Frontiers in Physiology (Dec 2022)
In silico mechanisms of arsenic trioxide-induced cardiotoxicity
Abstract
It has been found that arsenic trioxide (ATO) is effective in treating acute promyelocytic leukemia (APL). However, long QT syndrome was reported in patients receiving therapy using ATO, which even led to sudden cardiac death. The underlying mechanisms of ATO-induced cardiotoxicity have been investigated in some biological experiments, showing that ATO affects human ether-à-go-go-related gene (hERG) channels, coding rapid delayed rectifier potassium current (IKr), as well as L-type calcium (ICaL) channels. Nevertheless, the mechanism by which these channel reconstitutions induced the arrhythmia in ventricular tissue remains unsolved. In this study, a mathematical model was developed to simulate the effect of ATO on ventricular electrical excitation at cellular and tissue levels by considering ATO’s effects on IKr and ICaL. The ATO-dose-dependent pore block model was incorporated into the IKr model, and the enhanced degree of ATO to ICaL was based on experimental data. Simulation results indicated that ATO extended the action potential duration of three types of ventricular myocytes (VMs), including endocardial cells (ENDO), midmyocardial cells (MCELL), and epicardial cells (EPI), and exacerbated the heterogeneity among them. ATO could also induce alternans in all three kinds of VMs. In a cable model of the intramural ventricular strand, the effects of ATO are reflected in a prolonged QT interval of simulated pseudo-ECG and a wide vulnerable window, thus increasing the possibility of spiral wave formation in ventricular tissue. In addition to showing that ATO prolonged QT, we revealed that the heterogeneity caused by ATO is also an essential hazard factor. Based on this, a pharmacological intervention of ATO toxicity by resveratrol was undertaken. This study provides a further understanding of ATO-induced cardiotoxicity, which may help to improve the treatment for APL patients.
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