An Investigation Into The Cardiovascular Disease (CVD) Phenotypes Underlying Increased Susceptibility To Cardiac Remodeling During Menopause With A Focus On AMPK Activator A769662 Intervention

Abstract

The occurrence of heart disease increases in menopausal women compared to premenopausal women due to the loss of protection from estrogen. Premenopausal women produce sex hormones while menopausal women experience a loss of estrogen production and signaling. Therefore, it is theorized that premenopausal women are protected against hypertension and hypertrophic cardiac remodeling compared to age-matched men and menopausal women. Additionally, detrimental outcomes in heart failure are the highest in women since disease progression is difficult to properly diagnose due current research lacking sex-specific cardiovascular disease scoring guidelines. It is clinically shown that women in menopause may show signs and symptoms of various disease phenotypes such as ischemic heart disease (IHD), nonobstructive coronary artery disease (CAD), heart failure with normal ejection fraction (HFNEF), and hypertrophic cardiomyopathy (HCM), leaving the model of heart failure in menopausal women unclear. In our study we aim to look at heart disease progression into menopause and across both short-term and long-term menopause to better understand pathological cardiac remodeling and determine therapeutic targets in the senescent women. In order to study heart disease in menopausal women, we used the VCD (4-vinyl-cyclohexane diepoxide) mouse model of menopause to chemically induce short-term and long-term menopause. Echocardiography measurements evaluate the functional and morphological changes in the heart, specifically EF, FS, LVIDd, LVol_d, LVol_s, E/A, and RWTd. Also, H&E and PSR staining determine the extent of fibrous and the general morphology of the heart. We hypothesize that the VCD model of menopause will reveal that the pathological cardiac remodeling that progresses with menopause, occurs due to the loss of estrogen. Additionally, we implemented an AMP-activated protein kinase (AMPK) activator A769662 which, we hypothesize will prevent pathological cardiac remodeling seen in the transition to menopause. The results of our study determine that short-term menopause and respective transition groups (premenopause and perimenopause) has an increase in the heart weight with angiotensin II (Ang II) treatment. However, AMPK activated by A769662 mitigates hypertrophy by reducing heart weight and fibrosis in premenopausal, and perimenopausal groups. Consequently, observations in the long-term groups demonstrates there are AMPK activation dysfunctions, and heart weight is increased with ANG II treatment.