title: Increased expression of HCN channels in the ventricular myocardium contributes to enhanced arrhythmicity in mouse failing hearts.
abstract: BACKGROUND
  The efficacy of pharmacological interventions to prevent sudden arrhythmic death in patients with chronic heart failure remains limited. Evidence now suggests increased ventricular expression of hyperpolarization-activated cation (HCN) channels in hypertrophied and failing hearts contributes to their arrythmicity. Still, the role of induced HCN channel expression in the enhanced arrhythmicity associated with heart failure and the capacity of HCN channel blockade to prevent lethal arrhythmias remains undetermined.
  
  
  RESULTS
  We examined the effects of ivabradine, a specific HCN channel blocker, on survival and arrhythmicity in transgenic mice (dnNRSF-Tg) expressing a cardiac-specific dominant-negative form of neuron-restrictive silencer factor, a useful mouse model of dilated cardiomyopathy leading to sudden death. Ivabradine (7 mg/kg per day orally) significantly reduced ventricular tachyarrhythmias and improved survival among dnNRSF-Tg mice while having no significant effect on heart rate or cardiac structure or function. Ivabradine most likely prevented the increase in automaticity otherwise seen in dnNRSF-Tg ventricular myocytes. Moreover, cardiac-specific overexpression of HCN2 in mice (HCN2-Tg) made hearts highly susceptible to arrhythmias induced by chronic β-adrenergic stimulation. Indeed, ventricular myocytes isolated from HCN2-Tg mice were highly susceptible to β-adrenergic stimulation-induced abnormal automaticity, which was inhibited by ivabradine.
  
  
  CONCLUSIONS
  HCN channel blockade by ivabradine reduces lethal arrhythmias associated with dilated cardiomyopathy in mice. Conversely, cardiac-specific overexpression of HCN2 channels increases arrhythmogenicity of β-adrenergic stimulation. Our findings demonstrate the contribution of HCN channels to the increased arrhythmicity seen in failing hearts and suggest HCN channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuwabara
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Makoto
authors.initials: M
authors.lastname: Takano
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Yuji
authors.initials: Y
authors.lastname: Arai
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuno
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Igata
authors.forename: Satoru
authors.initials: S
authors.lastname: Usami
authors.forename: Takeya
authors.initials: T
authors.lastname: Minami
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakao
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Yamada
authors.forename: Junko
authors.initials: J
authors.lastname: Shibata
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikimi
authors.forename: Kenji
authors.initials: K
authors.lastname: Ueshima
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D001552:Benzazepines / Q000494:pharmacology; D002412:Cations; D006333:Heart Failure / Q000150:complications*; D006352:Heart Ventricles / Q000378:metabolism*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000077550:Ivabradine; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D001552:Benzazepines; D002412:Cations; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D000077550:Ivabradine
keywords: HCN channel; arrhythmia; heart failure; ion channels