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<p>Heavy metal cadmium (Cd) exposure is associated with increased cardiovascular disease (CVD) risk, yet sex-specific differences in Cd exposure’s impact on CVD patient mortality and underlying mechanisms remain unclear. Using the national health and nutrition examination survey (NHANES) database and its follow-up mortality data (1,413 CVD patients: 652 deaths [46.14%], 761 survivors [53.86%]), we investigated the specific roles of Cd exposure in CVD. Cox regression showed that elevated blood Cd were more strongly associated with increased all-cause mortality risk in males (HR = 1.67, 95% CI: 1.00-2.78), whereas higher urinary Cd conferred a greater risk in females (HR = 2.17, 95% CI: 1.20–3.92). Restricted cubic spline analysis showed that, in males, blood Cd exhibited a linear dose-response with all-cause mortality (<i>P</i> for nonlinear = 0.128), while urinary Cd demonstrated a significant nonlinear relationship (<i>P</i> for nonlinear = 0.016). Interaction models further revealed that the interactions between blood Cd and diabetes mellitus (DM) (<i>P</i> for interaction = 0.013), as well as between urinary Cd and DM (<i>P</i> for interaction = 0.017), significantly amplified all-cause mortality risk in males. Network toxicology and bioinformatics analyses identified formyl peptide receptor 1 (FPR1) as a key mediator of CdCl₂-associated CVD progression, with elevated expression in CVD patients (log<sub>2</sub>FC = 0.71, <i>P</i> &lt; 0.001). Molecular docking (free energy = -2.620&#xa0;kcal/mol), Western blot, and qPCR confirmed that FPR1 can bind CdCl₂ and is dose-dependently upregulated in AC16 cardiomyocytes. Overall, we found that male CVD patients exhibit a marked, dose-dependent increase in all-cause mortality risk associated with Cd exposure, which is further exacerbated by its synergy with DM. Mechanistically, Cd appears to promote CVD progression by disrupting FPR1 signaling in cardiomyocytes. These findings suggest that prevention strategies should integrate metabolic disease management with environmental Cd control, and highlight FPR1 as a promising therapeutic target.</p>

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Sex-Specific Associations Between Cadmium Exposure and Mortality Risk in Cardiovascular Disease Patients: A Cohort Study Integrating Molecular Mechanisms of Myocardial Dysfunction

  • 期刊论文

  • 发表日期：

    2026年4月17日

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  • Caili He,
  • Kaiwen Wang,
  • Ruiqi Yang,
  • Xinyi Li,
  • Zicong Shao,
  • Li Ma,
  • Yongbin Lu,
  • Xiaowei Niu,
  • Siyu Zhang,
  • Yongxiang Wang

摘要

Heavy metal cadmium (Cd) exposure is associated with increased cardiovascular disease (CVD) risk, yet sex-specific differences in Cd exposure’s impact on CVD patient mortality and underlying mechanisms remain unclear. Using the national health and nutrition examination survey (NHANES) database and its follow-up mortality data (1,413 CVD patients: 652 deaths [46.14%], 761 survivors [53.86%]), we investigated the specific roles of Cd exposure in CVD. Cox regression showed that elevated blood Cd were more strongly associated with increased all-cause mortality risk in males (HR = 1.67, 95% CI: 1.00-2.78), whereas higher urinary Cd conferred a greater risk in females (HR = 2.17, 95% CI: 1.20–3.92). Restricted cubic spline analysis showed that, in males, blood Cd exhibited a linear dose-response with all-cause mortality (P for nonlinear = 0.128), while urinary Cd demonstrated a significant nonlinear relationship (P for nonlinear = 0.016). Interaction models further revealed that the interactions between blood Cd and diabetes mellitus (DM) (P for interaction = 0.013), as well as between urinary Cd and DM (P for interaction = 0.017), significantly amplified all-cause mortality risk in males. Network toxicology and bioinformatics analyses identified formyl peptide receptor 1 (FPR1) as a key mediator of CdCl₂-associated CVD progression, with elevated expression in CVD patients (log2FC = 0.71, P < 0.001). Molecular docking (free energy = -2.620 kcal/mol), Western blot, and qPCR confirmed that FPR1 can bind CdCl₂ and is dose-dependently upregulated in AC16 cardiomyocytes. Overall, we found that male CVD patients exhibit a marked, dose-dependent increase in all-cause mortality risk associated with Cd exposure, which is further exacerbated by its synergy with DM. Mechanistically, Cd appears to promote CVD progression by disrupting FPR1 signaling in cardiomyocytes. These findings suggest that prevention strategies should integrate metabolic disease management with environmental Cd control, and highlight FPR1 as a promising therapeutic target.