Sex-specific molecular drivers of cardiac fibrosis in aging hearts

The aging population, defined as individuals 65 years or older, is rapidly increasing, with age as the most significant and independent risk factor for cardiovascular diseases (CVD). Older women show greater susceptibility to cardiac remodeling and dysfunction compared to men. Despite this, the specific molecular drivers of sex differences in cardiac aging remain poorly understood. In this study, cardiac fibrosis and gene expression profiles were investigated in left atrial appendage samples obtained from 24 consecutive patients undergoing cardiac surgery. Using Masson's trichrome staining, we found that cardiac fibrosis significantly increased with age in females (p = 0.02) but not in males (p = 0.27). A subsequent medium-throughput gene expression analysis targeting approximately 800 cardiovascular genes revealed no differences in overall cardiac gene expression between sexes based on principal component analyses (PCA). However, pathway-specific analyses identified the thrombosis and hemostasis pathway as prominently dysregulated in females. Specifically, older females showed significant upregulation of PTPN1, PTPN11, and RAPGEF4, genes implicated in cardiac remodeling and metabolic health, compared to younger females, while males exhibited no significant changes across the age range. Correlation analyses confirmed significant positive associations between PTPN1, PTPN11, and RAPGEF4 expression and age in females but not in males. These findings suggest that aging in females is associated with cardiac fibrosis, which is likely driven by the sex-specific upregulation of key genes within the thrombosis and hemostasis pathway.