title: Ionic mechanisms of acquired QT prolongation and torsades de pointes in rabbits with chronic complete atrioventricular block.
abstract: BACKGROUND
  The ionic basis of acquired QT prolongation and torsade de pointes (TdP) unrelated to drugs is not fully understood.
  
  
  RESULTS
  We created a rabbit model with chronic complete atrioventricular block (AVB) (n=34), which showed prominent QT prolongation (by 120%), high incidence of spontaneous TdP (71%), and cardiac hypertrophy. Patch-clamp experiments were performed in left ventricular myocytes from 9 rabbits (8 with TdP, 1 without TdP) at approximately 21 days of AVB and from 8 sham-operated controls with sinus rhythm. Action potential duration was prolonged in AVB myocytes compared with control (+61% at 0.5 Hz, +21% at 3 Hz). Both rapidly and slowly activating components of the delayed rectifier K(+) current (I(Kr) and I(Ks)) in AVB myocytes were significantly smaller than in control by 50% and 55%, respectively. There was no significant difference in Ca(2+)-independent transient outward current (I(to1)). L-type Ca(2+) current (I(Ca,L)) in control and AVB myocytes was similar in peak amplitude, but the half voltage for activation was shifted to the negative direction (5.9 mV) in AVB myocytes. Voltage dependence of I(Ca,L) inactivation was not different in control and AVB myocytes. The inward rectifier K(+) current (I(K1)) significantly increased in AVB myocytes compared with control.
  
  
  CONCLUSIONS
  In the rabbit, chronic AVB leads to prominent QT prolongation and high incidence of spontaneous TdP. Downregulation of both I(Kr) and I(Ks) in association with altered I(Ca,L) activation kinetics may underlie the arrhythmogenic ventricular remodeling.
authors.affiliation: Department of Circulation, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. y-tsuji@hh.iij4u.or.jp
authors.forename: Yukiomi
authors.initials: Y
authors.lastname: Tsuji
authors.forename: Tobias
authors.initials: T
authors.lastname: Opthof
authors.forename: Kenji
authors.initials: K
authors.lastname: Yasui
authors.forename: Yasuya
authors.initials: Y
authors.lastname: Inden
authors.forename: Haruki
authors.initials: H
authors.lastname: Takemura
authors.forename: Noriko
authors.initials: N
authors.lastname: Niwa
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Lu
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Lee
authors.forename: Haruo
authors.initials: H
authors.lastname: Honjo
authors.forename: Kaichiro
authors.initials: K
authors.lastname: Kamiya
authors.forename: Itsuo
authors.initials: I
authors.lastname: Kodama
mesh_terms: D000200:Action Potentials; D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology; D002908:Chronic Disease; D051668:Delayed Rectifier Potassium Channels; D015536:Down-Regulation; D004452:Echocardiography; D004553:Electric Conductivity; D004562:Electrocardiography; D006321:Heart / Q000503:physiopathology; D006327:Heart Block / Q000150:complications* / Q000175:diagnosis / Q000401:mortality; D015994:Incidence; D007700:Kinetics; D008133:Long QT Syndrome / Q000209:etiology* / Q000503:physiopathology; D008955:Models, Cardiovascular; D015221:Potassium Channels / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011817:Rabbits; D016019:Survival Analysis; D016171:Torsades de Pointes / Q000453:epidemiology / Q000209:etiology* / Q000503:physiopathology
chemical_list: D020746:Calcium Channels, L-Type; D051668:Delayed Rectifier Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated