Mediation analysis of adiposity and inflammation in the associations of Life’s Crucial 9 and Life’s Essential 8 with mortality among postmenopausal women

Objective: Life’s Essential 8 (LE8) and Life’s Crucial 9 (LC9) summarize overall cardiovascular health. This study investigated the associations between LC9 and LE8 with all-cause and cardiovascular mortality in postmenopausal women and further assessed whether adiposity-related and inflammation-related indicators statistically mediated these associations. Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 2005-2018, with mortality follow-up through December 31, 2019. The primary outcome was all-cause mortality, and the secondary outcome was cardiovascular mortality. Survey-weighted Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cardiovascular mortality. Nonlinear dose-response relationships were assessed using generalized additive models with penalized splines, and survival differences were visualized by Kaplan-Meier curves with log-rank tests. Stratified analyses were performed across demographic and clinical subgroups. Mediation analyses further quantified the indirect effects of adiposity-related indices (a body shape index [ABSI], weight–waist index [WWI]) and inflammation-related indicators (systemic inflammation response index [SIRI], red cell distribution width [RDW]). Results: Among 7,842 postmenopausal women, there were 1,313 all-cause deaths and 395 cardiovascular deaths during follow-up. In Cox models, higher cardiovascular health scores were associated with lower mortality. For LE8, each 1-SD increase (14.4 points) was associated with lower all-cause mortality (HR=0.72, 95% CI=0.68-0.77) and cardiovascular mortality (HR=0.67, 95% CI=0.60-0.75). LC9 analyses were restricted to participants with nonmissing LC9 (n=7,496). For LC9, each 1-SD increase (14.0 points) was associated with lower all-cause mortality (HR=0.70, 95% CI=0.65-0.75) and cardiovascular mortality (HR=0.62, 95% CI=0.55-0.70). Categorized analyses showed graded associations, with lower mortality at higher score levels. In mediation analyses, adiposity-related and inflammation-related indicators explained a small proportion of these associations. For LE8, the proportion mediated was ∼5.4% (ABSI), 6.6% (WWI), 8.7% (SIRI), and 10.5% (RDW). For LC9, SIRI, and RDW–mediated ∼8.7% and 10.3%, respectively (all indirect effects P <0.001). Conclusions: We observed inverse associations between LE8 and LC9 scores and both all-cause and cardiovascular mortality in postmenopausal women. Indicators of adiposity and systemic inflammation showed partial statistical mediation of these observed associations.