AIMS: The chronic complete atrioventricular block (CAVB) dog is highly sensitive for drug-induced torsade de pointes (TdP) arrhythmias. Focal mechanisms have been suggested as trigger for TdP onset; however, its exact mechanism remains unclear. In this study, detailed mapping of the ventricles was performed to assess intraventricular heterogeneity of repolarization in relation to the initiation of TdP. METHODS AND RESULTS: In 8 CAVB animals, 56 needles, each containing 4 electrodes, were inserted in the ventricles. During right ventricular apex pacing (cycle length: 1000-1500 ms), local unipolar electrograms were recorded before and after administration of dofetilide to determine activation and repolarization times (RTs). Maximal RT differences were calculated in the left ventricle (LV) within adjacent electrodes in different orientations (transmural, vertical, and horizontal) and within a square of four needles (cubic dispersion). Dofetilide induced TdP in five out of eight animals. Right ventricle-LV was similar between inducible and non-inducible dogs at baseline (327 ± 30 vs. 345 ± 17 ms) and after dofetilide administration (525 ± 95 vs. 508 ± 15 ms). All measurements of intraventricular dispersion were not different at baseline, but this changed for horizontal (206 ± 20 vs. 142 ± 34 ms) and cubic dispersion (272 ± 29 vs. 176 ± 48 ms) after dofetilide: significantly higher values in inducible animals. Single ectopic beats and the first TdP beat arose consistently from a subendocardially located electrode terminal with the shortest RT in the region with largest RT differences. CONCLUSION: Chronic complete atrioventricular block dogs susceptible for TdP demonstrate higher RT differences. Torsade de pointes arises from a region with maximal heterogeneity of repolarization suggesting that a minimal gradient is required in order to initiate TdP. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: The chronic complete atrioventricular block (CAVB) dog is highly sensitive for drug-induced torsade de pointes (TdP) arrhythmias. Focal mechanisms have been suggested as trigger for TdP onset; however, its exact mechanism remains unclear. In this study, detailed mapping of the ventricles was performed to assess intraventricular heterogeneity of repolarization in relation to the initiation of TdP. METHODS AND RESULTS: In 8 CAVB animals, 56 needles, each containing 4 electrodes, were inserted in the ventricles. During right ventricular apex pacing (cycle length: 1000-1500 ms), local unipolar electrograms were recorded before and after administration of dofetilide to determine activation and repolarization times (RTs). Maximal RT differences were calculated in the left ventricle (LV) within adjacent electrodes in different orientations (transmural, vertical, and horizontal) and within a square of four needles (cubic dispersion). Dofetilide induced TdP in five out of eight animals. Right ventricle-LV was similar between inducible and non-inducible dogs at baseline (327 ± 30 vs. 345 ± 17 ms) and after dofetilide administration (525 ± 95 vs. 508 ± 15 ms). All measurements of intraventricular dispersion were not different at baseline, but this changed for horizontal (206 ± 20 vs. 142 ± 34 ms) and cubic dispersion (272 ± 29 vs. 176 ± 48 ms) after dofetilide: significantly higher values in inducible animals. Single ectopic beats and the first TdP beat arose consistently from a subendocardially located electrode terminal with the shortest RT in the region with largest RT differences. CONCLUSION: Chronic complete atrioventricular block dogs susceptible for TdP demonstrate higher RT differences. Torsade de pointes arises from a region with maximal heterogeneity of repolarization suggesting that a minimal gradient is required in order to initiate TdP. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Valerie Y H van Weperen; Albert Dunnink; Alexandre Bossu; Jet D M Beekman; Veronique M F Meijborg; Jacques M T de Bakker; Ruben Coronel; Rosanne Varkevisser; Marcel A G van der Heyden; Marc A Vos Journal: Front Physiol Date: 2021-04-26 Impact factor: 4.566
Authors: Alexandre Bossu; Rosanne Varkevisser; Henriette D M Beekman; Marien J C Houtman; Marcel A G van der Heyden; Marc A Vos Journal: J Cardiovasc Pharmacol Date: 2017-06 Impact factor: 3.105
Authors: Muge Qile; Henriette D M Beekman; David J Sprenkeler; Marien J C Houtman; Willem B van Ham; Anna Stary-Weinzinger; Stanislav Beyl; Steffen Hering; Dirk-Jan van den Berg; Elizabeth C M de Lange; Laura H Heitman; Ad P IJzerman; Marc A Vos; Marcel A G van der Heyden Journal: Br J Pharmacol Date: 2019-08-30 Impact factor: 8.739
Authors: Alexandre Bossu; Marien J C Houtman; Veronique M F Meijborg; Rosanne Varkevisser; Henriette D M Beekman; Albert Dunnink; Jacques M T de Bakker; Nevena Mollova; Sridharan Rajamani; Luiz Belardinelli; Marcel A G van der Heyden; Marc A Vos Journal: Br J Pharmacol Date: 2018-05-06 Impact factor: 8.739
Authors: Yvonne Sleiman; Monia Souidi; Ritu Kumar; Ellen Yang; Fabrice Jaffré; Ting Zhou; Albin Bernardin; Steve Reiken; Olivier Cazorla; Andrey V Kajava; Adrien Moreau; Jean-Luc Pasquié; Andrew R Marks; Bruce B Lerman; Shuibing Chen; Jim W Cheung; Todd Evans; Alain Lacampagne; Albano C Meli Journal: EBioMedicine Date: 2020-09-24 Impact factor: 8.143