Cardiovascular disease (CVD) is a leading global cause of mortality, with air pollution increasingly implicated as a risk factor. Volatile organic compounds (VOCs), widespread ambient pollutants, pose significant health risks; however, their specific association with CVD risk remains insufficiently explored. This study investigated associations between VOC exposure and CVD risk and evaluated the mediating roles of sleep duration and depressive symptoms. We analyzed data from 2918 U.S. adults in the National Health and Nutrition Examination Survey. Associations of six VOCs with CVD risk were assessed using weighted logistic regression, weighted quantile sum (WQS) regression, and quantile-based g-computation (QGC). Mediation analyses examined the contributions of sleep duration and depressive symptoms. After full covariate adjustment, benzene, styrene, and toluene were significantly associated with elevated CVD risk (odds ratios [ORs] = 1.77–2.09). Mixed-exposure analyses confirmed positive associations, with styrene contributing the highest weights (WQS: OR = 1.56, 95 % CI: 1.05, 2.30; QGC: OR = 1.62, 95 % CI: 1.25, 2.10). Subgroup analyses indicated stronger associations among women and smokers. Sleep duration and depressive symptoms partially mediated the relationships between individual VOCs (benzene, styrene, toluene), combined VOC exposure, and CVD risk, explaining 6.39 %–22.78 % of the total effect. Furthermore, a serial mediation pathway (sleep duration → depressive symptoms) mediated these associations (proportion mediated: 2.44 %–2.63 %). These findings suggest that VOC exposure may increase CVD risk, partly through adverse effects on sleep and mental health. Addressing sleep deficits and depressive symptoms in exposed populations could be critical for mitigating CVD burden and improving public health outcomes.
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