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(Circulation. 2002;106:2012.)
© 2002 American Heart Association, Inc.

Basic Science Reports

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; 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.

Correspondence to Dr Yukiomi Tsuji, MD, Furo-cho Chikusa-ku, Nagoya 464-8601, Japan. 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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