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

Abstract

9Background: In vitro hERG blockade assays alone provide insufficient information to accurately discriminate 10 "safe" from "dangerous" drugs. Recent studies have suggested that the integration of multiple ion channel 11 inhibition data can improve the prediction of drug-induced arrhythmogenic risks. In this study, using a family 12 of cardiac cell models representing electrophysiological heterogeneities across the ventricular wall, we 13 quantitatively evaluated transmural and rate-dependent properties of drug-induced arrhythmogenicity through 14 computer simulations of multichannel pharmacology. 15 Methods and Results: Rate-dependent drug effects of multiple ion channel inhibition on cardiac 16 electrophysiology at their effective free therapeutic plasma concentrations (EFTPCs) were investigated using 17 a group of in silico cell models (Purkinje (P) cells, endocardial (Endo) cells, mid-myocardial (M) cells and 18 epicardial (Epi) cells). We found that (1) M cells are much more sensitive than the other cell types to drug-19 induced arrhythmias and can develop early afterdepolarization (EAD) in response to bepridil, dofetilide, 20 sotalol, terfenadine, cisapride or ranolazine. (2) Most drug-induced adverse effects, such as pronounced action 21 potential prolongations or EADs, occur at slower pacing rates. (3) Although most drug-induced EADs occur 22 30Author summary 33 In vitro hERG blockade assays alone provide insufficient information to accurately discriminate "safe" 34 from "dangerous" drugs, and computer simulation of ventricular action potential using multichannel inhibition 35 3 data could be a useful tool to evaluate drug-induced arrhythmogenic risks. Our study suggested that the 36 profiling of drug-induced transmural heterogeneities in cellular electrophysiology at all 37 physiological pacing frequencies can be essential for the comprehensive evaluation of drug safety, and for the 38 quantitative investigation into ionic mechanisms underlying drug-specific arrhythmogenic events. These in 39 silico models and approaches may contribute to the ongoing construction of a comprehensive paradigm for 40 the evaluation of drug-induced arrhythmogenic risks, potentially increase the success rate and accelerate the 41 process of novel drug development. 42 43