Spatial Patterns of Excitation at Tissue and Whole Organ Level Due to Early Afterdepolarizations

Vandersickel, Nele; Nieuwenhuyse, Enid Van; Seemann, Gunnar; Panfilov, Alexander V.

doi:10.3389/fphys.2017.00404

Cited by 15 publications

(9 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…EADs are cell-level phenomena that interact with several other factors in the onset of TdP in tissue. 67 The effects of spatial heterogeneity in ion channel expression and in fibre organisation on the arrhythmogenic effects of EAD susceptibility induced by drug block are likely to be significant in the translation from single-cell EADs to tissue- and organ-level effects.…”

Section: Discussionmentioning

confidence: 99%

Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator

2017

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator

2017

View full text Add to dashboard Cite

show abstract

“…As a result, the projection of the heart vector that defines the electrocardiogram trace in Figure displays an irregular sequence of rapid, widened irregular QRS complexes . These observations agree well with simulated reentry patterns in human ventricles in response to drugs, and with recent simulations of torsades de pointes in heterogeneous ventricles . A unique asset of our multiscale computational model is that these abnormal macroscopic patterns emerge naturally from abnormalities on the microscopic scale.…”

Section: Discussionmentioning

confidence: 99%

“…A unique asset of our multiscale computational model is that these abnormal macroscopic patterns emerge naturally from abnormalities on the microscopic scale. While previous computer models had to initiate reentrant spiral waves artificially through an external stimulus in the repolarizing wave tail or trigger torsades de pointes through external pacing, our model naturally predicts the spontaneous transition from a regular rhythm into ventricular tachycardia as a natural consequence of high‐risk drugs. Strikingly, our model also predicts a spontaneous termination of the episode of torsades de pointes and a natural return to the resting state.…”

Section: Discussionmentioning

confidence: 99%

Predicting drug‐induced arrhythmias by multiscale modeling

Costabal

Jiang

Kuhl

2018

Numer Methods Biomed Eng

View full text Add to dashboard Cite

Drugs often have undesired side effects. In the heart, they can induce lethal arrhythmias such as torsades de pointes. The risk evaluation of a new compound is costly and can take a long time, which often hinders the development of new drugs. Here, we establish a high-resolution, multiscale computational model to quickly assess the cardiac toxicity of new and existing drugs. The input of the model is the drug-specific current block from single cell electrophysiology; the output is the spatio-temporal activation profile and the associated electrocardiogram. We demonstrate the potential of our model for a low-risk drug, ranolazine, and a high-risk drug, quinidine: For ranolazine, our model predicts a prolonged QT interval of 19.4% compared with baseline and a regular sinus rhythm at 60.15 beats per minute. For quinidine, our model predicts a prolonged QT interval of 78.4% and a spontaneous development of torsades de pointes both in the activation profile and in the electrocardiogram. Our model reveals the mechanisms by which electrophysiological abnormalities propagate across the spatio-temporal scales, from specific channel blockage, via altered single cell action potentials and prolonged QT intervals, to the spontaneous emergence of ventricular tachycardia in the form of torsades de pointes. Our model could have important implications for researchers, regulatory agencies, and pharmaceutical companies on rationalizing safe drug development and reducing the time-to-market of new drugs.

show abstract

“…EADs are a cell-level phenomenon that interact with several other factors in the onset of TdP in tissue. [67] The effects of spatial heterogeneity in ion channel expression and in fibre organisation on the arrhythmogenic effects of EAD susceptibility induced by drug block are likely to be significant in the translation from single-cell EADs to tissue- and organ-level effects.…”

Section: Discussionmentioning

confidence: 99%

Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator

McMillan

Gavaghan

Mirams

2017

Preprint

View full text Add to dashboard Cite

Drug-induced Torsades de Pointes (TdP) arrhythmia is of major interest in predictive toxicology. Drugs which cause TdP block the hERG cardiac potassium channel. However, not all drugs that block hERG cause TdP. As such, further understanding of the mechanistic route to TdP is needed. Early afterdepolarisations (EADs) are a cell-level phenomenon in which the membrane of a cardiac cell depolarises a second time before repolarisation, and EADs are seen in hearts during TdP. Therefore, we propose a method of predicting TdP using induced EADs combined with multiple ion channel block in simulations using biophysically-based mathematical models of human ventricular cell electrophysiology. EADs were induced in cardiac action potential models using interventions based on diseases that are known to cause EADs, including: increasing the conduction of the L-type calcium channel, decreasing the conduction of the hERG channel, and shifting the inactivation curve of the fast sodium channel. The threshold of intervention that was required to cause an EAD was used to classify drugs into clinical risk categories. The metric that used L-type calcium induced EADs was the most accurate of the EAD metrics at classifying drugs into the correct risk categories, and increased in accuracy when combined with action potential duration measurements. The EAD metrics were all more accurate than hERG block alone, but not as predictive as simpler measures such as simulated action potential duration. This may be because different routes to EADs represent risk well for different patient subgroups, something that is difficult to assess at present.

show abstract

Spatial Patterns of Excitation at Tissue and Whole Organ Level Due to Early Afterdepolarizations

Cited by 15 publications

References 77 publications

Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator

Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator

Predicting drug‐induced arrhythmias by multiscale modeling

Early afterdepolarisation tendency as a simulated pro-arrhythmic risk indicator

Contact Info

Product

Resources

About