Abstract
Arsenic trioxide (As2mathrmO_3), an antileukemia drug, has been used to treat acute promyelocytic leukemia (APL) for more than fifty years, and its therapeutic effect has been elucidated at the molecular level. However, several side effects were observed in APL patients administrated with As2mathrmO_3, such as long QT (LQT) syndrome, torsade de pointes tachycardia, and even sudden cardiac death. This means that the clinically relevant dosage may induce severe cardiotoxicity. Accordingly, it is essential to determine the underlying mechanisms of arrhythmia induced by mathrmAs2mathrmO_3. Some biological experiments indicated that mathrmAs2mathrmO_3 can impair the human ether-à-go-gorelated gene (hERG), thus inhibiting rapid delayed rectifier potassium current (I_Kr) and prolonging action potential duration (APD), which was regarded as the reason for LQT syndrome. However, previous experiments did not illuminate the deep mechanisms of mathrmAs2mathrmO_3-induced side effects, which is important in clinical treatment. In addition, the experimental data were restricted to animal studies, so human cellular data were lacking. In this study, we investigated mathrmAs2mathrmO_3-related cardiotoxicity through a human ventricular model study. Based on the current experimental data, the effects of mathrmAs2mathrmO_3 on ventricular myocytes (VMs) were predicted at various mathrmAs2mathrmO_3 concentrations. In addition, the potential hazard of mathrmAs2mathrmO_3 was simulated and illustrated under different stimulation protocols. Moreover, electrocardiograms (ECGs) were estimated in heterogeneous ventricular cables, by which the clinical phenomenon was verified and explained. Based on the present modeling study, deep reasons for arrhythmia caused by mathrmAs2mathrmO_3 were uncovered. mathrmAs2mathrmO_3 not only led to a prolonged APD but also alternated action potentials and exacerbated heterogeneity among VMs. Moreover, the degree of arrhythmia risk was susceptible to mathrmAs2mathrmO_3 dosage. These new findings may provide targets for attenuating mathrmAs2mathrmO_3 toxicity and may help to improve the APL therapeutic regimen.
