Upregulation of the Hyperpolarization Activated Current Increases Pacemaker Activity of the Sino-Atrial 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±14bpm) compared to non-pregnant (NP) mice (470±27bpm, p<0.03). Results obtained with Langendorff-perfused hearts showed that this difference persisted in the absence of autonomic nervous innervation (NP: 327±16bpm, P: 385±18bpm, p<0.02). Spontaneous action potentials of sino-atrial node (SAN) cells from pregnant mice exhibited higher automaticity (NP: 292±13bpm, P: 330±12bpm, p=0.047) and steeper diastolic depolarization (NP: 0.20±0.03V/s, P: 0.40±0.06V/s, p=0.004). Pregnancy increased the density of the hyperpolarization-activated current (If) (at -90mV, NP: -15.2±1.0pA/pF, P: -28.6±2.9pA/pF, p=0.0002) in SAN cells. Voltage-dependence of the If activation curve and the intracellular cAMP levels were unchanged in SAN 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 If 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 to that of HCN4.
Conclusions—This study shows that an increase in If current density contributes to the acceleration of SAN automaticity and explains, in part, the higher HR observed in pregnancy.
- Received January 30, 2013.
- Revision received March 14, 2013.
- Accepted March 21, 2013.