Environmental toxicants associated with cardiovascular disease and a novel LE8 indicator approach for screening...

Environmental chemicals are emerging as inducers of cardiovascular disease (CVD), but identifying CVD-relevant toxicants across the exposome remains challenging. In this study, we analyzed 149 environmental chemicals from the 2013-2016 National Health and Nutrition Examination Survey using analyte-specific survey-weighted single-pollutant models, mixture analyses, mediation and interaction analyses, and network toxicology to identify CVD-relevant toxicants. Adjusted data found no direct CVD correlations for many chemicals. Yet, using Life's Essential 8 (LE8) score (which covers diabetes, hyperlipidemia, and hypertension) as a quantitative cardiovascular health index revealed inverse associations with 41 chemicals after multiple-testing correction. These chemicals mainly included several volatile organic compound (VOC) metabolites, polycyclic aromatic hydrocarbon (PAH), and aromatic amines. BKMR analysis further suggested potential CVD associations for selected exposure mixtures, particularly serum metals and urinary PAHs. Exploratory mediation analysis identified significant positive indirect associations through LE8 for 37 chemicals, most of which showed directionally consistent patterns. Interaction analyses also indicated that several exposure-CVD associations may vary by LE8 health behaviors, with smoking-related interactions particularly evident for PAH- and VOC-related chemicals. Network toxicology linked LE8-associated toxicants to CVD-relevant pathways and protein modules involving vascular, cardiometabolic, inflammatory, and hemostatic processes, with PTGS2, ESR1, and MAPK1 among the most frequently connected genes. These findings support LE8 as a effective cardiovascular health indicator, and provide a framework for identifying CVD-relevant chemicals from the exposome via LE8.