IKs Activator ML277 Mildly Affects Repolarization and Arrhythmic Outcome in the CAVB Dog Model

Long QT syndrome type 1 with affected I-Ks is associated with a high risk for developing Torsade de Pointes (TdP) arrhythmias and eventually sudden cardiac death. Therefore, it is of high interest to explore drugs that target I-Ks as antiarrhythmics. We examined the antiarrhythmic effect of I-Ks channel activator ML277 in the chronic atrioventricular block (CAVB) dog model. TdP arrhythmia sensitivity was tested in anesthetized mongrel dogs (n = 7) with CAVB in series: (1) induction experiment at 4 +/- 2 weeks CAVB: TdP arrhythmias were induced with our standardized protocol using dofetilide (0.025 mg/kg), and (2) prevention experiment at 10 +/- 2 weeks CAVB: the antiarrhythmic effect of ML277 (0.6-1.0 mg/kg) was tested by infusion for 5 min preceding dofetilide. ML277: (1) temporarily prevented repolarization prolongation induced by dofetilide (QTc: 538 +/- 65 ms at induction vs. 393 +/- 18 ms at prevention, p < 0.05), (2) delayed the occurrence of the first arrhythmic event upon dofetilide (from 129 +/- 28 s to 180 +/- 51 s, p < 0.05), and (3) decreased the arrhythmic outcome with a significant reduction in the number of TdP arrhythmias, TdP score, arrhythmia score and total arrhythmic events (from 669 +/- 132 to 401 +/- 228, p < 0.05). I-Ks channel activation by ML277 temporarily suppressed QT interval prolongation, delayed the occurrence of the first arrhythmic event and reduced the arrhythmic outcome in the CAVB dog model.

Automated summary

Long QT syndrome type 1 with affected I-Ks carries a high risk of Torsade de Pointes (TdP) arrhythmias and sudden cardiac death. This study explored the antiarrhythmic effect of I-Ks channel activator ML277 in the chronic atrioventricular block (CAVB) dog model. ML277 temporarily prevented repolarization prolongation induced by dofetilide, delayed the first arrhythmic event, and reduced the overall arrhythmic outcome in the CAVB dog model.