Exploring The Mechanism Of Arrhythmia And Myocardial Ischemia With Signal Pathways By Computer Models

Cardiovascular diseases have been the main killers of human being.These diseases account for about 40%of deaths in our country.Heart works all day,and rhythmic contraction and relaxation are the basis of its circulation functions.Common disease such as ventricular fibrillation or myocardial ischemia which will destroy the organ's rhythm of contraction and relaxation is originated from the disequilibrium of chemicals in myocardial cell,especially ion currents and calcium related substances.Therefore,physical and chemical equilibrium,characteristic of ion currents,excitation-contraction coupling and signal transduction pathways of single myocardial cell have always been the focus of research work.Heart provides functions through cooperation of its cells and tissues.Researches in different hierarchies need to be carried out in an integrative way.Although,more micro experimental targets are taken and more data are acquired,there are still some physiological phenomenons that can't be explained without integrative method.Computational modeling is capable of describing the mechanisms running behind physiological targets through utilizing experimental data and basic laws.Once models are built,they would be simulated when independent controls are exerted on specific subpart.In this way,they would be powerful instruments that could be taken in physiological and pathological fields.In this thesis,we developed an human ventricular cell model that integrated signal transduction pathways based on experimental data.Using this model,we simulated behaviors of the cell when signal agonists are added,and made attempts to recover the mechanisms and potential therapies.Following sections are included.1)Model of signal transduction pathwaysWe integrated CaMKII and ?-adrenergic signaling pathways into an modified normal human ventricular cell model and validated this new model with experimental data.Through this model,we simulated the combined effect of CaMKII overexpression and activation of ?-adrenergic signaling pathway to early afterdepolarization(EAD).Simulation results suggests that this combined effect further increases the risk of EAD.And CaMKII overexpression independently facilitates EAD through the prolongation of late sodium current(INaL)deactivation process.2)Ischemia of ventricular cell under ?-adrenergic activationWe integrated ischemia conditions(increase in extracellular potassium,intracelluar and extracelluar acidosis,ATP-sensitive potassium channel)into the model above.Simulation results of ischemia under ?-adrenergic activation suggests that the excitation and contraction abilities are improved by the augmentation of L-type calcium current(ICaL),and the relationship between EAD occurrence and blockage of rapid delayed rectifier potassium current(IKr)is piecewise.3)Magnetocardiography(MCG)simulation of ischemia ventricular tissueWe simulated MCG and ECG signals when excitation was propagated in a 2D ischemia ventricular tissue and evaluated their sensibility.MCG was computed by BEM method and mono-domain model was chose to solve propagation equations.This demonstrates the potential application meaning of cell model.4)Alternans and transmural heterogeneity simulation under P-adrenergic activationWe applied ?-adrenergic stimulation independently on each target in turn.When ICaL is stimulated,alternans are inhibited because Ca2+ concentration is raised and this effectcompensates the refractoriness of SR Ca2+ release.When Ikr is stimulated,active potential period(APD)is shorted and alternans are enhanced for the enforcement of SR Ca2+release refractoriness.Transmural heterogeneity of APD90 is slightly reduced under?-adrenergic stimulation and this may change ECG.