Abstract Body (Do not enter title and authors here): Background: Exposure to per- and polyfluoroalkyl substances (PFAS) has been linked to increased atherosclerosis. However, longitudinal studies are limited, particularly in postmenopausal women who are at high risk of atherosclerosis.
Hypothesis: We hypothesized that PFAS exposure was associated with accelerated atherosclerosis progression.
Methods: This study included 641 women (60.6 ± 6.9 years) from the Early versus Late Intervention Trial with Estradiol. Plasma concentrations of 2-(N-methyl-perfluorooctane sulfonamido) acetate (MeFOSAA), perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnDA), sum of perfluoromethylheptane sulfonates (Sm-PFOS), linear perfluorooctane sulfonate (n-PFOS), and linear perfluorooctanoate (n-PFOA) were measured at a pre-randomization visit and 36-month follow-up using online solid phase extraction–high performance liquid chromatography–isotope dilution–tandem mass spectrometry. Subclinical atherosclerosis was assessed biannually over a median 5-year follow-up using high-resolution B-mode ultrasound. Linear regression and linear mixed-effects models were used to assess cross-sectional and longitudinal associations between log₂-transformed PFAS levels and atherosclerosis measures, adjusting for baseline age, race/ethnicity, education, smoking, lipid-lowering medication, time since menopause (<6 years or ≥10 years), and treatment (estradiol or placebo).
Results: Carotid-artery intima-media thickness (CIMT) increased, and gray-scale median of intima-media complex (IM-GSM) decreased over the follow-up period. At baseline, CIMT was 8.4 µm thicker (95% confidence interval: 4.1, 16.4) per doubling of PFUnDA levels. During the follow-up, each doubling of average PFHxS, PFNA, PFDA, PFUnDA, and n-PFOA levels across baseline and follow-up was associated with a faster increase in CIMT by 0.49 (0.20, 0.79), 0.64 (0.23, 1.04), 0.84 (0.48, 1.21), 0.51 (0.23, 0.78), and 0.82 (0.44, 1.21) µm/year, respectively. Each doubling of average PFDA and n-PFOA levels was associated with a faster decrease in IM-GSM by -0.23 (-0.38, -0.07) and -0.27 (-0.44, -0.10) per year, respectively.
Conclusion: Our findings suggest that PFAS exposure may accelerate atherosclerosis progression in postmenopausal women, independent of key treatments and risk factors, highlighting the potential for incorporating PFAS, a modifiable environmental factor, into the cardiovascular disease prevention efforts.