Metal Mixture-Related Inflammatory Burden and Stroke Risk: A NHANES-Based Mediation Analysis via Central Adiposity

Background Growing evidence suggests that exposure to heavy metal mixtures may contribute to increased risk of stroke and premature mortality, potentially through inflammation-mediated mechanisms. The Metal Mixture Inflammatory Index (MMII) has recently been proposed as a composite metric to quantify the systemic inflammatory potential of metal co-exposure. However, the relationship between MMII and cerebrovascular outcomes, and the potential mediating role of central adiposity measured by the weight-adjusted waist index (WWI), remains unclear. Methods We analyzed data from 11,563 adults in the U.S. National Health and Nutrition Examination Survey (NHANES, 2005–2018). MMII was calculated by standardizing and averaging the concentrations of nine urinary heavy metals. WWI was computed as waist circumference divided by the square root of weight. Multivariable logistic and Cox regression models were used to assess the associations of MMII and WWI with stroke and all-cause mortality. Restricted cubic spline (RCS) models evaluated dose–response patterns, and mediation analysis was performed to assess the indirect effect of WWI on the MMII–stroke relationship. Results Higher MMII and WWI were independently associated with increased odds of stroke and risk of all-cause mortality after adjusting for demographic and clinical covariates. The associations were approximately linear in RCS models. Subgroup analyses confirmed robustness across various strata. Mediation analysis revealed that WWI explained 9.87% of the association between MMII and stroke (indirect effect: 3.09 × 10⁻³, P < 0.001). Conclusion This study provides evidence that MMII is positively associated with stroke and mortality risk, and that WWI partially mediates the relationship between MMII and stroke. These findings highlight the interplay between environmental exposure and central adiposity in shaping cerebrovascular risk and support the utility of MMII and WWI as informative risk indicators in population health research.