Transmural and Rate-dependent Properties of Drug-induced Arrhythmogenic Risks Obtained through in Silico Simulations of Multichannel Pharmacology

平安 赵, Pan Li, Mengya Yuan
Xinxiang Medical University


Background: In vitro hERG block assays alone provide insufficient in-formation to accurately discriminate “safe” from “dangerous” drugs. Re-cent studies have suggested that the integration of multiple ion channel inhibition data can improve the prediction of drug-induced arrhythmo-genic risks. In this study, using a family of cardiac cell models represent-ing electrophysiological heterogeneities across the ventricular wall, we quantitatively evaluated transmural and rate-dependent properties of drug-induced arrhythmogenicity through computer simulations of multi-channel pharmacology. Methods and Results: Rate-dependent drug effects of multiple ion chan-nel inhibition on cardiac electrophysiology were investigated using a group of in silico cell models (Purkinje (P) cells, endocardium (Endo) cells, mid-myocardium (M) cells and epicardium (Epi) cells) at their ef-fective free therapeutic plasma concentrations (EFTPCs). We found that (1) compared to other cell types, M cells are much more sensitive to drug-induced arrhythmias and can develop early afterdepolarization (EAD) with the application of bepridil, dofetilide, sotalol, terfenadine, cisapride or ranolazine. (2) Most drug-induced adverse effects, such as pronounced action potential prolongations or EADs, occur at slower pac-ing rates. (3) Although most drug-induced EADs occur in M cells, the application of quinidine at its EFTPC can cause EADs in all four cell types. (4) The ionic underlying mechanism of drug-induced EADs differs in different cell types; while INaL is the major depolarizing current during the generation of EAD in P cells, ICaL is mostly responsible in other cell types. Conclusions: In silico analysis of transmural and rate-dependent proper-ties using multichannel inhibition data can be useful to accurately predict drug-induced arrhythmogenic risks and can also provide mechanistic insights into drug-induced adverse events related to cardiac arrhythmias.