# The Impact of the Metal Mixture Inflammation Index on All‐Cause Mortality in Patients With Cardiovascular‐Kidney‐Metabolic Syndrome Stages 0–3: A Study Based on NHANES 1999–2010

## TL;DR

This study shows that higher levels of a metal mixture inflammation index are linked to increased all-cause mortality in early-stage cardiovascular-kidney-metabolic syndrome patients.

## Contribution

The study is the first to investigate the association between the Metal Mixture Inflammation Index and all-cause mortality in CKM syndrome stages 0–3.

## Key findings

- Higher MMII levels were significantly associated with increased all-cause mortality.
- A nonlinear dose–response relationship was found between MMII and mortality risk.
- Above a specific MMII threshold, mortality risk increased significantly.

## Abstract

Environmental exposure to metals is recognized as a significant trigger of chronic inflammation and various systemic diseases, with inflammatory processes playing a central role in the development and progression of CKM syndrome. The MMII, which integrates multiple metal exposures and inflammatory responses, has demonstrated sensitivity in predicting population health risks. However, its association with all‐cause mortality in individuals with CKM Stages 0–3 has not been previously investigated.

This study analyzed publicly available data from the NHANES 1999–2010, including adults aged 20 years and older with CKM syndrome Stages 0–3. The MMII was constructed based on urinary concentrations of heavy metals (mercury, cadmium, cobalt, molybdenum, lead, and tungsten) along with C‐reactive protein and white blood cell count. The primary outcome was all‐cause mortality. Cox proportional hazards regression models were employed to assess the association between MMII and all‐cause mortality, with sequential adjustment for potential confounders, complemented by sensitivity and subgroup analyses.

The final analysis included 2643 participants (mean age: 44.24 years; 56.77% female). Higher MMII levels were significantly associated with increased all‐cause mortality. In the fully adjusted model, participants in the highest MMII quartile exhibited a hazard ratio (HR) for all‐cause mortality of 1.50 (95% CI: 1.01–2.22, p = 0.04). Restricted cubic spline analysis revealed a nonlinear dose–response relationship between MMII and mortality risk (P for nonlinearity = 0.007). Threshold effect analysis identified an inflection point at MMII = 0.10594.

Threshold effect analysis identified an inflection point at MMII = 0.10594. Below this threshold, the association between MMII and all‐cause mortality was not statistically significant, with a point estimate below 1 and wide confidence intervals (HR: 0.554, 95% CI: 0.171–1.795). Above the threshold, higher MMII was associated with greater mortality risk (HR: 3.977, 95% CI: 1.777–8.901). Sensitivity analyses yielded consistent results. Subgroup analysis revealed a significant interaction between MMII and age group for mortality risk (p < 0.05).

In the U.S. population with CKM Stages 0–3, MMII is significantly associated with all‐cause mortality. These findings highlight the importance of the inflammatory burden resulting from multiple metal exposures as a significant risk factor for all‐cause mortality in early‐stage CKM syndrome, underscoring the need for environmental health management and integrated approaches to chronic disease prevention.