Uncovering the missing X factors to understand sex bias in cardiovascular disease

Introduction

Cardiovascular diseases (CVD) occur and progress differently in men and women, and the risk dramatically increases with age. Hormone differences have been suggested to account for the sex difference by observing that younger women are regularly protected from CVD until post-menopause.

Hormone Replacement Therapies

However, hormone replacement therapies failed to provide cardioprotection, suggesting that other biological factors contribute to sex disparities in CVD development.

Contributors to Sex Bias

Other likely contributors to sex bias are genes that escape female X chromosome inactivation, an understudied epigenetic phenomenon that has so far not been linked to sex differences in CVD. These so-called escaper genes have twice the gene dose in females compared to males and thus are likely to contribute to sex-based differences.

Project Aim

EscapeX aims to identify sex-specific protective mechanisms by disentangling the impact of hormones and sex chromosomes on sex bias in CVD.

Methodology

1. Transgenic Mouse Model: First, we will combine the transgenic FCG mouse model, in which the sex chromosome complement (XX or XY) is independent of the gonadal hormones, with the pressure overload heart failure model, which shows a sex-specific phenotype.
2. Escaper Detection Pipeline: Next, EscapeX uses our established escaper detection pipeline to map and characterize escaping during cardiac aging and disease.

Expected Outcomes

The resulting dataset will uncover the escaper gene function, the extent of lineage-specific escaping, and how the escaper landscape changes during aging and disease.

Future Directions

Building on those findings, EscapeX aims to overexpress the identified escapers in the disease model using viral vectors with the ambitious goal to rescue the sex-specific phenotype.

Exploration of X-Reactivation

Finally, we will combine allele-specific genomics and single-cell technology to explore if X-reactivation occurs in cardiac aging and disease and if such a novel disease mechanism further contributes to sex differences.

Conclusion

EscapeX will elucidate new regulatory disease mechanisms and relevant therapeutic candidates, forming the basis of new sex-specific therapies.