Transmural and rate-dependent profiling of drug-induced arrhythmogenic risks through in silico simulations of multichannel pharmacology

Ping’An Zhao,Pan Li

doi:10.1038/s41598-019-55032-x

Abstract

In vitro human ether-à-go-go related gene (hERG) inhibition assay alone might provide insufficient information to discriminate “safe” from “dangerous” drugs. Here, effects of multichannel inhibition on cardiac electrophysiology were investigated using a family of cardiac cell models (Purkinje (P), endocardial (Endo), mid-myocardial (M) and epicardial (Epi)). We found that: (1) QT prolongation alone might not necessarily lead to early afterdepolarization (EAD) events, and it might be insufficient to predict arrhythmogenic liability; (2) the occurrence and onset of EAD events could be a candidate biomarker of drug-induced arrhythmogenicity; (3) M cells are more vulnerable to drug-induced arrhythmias, and can develop early afterdepolarization (EAD) at slower pacing rates; (4) the application of quinidine can cause EADs in all cell types, while INaL is the major depolarizing current during the generation of drug-induced EAD in P cells, ICaL is mostly responsible in other cell types; (5) drug-induced action potential (AP) alternans with beat-to-beat variations occur at high pacing rates in P cells. These results suggested that quantitative profiling of transmural and rate-dependent properties can be essential to evaluate drug-induced arrhythmogenic risks, and may provide mechanistic insights into drug-induced arrhythmias.

Highlights

In vitro human ether-à-go-go related gene inhibition assay alone might provide insufficient information to discriminate “safe” from “dangerous” drugs
We quantitatively evaluated the transmural characteristics and rate dependence of drug-induced arrhythmogenicity through simulations of multichannel pharmacology using a family of cardiac cell models
Our simulation results suggest QT prolongation alone might be insufficient in predicting Torsade de Pointes (TdP) risk, since major AP duration (APD) prolongation can be observed with the application of diltiazem or www.nature.com/scientificreports verapamil with no early afterdepolarization (EAD) events

Summary

Introduction

In vitro human ether-à-go-go related gene (hERG) inhibition assay alone might provide insufficient information to discriminate “safe” from “dangerous” drugs. The Comprehensive in vitro Proarrhythmia Assay (CiPA) has been proposed to address the misidentification issue of drug-associated TdP risk based on hERG inhibition and QT prolongation data This new paradigm is based on integrated assessment of a wider range of ion channel dynamics (including Nav1.5 (peak and late), Cav1.2, hERG, Kv4.3, KCNQ1/KCNE1, Kir2.1) in delayed ventricular repolarization; alterations to this process lead to repolarization instability and arrhythmias[11]. We employed a family of in silico cardiac cell models (Purkinje(P), endocardial(Endo), mid-myocardial(M) and epicardial(Epi)) and performed quantitative profiling of drug-induced arrhythmogenic risk at physiological pacing frequencies, to identify potential novel characteristics associated with drug-induced TdP risk, and to provide possible mechanistic insights into drug-specific cardiotoxicity that may facilitating the process of drug development

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Results

Conclusion