Pregnancy and oestrogen regulate sinoatrial node calcium homeostasis and accelerate pacemaking

AIMS: During pregnancy, there is a significant increase in heart rate (HR) potentially associated with an increased risk of arrhythmias or exacerbation of pre-existing cardiac conditions endangering both mother and foetus. Calcium homeostasis plays an important role in regulating automaticity of the sinoatrial node (SAN); however, its contribution to the accelerated HR during pregnancy remains unknown. METHODS AND RESULTS: Using murine SAN cells, we showed that pregnancy increased L-type Ca(2+) current (I(CaL)) and Ca(V)1.3 mRNA expression, whereas T-type Ca(2+) current (I(CaT)) and its underlying channel were unchanged. Analysis of SAN intra-cellular Ca(2+) oscillations showed that the rate of spontaneous Ca(2+) transients was significantly higher in pregnant mice along with a higher mRNA expression of ryanodine receptor. Assessment of supra-ventricular arrhythmias using programmed electrical stimulation protocols on anaesthetized mice revealed higher susceptibility in pregnancy. Of note, the modifications associated with pregnancy were reversible following delivery. Furthermore, chronic administration of 17β-estradiol (E(2)) to nodal-like human-induced pluripotent stem cell-derived cardiomyocytes (N-hiPSC-CM), control mice, oestrogen-receptor-β knockout (ERKOβ) but not ERKOα mice, accelerated cardiac automaticity, recapitulating the pregnancy phenotype in both mouse and human SAN cell models. CONCLUSION: Together, these results indicate that pregnancy considerably alters intra-cellular Ca(2+) homeostasis sustaining faster HR during pregnancy. Importantly, these changes were dependent on an oestrogen receptor α (ERα) mechanism that resulted in increased I(CaL) and spontaneous Ca(2+) release from the sarcoplasmic reticulum, highlighting a novel role for oestrogen in regulating HR.