Cardiovascular

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

TL;DR

Higher blood selenium was associated with reduced all-cause mortality in CKM syndrome populations, with inflammatory biomarkers partially mediating this association, while heavy metals showed more complex relationships with mortality.

Key Findings

Higher blood selenium levels were significantly associated with reduced all-cause mortality in CKM syndrome populations.

  • Study included 6,072 NHANES participants (2011-2018) with CKM syndrome, among whom 409 deaths occurred during follow-up
  • 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 between selenium and all-cause mortality (P for nonlinear = 0.002)
  • Association remained consistent in fully adjusted multivariable Cox regression models

The inverse association between blood selenium and all-cause mortality was consistent across both non-advanced and advanced CKM stages.

  • Subgroup analyses confirmed significant associations in both non-advanced CKM (stages 0-2) and advanced CKM (stages 3-4)
  • All subgroup P-values were < 0.05
  • P for interaction = 0.163, indicating no significant effect modification by CKM stage
  • Kaplan-Meier curves were used to visualize survival differences across selenium quartiles

Inflammatory biomarkers NLR, MLR, NMLR, and SIRI partially mediated the association between blood selenium and all-cause mortality.

  • Mediation analysis was employed to explore the mediating effects of four inflammatory biomarkers: neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), neutrophil-monocyte-to-lymphocyte ratio (NMLR), and systemic inflammation response index (SIRI)
  • Mediated proportions were relatively modest, ranging from 3.57 to 5.29%
  • All four inflammatory biomarkers showed statistically significant partial mediation (all P < 0.05)
  • The mediation findings suggest a potential partial role of inflammation in the selenium-mortality association

The study used a Weighted Quantile Sum (WQS) model to estimate the combined effects of blood metal exposures including lead, cadmium, mercury, manganese, and selenium.

  • Blood heavy metals assessed included lead (Pb), cadmium (Cd), mercury (Hg), and manganese (Mn), in addition to selenium (Se)
  • WQS modeling was employed to evaluate the mixture effect of combined metal exposures on all-cause mortality
  • Cross-sectional study design with prospective mortality follow-up using NHANES 2011-2018 data
  • Subgroup and interaction analyses evaluated risks across demographic strata

The study population consisted of 6,072 CKM syndrome participants with 409 deaths occurring during the follow-up period.

  • Participants were drawn from NHANES cycles spanning 2011-2018
  • CKM syndrome is characterized by the pathophysiological interplay among metabolic disorders, chronic kidney disease (CKD), and cardiovascular disease (CVD)
  • Participants were categorized by CKM stages 0-2 (non-advanced) and stages 3-4 (advanced)
  • Analytical methods included Kaplan-Meier curves, multivariable Cox regression models, restricted cubic spline analyses, and mediation analysis

What This Means

This research examined how blood levels of heavy metals (lead, cadmium, mercury, and manganese) and selenium relate to the risk of death in people with cardiovascular-kidney-metabolic (CKM) syndrome — a condition involving the interconnected problems of heart disease, kidney disease, and metabolic disorders like diabetes and obesity. The researchers followed 6,072 adults from a large U.S. national health survey (NHANES, 2011-2018), during which 409 participants died. The main finding was that people with higher blood selenium levels had a substantially lower risk of dying from any cause: those in the highest selenium group had a 38% lower mortality risk compared to those in the lowest selenium group. The relationship followed an 'L-shaped' pattern, meaning mortality risk dropped sharply with initial selenium increases and then leveled off. The study also investigated whether inflammation might explain part of the selenium-mortality link. Using four different markers of systemic inflammation (NLR, MLR, NMLR, and SIRI), the researchers found that inflammation did partially mediate the relationship — meaning some of selenium's apparent protective effect may work through reducing inflammation. However, this mediating role was modest, with inflammation accounting for only about 3.6% to 5.3% of the total association, suggesting other biological pathways are also involved. The protective association between selenium and survival was consistent regardless of whether patients had early-stage or advanced CKM syndrome. This research suggests that selenium status may be an important factor in survival outcomes for people with CKM syndrome, and that environmental or nutritional exposures to metals and selenium could be relevant to this high-risk population's prognosis. The findings highlight the potential value of monitoring trace element levels and inflammatory markers in people with CKM syndrome, though as an observational study it cannot prove that selenium directly causes reduced mortality.

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Citation

Niu H, Zhang L, Wang Y, He W, Wang R, Li X. (2026). 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 toxicology. https://doi.org/10.1007/s12012-026-10179-8