In Silico Prediction Of Drug-induced Arrhythmogenic Risks And Underlying Mechanisms Through Computer Simulations Of Multichannel Pharmacology

Background:Drug-induced cardiotoxicity has been a major concern since the early stage of novel drug development.Unexpected post-marketing occurrence of cardiotoxic effects remains a leading cause of drug withdrawal and relabelling.As defined by the International Conference of Harmonization Expert Working Group for all drugs in development,QT interval prolongation has been used as a biomarker to predict the potential risk of Torsade de Pointes?TdP?.Most drugs that prolong the QT interval inhibit cardiac potassium channels encoded by human ether-à-go-go related gene?hERG?;therefore,the level of hERG channel inhibition has been the"gold standard"to predict the TdP risk.However,recent studies suggested that the in vitro hERG blockade assay alone provides insufficient information to accurately discriminate“safe”from“dangerous”drugs.For instance,QT prolongation can be induced by drugs that inhibit other ionic channels such as IKs,and it has been known for years that the arrhythmia associated with hERG blockade is mitigated by concurrent blockade of Na⁺or Ca²⁺channels.Other electrocardiogram?ECG?abnormalities,such as QT shortening or T wave alternation,are also frequently associated with TdP.Recently,the Comprehensive in vitro Proarrhythmia Assay?CiPA?has been proposed to improve the accuracy and effectiveness of preclinical drug screening.An important component of the CiPA project is a comprehensive assessment of six ion channels that affect ventricular depolarization and repolarization.In this study,using computer models combined with six ion channel blocking data was used to quantify the effects of different drugs on the action potentials,and to predict the potential cardiac toxicity of the drugs in different cell types and under different frequencies.Objective:1.Quantitative assessment of cardiotoxicity of 12 drugs2.Analyze the ionic mechanism of the drug's cardiotoxicity.3.Provide new ideas for accurate assessment of drug cardiotoxicity.Results:?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 I_naL is the major depolarizing current during the generation of drug-induced EAD in P cells,I_caL 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.Conclusion:1.The results of the simulation based on the mathematical model of heart cells can predict the cardiotoxicity of drugs more accurately.Chlorpromazine,Cisapride,terfenadine and Ondansetron were medium risk drugs.Diltiazem,Mexiletine,Ranolazine and verapamil were low risk drugs.These were predictions consistent with the drug's known cardiotoxicity.2.The ionic mechanism of arrhythmia-induced toxicity of different drugs has great differences in heart rate and cell dependence.In the evaluation of cardiac toxicity of drugs,quantitative prediction of the changes of multi-ion channel pharmacology under different cell types and heart rate conditions is one of the important evaluation factors.