Contribution of estrogen to the pregnancy-induced increase in cardiac automaticity

Background The heart rate progressively increases throughout pregnancy, reaching a maximum in the third trimester. This elevated heart rate is also present in pregnant mice and is associated with accelerated automaticity, higher density of the pacemaker current I f and changes in Ca 2+ homeostasis in sinoatrial node (SAN) cells. Strong evidence has also been provided showing that 17β-estradiol (E 2 ) and estrogen receptor α (ERα) regulate heart rate. Accordingly, we sought to determine whether E 2 levels found in late pregnancy cause the increased cardiac automaticity associated with pregnancy. Methods and results Voltage- and current-clamp experiments were carried out on SAN cells isolated from female mice lacking estrogen receptor alpha (ERKOα) or beta (ERKOβ) receiving chronic E 2 treatment mimicking late pregnancy concentrations. E 2 treatment significantly increased the action potential rate (284 ± 24 bpm, +E 2 354 ± 23 bpm, p = 0.040) and the density of I f (+52%) in SAN cells from ERKOβ mice. However, I f density remains unchanged in SAN cells from E 2 -treated ERKOα mice. Additionally, E 2 also increased I f density (+67%) in nodal-like human-induced pluripotent stem cell-derived cardiomyocytes (N-hiPSC-CM), recapitulating in a human SAN cell model the effect produced in mice. However, the L-type calcium current (I CaL ) and Ca 2+ transients, examined using N-hiPSC-CM and SAN cells respectively, were not affected by E 2 , indicating that other mechanisms contribute to changes observed in these parameters during pregnancy. Conclusion The accelerated SAN automaticity observed in E 2 -treated ERKOβ mice is explained by an increased I f density mediated by ERα, demonstrating that E 2 plays a major role in regulating SAN function during pregnancy.