Upregulation Of The Hyperpolarization-Activated Current Increases Pacemaker Activity Of The Sinoatrial Node And Heart Rate During Pregnancy In Mice

Background-Pregnancy is associated with a faster heart rate (HR), which is a risk factor for arrhythmias. However, the underlying mechanisms for this increased HR are poorly understood. Therefore, this study was performed to gain mechanistic insight into the pregnancy-induced increase in HR.Methods and Results-Using surface ECG we observed that pregnant (P) mice have faster HR (531+/-14 beats per minute [bpm]) compared with nonpregnant (NP) mice (470+/-27 bpm; P<0.03). Results obtained with Langendorff-perfused hearts showed that this difference persisted in the absence of autonomic nervous innervation (NP, 327+/-16 bpm; P, 385+/-18 bpm; P< 0.02). Spontaneous action potentials of sinoatrial node cells from pregnant mice exhibited higher automaticity (NP, 292+/-13 bpm; P, 330+/-12 bpm; P=0.047) and steeper diastolic depolarization (NP, 0.20+/-0.03 V/s; P, 0.40+/-0.06 V/s; P= 0.004). Pregnancy increased the density of the hyperpolarization-activated current (I-f) (at -90mV: NP, -15.2+/-1.0 pA/pF; P, -28.6+/-2.9 pA/pF; P= 0.0002) in sinoatrial node cells. Voltage dependence of the I-f activation curve and the intracellular cAMP levels were unchanged in sinoatrial node cells of pregnant mice. However, there was a significant increase in HCN2 channel protein expression with no change in HCN4 expression. Maximal depolarizing shift of the I-f activation curve induced by isoproterenol was attenuated in pregnancy. This reduced response to isoproterenol may be attributable to the lower cAMP sensitivity of HCN2 isoform compared with that of HCN4.Conclusions-This study shows that an increase in I-f current density contributes to the acceleration of sinoatrial node automaticity and explains, in part, the higher HR observed in pregnancy.