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 (If) (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 If 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 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 with that of HCN4. CONCLUSIONS: This study shows that an increase in If current density contributes to the acceleration of sinoatrial node automaticity and explains, in part, the higher HR observed in pregnancy.
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 (If) (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 If 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 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 with that of HCN4. CONCLUSIONS: This study shows that an increase in If current density contributes to the acceleration of sinoatrial node automaticity and explains, in part, the higher HR observed in pregnancy.
Entities:
Keywords:
heart rate; ion channels; pacemakers, biological; pregnancy; sinoatrial node
Authors: Kenneth A Mayuga; Artur Fedorowski; Fabrizio Ricci; Rakesh Gopinathannair; Jonathan Walter Dukes; Christopher Gibbons; Peter Hanna; Dan Sorajja; Mina Chung; David Benditt; Robert Sheldon; Mirna B Ayache; Hiba AbouAssi; Kalyanam Shivkumar; Blair P Grubb; Mohamed H Hamdan; Stavros Stavrakis; Tamanna Singh; Jeffrey J Goldberger; James A S Muldowney; Mark Belham; David C Kem; Cem Akin; Barbara K Bruce; Nicole E Zahka; Qi Fu; Erik H Van Iterson; Satish R Raj; Fetnat Fouad-Tarazi; David S Goldstein; Julian Stewart; Brian Olshansky Journal: Circ Arrhythm Electrophysiol Date: 2022-09-08
Authors: Norman C Wang; Carlita Shen; Terence J McLaughlin; Jack Z Li; Alisse Hauspurg; Kathryn L Berlacher; Aditya Bhonsale; Sandeep K Jain; Krishna Kancharla; Samir Saba Journal: J Cardiovasc Electrophysiol Date: 2020-09-21