Published Online
on September 16, 2002

A more recent version of this article appeared on October 8, 2002

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Submitted on March 19, 2002
Revised on July 1, 2002
Accepted on July 11, 2002

Ionic Mechanisms of Acquired QT Prolongation and Torsades de Pointes in Rabbits With Chronic Complete Atrioventricular Block

Yukiomi Tsuji MD^*, Tobias Opthof PhD, Kenji Yasui MD, Yasuya Inden MD, Haruki Takemura MD, Noriko Niwa MD, Zhibo Lu MD, Jong-Kook Lee MD, Haruo Honjo MD, Kaichiro Kamiya MD, and Itsuo Kodama MD

From the Departments of Circulation and Humoral Regulation, Research Institute of Environmental Medicine, and the First Department of Medicine, Division of Cardiology (Y.I.), Nagoya University, Nagoya, Japan; and Department of Medical Physiology (T.O.), University Medical Center Utrecht, the Netherlands.

^* To whom correspondence should be addressed. E-mail: y-tsuji{at}hh.iij4u.or.jp.

Background—The ionic basis of acquired QT prolongation and torsade de pointes (TdP) unrelated to drugs is not fully understood.

Methods and 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 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 Ca²⁺-independent transient outward current (I_to1). L-type Ca²⁺ 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.

Key words: electrophysiology • long-QT syndrome • torsade de pointes • ion channels • action potentials

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