Abstract Body: Background. The incidence of HFpEF in women significantly escalates following the age of menopause. This trend cannot solely be attributed to chronological aging, as evidenced by the more gradual increase in prevalence among men with HFpEF. This pattern suggests that menopause is a provocative event for HFpEF. However, the underlying mechanisms remain elusive and challenging to investigate in human subjects; moreover, the attempt to create HFpEF in ovariectomized (OVX) mice was unsuccessful. We aim to create an animal model of postmenopausal HFpEF that resembles the characteristics of HFpEF in women with natural menopause.
Methods. We use the 4-vinyl cyclohexene dioxide (VCD) to induce “ovary-intact” menopause, combined with the 2hit regimen (HFpEF inducing regimen elicited by high-fat diet and nitric oxide synthase inhibitor) to model postmenopausal HFpEF. VCD gradually causes ovarian failure, providing the perimenopausal transition and preserving residual ovarian stroma, mimicking natural menopause. The HFpEF phenotypes were studied at the in vivo LV by pressure-volume (PV) analysis and at the single cell level by intact cell force measurement.
Results. The Female-VCD-2hit model demonstrates diastolic dysfunction at both the LV and the cellular levels. At the LV level, the increase in the end-diastolic pressure-volume relation (EDPVR) stiffness coefficient and LV end-diastolic pressure (LVEDP) indicates a heightened stiffness of the LV chamber and an elevation in LV filling pressure, an HFpEF-like condition. At the cardiomyocyte level, the female-VCD-2hit model exhibits an increase in cellular diastolic stiffness, suggesting that the observed LV diastolic stiffness is derived from the stiffness of the cardiomyocytes. We compared the female-VCD-2hit mice with the OVX mice subjected to the 2hit regimen. The 2hit-OVX model showed a milder form of diastolic dysfunction, observed as a smaller increase in LV diastolic stiffness (EDPVR) and normal LV filling pressure (LVEDP).
Conclusions. Female mice, either premenopausal or ovariectomized, are more resistant to the development of HFpEF, unlike their ovary-intact menopausal (VCD-treated) counterparts, which exhibit a vulnerability to HFpEF, making the VCD-2hit model a suitable model to study postmenopausal HFpEF. The LV diastolic dysfunction observed in the 2hit model is attributed to mechanical dysfunction at the cardiomyocyte level.