Disease-oriented Modeling And Simulation Of Ventricular Arrhythmias Induced By CaMK?

Ventricular arrhythmia,which is the most common clinical manifestation of cardiovascular diseases,is characterized by rapid and disordered activities of ventricles,resulting in loss of pump blood function.In cardiovascular diseases,the fatality rate of ventricular arrhythmia is as high as 90%.Formation o f ventricular arrhythmia is not only confined to changes in single protein function,but also associated with age,lack of oxygen,ischemia,inflammation and tissue damage.These pathogenic factors are closely related to the pathogenesis of c ardiac electrical remodeling and structural remodeling.Although it was found that calcium/calmodulin-dependent protein kinase II(Ca MKII)is involved in the whole process of cardiac remodeling,the exact mechanism of arrhythmias induced by Ca MKII remains unclear.Modeling studies had shed valuable light on arrhythmia mechanisms.Cardiac electrophysiology model is used to simulate the electrophysiological phenomena of ion channel,cell,fiber,slice,cardiac organs and body surfaces.It achieves the unity of micro experimental research and macroscopic clinical diagnosis,and becomes a powerful tool for systematic analysis of laws of heart disease occurrence,development and transformation from health heart at cellular,fiber as well as tissue levels.This dissertation studied cardiac pathological problems with macroscopic and microcosmic perspectives by simulating the electrophysiological phenomena by using the disease-oriented mathematical model and explained the mechanism of Ca MKII-induced ventricular arrhythmia occurrence,development and transformation.The main contents of the dissertation are organized as follows:The major defect of the human ventricular cell model is the inability to reproduce the cellular signaling function of experiments.In this dissertation,based on the Ca MKII activation process and considered the role of Ca MKII in regulation of ion currents,we integrated the Ca MKII activation model and regulatory function of Ca MKII into the human ventricular cell model and thereby established a human ventricular cell model with Ca MKII regulation.Based on the cell model,we analyzed the effect of the reactive oxygen species(ROS)on Ca MKII activation,ion current,ion concentration and action potential,and expounds the internal mechanism of the relationship between the change of micro ROS and macro changes in action potential.The simulated results show that the model can accurately simulate the cell electrophysiology,calculate the vivid action potential,reproduce Ca MKII regulation function and better assist experiment design and pathogenic mechanism study,highlighting the application value of the model.The mechanism of Ca MKII induced arrhythmias varies with disease,the role of currents regulated by Ca MKII in the pathogenesis of arrhythmias remains unclea r and the antiarrhythmic targets for cardiac diseases are urgently to be determined.In this dissertation,we constructed a cell electrophysiological model based on the latest electrophysiological data on the N2091 S gene mutation,used ion diffusion function to describe the transmembrane ionic currents,used the Ca MKII activation model to achieve its regulatory function and screened potential antiarrhythmic targets according to the single ion channel blocking theory.The simulated results show that the model can well reproduce the ion current kinetic characteristics in the N2091 S gene mutation.The mechanism of arrhythmia occurrence is that N2091S-induced calcium influx is an upstream initiating event for arrhythmia phenotypes that are ultimately dependent on Ca MKII activation.Calcium pump of the sarcoplasmic reticulum is a more effectively antiarrhythmic target than the L type calcium channel.This work provides new ideas for screening drug,reducing blindness of drug design,speeding up the development process of drugs,greatly reducing development costs and accelerating clinical transformation of achievements in biological experiments.In studies of mechanisms underlying the Ca MKII-induced arrhythmia development,micro researches of heart physiological pathologists and macro studies of clinical doctors cannot accurately illustrate the evolution of micro changes into macro performance.In this dissertation,based on the latest electrophysiological data on the G1911 R mutation,we built the L-type calcium channel,cell,fiber,tissue and three-dimensional heart models,and simulated ion currents,action potentials,conduction process of electric excitation,spiral waves and corresponding ECG.The simulated results show that these models establish the brigde between the ‘mutant' ion current and the characteristics of ECG.The mechanism of arrhythmia development is that G1911R-induced electrical heterogeneity promotes the formation of ventricular tachycardia,Ca MKII can cause triggered activities and these triggered activities can promote ventricular tachycardia to form ventricular fibrillation.This work provides ideas for investigating effects of microscopic changes on the functions of the whole complex system and gives theoretical and technical support for the understanding of cardiac physiological function,the deduction of disease,the design of individualized diagnosis plan,and the development of medical equipment.In studies of mechanisms underlying the Ca MKII-induced arrhythmia transformation,experimental studies cannot fully capture the process of human heart disease.For the typical heart disease process ischemia-reperfusion,in this dissertation,we constructed electrophysiological models of the normal,acidosis and post acidosis conditions,simulated trigger activities,premature ventricular complex and ventricular tachycardia for discovering causes of arrhythmia and obtained the safe time for preventing arrhythmia.The simulated results show that this model can reproduce the electrophysiological phenomena in biological experiments well and can accurately capture the key nodes of arrhythmias.The mechanism of arrhythmia transformation is that sarcoplasmic reticulum calcium overload,electric heterogeneity and structure remodeling are three substrates of arrhythmia transformation that is ultimately dependent of Ca MKII activation.The safe time for preventing these arrhythmias is 4 min.The work provides a new way to study heart disease and has important theoretical guidance of clinicians to treat heart diseases.