W3 - Investigating the Role of Estrogen Receptor Alpha in Cardiac Adaptation to Pressure Overload

Friday, October 10, 2025

10:00 AM - 11:00 AM PDT

Location: Exhibit Hall F, G & H

Presenting Author(s)

Pratima Prabala

Graduate Student
University of California, Irvine
Irvine, California, United States

Co-Author(s)

LC

Leticia Charco

Animal Specialist
University of California, Irvine, United States
FT

Fernando Trinidad

Graduate Student
University of California Irvine, United States

Primary Investigator(s)

Naomi C. Chesler, PhD

Professor
University of California, Irvine
Irvine, California, United States

Introduction: : Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired myocardial relaxation and increased ventricular stiffness during diastole, resulting in diastolic dysfunction despite a normal or near-normal ejection fraction (≥50%). HFpEF accounts for approximately half of all heart failure cases and is pathologically distinct from heart failure with reduced ejection fraction (HFrEF). It is frequently associated with comorbidities such as obesity, diabetes, and hypertension. Notably, HFpEF is more prevalent in post-menopausal women, who also exhibit greater symptom burden, more severe diastolic dysfunction, and increased left ventricular stiffness compared to men of similar ages. The molecular basis of this sex disparity remains unclear, particularly in the context of estrogen deficiency and cardiometabolic stress. Estrogen receptor alpha (ERα), a key mediator of estrogen signaling, supports cardiovascular structure and function, and its loss has been linked to myocardial fibrosis and diastolic dysfunction. To investigate the role of ERα in HFpEF pathogenesis, we used a female rat model of pressure overload and metabolic stress using transverse aortic constriction (TAC) combined with high-fat diet (HFD) exposure. By comparing wild-type (ERαWT) and knockout (ERαKO) rats, we aim to determine how loss of ERα signaling influences HFpEF progression. We hypothesize that ERα deficiency exacerbates cardiac remodeling through enhanced fibrosis, diastolic dysfunction, and metabolic maladaptation.

Materials and

Methods: : To investigate the role of ERα in HFpEF development, we used a rat model of pressure overload and metabolic stress. Seven 40-week-old female Sprague-Dawley rats were subjected to transverse aortic constriction (TAC), including three rats with a targeted loss-of-function mutation in ERα (ERαKO) and four wild-type (ERαWT) littermates. Baseline echocardiography was performed to assess cardiac function and measure the aortic diameter. For TAC, rats were anesthetized with 5% isoflurane, intubated, and mechanically ventilated after which a suture was placed around the transverse aorta, between the brachiocephalic trunk and left common carotid artery. A spacer needle was used to achieve ~65% constriction relative to the baseline aortic diameter. Following recovery, all rats were fed a Western-style, high-fat diet (HFD). Body weight, food intake, and blood pressure were monitored weekly for 9 weeks. HFpEF progression was assessed via echocardiography at baseline, 3 weeks, 6 weeks, and 9 weeks (study endpoint), evaluating parameters such as left ventricular hypertrophy, chamber dimensions, ejection fraction, and diastolic function. After 9 weeks, gross anatomical and histological analyses were performed to assess cardiac remodeling and fibrosis in response to ERα deficiency and metabolic stress.

Results, Conclusions, and Discussions:: Compared to ERαWT rats, the ERαKO rats exhibited significantly higher body weights over the 6-week post-TAC period, along with consistently elevated weekly food intake. This suggests that loss of ERα may impair metabolic homeostasis and appetite regulation in the context of HFD exposure. Echocardiographic assessment revealed preserved ejection fraction (>55%) and fractional shortening (>40%) across all timepoints in both genotypes, consistent with the HFpEF phenotype. While systolic function remained intact, ERαKO rats showed evidence of worsened diastolic dysfunction. At 3 and 6 weeks post-TAC, ERαKO rats had higher E/A ratios compared to ERαWT rats, indicating increased early filling and impaired ventricular relaxation, hallmarks of diastolic dysfunction. At the same timepoints, left ventricular mass was also greater in ERαKO rats, suggesting that loss of ERα may exacerbate hypertrophic remodeling in response to pressure overload.

These preliminary findings support the hypothesis that ERα plays a protective role in HFpEF development by modulating diastolic function, vascular compliance, and metabolic responses. Loss of ERα signaling under combined pressure overload and metabolic stress accelerates diastolic dysfunction and promotes metabolic dysregulation. Despite preserved systolic performance, the distinct diastolic phenotype in ERαKO rats reinforces the importance of sex hormone signaling in HFpEF pathophysiology. These findings underscore the need for sex-specific approaches to HFpEF research and highlight ERα as a potential regulator of cardiometabolic resilience. Ongoing histological and molecular analyses will further elucidate ERα-dependent mechanisms driving fibrosis and functional decline.

Acknowledgements and/or References (Optional): :