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

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 Ca²⁺ homeostasis in sinoatrial node (SAN) cells. Strong evidence has also been provided showing that 17β-estradiol (E₂) and estrogen receptor α (ERα) regulate heart rate. Accordingly, we sought to determine whether E₂ levels found in late pregnancy cause the increased cardiac automaticity associated with pregnancy.

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 E₂ treatment mimicking late pregnancy concentrations. E₂ treatment significantly increased the action potential rate (284 ± 24 bpm, +E₂ 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 E₂-treated ERKOα mice. Additionally, E₂ 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 Ca²⁺ transients, examined using N-hiPSC-CM and SAN cells respectively, were not affected by E₂, indicating that other mechanisms contribute to changes observed in these parameters during pregnancy.

The accelerated SAN automaticity observed in E₂-treated ERKOβ mice is explained by an increased I_f density mediated by ERα, demonstrating that E₂ plays a major role in regulating SAN function during pregnancy.