Metabolic vulnerability index and Life's Essential 8 with risk of major adverse cardiovascular events.

The metabolic vulnerability index (MVX) captures metabolic-inflammatory vulnerability, but its joint relevance with Life's Essential 8 (LE8) for major adverse cardiovascular events (MACE) is unclear. We analyzed 239,135 UK Biobank participants free of baseline MACE. MVX was calculated from six NMR-based biomarkers. LE8 scores were classified as low (<60), moderate (60-79), or high (≥80) cardiovascular health (CVH). Cox models evaluated associations of MVX and LE8 with incident MACE; joint-effect, interaction, counterfactual, and mediation analyses were conducted. Over a median 13.6 years, 17,146 MACE occurred. Higher MVX was associated with higher MACE risk (HR = 1.08, 95% CI: 1.07, 1.10), whereas high CVH was associated with lower risk compared to low CVH (HR = 0.44, 95% CI: 0.41, 0.47). Participants with low CVH and MVX Q4 had the highest risk (HR = 2.84, 95% CI: 2.60, 3.12). Additive interaction was evident for MACE and myocardial infarction. Counterfactual and mediation analyses suggested that better CVH could prevent a substantial proportion of events, partly through lower metabolic vulnerability. Combined MVX and LE8 assessment may improve cardiovascular risk stratification and support targeted prevention.