Simulation Research On The Side Effect Of Drug On Ventricular Calculation Model

Arrhythmias caused by the interaction between drug molecules and cardiac ion channels, is one of the severest drug adverse side effects. As one of the most life-threatening angicardiopathy, arrhythmias can cause heart failure with continuous onsets and even cause sudden cardiac death when it attacks abruptly. During drug development process, it is essential to assess the pro-arrhythmic effects of drugs as soon as possible. Due to the limit of experiment condition, it is hard to learn the mechanisms of drug-induced pro-arrhythmias from the cell level to the whole organ level. Modeling and simulation research of the virtu al heart provides a powerful tool. During the early stage of drug development process, the virtual heart model can be used to simulate the effects of drugs, analyze the multi-scale side effects of drugs and predict their pro-arrhythmia effects.This paper aimed at simulating and assessing the pro-arrhythmia effects of drugs based on virtual ventricular model, a cellular and a 1-D tissue ventricular electrophysiological models were built, a simulation and assessment model of drug pro-arrhythmia effects was built based on the electrophysiological model, bio-markers such as action potential, pseudo-electrocardiogram, conduction velocity and vulnerable window were simulated and analyzed to assess the pro-arrhythmic effects of drugs. This paper included three simulating cases based on the simulation and assessment model.Firstly, the pro-arrhythmic gastrointestinal prokinetic agent cisapride was taken as an example to study its impact on ventricle with different concentrations at different heart rates. Simulated results showed that cisapride influenced the recovery process of myocytes, higher concentrations was consistent with higher risks of inducing arrhythmias, and the side effects of high concentration cisapride exaggerated at fast heart rates.Secondly, the pro-arrhythmic drug cisapride and the anti-arrhythmic drug amiodarone which could both prolong QT interval were simulated and compared to learn the mechanism of arrhythmias induced by drugs explorativ ely. Simulated results showed that compared to amiodarone, cisapride increased the incidence of generating action potential alternans and unidirectional conductions, which leaded to higher risks of pro-arrhythmias. Thus during the simulating and assessing process of drugs, it was strongly recommended to take drug effects on multi ion channels into consideration, and avoid the deficiency of only considering one ion channel.Thirdly, the alternative drug to cisapride, domperidone was simulated to predict its chance of inducing arrhythmias. Simulated results showed that the effects of domperidone were similar to cisapride. It influenced the recovery process of myocytes and higher concentration domperidone would lead to higher risks of arrhythmias, which indicated that domperidone should not be considered as a no-risk alternative to cisapride.At last, the ventricular computation model and the bio-markers used precedingly were integrated into a software system which aimed at simulating drug pro-arrhythmia effects to assist further studies.The means adapted in this paper can help us learn the mechanism of drug pro-arrhythmia effects and provide recommendations for new medicinal product development. It is of great theoretical and economic values and it is a large leap of interdisciplines.