Ionic mechanisms of acquired QT prolongation and torsades de pointes in rabbits with chronic complete atrioventricular block.
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.
Tsuji
Yukiomi
Y
Department of Circulation, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. y-tsuji@hh.iij4u.or.jp
Opthof
Tobias
T
Yasui
Kenji
K
Inden
Yasuya
Y
Takemura
Haruki
H
Niwa
Noriko
N
Lu
Zhibo
Z
Lee
Jong-Kook
JK
Honjo
Haruo
H
Kamiya
Kaichiro
K
Kodama
Itsuo
I
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
D020746:Calcium Channels, L-Type; D051668:Delayed Rectifier Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated