Combined Effects of Arsenic, Cadmium, and Mercury with Cardiovascular Disease Risk: Insights from the All of Us Research Program

Background: Environmental exposures to heavy metals/metalloids such as arsenic, cadmium, and mercury have been implicated in adverse cardiovascular health outcomes. Using data from the All of Us research program, we investigated the associations between these metals/metalloids and six cardiovascular-related biomarkers: systolic blood pressure (SBP), HDL cholesterol, LDL cholesterol, C-reactive protein (CRP), total cholesterol, and triglycerides. Methods: This study explored the relationship between outcome cardiovascular variables (SBP, CRP, LDL, HDL, triglycerides, and total cholesterol) and predictor metal/metalloid variables (cadmium, mercury, and arsenic) among 136 participants (53.4 percent women). We initially conducted linear regression to determine the association between variables of interest. Bayesian Kernel Machine Regression (BKMR) analysis was subsequently performed to capture potential non-linear relationships, as well as interactions among metal/metalloid exposures. In the BKMR analysis, posterior inclusion probabilities (PIPs) quantified the contribution of each metal/metalloid to the outcomes, with higher PIP values indicating a greater likelihood of a specific exposure being a key predictor for a given cardiovascular biomarker. Within the BKMR framework, univariate, bivariate, and overall exposure–response analyses provided insights into the individual and combined effects of metal/metalloid exposures. These analyses identified the factors with the strongest associations and highlighted interactions between exposures. Results: In this study, the average age of male participants was 58.2 years, while female participants had an average age of 55.6 years. The study population included 104 individuals identifying as White (mean age: 57.5 years), 10 as Black or African American (mean age: 63.2 years), 7 as Hispanic (mean age: 48.2), 3 as Asian (mean age: 49.7 years), and 12 as Other race (mean age: 48.8 years). In our study, men exhibited higher levels of SBP, triglycerides, mercury, and arsenic, while women had higher levels of CRP, LDL cholesterol, HDL cholesterol, total cholesterol, and cadmium. Black people exhibited higher levels and greater variability in markers of cardiovascular risk and inflammation (e.g., blood pressure and CRP), Asians consistently showed the lowest levels across most biomarkers, while White people, Hispanics, and the “Other” group demonstrated moderate levels with some variability. In linear regression, we identified significant positive associations between mercury and HDL cholesterol, arsenic and triglycerides, and arsenic and total cholesterol. In BKMR analysis, PIP results revealed that mercury had the highest predictive contribution for SBP, HDL cholesterol, and triglycerides; cadmium for CRP; and arsenic for LDL and total cholesterol. Univariate and bivariate exposure–response analyses in BKMR demonstrated non-linear exposure–response patterns, including U-shaped and inverted U-shaped patterns for cadmium, particularly CRP and total cholesterol. Traditional linear regression techniques would have missed these patterns. Conclusion: Our study results highlight the influence of environmental metal/metalloid exposures on cardiovascular biomarkers, providing evidence of non-linear and interactive effects that warrant further investigation to understand their role in cardiovascular disease risk better.