AbstractAimsTo evaluate the independent, mediating, interactive, and associated effects of Life's Essential 8 (LE8) and genetic predisposition on the risk of cardiovascular outcomes and all-cause mortality.Methods and resultsWe retrieved a total of 254 783 individuals from the UK Biobank. LE8 was determined by eight metrics (nicotine exposure, physical activity, diet, sleep, body mass index, blood pressure, blood glucose, and blood lipids), and was characterized as low, moderate, and high cardiovascular health (CVH). Genetic predisposition was estimated using the polygenic risk score (PRS). Cox regressions were performed to evaluate the associations between LE8, PRS, and outcomes. During a median follow-up of 12.53 years, all-cause mortality occurred in 10 257 of 197 473 participants, cardiovascular mortality in 2074 of 215 675, and incident cardiovascular disease (CVD) in 71 774 of 215 675. Individuals with moderate or high CVH experienced a lower risk [hazard ratios (HRs) 0.33 to 0.81] of adverse health outcomes compared with their counterparts with low CVH. A substantial proportion (16.1∼69.8%) of health outcomes could be attributable to moderate or high LE8, and up to 51.2% of the associations between PRS and adverse outcomes were mediated by LE8. In high PRS group, individuals with high CVH had lower CVD mortality (HR: 0.26, 95% confidence interval: 0.18, 0.39), compared to those with low CVH.ConclusionIdeal CVH was associated with lower risks of cardiovascular outcomes and all-cause mortality, with a more pronounced association observed in individuals with high PRS for CVD. Improving CVH according to LE8 guidelines should be encouraged, especially for those with PRS that indicate high CVD risk.