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 approximate to21 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,I-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,I-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,I-L activation kinetics may underlie the arrhythmogenic ventricular remodeling.