Cardiovascular disease (CVD) is the leading cause of death worldwide. Pre-menopausal women have a lower incidence and severity of CVD compared to age-matched men. However, at the onset of menopause, CVD increases. A central feature in patients with CVD is excessive chronic sympathetic stimulation (CSS) of β-adrenergic receptors (β-AR’s). Clinical and animal studies show estrogen deficiency and age exacerbate cardiac β-AR signaling and contractile function. This led to the hypothesis that prolonged estrogen deficiency followed by CSS worsens left ventricular cardiac function and hypertrophy in the aged female heart. Female mice underwent bilateral ovariectomy or SHAM surgery at 2.5 months of age. At 12 months post-ovariectomy, mice were infused with Isoproterenol (400μg/kg/h) via mini-osmotic pumps for three days to induce CSS. This observation demonstrates prolonged estrogen deficiency worsens cardiac function and structure in aged female hearts. Thereby emphasizing the importance of clinical intervention and prevention for CVD in menopausal women.

Cardiovascular disease (CVD) is the leading cause of death worldwide. The risks for women increase at the onset of menopause. A central feature in CVD patients is excessive sympathetic stimulation of beta-adrenergic receptors (β-ARs). Both clinical and animal studies show that estrogen loss and age exacerbate cardiac β-AR signaling and contractile function. We, therefore, examined the hypothesis that prolonged estrogen deficiency followed by chronic sympathetic injury worsens left ventricular cardiac function in the aged female heart. Bilateral ovariectomy (OVX) or SHAM surgery was performed in female mice at 2.5 months of age and infused with Isoproterenol (ISO; 400μg/kg/h) at 12 months (12M) post OVX for 3 days to induce chronic sympathetic stimulation. Transthoracic two-dimensional M-mode echocardiography was used to measure left ventricular (LV) wall thickness and left ventricular end-systolic diameter (LVESD) and left ventricular end-diastolic diameter (LVEDD), percent fractional shortening (%FS), and ejection fraction (EF). Animal body weight was measured to calculate the heart-body ratio, followed by the removal of the heart, left lung, and uterus during euthanasia. Tissue samples were treated with wheat germ agglutinin staining to measure cardiac myocyte cross-sectional area (hypertrophy). Results show that prolonged ovariectomy increased mortality in mice treated with ISO post-ovariectomy (OVX +ISO) compared to the SHAM+ISO group. Echocardiography imaging demonstrated a smaller systolic diameter and increased contractility in the ISO and ISO+OVX groups. OVX, ISO, and ISO+OVX treatment had a significant decrease in LVESD versus SHAM and OVX groups. The LVEDD resulted in a significant decrease with ISO treatment compared to the SHAM group, and no significant difference was observed between the OVX and ISO+OVX groups compared to the SHAM. Percent FS presented a significant increase in cardiac function in OVX, ISO, and ISO+OVX groups compared to the SHAM. There was an increased %FS in the ISO+OVX compared to the OVX group, and no significant difference between the ISO+OVX and ISO treatment groups. Percent EF significantly increased in the OVX, ISO, and ISO+OVX treatment groups from the SHAM and OVX group, and no significant difference between the ISO+OVX and ISO treatment groups. OVX increased left ventricular mass compared to SHAM. While ISO treatment did not increase LV mass ISO+OVX treatment group significantly increased in LV mass when compared to the ISO treatment group. There was no significant difference in the left ventricular mass between the ISO+OVX vs. OVX group. There was no significant difference in cardiac myocyte cross-sectional area in the SHAM, OVX vs ISO groups. There was however a significant increase in myocyte cross-sectional area in the ISO+OVX group compared to OVX treatment and ISO groups. The results presented here show that estrogen loss impairs left ventricular cardiac function and increases remodeling in response to β-AR stimulation and that prolonged estrogen loss may blunt the sympathetic response in the heart. These results highlight the importance of the long-term effects of estrogen loss during menopause in the treatment and management of heart disease.