Constituent-specific cardiovascular risks of fine particulate matter: Mediation by metabolomic perturbations and...

Exposure to fine particulate matter (PM_2.5) and its constituents has been linked to increased risk of cardiovascular diseases (CVD), yet the metabolic mechanisms underlying this association remain unclear.

This study included 236,549 adults free of CVD at baseline from a large prospective cohort. Long-term exposure to PM_2.5 and its constituents were estimated, including elemental carbon, organic matter, ammonium, nitrate, and sulfate. Constituent-related metabolites were identified via elastic net regression, and metabolic scores were constructed. Biological age acceleration was estimated using the PhenoAge algorithm. Associations of PM_2.5 constituents and metabolic scores with incident CVD were examined using Cox models, and serial mediation analyses assessed pathways involving metabolic alterations and biological aging.

During a median follow-up of 12.38 years, 30,885 participants developed CVD. Higher exposures to PM_2.5 and its constituents were associated with elevated CVD risks (hazard ratios per standard deviation: 1.02-1.04). Constituent-specific metabolic signatures were identified, including 63 metabolites for PM_2.5, 82 for elemental carbon, 85 for organic matter, 28 for sulfate, 30 for nitrate, and 12 for ammonium. The PM_2.5-related metabolic signature was positively associated with CVD risk (hazard ratio: 1.04), while most constituent-specific signatures showed consistent directions of association with CVD risk. Mediation analyses indicated that metabolic signatures explained 5.18-10.08% of PM_2.5 constituents-CVD association, while serial mediation through biological aging accounted for an additional 0.30-1.19%.

Long-term exposure to PM_2.5 constituents was associated with increased cardiovascular risk, while metabolomic signatures and biological aging were potential intermediate factors underlying these associations.