title: Ectopic automaticity induced in ventricular myocytes by transgenic overexpression of HCN2.
abstract: Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) are expressed in the ventricles of fetal hearts but are normally down-regulated as development progresses. In the hypertrophied heart, however, these channels are re-expressed and generate a hyperpolarization-activated, nonselective cation current (Ih), which evidence suggests may increase susceptibility to arrhythmia. To test this hypothesis, we generated and analyzed transgenic mice overexpressing HCN2 specifically in their hearts (HCN2-Tg). Under physiological conditions, HCN2-Tg mice exhibited no discernible abnormalities. After the application of isoproterenol (ISO), however, ECG recordings from HCN2-Tg mice showed intermittent atrioventricular dissociation followed by idioventricular rhythm. Consistent with this observation, 0.3 μmol/L ISO-induced spontaneous action potentials (SAPs) in 76% of HCN2-Tg ventricular myocytes. In the remaining 24%, ISO significantly depolarized the resting membrane potential (RMP), and the late repolarization phase of evoked action potentials (APs) was significantly longer than in WT myocytes. Analysis of membrane currents revealed that these differences are attributable to the Ih tail current. These findings suggest HCN2 channel activity reduces the repolarization reserve of the ventricular action potential and increases ectopic automaticity under pathological conditions such as excessive β-adrenergic stimulation.
authors.affiliation: Department of Physiology, Kurume University School of Medicine, Kurume, Japan; Department of Anesthesiology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Oshita
authors.affiliation: Department of Physiology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Itoh
authors.affiliation: Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Hirashima
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuwabara
authors.affiliation: Department of Physiology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ishihara
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.affiliation: Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Division of Microscopic and Developmental Anatomy, Department of Anatomy, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Kei-Ichiro
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Anesthesiology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ushijima
authors.affiliation: Department of Physiology, Kurume University School of Medicine, Kurume, Japan. Electronic address: takanom@med.kurume-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takano
mesh_terms: D016170:Accelerated Idioventricular Rhythm / Q000139:chemically induced; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004562:Electrocardiography; D015870:Gene Expression; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics* / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007545:Isoproterenol
keywords: Arrhythmia; Cardiomyocyte; Electrophysiology; HCN2; Ion channel