Association Between Blood Heavy Metals and Selenium with All-Cause Mortality in Cardiovascular-Kidney-Metabolic Syndrome Populations: Exploring the Mediating Effects of Inflammatory Biomarkers.

Cardiovascular-kidney-metabolic (CKM) syndrome, characterized by the pathophysiological interplay among metabolic disorders, chronic kidney disease (CKD), and cardiovascular disease (CVD), significantly elevates mortality risk. Environmental heavy metal exposure and selenium deficiency are implicated in these conditions, but their combined impact on CKM syndrome is unclear. To investigate the associations of blood heavy metals (lead [Pb], cadmium [Cd], mercury [Hg], manganese [Mn]) and selenium (Se) with all-cause mortality in CKM populations, and examine the mediating role of inflammatory biomarkers. This cross-sectional study with prospective mortality follow-up included 6,072 participants from NHANES (2011-2018). Kaplan-Meier curves, multivariable Cox regression models, and restricted cubic spline (RCS) analyses were employed to assess all-cause mortality associations. Subgroup and interaction analyses evaluated risks across demographic strata. Mediation analysis was employed to explore the mediating effects of inflammatory biomarkers (NLR, MLR, NMLR, and SIRI). The Weighted quantile sum (WQS) model was utilized to estimate the effects of combined blood metal exposures. Among 6,072 participants, 409 deaths occurred during follow-up. In the fully adjusted model, there was a significant negative correlation between blood selenium levels and all-cause mortality in the CKM population. Compared with the lowest quartile (Q1), the highest selenium quartile (Q4) was associated with a 38% reduced mortality risk (HR = 0.62, 95% CI: 0.45-0.85, P = 0.003). RCS analysis revealed an L-shaped dose-response relationship (P for nonlinear = 0.002). Subgroup analyses confirmed consistent associations in both non-advanced CKM (stages 0-2) and advanced CKM (stages 3-4) (all P < 0.05, P for interaction = 0.163). Mediation analysis revealed that NLR, MLR, NMLR, and SIRI partially mediated the association between blood selenium and all-cause mortality, and the mediated proportions were relatively modest (ranging from 3.57 to 5.29%). Higher blood selenium was associated with reduced all-cause mortality in CKM syndrome after adjustment for measured confounders, and mediation analysis suggested a potential partial role of inflammation in this association. These findings underscore the need for targeted interventions to mitigate mortality in this high-risk population.