Perpetuation of torsade de pointes in heterogeneous hearts: competing foci or re‐entry?

Abstract

Torsade de pointes (TdP) can be the consequence of cardiac remodelling, drug effects or a combination of both. The mechanism underlying TdP is unclear, and may involve triggered focal activity or re-entry. Recent work by our group has indicated that both cases may exist, i.e. TdPs induced in the chronic atrioventricular block (CAVB) dog model may have a focal origin or are due to re-entry. Also it was found that heterogeneities might play an important role. In the current study we have used computational modelling to further investigate the mechanisms involved in TdP initiation and perpetuation, especially in the CAVB dog model, by the addition of heterogeneities with reduced repolarization reserve in comparison with the surrounding tissue. For this, the TNNP computer model was used for computations. We demonstrated in 2D and 3D simulations that ECGs with the typical TdP morphology can be caused by both multiple competing foci and re-entry circuits as a result of introduction of heterogeneities, depending on whether the heterogeneities have a large or a smaller reduced repolarization reserve in comparison with the surrounding tissue. Large heterogeneities can produce ectopic TdP, while smaller heterogeneities will produce re-entry-type TdP.

Blinded In Silico Drug Trial Reveals the Minimum Set of Ion Channels for Torsades de Pointes Risk Assessment

“…In addition, cellular coupling has important roles in modulating EAD generations at tissue level (Pueyo et al, 2011). Although electrotonic coupling can smooth the chaotic EAD behavior (Weiss et al, 2010), regional EADs can propagate into the heterogeneous substrates, resulting in reentry and TdP patterns (Dutta et al, 2016;Vandersickel et al, 2016).…”

“…One effective approach to include the tissue effects in TdP risk predictions is whole ventricle simulations (Sato et al, 2009;Moreno et al, 2011;Trayanova, 2011;Dutta et al, 2016;Vandersickel et al, 2016;Martinez-Navarro et al, 2019), however they are computationally much more expensive than the current cell model population which has already shown strong performance. In this study we did not aim to equate EADs and TdP, but rather to use EADs as a pro-arrhythmic risk marker that is mechanistically linked to TdP.…”

Computational modeling for cardiac safety pharmacology analysis: Contribution of fibroblasts

“…Little is known about the effects of the other drugs simulated here, nebivolol and vardenafil, on fibroblast ion channels. As described previously, proarrhythmic phenomena causing Torsades de pointes (TdP) may be due to action potential heterogeneity in different parts of myocardium, which requires simulations using 2D and 3D special resolutions with different scales (Vandersickel et al 2016). To validate such computational simulations will require experimental samples by which a composition of fibroblasts and cardiomyocytes can be varied.…”

Acquired long QT syndrome and torsade de pointes

“…On the other hand, there is considerable debate regarding the mechanism of perpetuation of TdP beyond the initiating beat. A recent report provides good review of this subject . In a study using 2D and 3D simulation, it was shown that ECG with the typical TdP morphology can be caused by both multiple competing foci and reentrant activity depending on the degree of repolarization heterogeneity .…”

“…16 In a study using 2D and 3D simulation, it was shown that ECG with the typical TdP morphology can be caused by both multiple competing foci and reentrant activity depending on the degree of repolarization heterogeneity. 16 Large homogeneity can produce ectopic TdP, while small heterogeneity will produce reentry-type TdP. However, the significance of the degree of homogeneity was not shown in other studies.…”