Multi-scale Modeling And Simulation Of Sinoatrial Node Ischemia

The sinoatrial node?SAN?is the pacemaker of the heart,which spontaneously forms periodic excitation and transmit it to the whole heart through cardiac conduction system,resulting in myocardial contraction and relaxation.It can be seen that the SAN is like the chief commander of the heart,leading the entire heart system for regular activities.In recent years,scientific research on sick sinus syndrome has been well developed,but the deeper understanding of sick sinus syndrome and the development of prevention and treatment strategies for such diseases are still limited.In this study,we constructed multi-scale electrophysiological models of the rabbit SAN based on computer technology,cardiac dynamics and mathematical knowledge to elaborate the mechanism of SAN ischemia and the treatment of this disease which are difficult to be explored by means of physiological experiments.The main contents of this Ph.D.thesis are as follows:Firstly,pacemaker current?I_f?block effects on pacemaker rate was investigated through theoretical analysis and simulation verification.Combined with theoretical derivation and simulation verification,we found that the smaller the sum of membrane currents during diastolic depolarization phase,the larger the increment of pacmaking cycle length when partially blocking of I_f.Then,based on the forward Euler method to analysis human and rabbit I_f?with different dynamic characteristics?block effects on pacemaker rate to reveal how clinical dose of IVA treat ischemic heart diseases?such as chronic angina pectoris and acute coronary syndrome,etc.?caused tachycardia.And further elucidated the reason why the effect of low dose of IVA on pacemaker rate at clinic similar to that of high dose of IVA in rabbit heart experiment.The result showed that clinical dose of IVA reduce pacemaker rate by the combined effects of membrane clock?I_f block?and acetylcholine?ACh?.Secondly,based on the Zhang SAN cell models and the related physiological experimental data,new rabbit heterogeneous SAN cell models were constructed.The new SAN cell models not only represent heterogeneous electrophysiology property between the central and peripheral cells,but also include mathematical models to represent the differences of cell volumes,intracellular calcium dynamic process and sodium concentration between the central and peripheral cells.The updated new cell models can more accurately modelling main ionic currents block effects on the APs as observed in experiments than the parent models.The validity of the new models were verified by comparing 85 characteristics with experimental data?including introducing the Marquardt algorithm,22 items of non-linear fitting and parameter validation of sub-cellular membrane electrodynamics parameters were carried out,10 items for the AP,14 items for calcium transient characteristics,4 items for the contributions of membrane calcium extrusion pathways,2 items for intracellular sodium ion homeostasis,29 items for membrane current effect on pacemaking,and 4 items for calcium transient effect on pacemaking?.The new heterogeneous SAN models would be effective tools to investigate the mechanism of pathological activity of the SAN.Thirdly,heterogeneous ischemic SAN cell models were developed based on the experimental data to elucidate ischemia induced bradycardia.The simulation results showed that:the reduction of T-type calcium current,the activation of K-ATP current,the increase of sodium-potassium pump current(I_NaK)and the increase of reverse activity of sodium-calcium exchange current(I_NaCa)during intracellular sodium overload resulted in the prolonged pacmaking cycle length of central cells;while the increase of L-type calcium current,ischemia caused hyperkalemia,I_NaKaK and inverse I_NaCa increment during intracellular sodium overload were the main causes of prolonged pacmaking cycle length of peripheral cells.The SAN-atrium two-dimensional tissue was generated into standard Cartesian grid to construct a SAN-atrium tissue conduction model with real anatomical structure,to explore the changes of APs generation and conduction in the ischemic tissue and with the additional effect of ACh.The results showed that at tissue level,ischemia induced the pacemaker rate reduction,the activation time prolongation and the conduction velocity of excitation decrement,which were mainly caused by the decrease of depolarization velocity of the ischemic SAN in the tissue;the action of ACh resulted in further reduction of the pacemaking rate and will fail to excitation with the increasing of ACh concentration which indicated patients with SAN ischemia may have sinus arrest or even sudden cardiac death at night.This study not only reveals the mechanism of SAN ischemia induced bradycardia,but also fully reflects the practical value of the virtual heart model.Finally,we predicted pharmacotherapy on the SAN ischemia by simulation study.Combined with myocardial electrophysiology knowledge and pharmacotherapy modeling mechanism,the multi-scale pharmacotherapy models of ischemic SAN were constructed,and the therapeutic effect of Chinese medicine?Yiqi Tongyang?on SAN ischemia was investigated.Simulation result showed that Yiqi Tongyang can effectively treat SAN ischemia induced bradycardia,and the increase of pacemaker rate is positively correlated with medicine effect on the increasing of I_f.This study not only successfully predicted the curative effect of Chinese medicine?Yiqi Tongyang?,but also indicated that virtual heart is a powerful tool to predict pharmacotherapy on heart disease.The results of this study revealed the main reason of SAN ischemia induced bradycardia and provided the theoretical basis for clinical medicine treatment.In addition,the new heterogeneous SAN cell models are also of general application value and important scientific significance to study the pathogenesis of sick sinus syndrome.