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

Yukiomi Tsuji, Tobias Opthof, Kenji Yasui, Yasuya Inden, Haruki Takemura, Noriko Niwa, Zhibo Lu, Jong-Kook Lee, Haruo Honjo, Kaichiro Kamiya, Itsuo Kodama
2002 Circulation  
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) (nϭ34), 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 Ϸ21 days of AVB and from 8
more » ... ted controls with sinus rhythm. Action potential duration was prolonged in AVB myocytes compared with control (ϩ61% at 0.5 Hz, ϩ21% at 3 Hz). Both rapidly and slowly activating components of the delayed rectifier K ϩ 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 2ϩ -independent transient outward current (I to1 ). L-type Ca 2ϩ 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 ϩ 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.
doi:10.1161/01.cir.0000031160.86313.24 pmid:12370228 fatcat:6a2ekshimnfjxhxh4ha53lneti