Aortic stenosis risk and Life’s Crucial 9: the role of proteomics and inflammation

AIMS: This study aims to investigate the association between Life's Crucial 9 (LC9) and the risk of aortic stenosis and the mediating roles of plasma proteomics and inflammatory biomarkers. METHODS AND RESULTS: This study analysed 295 828 UK Biobank participants (including 31 522 with available proteomics data) without aortic stenosis at baseline. Life's Crucial 9 score was categorized into three groups: low (0-49 points), moderate (50-79 points), and high (80-100 points). Compared with participants in the low LC9 group, those in the moderate [hazard ratio (HR), 0.49; 95% confidence interval (CI), 0.44-0.55] and high groups (HR, 0.28; 95% CI, 0.23-0.34) had a significantly lower aortic stenosis risk. The population attributable risk for aortic stenosis risk associated with low/moderate LC9 was 43.6% (95% CI, 34.1-53.0). A proteomic signature for LC9, consisting of 549 proteins, was constructed and found to be primarily involved in pathways related to lipid metabolism, immune function, and inflammation. The proteomic signature significantly mediated 35.9% of the association between LC9 and aortic stenosis risk, with adrenomedullin showing the highest mediating proportion at 20.9%, followed by fatty acid-binding protein 4 (18.6%), hepatocyte growth factor (17.3%), hepatitis A virus cellular receptor 1 (17.0%), and growth differentiation factor 15 (15.8%). Inflammatory biomarkers also mediated a small but significant proportion of LC9-related aortic stenosis risk, with mediating proportions ranging from 1.0 to 5.9%. CONCLUSION: Higher LC9 score was associated with reduced aortic stenosis risk. This inverse relationship was significantly mediated by plasma proteomics and inflammatory biomarkers. These findings underscore the importance of adherence to LC9 guidelines for the prevention of aortic stenosis and provide insights into the biological pathways linking cardiovascular health to aortic stenosis.