Spatiotemporal Dynamics Of Drug-induced Early Afterdepolarization In A One-dimensional Model Of The Purkinje-Ventricular System

Background:Drug-induced ventricular arrhythmia,e.g.life-threatening torsade de pointes,has been a major concern since the early stage of drug development.In vitro human ether-à-go-go related gene（h ERG）inhibition assay,or more recently multi-channel inhibition assay,has been effective to predict drug-induced cardiotoxicity.However,experimental or computational studies at sub-cellular or cellular level could be insufficient in predicting tissue-level drug-induced arrhythmogenic events and providing mechanistic insights underlying these events.In addition,it remains unclear if intrinsic tissue-level electrophysiological or structural heterogeneities in the Purkinje-Ventricular system（PVS）have a role in the onset and development of drug-induced ventricular arrhythmogenicity.Early afterdepolarization（EAD）is an important trigger of ventricular arrhythmia under pathological conditions,e.g.inherited or drug-induced long QT syndrome（LQTS）.However,it remains unclear how EAD events at the cellular level are spatially organized at the tissue-level to induce and maintain ventricular arrhythmias and whether the spatial-temporal patterns of EAD at the tissue level are associated with abnormal T-wave morphologies that are often observed in LQTS.Objective:1.To quantitatively investigate complex spatiotemporal dynamics of EAD;2.To study the relationship between the spatial-temporalcharacteristics of EAD events and abnormal T-wave morphologies;3.To predict and investigate drug-induced arrhythmogenicity using heterogeneous PVS tissue models.Methods:A one-dimensional（1D）tissue model of the canine PVS（～2 cm in length）was developed based on canine cardiac cell models（P,Endo,M and Epi）were derived from the previously published Purkinje and ventricular cell models.To induce diverse spatiotemporal patterns of EAD,I_Kr and L-type Calcium channel(I_{Ca L})were randomly inhibited at different levels.By varying the abundance,location of M-tissue and conduction delay across Purkinje-ventricular junction（PVJ）,a group of heterogeneous PVS tissue models with intrinsic electrophysiologic or structural variations were derived to quantitatively predict and investigate drug-induced arrhythmogenicity at physiological pacing frequencies（1～4Hz）,including quinidine,bepridil,sotalol,dofetilide,chlorpromazine,cisapride,terfenadine,ondansetron,diltiazem,mexiletine,ranolazine,verapamilat their effective free therapeutic plasma concentrations.Results:1.Localized EAD eventsexclusively arise from midmyocaridal tissueswith a late-appearing and pointed T-wave morphology,and localized EAD events may trigger slow uni-directional electric propagation with inverted（antegrade）or upright（retrograde）broad-based T-waves;2.Spatially-discordent EAD were typically characterized by dyssynchronized spontaneous onsets of EAD events between two groups of PVS tissues with biphasic T-wave morphologies,and they can evolve into spatially-discordent oscillating EAD patterns with sustained or self-terminated alternating EAD and electrocardiogram（ECG）patterns.3.An increase in the abundance of mid-myocardial tissue can enhance drug-induced arrhythmogenicity with the application of quinidine or bepridil,and induce abnormal excitation patterns such as electric alternans,localized EAD,retrograde conduction and reentrant excitations,at all physiological（quinidine）or low（bepridil）pacing frequencies,and in addition,a reduction in the abundance of endo-myocardial tissue can increase quinidine-induced arrhythmogenicity;4.With the application of dofetilide,cisapride or terfenadine,drug-induced EAD events preferentially occur at low pacing frequencies in PVS tissue models with a higher abundance of mid-myocardial tissue and a smaller conduction delay across the PVJ;5.Diltiazem-induced arrhythmogenic events were limited to electric alternans of excitaion at high pacing frequencies with a larger conduction delay across the PVJ;6.With the application of mexiletine,ranolazine or verapamil,only minor drug-induced QT prolongation or shorten can be observed,likely due to concurrent blockade of both inward(I_{Ca L} or I_{Na L})and outward(I_Kr)ionic currents;7.Little drug-induced arrhythmogenicicty can be observed with the application of sotalol,chlorpromazine or ondansetron.Conclusion:Heterogeneous tissue models of the PVS provide new insights into the spatiotemporal aspects of the onset and development of EAD,and suggests possible mechanistic links between complex spatial dynamics of EAD and T-wave morphologies,and may serve as useful in silico tools to quantitatively predict drug-induced arrhythmogenic risk.