Grant: Project Grant

Females have lower rates of cardiovascular disease death (CVD) than males early in life. After menopause this trend reverses and women have higher mortality rates. In fact, women who have a heart attack are more likely to die than men. Higher rates of heart attack mortality for females are partly due to inequities in healthcare access and delivery, but differences remain when these disparities are removed. A barrier to understanding how menopause impacts women's heart attack survival has been the lack of an animal model that mimics the changes of menopause. Removal of ovaries from lab animals replicates the decrease in estrogens, but its sudden onset mimics how <20% of women enter menopause. Most women undergo a gradual transition called 'perimenopause' which lasts up to a decade. We have a model of menopause in which mice injected with 4-vinylcyclohexene diepoxide experience perimenopause before developing the ovarian failure of menopause. We will use this model to investigate how the heart changes across the phases of menopause. We will expose hearts to coronary artery ligation to mimic a heart attack and measure molecules that protect the heart against the stress of a heart attack to understand when and how the increased risk of mortality rises in peri- and postmenopausal women. Estrogens protect against CVD in premenopausal women and their loss contributes to the increased risk of CVD mortality after menopause. Chronic estrogen supplementation has unclear benefits for cardiovascular health, but our preliminary data show a novel treatment in which hearts are acutely exposed to estrogen mimetics after a heart attack limits injury. Whether this clinically viable treatment is effective after menopause has not been tested. We propose to use our mouse models of menopause to determine if acute exposure to estrogenic compounds protects against heart attack injury in the postmenopausal environment and identify the molecular mechanisms that mediate protection.