Severe Bradycardia Increases the Incidence and Severity of Torsade de Pointes Arrhythmias by Augmenting Preexistent Spatial Dispersion of Repolarization in the CAVB Dog Model

Abstract

IntroductionTorsade de pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog model result from proarrhythmic factors, which trigger TdP and/or reinforce the arrhythmic substrate. This study investigated electrophysiological and arrhythmogenic consequences of severe bradycardia for TdP.MethodsDofetilide (25 μg/kg per 5 min) was administered to eight anesthetized, idioventricular rhythm (IVR) remodeled CAVB dogs in two serial experiments: once under 60 beats per minute (bpm), right ventricular apex paced (RVA60) conditions, once under more bradycardic IVR conditions. Recordings included surface electrocardiogram and short-term variability (STV) of repolarization from endocardial unipolar electrograms. TdP inducibility (three or more episodes within 10 min after start of dofetilide) and arrhythmic activity scores (AS) were established. Mapping experiments in 10 additional dogs determined the effect of lowering rate on STV and spatial dispersion of repolarization (SDR) in baseline.ResultsIVR-tested animals had longer baseline RR-interval (1,403 ± 271 ms) and repolarization intervals than RVA60 animals. Dofetilide increased STV similarly under both rhythm strategies. Nevertheless, TdP inducibility and AS were higher under IVR conditions (6/8 and 37 ± 27 vs. 1/8 and 8 ± 12 in RVA60, respectively, both p < 0.05). Mapping: Pacing from high (128 ± 10 bpm) to middle (88 ± 10 bpm) to experimental rate (61 ± 3 bpm) increased all electrophysiological parameters, including interventricular dispersion, due to steeper left ventricular restitution curves, and intraventricular SDR: maximal cubic dispersion from 60 ± 14 (high) to 69 ± 17 (middle) to 84 ± 22 ms (p < 0.05 vs. high and middle rate).ConclusionIn CAVB dogs, severe bradycardia increases the probability and severity of arrhythmic events by heterogeneously causing electrophysiological instability, which is mainly reflected in an increased spatial, and to a lesser extent temporal, dispersion of repolarization.

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

“…These animals were paced at a rate of 100–110 bpm from the start of the arrhythmia induction protocol and upon the occurrence of the first ectopic beat respectively ( Oosterhoff et al, 2010 ; Wijers et al, 2017 ). Correspondingly, severe bradycardia was shown to increase the probability of arrhythmia occurrence and episode severity in CAVB dogs, accompanied by an elevated SDR ( van Weperen et al, 2021 ). Prior studies reported an increased inter ventricular dispersion of repolarization under bradycardic conditions and demonstrated its significance in the development of TdP as well ( Restivo et al, 2004 ; Kim et al, 2013 ).…”

“…This highlights how a faster pace, specifically 100 beats per minute, emerges as the most efficacious approach for preventing ventricular arrhythmias in the CAVB dog model. However, since chronic right-ventricular pacing has been demonstrated to jeopardize LV function, resulting from ventricular remodeling induced by asynchronous activation, HRP should be utilized only in cases where a distinct arrhythmic threat is evident (Tops et al, 2009;van Weperen et al, 2023).…”

“…Correspondingly, HRP reduces STV in CAVB dogs challenged with the specific I Kr blocker dofetilide ( Wijers et al, 2017 ; Smoczynska et al, 2020a ). Moreover, pacing at lower rates was shown to increase spatial heterogeneity of repolarization ( van Weperen et al, 2021 ). However, these SDR measurements were conducted in absence of a pharmacological challenge.…”

Chronically altered ventricular activation causes pro-arrhythmic cardiac electrical remodelling in the chronic AV block dog model

“…In IVR animals, dofetilide was administered under more bradycardic conditions. Bradycardia promotes arrhythmogenesis in the CAVB dog model 10 and might have contributed to the increased TdP susceptibility.…”

“… 8 Adversely, electrical remodelling, which includes downregulation of potassium channels, results in susceptibility for Torsade de Pointes arrhythmia (TdP). Especially in combination with additional (acute) impediments of cardiac repolarization such as anaesthetics, 9 bradycardia 10 and/or administration of specific I Kr -blocker dofetilide, 11 TdP inducibility is reached in ± 75% of animals. 8 …”