Abstract
AIM: Per- and polyfluoroalkyl substances (PFASs) are widespread environmental pollutants that were previously associated with dyslipidemia and type 2 diabetes mellitus (T2DM). We therefore investigated the association between PFAS exposure and clinical outcomes after percutaneous coronary intervention (PCI) in patients with T2DM and assessed the extent to which lipidomic alterations mediate this association. METHODS: This case-control study was nested within a prospective cohort of patients with type 2 diabetes who underwent primary PCI for obstructive coronary artery disease between September 2017 and September 2019. During the 2-year follow-up after PCI, 150 matched pairs of patients with T2DM who did not experience major adverse cardiovascular and cerebrovascular events (MACCEs) were included. Serum PFASs and lipidomes were measured at baseline using liquid chromatography-mass spectrometry and analyzed using multipollutant models and integrative approaches. RESULTS: Overall, a higher exposure to a mixture of nine PFASs was associated with an increased odds of two-year MACCEs after PCI, with perfluoroundecanoic acid and perfluorodecanoic acid contributing the most to the association. Integration with the serum lipidome generated a network of 110 PFAS-associated lipids with differential contributions to discriminating MACCEs, half of which were identified as significant mediators explaining 9.6%-56.4% of the PFAS-MACCE association. Furthermore, we estimated a cluster of patients with high probabilities of developing MACCEs after PCI, characterized by high PFAS levels; increased abundance of phosphatidylcholine, triacylglycerol, diacylglycerol, and acylcarnitine lipids; and decreased abundance of phosphatidylethanolamine and phosphatidylethanol lipids. CONCLUSION: With mediation by serum lipidomic perturbations, PFAS exposure contributes to poor outcomes after PCI in patients with T2DM.