Point of View: Electrophysiological Endpoints Differ When Comparing the Mode of Action of Highly Successful Anti-arrhythmic Drugs in the CAVB Dog Model With TdP

Abstract

In the anaesthetized, chronic atrioventricular block (CAVB) dog, ventricular ectopic beats and Torsade de pointes arrhythmias (TdP) are believed to ensue from an abrupt prolongation of ventricular repolarization and increased temporal dispersion of repolarization, quantified as short-term variability (STV). These TdP stop spontaneously or, when supported by substantial spatial dispersion of repolarization (SDR), degenerate into ventricular fibrillation. However, most studies involving ventricular arrhythmias do not quantify SDR by means of an electrophysiological parameter. Therefore, we reviewed the effects of 4 highly effective anti-arrhythmic drugs (flunarizine, verapamil, SEA-0400, and GS-458967) on the repolarization duration and associated STV. All drugs were tested as anti-arrhythmic strategies against TdP in CAVB dogs, their high anti-arrhythmic efficacy was defined as suppressing drug-induced TdP in 100% of the experiments. This comparison demonstrates that even though the anti-arrhythmic outcome was similar for all drugs, distinct responses of repolarization duration and associated STV were observed. Moreover, the aforementioned and commonly adopted electrophysiological parameters were not always sufficient in predicting TdP susceptibility, and additional quantification of the SDR proved to be of added value in these studies. The variability in electrophysiological responses to the different anti-arrhythmic drugs and their inconsistent adequacy in reflecting TdP susceptibility, can be explained by distinct modes of interference with TdP development. As such, this overview establishes the separate involvement of temporal and spatial dispersion in ventricular arrhythmogenesis in the CAVB dog model and proposes SDR as an additional parameter to be included in future fundamental and/or pharmaceutical studies regarding TdP arrhythmogenesis.

The canine chronic atrioventricular block model in cardiovascular preclinical drug research

“…This is highly relevant in the formation of severe arrhythmias. Short lasting Torsade de Pointes are maintained by focal activity, whereas non-selfterminating Torsade de Pointes are maintained by re-entry mechanisms(Vandersickel et al, 2017) Van Weperen et al (2019). underlined the importance of SDR in arrhythmogenesis as they demonstrated that the anti-arrhythmic efficacy of four highly effective anti-arrhythmic drugs was best reflected by SDR.…”

“…They concluded that SDR and STV are separately involved in arrhythmogenesis. The exact interplay however between spatial and temporal dispersion of repolarization in the formation of arrhythmias remains to be elucidated(Van Weperen et al, 2019).…”

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

“…Despite the reduced repolarization prolongation and arrhythmic outcome, the sustained occurrence of TdP arrhythmias after ML277 upon dofetilide infusion fails to consider this I Ks activator as an antiarrhythmic drug in our preclinical model [ 33 ]. Yet, this study is the first to determine I Ks activating effects of the compound in an animal model with bradycardia-induced sensitivity to ventricular arrhythmias.…”

High-rate pacing suppresses Torsade de Pointes arrhythmias and reduces spatial dispersion of repolarization in the chronic AV-block dog model

“…In contrast, SDR elevated significantly in the development from EB to TdP ( Smoczynska et al, 2021 ). This suggests that temporal dispersion of repolarization contributes to the initiation of arrhythmic events, while SDR gains prominence in perpetuating these events ( van Weperen et al, 2019 ; Smoczynska et al, 2021 ). Further supporting this notion, it has been discovered that brief TdP episodes originate from and are sustained by localized activity, whereas persistent TdP rely on re-entry mechanisms ( Vandersickel et al, 2017 ; Rivaud et al, 2021 ).…”