Modeling And Simulation Of The Complex Mechanism Of Quinidine In Hereditary Cardiac Ion Channel Disease Based On Cardiac Cell Mathematical Model

BackgroundSudden cardiac death（SCD）is one of the main ways of death in human beings.Most of SCD is caused by acute arrhythmias caused by structural heart disease,that is,sudden change of ventricular rhythm too fast,too slow,or irregular.Sudden cardiac death caused by ventricular arrhythmias caused by hereditary cardiac ion channel disease is low in the general population,but the fatality rate is high,and the onset age tends to be younger.Hereditary ventricular arrhythmias a disease in which there is no significant abnormality of the cardiac anatomy,Long QT syndrome（LQTS）,short QT syndrome（SQTS）,Brugada syndrome（Brugada syndrome）,Br S,catecholaminergic polymorphic ventricular tachycardia,CPVT)and idiopathic ventricular fibrillation（IVF）are also referred to as hereditary cardiac ion channel disease.As an antiarrhythmic drug,quinidine has a long history and was first used to treat arrhythmia in the 18th century.Quinidine has been used to treat premature beats and atrial fibrillation,but studies have found that quinidine induces ventricular arrhythmias and fibrillation,which can lead to high mortality and other side effects.Although it is a controversial drug,the research on quinidine has not stopped.A recent study found that quinidine,as the only oral drug,can be used to treat inherited heart ion channel diseases such as Brugada syndrome,idiopathic ventricular fibrillation,short QT syndrome and early repolarization syndrome.The seemingly contradictory relationship between quinidine and arrhythmia and the underlying mechanism remain unclear.Objective1.To study the pathogenesis of inherited cardiac ion channel disease;2.To study the cardiotoxicity and mechanism of quinidine;3.To study the effect of quinidine on ion channel disease.MethodsIt has been reported that cardiac cells have Purkinje（P）and ventricular myocytes,and it has been reported that ventricular myocytes have endocardial（Endo）cells,midmyocardial（M）cells and epicardial（Epi）cells.A one-dimensional canine Purkinje myocardial tissue model was constructed based on four cell models（50 cells of each type,tissue length 2 cm）.Based on normal cell and tissue models,ion channel disease models have been constructed,including Brugada syndrome,Br S（G1319V,D211G,L450F,G600R,T152I,R164C,G490R,and S481L）,long QT syndrome（LONG QT Syndrome,LQTS）（D1790G and T587M）,short QT syndrome（SQTS）（S631A and N588K）,and idiopathic ventricular fibrillation,IVF)（T1787M and V54G）and other 4 ion channel diseases and 14 gene mutations.To study the pathogenesis of ion channel disease and the toxicity of quinidine to cells at different concentrations and frequencies,as well as its effect on ion channel disease.Results1.Among Endo,Epi,M and P cells,P cells had the longest action potential duration（APD）at the same heart rate.Among ventricular myocytes,Endo cells repolarized the fastest,while M cells repolarized the slowest.Epi and M cells showed characteristic notch and dome action potential morphology,which was not obvious in Endo cells.2.In the same ion channel mutation of ion channel disease,the action potential morphology and action potential time-history heart-rate dependence curve were similar,and there were significant differences between the action potential morphology and action potential time-history heart-rate dependence curve of different ion channel mutations.3.In the simulation at the tissue level,The G490R mutant of Br S had ST segment elevation and shortened QT interval,the T587M mutant of LQT had ST segment elevation and prolonged QT interval,and the N588K mutant of SQT had shortened QT interval.The simulation results were consistent with the phenotype characteristics in clinical studies.4.The toxicity of quinidine to the action potential morphology of Endo,Epi,M and P cells showed continuous dynamic changes with time and concentration.Among them,quinidine had the highest toxicity to M cells,M cells produced EAD under normal pacing condition（CL=1000ms）,1000,2000 and 3000nmol/L quinidine,and quinidine had the lowest toxicity to P cells.EAD was only produced under the condition of slow frequency（CL=2000ms）and high concentration（3237nmol/L）.In ventricular myocytes,EAD was caused by I_{Ca L},while I_{Na L}played a major role in purkinye cells.5.The toxicity of quinidine to P cells was dependent on heart rate and concentration.The higher the heart rate and the slower the heart rate,the greater the toxicity,and the higher the concentration,the greater the toxicity.The effect of quinidine on the morphology of action potential is due to the reactivation of ion channel currents caused by the change of intracellular ions such as sodium,potassium and calcium with the change of concentration and time.6.Quinidine has different effects on different inherited ion channel diseases.N588K mutant of SQT syndrome and R164C mutant of Br S syndrome have protective effects on quinidine toxicity,while T587M mutant of LQT syndrome has aggravating effects on quinidine toxicity.Conclusion1.The difference of action potential morphology and heart-rate dependence curve of action potential duration of Endo,Epi,M and P cells is an important basis for normal electrophysiological activities of cells.2.The pathogenesis of ion channel disease is that the superposition effect of introverted and extroverted currents leads to the change of action potential morphology and ultimately leads to ventricular arrhythmias by affecting a variety of ion channel currents.3.The toxicity of quinidine to cell action potential morphology showed continuous and dynamic changes with concentration and heartbeat frequency.The toxicity of quinidine to Endo,Epi,M and P cells was cell dependent,and the toxicity mechanism was different in ventricular myocytes and Purkinje cells.4.Quinidine can prolong the duration of action potential,so quinidine can aggravate the ion channel disease（LQT）that prolongs the duration of action potential,and treat the ion channel disease（SQT and Br S）that shortens the duration of action potential.