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 and changes in Ca homeostasis in sinoatrial node (SAN) cells. Strong evidence has also been provided showing that 17β-estradiol (E) and estrogen receptor α (ERα) regulate heart rate. Accordingly, we sought to determine whether E 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 treatment mimicking late pregnancy concentrations. E treatment significantly increased the action potential rate (284 ± 24 bpm, +E 354 ± 23 bpm, p = 0.040) and the density of I (+52%) in SAN cells from ERKOβ mice. However, I density remains unchanged in SAN cells from E-treated ERKOα mice. Additionally, E also increased I 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) and Ca transients, examined using N-hiPSC-CM and SAN cells respectively, were not affected by E, indicating that other mechanisms contribute to changes observed in these parameters during pregnancy.

Conclusion: The accelerated SAN automaticity observed in E-treated ERKOβ mice is explained by an increased I density mediated by ERα, demonstrating that E plays a major role in regulating SAN function during pregnancy.