Abstract P3119: Identifying The Windows Of Cardiac Risk And Opportunity In Menopause

Post-acute myocardial infarction (AMI) mortality has significant sex differences with a bias towards higher rates in women. While treatment inequities and access to care profoundly impact outcomes, biological factors also contribute to survival discrepancies. One complicating factor that drives worse outcomes in women is menopause. Understanding the biological basis for AMI mortality risk and the exacerbating role of menopause has been hampered by the lack of an animal model that recapitulates the dynamic changes associated with the perimenopausal transition. We used a mouse model of menopause in which ovarian failure is gradually induced following treatment with 4-vinylcyclohexene diepoxide (VCD, 160 mg/kg, 15d), allowing for examination of cardiac alterations established during perimenopause. Echocardiography revealed no contractile changes during perimenopause, but cardiac myofilament activation was significantly affected. Calcium re-uptake by SERCA was impaired by the end of perimenopause. Changes in calcium handling were associated with alterations in calcium handling protein expression and phosphorylation. Activation of RISK and SAFE signaling molecules that protect against ischemia-reperfusion (IR) injury was altered throughout perimenopause, and the RISK-SAFE response to IR differed at points during perimenopause. The myocardial response to cardioprotective estrogen receptor activation also varied throughout perimenopause. Together these data reveal significant, nonlinear alterations in myocardial physiology and endogenous protective signing pathways during perimenopause. Disruptions in endogenous protection and calcium handling are established prior to menopause, providing possible mechanisms for worse post-menopausal AMI outcomes. The altered response to estrogen receptor activation preceding menopause may explain the inconsistent effectiveness of post-menopausal estrogen replacement therapy.