that used plasma proteomics, cardiac imaging, and event surveillance of participants in a longitudinal cohort study identified 52 circulating proteins with significant links to aortic valve (AV) hemodynamics and the risk for AV-related hospitalizations. Two of these biomarkers had particularly robust associations, researchers said.
METHODOLOGY:
- 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.
TAKEAWAY:
- 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.
IN PRACTICE:
"These findings highlight the potential of MMP12 as a novel circulating biomarker of AS risk and C1QTNF1 as a new putative target to prevent CAVD [calcific aortic valve disease] progression," the authors concluded.
In an accompanying editorial, Brian R. Lindman, MD, Structural Heart and Valve Center, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, called the work "highly innovative" and said it "undoubtedly opens new avenues for discovery," adding that understanding the biology and potential predictive markers "could be useful for screening for AS." He cautioned, however, that it's unclear whether findings will "prove meaningful for clinical action or pharmacologic targeting."
SOURCE:
The study was led by Khaled Shelbaya, MD, MMSCI, Brigham and Women's Hospital, Boston, Massachusetts. It was published online on January 29, 2024, in the Journal of the American College of Cardiology.
LIMITATIONS:
AV hospitalizations in ARIC were based on International Classification of Diseases codes and not adjudicated, which may have resulted in hospitalizations not related to significant AS being included in the AV-related hospitalization outcome. While participants with an AV-related hospitalization before visit 3 were excluded from the incident AV-related hospitalization analysis, echocardiographic data regarding AV stenosis were not available at or before visit 3 in ARIC. Power for external replication in CHS was limited. Bioinformatics pathway analyses are hypothesis generating and require further experimental validation.
DISCLOSURES:
The ARIC study received funding from the National Heart, Lung, and Blood Institute; National Institutes of Health; and Department of Health and Human Services. Shelbaya had no relevant conflicts of interest; see paper for disclosures of other study authors. Lindman received research grants from and served as a consultant for Edwards Lifesciences and served as a consultant for AstraZeneca.