Abstract Body (Do not enter title and authors here): Background: Ambient air pollution is associated with ischemic heart disease (IHD), but the metabolic mechanisms mediating this relationship remain unclear.
Methods: In 218,047 UK Biobank participants without baseline IHD, we identified plasma metabolic signatures associated with air pollution (PM_2.5, PM₁₀, NO₂, NO_x) using elastic net regression. Cox proportional hazards models assessed relationships between air pollution, metabolic signatures, and incident IHD. Mediation analyses quantified the contribution of metabolic signatures to pollution-IHD associations.
Results: We identified 41 metabolites significantly associated with air pollution, primarily comprising lipoprotein lipid concentrations, fatty acids, and amino acids. During follow-up, 18,911 participants developed IHD. High metabolic signature scores were associated with 26% increased IHD risk compared to low scores (HR=1.26, 95% CI: 1.20-1.32). The metabolic signature mediated 19.49% of the total effect of air pollution on IHD risk, with stronger mediation for PM_2.5 (21.24%). Associations were more pronounced in older individuals (≥65 years) and those with lower genetic susceptibility to IHD.
Conclusions: Air pollution exposure induces specific plasma metabolic alterations that independently predict IHD risk and substantially mediate pollution-IHD associations. These findings provide novel insights into biological pathways linking environmental exposures to cardiovascular pathology and identify vulnerable subpopulations.