Of 52 circulating proteins significantly associated with both aortic valve (AV) hemodynamics and aortic stenosis (AS) severity, according to echocardiographic parameters, two show potential in assessing AS risk and treatment, a new study shows. Higher matrix metalloproteinase 12 (MMP12) values were associated with greater progression in AV hemodynamics over time, greater magnitude of AV calcification, and greater expression in calcified compared with normal or fibrotic human AV tissue. Complement C1q tumor necrosis factor-related protein 1 (C1QTNF1) demonstrated statistically robust Mendelian randomization (MR) findings of a potential causal effect on both AS and higher AVmax. The data on a novel approach to gain new insights into the pathology of AS were reported by Khaled Shelbaya, MD, MMSCI, Brigham and Women’s Hospital, Boston, Min a manuscript published Monday online and in the Feb. 6 issue of the Journal of the American College of Cardiology. Valve replacement, whether through surgery or transcatheter methods, remains the sole effective treatment for aortic stenosis. While various factors have been linked to AS development, their attributable risk is generally low. There is a pressing need for additional pharmacological targets to prevent the onset or decelerate the progression of the disease, along with the identification of biomarkers for AS screening and intervention guidance. The authors extensively analyzed the circulating proteome in large cohorts with extended follow-up, complemented by cardiac imaging, tissue transcriptomic, and genetic data. The authors utilized the SomaScan aptamer-affinity assay to measure 4,877 plasma proteins in participants of the Atherosclerosis Risk In Communities (ARIC) study during mid-life (Visit 3, Age 60±6 years, 43% males, mean AVmax 1.3 m/s) and late life (Visit 5, Age 76 ± 5 years, 46% males). Employing multivariate analysis and Cox proportional hazard regression, they identified 52 proteins that were cross-sectionally associated with AV peak velocity and dimensionless index through echocardiography at Visit 5, as well as incident AV-related hospitalization post-Visit 3. In the Cardiovascular Health Study, among 3,414 participants, six proteins showed significant associations with moderate or severe AS. These included MMP12, C1QTNF1, and growth differentiation factor-15. MMP12 exhibited associations with a greater increase in AVmax over 6 years, more extensive valve calcification, and higher expression in calcific tissue compared to normal or fibrotic tissue. C1QTNF1 displayed consistent potential causal effects on both AS and AVmax according to MR analysis. The study was limited by the fact that absolute quantification of protein concentration was not available, AV hospitalizations were based on International Classification of Diseases codes, and the hypothesis-generating nature of the analytic pathway. Writing in an accompanying editorial, Brian R. Lindman, MD, MSc, of Vanderbilt University Medical Center, Nashville, Tennessee, wrote: “Their findings seem most robust for identifying markers associated with incident AS with several reinforcing lines of evidence. However, it is unclear whether the observed adjusted hazard of 1.3 to 1.4 for incident AS will prove meaningful for clinical action or pharmacologic targeting.” He added that “the goals are to identify effective pharmacotherapies for AS and to develop tools that aid in the clinical management of individuals at risk for or diagnosed with AS. These goals may be considered insofar as they relate to: 1) incident AS; or 2) progression of established AS.” Lindman concluded: “In leveraging these innovative methods for discovery, the therapeutic and clinical objectives should provide guidance for study designs focused primarily on either incident AS or progression of established AS so that new observations have the best opportunity to translate into improved human health for individuals at risk for or diagnosed with AS.” Sources: Shelbaya K, Arthur V, Yang Y, et al. Large-Scale Proteomics Identifies Novel Biomarkers and Circulating Risk Factors for Aortic Stenosis. J Am Coll Cardiol. 2024;83:577–591. Lindman BR. Innovative Methods to Tackle Longstanding Goals in Aortic Stenosis. J Am Coll Cardiol. 2024;83:592–594. Image Credit: ArtemisDiana – stock.adobe.com