Benefits of Better Cardiovascular Health for Calcific Aortic Valve Stenosis Stratified by Polygenic Risk Score

With global aging, the prevalence of calcific aortic valve stenosis (CAVS) has significantly increased, and even mild CAVS elevates mortality risk, highlighting an urgent need for preventive strategies. In this study, we analyzed 153,312 participants from the UK Biobank. We found that a higher Life's Essential 8 (LE8) score was independently associated with a decreased CAVS risk [hazard ratio (HR)/standard deviation (SD): 0.72, 95% confidence interval (CI): 0.68-0.76, P < 2E-16], whereas a higher genetic risk score was independently associated with an increased CAVS risk (HR/SD: 1.63, 95% CI: 1.54-1.71, P < 2E-16). Restricted cubic spline analysis revealed approximately linear inverse associations between LE8 score and CAVS risk across all genetic risk groups. Although no multiplicative interaction was found between cardiovascular health (CVH) and genetic risk for CAVS, a significant additive interaction was identified (relative excess risk due to interaction: 3.77, 95% CI: 1.30-8.50). Among participants with high genetic risk, those with ideal CVH had a lower 10-year cumulative CAVS incidence rate than those with poor CVH (0.33% vs. 1.80%, P < 0.001). Besides, a significant multiplicative interaction was observed between LE8 score and age (P = 0.007). Similar trends were also observed for early-onset and late-onset CAVS. In conclusion, regardless of genetic risk groups, a higher LE8 score was associated with a lower CAVS risk in an approximately linear pattern. In particular, high genetic risk and poor CVH had a synergistic effect on CAVS risk, meaning that participants with high genetic risk and poor CVH would amplify their CAVS risk. Therefore, early and sustained optimization of CVH, particularly among those with high genetic risk, is essential to mitigate the risk of CAVS and its subtypes.