Quantitative Analysis Of Transmural And Rate-dependent Cardiac Electrophysiology In Brugada Syndrome

BackgroundCardiac sudden death is one of the most important causes of death in humans.Most of the sudden cardiac death is caused by acute arrhythmia.The incidence of ventricular arrhythmia caused by Brugada syndrome(BrS)is lower in the population,but due to its high fatality rate,it has received much attention.In the 27 years since the discovery of BrS in 1992,more than 450 mutations involving 24 genes have been reported to be associated with it.These mutations mainly cause changes in the expression and kinetic mechanisms of sodium,potassium and calcium channels,resulting in a decrease in inward current or an increase in outward current,but the complex mechanism between genotype and phenotype is unclear.ObjectiveIn this paper,we used the cardiac cell models to quantitatively analyze the transmural and rate-dependent cardiac electrophysiology in Brugada syndrome,and try to investigate the mechanism of BrS caused by related mutations,which may identify novel therapeutic targets.MethodsBased on the epicardial cell model and combined with thepublished experimental data we established the endocardial and midmyocardial cell models in a simulation way.9 well researched and documented mutations associated with BrS are used for further study.The published experimental data of BrS associated mutations are integrated into transmural cells to quantify the transmural(cell-dependence,purkinje,endocardial,middlemyocardium and epicardial cell dependence)and rate-dependent dependence of Brugada syndrome associated mutations.Results1.Purkinje cell has the longest action potential duration.From the endocardium to the endocardium,the endocardium repolarization is the fastest,on the contrary it is the slowest in M cell.The simulated epicardial cell has a characteristic notch and dome action potential morphology.This notch and dome morphology is not obvious in endocardial cell.2.The cell-dependence(transmural dependence)and frequency-dependent mutations of T152 I,W927G,R164 C,G1319V,and L450 F mutants were poor.3.The G600 R,D211G,and G490 R mutations showed strong cell-dependence and frequency-dependence.4.S481 L mutants showed strong cellular dependence but not a rate dependence.Conclusions1.Different gene mutations,through a rate or celluar dependent manner,can cause similar Brs phenotypes.2.Early afterdepolarization maybe one of the underlying mechanisms of BrS.3.Purkinje cells may be associated with the development of BrS.