# Sex differences in ischemic heart disease and evidence gathering related to exposure risk, prevention, and treatment of per- and poly-fluoroalkyl substances

## TL;DR

This study explores how men and women differ in heart disease outcomes and PFAS exposure, identifying potential targets for treatment.

## Contribution

The study identifies sex-specific differences in PFAS toxicity and survival rates in ischemic heart disease and discovers new gene targets for treatment.

## Key findings

- Men with ischemic heart disease have worse survival rates than women, despite higher overall mortality in men.
- PFAS chemicals like PFOA and PFOS significantly worsen survival and interact with genes linked to cardiovascular disease.
- Five genes (CASP3, PDK4, GDF15, RPL17, CTNNB1) show high binding stability with PFAS and are potential therapeutic targets.

## Abstract

To investigate the sex differences in environmental exposure to per- and poly-fluoroalkyl substances (PFAS) in ischemic heart disease (IHD) and to identify potential targets for future prevention and treatment of PFAS-associated IHD.

The Global Health Data Exchange database was used to explore the sex differences in IHD mortality and morbidity. The National Health and Nutrition Examination Survey (NHANES) database was used to identify sex differences in response to environmental exposure to PFAS, including survival probability and dose–response. The Comparative Toxicogenomics Database and Gene Expression Omnibus databases were used to search for critical signaling pathways involved in IHD pathogenesis and potential targets for the prevention and treatment of PFAS-associated IHD. The binding stability of these complexes was evaluated by molecular docking and molecular dynamics simulations.

Globally, the mortality, morbidity, years of life lost, and years lived with disability are higher for men than women. Among 42,742 participants from NHANES, including IHD and control groups as well as PFAS-affected IHD subjects, men had significantly lower survival rates than women. Four PFAS exposures, including perfluorooctane sulfonamide, perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and 2-(N-methyl-PFOSA) acetate, significantly worsened the survival of patients with IHD and interacted with 105 human genes associated with cardiovascular diseases. Combining differentially expressed genes from the pluripotent stem cell-derived cardiomyocyte dataset, five promising genes-CASP3, PDK4, GDF15, RPL17, and CTNNB1-were identified as having high binding stability to PFAS.

Men with IHD have significantly worse survival rates than women, yet women are more susceptible to PFOA and PFOS toxicity. This study also identifies several PFAS receptor genes that affect key pathways in IHD pathogenesis, which are promising potential targets for future prevention and treatment of PFAS-associated IHD.

Graphical abstract of evidence survey for this study.