Cell‐based hormone therapy prevents diastolic dysfunction after estrogen loss in the Spontaneously Hypertensive Rat (SHR)

Abstract

Introduction. Preclinical left ventricular diastolic dysfunction (LVDD) is a forerunner to heart failure with preserved ejection fraction, which is seen more often in older women than men of the same age. While hormone therapy plays an important role in the management of vasomotor and genitourinary symptoms experienced by many women during the menopausal transition, its efficacy with regard to maintenance of cardiac structure and function and prevention of LVDD disease progression with aging has not been tested due to the concern for off‐target health risks (e.g., cancer, blood clots). We developed a cell‐based hormone therapy (cHT) approach that recapitulates native cell–cell interactions between ovarian granulosa and theca cells in a 3D bioengineered construct to mimic the dynamic release of sex hormones into the circulation. Our first report in ovariectomized rats shows that ovarian constructs are able to ameliorate various somatic adverse effects of hormone deficiency (e.g. bone loss). To extend these findings to cardiac health, we sought to determine the efficacy of cHT in preserving cardiac diastolic function after estrogen loss using a hypertensive rodent model.Methods14 SHR females underwent bilateral ovariectomy (OVX) while 5 SHRs received sham surgery at 12 weeks of age; 8 weeks post‐surgery, OVX rats were randomized (n=4–5/group) to vehicle, cHT, or pharmacologic hormone therapy (pHT: E2 (10mg/kg/day) and P4 (2mg/kg/day) subcutaneous pellets) and compared to gonad‐intact rats treated with vehicle (VEH). Body weights and tail cuff systolic blood pressure (SBP) were measured biweekly. Following 10 weeks of treatment, rats were lightly anesthetized (isoflurane) for Doppler measures of diastolic function. Data were analyzed by one‐way ANOVA. P<0.05 was significant.ResultsOVX rats, irrespective of treatment, had higher body weights when compared to sham (P<0.001). Uterine atrophy by OVX was minimized by pHT and cHT, reflecting modest E2‐related effects (Figure A). SBP increased progressively over time (P<0.01), without overt differences across treatment groups. Even so, both cHT and pHT prevented adverse OVX‐related effects on myocardial relaxation (e') and Doppler‐derived filling pressures (E/e') when compared to vehicle (Figures B, C).ConclusionThese data show that novel cell‐based hormone therapy is effective in preventing diastolic dysfunction from surgically‐induced menopause in the SHR. Additional studies are underway to determine cHT’s long‐term (6 months) treatment efficacy in middle‐to‐advanced aged OVX rats.Support or Funding InformationNIH AG061588Figure 1