Associations of Serum PFAS with Electrocardiographic Abnormalities in Older Adults and Electrophysiological Characterization

Per- and polyfluoroalkyl substances (PFAS) are highly persistent pollutants increasingly implicated in cardiovascular toxicity, yet their impacts on cardiac electrophysiology remain poorly defined. In this cross-sectional, community-based study of 3450 adults aged ≥ 60 years, we assessed associations between individual and combined PFAS exposures and electrocardiographic (ECG) abnormalities. Based on Minnesota Code classification, higher serum concentrations of multiple PFAS were associated with greater odds of both minor and major ECG abnormalities, with near-linear exposure-response trends. Weighted quantile sum regression assigned the highest mixture weights to 6:2 Cl-PFESA and several long-chain PFAS. Higher PFAS burden was linked to prolonged QRS duration and QTc and shortened T-wave duration, consistent with altered ventricular depolarization and repolarization. Domain-stratified and leave-one-domain-out analyses supported domain-dependent associations with repolarization metrics most consistently linked to 6:2 Cl-PFESA in minor abnormalities. Integrating in vitro electrophysiology with in silico molecular dynamics provided biological plausibility for the population findings. Overall, the study outlines a domain-resolved framework for subclinical cardiac electrical alterations associated with environmental chemical exposure and provides multilevel evidence of domain-specific associations between PFAS exposure and cardiac electrophysiological patterns.