The Impact of Prolonged Estrogen Loss on the Sympathetic Response and Cardiac Remodeling Following Heart Failure

Cardiovascular disease (CVD) is the leading cause of death worldwide, and research indicates that it affects men and women differently. However, there is still a significant gap in understanding the underlying mechanisms driving these differences. Estrogen may be one of the missing links in explaining this disparity. Studies have shown that premenopausal women are somewhat protected against the development of CVD when compared to age matched men. However, this protection is diminished after menopause, likely due to estrogen loss. Our hypothesis is that prolonged estrogen loss exacerbates cardiac function with sympathetic stimulation, leading to increased cardiac remodeling, ultimately leading to cardiac dysfunction. Seven month post-ovariectomized and sham female mice were treated with isoproterenol (400g/kg/hour) to simulate chronic sympathetic stimulation for 7 days (concentration), and we measured heart function at day 7 through transthoracic echocardiography. To determine the impact on cardiac remodeling, we evaluated cardiac hypertrophy, apoptosis, and fibrosis using paraffin-embedded hearts, sectioned at 4 µm on slides, and imaged at 20x using an EVOS microscope. Cardiac hypertrophy was assessed by Wheat Germ Agglutinin (WGA) staining, to measure the cross-sectional area of individual cardiac myocytes using NIS Elements Nikon software. Apoptosis was quantified using TUNEL staining. NIS elements was used to calculate the percentage of TUNEL-positive nuclei. Fibrosis was evaluated using Masson’s Trichrome staining to identify collagen deposition. Results show that prolonged estrogen loss increases mortality by 45% following sympathetic stimulation. Functionally, the results show an increase in percent fractional shortening and ejection fraction compared to only prolonged estrogen loss or heart failure. The results also show that when cardiac sympathetic stimulation is combined with prolonged estrogen loss, cardiac fibrosis, hypertrophy, and apoptosis significantly increase compared to only prolonged estrogen loss or heart failure. Overall, these results indicate that prolonged estrogen loss plays a major role in survival and cardiac remodeling.