Cardiac remodeling in response to chronic stress is a key process in the development of chronic non-ischemic heart failure and contributes substantially to the global disease burden. This process often involves cardiac hypertrophy, in which the heart muscle becomes abnormally thickened due to long-term increased workload, such as in conditions like high blood pressure, aortic stenosis, or aging. Notably, cardiac hypertrophy and the progression to heart failure show important differences between women and men, indicating that biological sex influences disease development, progression, and clinical outcomes. While sex hormones contribute to these differences, genetic factors linked to the X chromosome are increasingly recognized as additional contributors. Women carry two X chromosomes, whereas men carry one, and to ensure balanced gene expression between sexes, one X chromosome is normally silenced in female cells through a process known as X-chromosome inactivation. However, some genes escape this silencing and remain active on the otherwise inactive X chromosome. The resulting higher expression of these genes in female cells may contribute to sex-specific differences in cellular function and disease mechanisms, but their role in cardiac hypertrophy and heart failure remains largely unknown. EscapeX aims to determine how X-chromosome escape changes during chronic cardiac stress and investigate whether altered gene dosage influences disease progression. The project is expected to provide new mechanistic insight into sex differences in cardiac remodeling and heart failure and identify potential targets for future therapeutic strategies.
