Life’s Essential 8 and risk of cardiovascular disease and mortality among individuals with early cardiovascular-kidney-metabolic syndrome: a prospective study in UK Biobank and NHANES With metabolomic analyses

Cardiovascular-kidney-metabolic (CKM) syndrome reflects the overlap of cardiovascular, kidney, and metabolic dysfunction and is associated with increased cardiovascular disease (CVD) risk. Whether cardiovascular health, assessed by Life’s Essential 8 (LE8), is associated with adverse outcomes in early-stage CKM remains insufficiently characterized, and the related metabolomic profiles are unclear. We conducted an observational dual-cohort study including adults with early-stage CKM (stages 0–2) from the UK Biobank and the National Health and Nutrition Examination Survey (NHANES). LE8 total, lifestyle, and biological scores were categorized as low, medium, or high according to American Heart Association criteria. Cox proportional hazards models were used to examine associations with incident CVD and mortality in the UK Biobank and all-cause mortality in NHANES. Exploratory metabolomic mediation analyses were performed in the UK Biobank using 168 non-derived nuclear magnetic resonance biomarkers. During a median follow-up of 14.4 years in the UK Biobank, participants with high LE8 scores (80–100) had a significantly lower risk of incident CVD (HR = 0.50, 95% CI 0.44–0.56) and all-cause mortality (HR = 0.48, 95% CI 0.40–0.58) compared with those with low LE8 scores (0–49) . In NHANES, high LE8 scores were associated with a lower risk of all-cause mortality (HR = 0.41, 95% CI 0.19–0.86). Associations were generally consistent across age and sex subgroups. Metabolomic analyses identified GlycA and lipid-related metabolites as statistical indirect-effect markers linking LE8 with clinical outcomes. Higher LE8 scores were consistently associated with lower incident CVD and mortality among adults with early-stage CKM. Exploratory metabolomic findings suggest involvement of inflammatory and lipid-related profiles, requiring external validation.