Multiscale Modelling Of Myocardial Ischemia In Multi-pathological Stages And Study On Drug Action Mechanism

The maintenance of normal cardiac pacing function depends on the continuous blood supply of the coronary artery.When the coronary artery is narrowed due to atherosclerosis,insufficient blood supply will cause myocardial ischemia.With the evolution of ischemia,the electrophysiological function of cardiomyocytes will change differently,and there are significant differences in electrophysiological characteristics of cardiomyocytes in different states.According to the state of cardiomyocytes,ischemia heart diseases is divided into different pathological stages:ischemia 1a（0-15 minutes）,ischemia 1b（15-45 minutes）,short-term myocardial infarction（MI）（within a few days）and long-term MI（within a few weeks）.Based on the technology of electrophysiological modeling and simulation,the thesis quantitatively studied the mechanism underlying arrhythmia induced by electrophysiological reconstruction and spatial distribution reconstruction during ischemia.In addition,by screening effective targets and revealing the mechanism of drug therapy,the thesis could provide new research ideas for the prevention and treatment of ischemia diseases.The main research contents of this thesis are as follows:（1）Myocardial single cell model is the basis of electrophysiological simulation research.Among the existing human ventricular cell models in ischemia,some are beyond the scope of experimental data,and some have not been constructed.Therefore,this thesis collected and sorted out the physiological experimental data during ischemia of human and other mammals ventricular at the subcellular,cell and tissue levels.Based on these data,the latest human ventricular cell models in four ischemia stages were constructed.The validity of the model was verified by comparing with experimental data.Finally,through the parameter sensitivity analysis of these models,it is found that the action potential of cell models in the short-term ischemia stage is the most sensitive to the changes of I_KATP and[K⁺]_o,and the action potential of cells in long-term MI is mainly affected by I_Ks,I_{Ca L} and I_Na.（2）At present,the electrophysiological simulation studies only focus on single ischemia pathological stages.However,some studies have found that different ischemia stages（ischemia 1a,1b,and short-term MI）may coexist in the same myocardial tissue within a few days of ischemia.The effect of the coexistence of multiple ischemia stages on the venerability to reentry is unclear.To solve this problem,this thesis constructed two different spatial distribution tissue models with multiple ischemia states,representing two different spatial distributions along and perpendicular to the blood flow direction.The simulation results showed that the mechanisms underlying arrhythmia in these two different tissues are different.One is caused by the spatial heterogeneity of refractory period caused by the difference of action potential duration and conduction velocity of excitatory wavefront,in which the difference of conduction velocity between ischemia 1b and short-term MI areas plays a major role.The other is due to the increase of excitation threshold in the short-term MI area and the decrease of coupling current at the tissue edge,the reentry wave was induced by the combined action of the two.（3）In the long-term MI stage,the number of fibrosis cells increases greatly,and myocardial fibrosis will slow down wave propagation,which is an important matrix for the formation of reentry.In order to study the effect of the reconstruction of spatial distribution of fibrosis cells and the infarcted areas on wave propagation,firstly,a comparative experiment between random fibrosis group and gradient fibrosis group was designed,based on the previously single cell model in long-term MI.The mechanism inducing reentry was analyzed in these two long-term MI tissues.At the same time,the effects of the spatial distribution of the length,width and position of the infarcted regions on the wave propagation were quantitatively studied.The results demonstrated that when the length of the infarcted area is more than 25%of the circumference of the ventricle,the width is close to half of the thickness of the ventricular wall,or the infarcted area is close to the inner or outer wall of the heart,it is easier to induce reentry in the long-term MI tissue.（4）At present,in the treatment of ischemia diseases,which targets are valid is unclear.In addition,the drug action mechanisms repairing the damaged cardiomyocytes are still unclear.Therefore,this thesis first selected the action targets,then simulated the therapeutic action of drugs for specific targets,and analyzed the action mechanism of these drugs,based on the previous single cell and tissue models in different ischemia stages.The simulation results showed that for short-term ischemia diseases,glibenclamide can restore the electrophysiological characteristics of damaged cardiomyocytes from different aspects,and plays a major antiarrhythmic effect by inhibiting the efflux of potassium ions.The drug simulation in long-term MI showed that telmisartan and nifedipine can restore the electrophysiological function of damaged cells from different aspects,and the therapeutic effect is remarkable when they are used together.