Mouse Atrial Cell Modelling And Mechanisms Underlying Cardiac Arrythmia

According to the statistics of the World Health Organization in 2016,cardiovascular disease is the number one killer in the world today threatening human health and life.It ranks first among the causes of noncommunicable deaths,leads to far more mortalities than cancer,noncommunicable respiratory diseases and diabetes.The direct cause of most cardiovascular deaths is sudden cardiac death and stroke,both of which are closely related to arrhythmia.Although reseachers have done a lot of work on arrhythmia,the mechanism underlying arrhythmia is still unclear,which is mainly limited by the isolation of and difficulties in obtaining and analysing physiological experiment data.In recent years,thanks to the advance in modern molecular biology,genomics,proteomics,and computer science,researchers have been able to re-understand life systems through the combination of model simulation and physiological experiments with the idea of system biology,and gain more insights into the behaviour of hearts,which has greatly accelerated the research of heart diseases.Mice,as one of the most common laboratory animals,are comprehensively measured in physiological experiments,but so far,no mouse atrial cell model has been published.Therefore,in this paper,mouse atrial cell modeling and arrhythmia is selected as the subject.First,the first mouse atrial cell model in the field of cardiac electrophysiology simulation is built in this paper.The model can correctly reproduce mouse atrial action potentials and calcium cycling,and contains two signaling pathways —calcium/calmodulin-dependent protein kinase II(Ca MKII)and ?-adrenergic receptor(?-Ad R).The electrophysiological heterogeneity of the left and right atrial cells is also considered,and the model is extended to left and right atrial cell models.Secondly,based on the cell model described above,the model of over-expressed and oxidated Ca MKII signaling pathway is further developed.Using this model,the effects of the above-mentioned dysfunction of Ca MKII on action potentials and calcium cycling in mice atria,and its arrhythmogenic effects are studied.Simulation shows that the oxidation and over-expression of Ca MKII will lead to a decrease in cell stability and sustained delayed after-depolarizations.This work suggests that the use of sodium channel or Ca MKII inhibitors may be an effective treatment strategy for heart failure.Thirdly,based on the mouse atrial cell model,the mechanism of the generation and inhibition of alternans in mouse atrial cells is studied.Compared with previous studies,it is proposed systematically for the first time that the imbalance of transmembrane calcium fluxes leaded sarcoplasmic reticulum calcium flux imbalance is one of the reasons calcium transient alternans.In terms of the inhibitory effect of?-Ad R stimulation on alternans,simulation shows that the L-type calcium current enhanced by ?-Ad R stimulation inhibits calcium transient alternans by restoring the balance of transmembrane calcium fluxes.In one-dimensional atrial tissue,?-Ad R stimulation can still eliminate calcium transient alternans,the mechanism behind which is basically the same as in single cells.Finally,high-throughput proteomics data of mouse sinoatrial nodes and atrial cells is obtained for the first time.Combined with modelling techniques,the conversion of sinoatrial node and atrial cell models is realized based on protein expression,which proves the validity of proteomics data.Through analysing the huge differences in protein abundance,it is found that the difference in the expression of ion channels on the cell membrane(rather than the difference in the expression calcium cycling proteins)is the reason why sinoatial node cells have a unique pacemaking behaviour.In addition,by constructing a stochastic single channel model,the number of major proteins in cardiomyocytes is estimated comprehensively for the first time,and is cross-validated with proteomics data.On the one hand,it proves that the rapid high-throughput proteomic analysis technique is accurate in measuring protein abundance.On the other hand,a new single cell model modeling method from ion channel recognition to single channel modeling to cell model integration is explored.In summary,starting with the construction of a mouse atrial cell model,several important theoretical issues related to mouse atrial arrhythmia are studied,and a new cell model construction method is explored,which contribute to the theory and practice of cardiac electrophysiology.