title: Upregulation of the hyperpolarization-activated current increases pacemaker activity of the sinoatrial node and heart rate during pregnancy in mice.
abstract: 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.
  
  
  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.
authors.affiliation: Research Center, Montreal Heart Institute, 5000 Bélanger, Montréal, Québec, Canada, H1T 1C8.
authors.forename: Nabil
authors.initials: N
authors.lastname: El Khoury
authors.forename: Sophie
authors.initials: S
authors.lastname: Mathieu
authors.forename: Laurine
authors.initials: L
authors.lastname: Marger
authors.forename: Jenna
authors.initials: J
authors.lastname: Ross
authors.forename: Gracia
authors.initials: G
authors.lastname: El Gebeily
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ethier
authors.forename: Céline
authors.initials: C
authors.lastname: Fiset
mesh_terms: D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000096:biosynthesis; D005260:Female; D006329:Heart Conduction System / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000096:biosynthesis*; D051379:Mice; D015221:Potassium Channels; D011247:Pregnancy / Q000502:physiology*; D012849:Sinoatrial Node / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels
keywords: heart rate; ion channels; pacemakers, biological; pregnancy; sinoatrial node