# Effects of cell-based hormone therapy on LV diastolic dysfunction and hypertrophy progression after mid-life estrogen loss

> **NIH NIH R21** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2020 · $203,472

## Abstract

Heart failure with preserved ejection fraction (HFpEF) is seen more often in women, and older women develop
HFpEF twice as often as men of the same age. Currently, there is a significant gap in our knowledge regarding
HFpEF and how to treat it. Preclinical left ventricular diastolic dysfunction (LVDD) is a forerunner to HFpEF,
and therapeutic strategies are needed that slow the development of LVDD along the aging continuum by
mitigating its associated cardiovascular risk factors, such as estrogen deficiency. Hormone replacement
therapy plays an important role in the management of vasomotor and genitourinary symptoms experienced by
many women during the menopausal transition; however, 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). Other drawbacks of current estrogen-progestin
supplementation include dosage issues and the inability to replicate dynamic circulating estradiol (E2) and
progesterone (P) concentrations or the body's feedback mechanism to control the dynamic release of ovarian
hormones. To address the various health issues associated with loss of ovarian hormone production, not only
due to aging and the menopause, but also secondary to surgery or chemotherapy, we developed a cell-based
hormone replacement therapy (cHRT) 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. We have shown these ovarian constructs are effective in ameliorating various adverse effects
of hormone deficiency, including on bone health, uterine health, and body composition, in an ovariectomized
(OVX) adult rat model. This exploratory project will examine the efficacy of cHRT in preserving cardiac
structure and function after estrogen loss. We hypothesize that cHRT, by recapitulating the dynamic
hypothalamus-pituitary-ovarian control loop, will prevent declines in diastolic function and slow the
development of LV hypertrophy and LVDD more effectively and safely than conventional pharmacologic
hormone replacement therapy (pHRT) in OVX rats. We will test this hypothesis in two specific aims: 1)
Demonstrate in vivo that prolonged (10 months) cHRT prevents the development of LVDD, hypertrophic
remodeling, and exercise intolerance among middle-aged (18 months of age) female Fischer 344 x Brown
Norway rats and adult hypertensive mRen2.Lewis rats after OVX-induced hormone loss; and 2) Establish ex
vivo that cHRT favorably modulates the cardiac nitric oxide synthase (NOS) system to prevent the adverse
effects of estrogen loss-induced ROS on interstitial and cardiomyocyte remodeling and lusitropic function. At
the completion of this pilot study, we hope to obtain preliminary proof-of-concept data that would enable us to
prepare an R01 application for furth...

## Key facts

- **NIH application ID:** 9849709
- **Project number:** 5R21AG061588-02
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** LEANNE GROBAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $203,472
- **Award type:** 5
- **Project period:** 2019-01-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849709

## Citation

> US National Institutes of Health, RePORTER application 9849709, Effects of cell-based hormone therapy on LV diastolic dysfunction and hypertrophy progression after mid-life estrogen loss (5R21AG061588-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9849709. Licensed CC0.

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