The role of estrogen in the sex difference for the risk factors of heart failure with preserved ejection fraction

Figures

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  Fig. 1. Estrogen and HFpEF-related risk factors. Common risk factors of HFpEF include obesity, hypertension, diabetes, and atrial fibrillation. As estrogen levels in women decline, the prevalence and severity of these risk factors continue to increase, directly or indirectly influencing the onset and progression of HFpEF

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  Fig. 2. Mechanisms by which estrogen influences hypertension. E2 binds to membrane GPR30, activating the MAPK/ERK or PI3K pathways, enhancing eNOS activity, and rapidly increasing NO production, leading to vasodilation and blood pressure reduction. Simultaneously, E2 inhibits the NF-κB pathway, reducing the expression of inflammatory mediators and mitigating damage to the vascular endothelium. E2 also interacts with ERα and ERβ, which then translocate to the nucleus and bind directly to estrogen response elements, regulating the transcription of target genes, such as VEGF, to promote angiogenesis and eNOS for vasodilation and blood pressure regulation

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  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