High-rate pacing guided by short-term variability of repolarization prevents imminent ventricular arrhythmias automatically by an implantable cardioverter-defibrillator in the chronic atrioventricular block dog model

Abstract

BACKGROUND The anesthetized, complete chronic atrioventricular block (CAVB) dog model allows reproducible inducibility of torsades de pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an I Kr blocker. High-rate pacing (HRP) prevents ventricular arrhythmias but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases before ventricular arrhythmias and has been proposed as a marker to guide HRP.OBJECTIVE The purpose of this proof-of-principle study was to show that automatically determined STV can guide HRP to prevent imminent ventricular arrhythmias.METHODS Eight CAVB dogs were implanted with an implantable cardioverter-defibrillator (ICD) with software to automatically determine STV (STV ICD ) in real time. During HRP, STV was measured offline from right ventricular (RV) electrograms (EGMs) and left ventricular (LV) monophasic action potential durations (MAPDs) (STV RV,EGM/LV,MAPD ). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg intravenously over 5 minutes or until the first TdP). In experiment 1, the individual STV ICD threshold before the first arrhythmic event was determined and programmed into the ICD. In experiment 2, HRP with 100 bpm was initiated automatically once the STV ICD threshold was reached. RESULTSIn experiment 1, 8 of 8 dogs had repetitive TdP, and STV ICD increased from 0.96 6 0.42 ms to 2.10 6 1.26 ms (P ,.05). In experiment 2, all dogs reached the STV threshold. HRP decreased STV RV,EGM/LV,MAPD from 2.02 6 1.12 ms to 0.78 6 0.28 ms, which was accompanied by prevention of TdP in 7 of 8 dogs.CONCLUSION STV can guide HRP automatically by an ICD to prevent ventricular arrhythmias.

The canine chronic atrioventricular block model in cardiovascular preclinical drug research

“…The latest developments that make use of the CAVB model are found in implantable device development and testing (e.g. Smoczyńska et al, 2020 ).…”

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

“…HRP exerts its anti-arrhythmic effects by increasing the delayed rectifier potassium current and, subsequently, bolstering the repolarization reserve ( Damiano and Rosen, 1984 ; Szentandrassy et al, 2015 ). 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 ).…”

“…Whereas triggered activity initiates arrhythmic episodes, advancement to more critical arrhythmias hinges on the presence of adequate SDR ( Dunnink et al, 2017 ; Smoczynska et al, 2021 ). Finally, high-rate pacing (HRP) is a well-established method to suppress and prevent arrhythmias in both the CAVB dog model ( Wijers et al, 2017 ; Smoczynska et al, 2020a ) and patients ( Eldar et al, 1987 ; Fisher et al, 1987 ; Gronefeld et al, 2002 ). HRP exerts its anti-arrhythmic effects by increasing the delayed rectifier potassium current and, subsequently, bolstering the repolarization reserve ( Damiano and Rosen, 1984 ; Szentandrassy et al, 2015 ).…”

Remodeling in the AV block dog is essential for tolerating moderate treadmill activity

“…The dog is described as the most predictive species in the cardiac electrophysiological research field [10] . The AV block dog model [11] was standardized over the last four decades as experimental model in pro- and antiarrhythmic drug screening [10] and testing of new device properties [12] . After induction of AV block, the acute bradycardia is accompanied with a decrease in cardiac output and therefore different adaptations are initiated in the subsequent weeks.…”