Research On The Mechamism Of TRPV4 In Atrial Fibrillation

Atrial fibrillation(AF)is one of the most common clinical arrhythmias,and revealing the pathogenesis and pathophysiological process of atrial fibrillation is the key to its diagnosis and treatment.The pathogenesis of atrial fibrillation is complex and usually caused by a variety of factors.However,at present,physiological experiments can only study the pathogenesis of atrial fibrillation from the microscopic level,such as proteins and molecules,and clinical studies can only study the macro results of atrial fibrillation by means of electrocardiogram.So it is difficult to achieve the unity of micro and macro.Multi-scale cardiac electrophysiological models can effectively overcome this difficulty.By integrating electrophysiological data at all levels from molecules to organs,quantitatively studying the physiological and pathological functions of each level,to study the pathogenesis of atrial fibrillation.There is a functional expression of TRPV4 in the heart.Previous studies have found that TRPV4 is involved in atrial fibrillation caused by sterile periccarditis in rats and is closely related to the development of myocardial fibrosis.However,the mechanism of TRPV4 in atrial fibrillation is not yet clear.Therefore,based on the advantages of a multi-scale cardiac electrophysiological model,this paper explores its mechanism of action in atrial fibrillation by constructing a TRPV4 model.First,this paper constructed the first rat atrial TRPV4 computational model in the field of cardiac electrophysiology simulation.The model can correctly reproduce the patch-clamp data of the ion channel and reflect the physiological function of the channel within a certain range.Secondly,based on the TRPV4 model,it was integrated into rat atrial cells and atrial fibroblasts,and the model parameters were optimized by the multiisland genetic algorithm to make it consistent with the physiological experimental data..Thereby constructing a rat atrial computational model and its electrically coupled computational models with fibroblasts to explore the effects of TRPV4 on electrophysiological properties and calcium cycling of atrial cells.Third,the simulation results show that abnormal activation of TRPV4 prolongs the repolarization time of the action potential,while its mediated Ca influx increases the intracellular calcium transient amplitude and further leads to the accumulation of calcium in the SR,which can eventually lead to Calcium cycle dysfunction,calcium alternation occurs.Finally,based on the atrial cell simulation model,this paper established a two-dimensional tissue electrical conduction model to explore the effect of TRPV4 on electrical excitation conduction in atrial tissue.The simulation results show that abnormal activation of TRPV4 in cells will hinder the conduction of electrical excitation,and eventually lead to disturbance of electrical excitation conduction in the tissue.In conclusion,starting from the establishment of a computational model of TRPV4,this paper makes full use of the advantages of cardiac electrophysiological modeling to construct a multi-scale model of the rat atrium from protein to cell to tissue,to explore the mechanism of TRPV4 in atrial fibrillation.It provides theoretical basis and basis for clinical treatment and drug development of atrial fibrillation,and has important scientific significance and application value.