An ovary-intact postmenopausal HFpEF mouse model; menopause is more than just estrogen deficiency.

The incidence of HFpEF in women significantly increases following menopause. This trend cannot solely be attributed to chronological aging, as evidenced by the more gradual increase in prevalence among men, suggesting that menopause is a provocative event for HFpEF. However, the underlying mechanisms remain elusive and challenging to investigate in human subjects; moreover, an attempt to create HFpEF in ovariectomized (OVX) mice was unsuccessful. In this study, we created an animal model that resembles HFpEF in women undergoing natural menopause. Methods: We used 4-vinylcyclohexene dioxide (VCD) to induce “ovary-intact” menopause, combined with the 2hit regimen (HFpEF inducing regimen) to model postmenopausal HFpEF. Results: The female-VCD-2hit mice demonstrate diastolic dysfunction. At the LV levels, the increased stiffness coefficient of end-diastolic pressure-volume relation (EDPVR), elevated LV end-diastolic pressure, and increased relaxation time constant indicate a heightened LV stiffness, delayed relaxation, and elevated LV filling pressure. At the cardiomyocyte level, the female-VCD-2hit mice exhibit increased cellular diastolic stiffness and delayed relaxation, suggesting that the observed LV dysfunction is derived from the cardiomyocytes. Additionally, plasma NT-pro-BNP levels were elevated, while Xbp1s transcript levels were reduced, further supporting the existence of HFpEF. Plasma-free testosterone was increased in VCD mice compared to pre-menopausal and OVX models. Further studies are required to determine whether the relative increase in testosterone is the factor driving HFpEF susceptibility in VCD mice. Conclusion: Ovary-intact postmenopausal status makes female mice vulnerable to HFpEF development. The VCD-2hit model develops a robust HFpEF-like phenotype and is suitable for studying female HFpEF.