Cardiovascular disease (CVD) occurs and progresses differently in men and women, and the risk dramatically increases with age. In women, the finding that CVD occurs less frequent at younger age than post menopause has led to the hypothesis that sex hormones may provide some protection from CVD. However, hormone replacement therapies failed to provide cardioprotection, suggesting that other biological factors contribute to sex disparities in CVD development. Other likely contributors to the sex bias in CVD are genes that escape female X chromosome inactivation. 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 (Andergassen et al. eLife 2017, Andergassen, Dotter et al. NAR 2015). Furthermore, by disrupting epigenetic pathways, we previously demonstrated X-reactivation in vivo (Andergassen, Smith et al. Dev. Cell 2021). The finding that these mechanisms occur during cardiac aging and disease suggests that they may contribute to sex bias in CVD. To test ths hypothesis, we apply allele-specific genomics by combining with genetic mouse models in disease context. This novel strategy will elucidate sex-specific regulation of gene expression by non-coding RNA, and form the basis of new therapies that address the sex bias in cardiovascular disease.