Fig. 3

Molecular mechanisms of sex difference in animal HFpEF models. In the HFpEF model induced by a high-fat diet combined with L-NAME, significant differences in HFpEF phenotypes were observed between male and female mice. In C57BL/6N mice, male mice exhibited concentric left ventricular hypertrophy, diastolic dysfunction, and significant cardiac remodeling, whereas female mice showed relatively milder changes, with a lower increase in the E/E′ ratio and minimal cardiac remodeling. However, in C57BL/6 J mice, although both male and female mice exhibited obesity and reduced exercise tolerance, female mice had higher E/A and E/E′ ratios and increased lung weight compared to males. Estrogen may also influence mitochondrial gene expression in cardiomyocytes, leading to a further reduction in mtDNA content and more pronounced mitochondrial dysfunction in female mice. These two studies yielded contradictory results, and further research is needed to determine which model better reflects the pathological features of human HFpEF