Noriko Niwa

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. 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 (IKr and IKs) 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 (Ito1). L-type Ca2+ current (ICa,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 ICa,L inactivation was not different in control and AVB myocytes. The inward rectifier K+ current (IK1) 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 IKr and IKs in association with altered ICa,L activation kinetics may underlie the arrhythmogenic ventricular remodeling.