Modelling And Analysis Of The Short QT Syndrome Based On Virtual Heart

The heart is one of the most important organs of human,and cardiac arrhythmias(i.e.disordered heart rhythm)are the most popular diseases causing morbidity and mortality.However,current treatment on cardiac arrhythmias is far from satisfactory due to the limited understanding of mechanisms of cardiac arrhythmias.In this Ph.D.thesis,we aim to utilize the computer technology to simulate and analyze the underlying mechanisms for initiation of malignant arrhythmias associated with patients with inherited short QT syndrome(SQTS).We develop multi-scale computational models of the human heart from microcosmic myocardial cell to macroscopic cardiac tissue,and develop a drug-screening model.The main contributions of this Ph.D.thesis are summarized as follows:Firstly,we investigate the underlying mechanisms of ventricular arrhythmia associated with patients with SQTS induced by gene mutations.Biophysically detailed mathematical models of mutant potassium channels associated with SQTS conditions were developed,and then they were integrated into fibre strand,tissue and organ models of ventricles.Based on the physiological characteristics at each level,a new quantitative analysis method for the pathogenesis of SQTS is proposed.The results reveal a deep reason of arrhythmia in SQTS,by comparing the simulation data and clinical physiological data.Each gene mutation is a gain-of-function mutation,which generates excessive potassium current during cellular repolarization.The excessive current leads to a shortening of the action potential duration and effective refractory period,which further shortens the QT interval on the ECG and alters the morphology of the T-wave.An increased vulnerable window for unidirectional conduction block generates a substrate favorable for re-entry and even sudden cardiac death.Secondly,we investigate the underlying mechanisms for initiation and maintenance of ventricular fibrillation.Based on the human ventricular cell model and human Purkinje fibre cell model,a human Purkinje fibre-ventricular compound electrical condution system model is developed.Using this model,we investigate the new pathogenesis of ventricular fibrillation associated with patients with inherited SQTS,and it is proved that multi-wavelet at a high speed is the cause of initiation and maintenance of ventricular fibrillation.The simulation results show that the action potential duration and effective refractory period are shortened when the heart rate speeds up to a certain extent,which leads to the electrical excitation wave conduction at a high speed.All these characteristics provide a theoretical explanation for the clinical phenomena of continuous re-entrant arrhythmia associated with SQTS paitents.Thirdly,we investigate the role of intrinsic heterogeneities due to island distribution of mid-cardiomyocytes(M island)in the initiation and maintenance of re-entrant arrhythmia.Based on the optimal mapping data of the cardiac tissue,an M island model for human ventricles is developed.The functional effects of the intrinsic spatial heterogeneities in cardiac tissue on the electrical instability under SQTS were investigated.The electrical excitation wave conduction is simulated and the corresponding ECG is computed,which verify the ventricular wall consisting of endocardial cells,middle layer cells and epicardial cells,and also verify that the mid-cardiomyocytes are distributed as an island form.The simulation data show that in SQTS conditions re-entry was more initiated and sustained in the M island model than in the continuous band model.It illustrates that the important role of the intrinsic spatial electrical heterogeneities of cardiac tissue in the increased incidence of ventricular arrhythmias associated with SQTS.At last,clinical specific drug is screened by using virtual phys iological heart modelling and simulation technology.Based on the channel-blocking effect of the drugs on ion currents in healthy and SQTS cells,a drug-in-action model is developed,and drug action emsamble process is defined.The simulation results show that,(1)the known clinical drugs amiodarone and quinidine can effectively treat the SQT1 variant,which further demonstrates the validity of the drug action emsamble method;(2)the possibilities of the specific drug chloroquine on SQT3 variant,which lays a theoretical foundation for the next clinical trials.The obtained results provide an initial theoretic base for pharmacological treatment of SQTS and anti-arrhythmic drug screening in general,which will be of great values in designing new drugs for treating general cardiac arrhythmias.