title: Multistep ion channel remodeling and lethal arrhythmia precede heart failure in a mouse model of inherited dilated cardiomyopathy.
abstract: BACKGROUND
  Patients with inherited dilated cardiomyopathy (DCM) frequently die with severe heart failure (HF) or die suddenly with arrhythmias, although these symptoms are not always observed at birth. It remains unclear how and when HF and arrhythmogenic changes develop in these DCM mutation carriers. In order to address this issue, properties of the myocardium and underlying gene expressions were studied using a knock-in mouse model of human inherited DCM caused by a deletion mutation ΔK210 in cardiac troponinT.
  
  
  RESULTS
  By 1 month, DCM mice had already enlarged hearts, but showed no symptoms of HF and a much lower mortality than at 2 months or later. At around 2 months, some would die suddenly with no clear symptoms of HF, whereas at 3 months, many of the survivors showed evident symptoms of HF. In isolated left ventricular myocardium (LV) from 2 month-mice, spontaneous activity frequently occurred and action potential duration (APD) was prolonged. Transient outward (I(to)) and ultrarapid delayed rectifier K(+) (I(Kur)) currents were significantly reduced in DCM myocytes. Correspondingly, down-regulation of Kv4.2, Kv1.5 and KChIP2 was evident in mRNA and protein levels. In LVs at 3-months, more frequent spontaneous activity, greater prolongation of APD and further down-regulation in above K(+) channels were observed. At 1 month, in contrast, infrequent spontaneous activity and down-regulation of Kv4.2, but not Kv1.5 or KChIP2, were observed.
  
  
  CONCLUSIONS
  Our results suggest that at least three steps of electrical remodeling occur in the hearts of DCM model mice, and that the combined down-regulation of Kv4.2, Kv1.5 and KChIP2 prior to the onset of HF may play an important role in the premature sudden death in this DCM model. DCM mice at 1 month or before, on the contrary, are associated with low risk of death in spite of inborn disorder and enlarged heart.
authors.affiliation: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Takao
authors.initials: T
authors.lastname: Shioya
authors.forename: Takashi
authors.initials: T
authors.lastname: Murayama
authors.forename: Masami
authors.initials: M
authors.lastname: Sugihara
authors.forename: Fuminori
authors.initials: F
authors.lastname: Odagiri
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakazato
authors.forename: Hiroto
authors.initials: H
authors.lastname: Nishizawa
authors.forename: Akihito
authors.initials: A
authors.lastname: Chugun
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Daida
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.forename: Nagomi
authors.initials: N
authors.lastname: Kurebayashi
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism*; D004562:Electrocardiography; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism; D020107:Troponin T / Q000235:genetics / Q000378:metabolism
chemical_list: D051605:Kv Channel-Interacting Proteins; D051666:Kv1.5 Potassium Channel; D051672:Shal Potassium Channels; D020107:Troponin T