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

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.