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

Figures

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  Figure 1. Schematic overview of the experimental setup. Two experiments were performed in series. (A) Induction experiment at chronic AV block 4 ± 2 weeks (CAVB4): baseline measurement followed by dofetilide (Dof) infusion until first Torsade de Pointes (TdP) arrhythmia or maximum infusion of 5 min. (B) Prevention experiment at CAVB 10 ± 2 weeks (CAVB10): baseline measurement followed by 5 min of ML277 and Dof infusion with identical duration as during the induction experiment. Recordings were followed up for 10 min after the start of Dof administration.

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  Figure 2. Effect of ML277 in dogs (n = 7) with chronic AV block (CAVB). (A) Progress of the delta QTc interval (in ms) in the induction experiment: chronic AV block (CAVB) 4 weeks at baseline (BL) and before the first arrhythmic event during dofetilide (Dof). The prevention experiment at CAVB10 included timepoints at BL, at 5 min of ML277 infusion (ML277), at the same timepoint as the first arrhythmic event during Dof at CAVB4 (Dof T1) and at the actual first arrhythmic event during Dof. Data of individual dogs in grey and mean ± SD in black, repeated measures one-way ANOVA with Tukey’s multiple comparisons test, * p < 0.05. (B) Time until the first arrhythmic event occurred during Dof at CAVB4 and during Dof after ML277 at CAVB10. Paired t-test, * p < 0.05. (C) Representative ECG lead II and left ventricular monophasic action potential (LV MAP) tracings (dog #7) with QT intervals (in ms) presented at each measured timepoint and before the shocked Torsade de Pointes (TdP) arrhythmia (example during Dof at CAVB4). The scale bar is 1000 ms.

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  Figure 3. Reduction in Torsade de Pointes (TdP) arrhythmias after ML277. (A) Relative TdP score and (B) number of TdP arrhythmias terminated by defibrillation during dofetilide (Dof) infusion and during Dof following ML277. (C) Overview of defibrillated and self-terminated TdP arrhythmias per dog during Dof and ML277 + Dof. (D) Arrhythmia score and (E) total of arrhythmic events during Dof and ML277 + Dof. Data of individual dogs in grey and mean ± SD in black, paired t-test with * p < 0.05. (F) Representative overview of arrhythmic events in the 10 min time window per minute after the start of Dof (left panel) and after Dof following ML277 (right panel). The score of arrhythmic events refers to single ectopic beats (sEB, 2 points), multiple ectopic beats (mEB, 3–5 points) and TdP arrhythmias (TdP, 6–75 points). A TdP terminated with one shock was scored with 50 points, and two defibrillations were scored with 75 points. A delay of 55 s of the 10 min time window is included in the results of ML277 + Dof. Results are from dog #7.