Mechanisms Of Heart Failure Induced Atrial Fibrillation Based On Atrial Multiscale Computing Model

Heart failure(HF)and atrial fibrillation(AF)commonly coexist and are associated with high morbidity,disability,and mortality.Epidemiological studies point out that HF can promote AF,but its pathological mechanism has not been fully elucidated.The prognosis is poor for HF patients with AF,and the dynamic evolution and pathophysiological interactions between HF and AF largely limit the long-term successful treatment.Therefore,a more comprehensive understanding of the mechanism of HF promoting AF is needed.Physiological experiments have found that HF can induce atrial remodeling with many factors.However,the current physiological experiment methods cannot measure experimental data at different physical levels at the same time.The Virtual Heart Model can overcome this difficulty.It can integrate the physiological and pathological information at multiscale,be used to analyze factors that affect heart function at different physical scales,and virtually reproduce the dynamic evolution process of the cardiac system.Therefore,the thesis makes full use of the advantages of the Virtual Heart Model and is dedicated to exploring the underlying mechanism of HF-induced atrial multi-remodeling promoting AF using the atrial multiscale computing model.The main work includes the following four aspects.(1)Physiological experimental data show that short-term HF in the canine induces electrophysiological remodeling of atrial cells,but it is not clear whether this remodeling promotes atrial alternans,which is pro-arrhythmic.Accordingly,the canine atrial cell model in HF is built.Using the model simulation,it is found that HF-induced electrophysiological remodeling increased susceptibility to alternans in atrial cells.Through the parameter sensitivity analysis,it is determined that the increase in phospholamban phosphorylation and the decrease in transient outward K~+current induced by HF are important remodeling factors that increase the susceptibility to alternans in atrial cells.By analyzing the correlation between action potentials,ion channel currents,and calcium handling,it reveals the internal mechanism of alternans in HF atrial cells caused by these two remodelings.(2)HF can promote fibroblast proliferation and atrial fibrosis.The electrical coupling between fibroblasts and atrial cells will affect the electrophysiological properties of atrial cells.However,there is currently no electrophysiological model of fibroblasts in the canine atria.Hence,the first fibroblast electrophysiological model in the canine atria is built,and the genetic algorithm is used to optimize its parameters to make it more in line with physiological experiment data.Then,this model is coupled to the canine atrial cell model,and a quantitative method of action potential duration(APD)alternans based on the Fourier transform spectrum and alternans ratio is proposed.Simulation results demonstrate that the proliferation of fibroblasts increases the susceptibility to alternans in atrial cells and its reason is also revealed.(3)The physiological experimental data indicate that the atrial gap junction in HF is remodeled,that is,the electrical remodeling of atrial tissue,which affects the electrical conduction in atrial tissue.If the electrical conduction in the tissue occurs spatially discordant alternans,it will cause arrhythmia.However,it is not clear whether HF promotes spatially discordant alternans in atrial tissue.For this reason,the one-dimensional tissue model of the canine atria in HF is built,and using this model,the effects of HF-induced multi-remodeling(electrophysiological remode-ling of atrial cells,atrial fibrosis,and electrical remodeling of atrial tissue)on the electrical conduction in atrial tissue are analyzed.It reveals the mechanism by which HF promotes spatially discordant alternans in atrial tissue and the mechanism by which gap junction remodeling increases spatial heterogeneity of atrial electrical conduction.(4)The reentry is one of the important mechanisms for triggering and maintaining AF in atrial tissue.The spatially discordant alternans in the one-dimensional tissue model can cause conduction block and form a functional conduction barrier.However,it is still not clear whether it will further develop into reentry.Therefore,the two-dimensional tissue mode of the canine atria in HF is built.Model simulations have verified that the spatially discordant alternans of atrial electrical conduction under the HF condition will further develop into pro-arrhythmic reentry,in which gap junction remodeling and fibroblast proliferation play the decisive role.The underlying mechanism has been suggested that the spatially discordant alternans in HF promotes the formation of functional conduction block that can provide an appropriate substrate for reentry,by increasing the spatial gradient of APD and enhancing the complexity of the APD nodal line.In summary,taking the cardiac alternans as the starting point,from the cellular level to the one-dimensional and two-dimensional tissue levels,this thesis systematically investigates how HF-induced atrial multi-remodeling promotes atrial alternans and reentry.These findings provide new insights into how HF promotes AF in association with atrial alternans,and have an important role and potential clinical value for preventing HF patients with AF and exploiting more effective therapeutic avenues.