Torsade de pointes arrhythmias arise at the site of maximal heterogeneity of repolarization in the chronic complete atrioventricular block dog

Abstract

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.

Selective late sodium current inhibitor GS‐458967 suppresses Torsades de Pointes by mostly affecting perpetuation but not initiation of the arrhythmia

“…TdP arrhythmias arise from a multifactorial process involving action potential prolongation and the associated occurrence of afterdepolarizations initiating events and an increase in intraventricular spatial dispersion of repolarization for arrhythmia perpetuation. In the current study, the use of in vitro assays using canine ventricular cardiomyocytes allowed us to study in detail the initiating mechanism of the arrhythmia, while the in vivo assay provided the next level of complexity by adding the component of spatial dispersion (Dunnink et al ., ). In general, we observed a statistically significant but modest effect of GS967 on the initiating events of TdP arrhythmia, as seen by a 60–65% reduction on EADs in vitro and the remaining presence of sEB in vivo in 65% of CAVB dogs.…”

“…min ‐1 , n = 4; 70 beats . min ‐1 , n = 1) and using the same experimental setting, the antiarrhythmic mechanism of GS967 was further characterized in a detailed electrical mapping experiment, which consisted of the insertion of a total of 56 needle electrodes at six different levels of the heart (from base to apex, Figure ) as previously described by our group (Dunnink et al ., ). The needles had four electrode terminals (4 mm interelectrode interval) to record intramural unipolar electrograms (ActiveTwo system; Biosemi, Amsterdam, The Netherlands).…”

“…Overview of needle location and calculation of spatial dispersion of repolarization in the detailed mapping experiments (adapted from Dunnink et al ., with permission). A total of 56 needles were inserted over six different levels of the heart, from base to apex (I to VI): in the LV, 30 needles were divided into five columns (posterior, postero‐lateral, lateral, antero‐lateral and anterior); in the RV, 18 needles were divided into three columns (posterior, lateral and anterior) and 8 needles in the septal wall (left and right sides, levels II to V, in three dogs).…”

Short-term Variability of Repolarization Is Superior to Other Repolarization Parameters in the Evaluation of Diverse Antiarrhythmic Interventions in the Chronic Atrioventricular Block Dog

“…Importantly, the increased local (intraventricular and transmural) heterogeneity of repolarization was found in dogs susceptible to TdP and also correlated with arrhythmic event severity, demonstrating that a minimum local gradient of repolarization was necessary for the initiation of a TdP. 21 In addition to the present observations, these findings suggest that ΔMAPD may not be specific for antiarrhythmic evaluation because this parameter does not capture the local change in repolarization heterogeneity.…”

“…39 Recently, a detailed mapping study investigating the mechanism of TdP in the CAVB dog model confirmed that interventricular difference in repolarization was not a determinant factor for TdP inducibility. 21 Moreover, it revealed that the focus of ectopic activity constantly arose from the site of maximal heterogeneity of repolarization. Importantly, the increased local (intraventricular and transmural) heterogeneity of repolarization was found in dogs susceptible to TdP and also correlated with arrhythmic event severity, demonstrating that a minimum local gradient of repolarization was necessary for the initiation of a TdP.…”