The Role Of Late Sodium Current In The Transmural Dispersion Of Repolarization Of Frequency Dependence

BackgroundsWith the increasing prevalence of cardiovascular diseases,various arrhythmia and arrhythmia sudden death are mounting.The increased ventricular repolarization dispersion is one of the main causes of arrhythmia,and rising ventricular repolarization dispersion can lead to malignant ventricular arrhythmia and even sudden cardiac death.A normal heart has transmural dispersion of repolarization(TDR)and has obvious frequency dependence.Some diseases and drugs can make TDR increase,which often leads to malignant arrhythmia during long R-R intervals and endanger people’s life.Cardiomyocyte repolarization involves many kinds of ions.Effective interventions can be taken if we make clear the main ion mechanism of cardiomyocyte repolarization.Experimental studies have found that late sodium current(INa-L)is very sensitive to heart rate change,and is unevenly distributed in different parts of myocardium.Its distribution density is closely related to the action potential duration(APD)of local myocardial cells and frequency dependence,which may play a major role in frequency dependence TDR.This project intends to establish a bradycardia model using formaldehyde wet compress on the sinus node,and stimulate the right atrium with a cardiac electrophysiological stimulator.Observation results:When stimulating the right atrium with different stimulation frequencies,using drugs block or enhance INa-L,the surface electrocardiogram reflects the changes of QT and Tp-Te interval(indicator of myocardial repolarization time and repolarization dispersion).That can testify whether INa-L is the main ion current that causes transmural repolarization dispersion.If it is,drug blocking INa-L can reduce or eliminate the repolarization dispersion and reduce the risk of malignant arrhythmia.ObjectiveTo observe whether frequency-dependent repolarization change and TDR of rabbit hearts in vivo can be measured through sinus node ablation and atrial electrical stimulation;to reveal whether INa-L is the main ion current causing frequency-dependent TDR,providing basis for clinical application of antiarrhythmic drugs and development of new drugs.Methods1.Subject and group:50 ordinary New Zealand white rabbits,half male and half female,were randomly divided into 5 groups(10 in each group).According to the medication,they were marked as control groups sotalol group,ATX-II group,mexiletine group and ATX-Ⅱ plus mexiletine group.2.Research method:(1)Anesthetized rabbits by Pentobarbital sodium(30mg/kg),the skin on neck,chest and limbs prepared for surgery and electrode placement.Inserted needle-shaped electrodes into these parts of chest and limbs,recorded the conventional synchronous 10-lead electrocardiogram(due to the reserved surgical field,V1,V2 lead ECG will not be recorded),at the same time,continuously observed the ECG signal.(2)Disinfected the neck and chest,performed a longitudinal incision,separated the subcutaneous tissue layer by layer,and covered the neck incision with saline gauze after exposing the trachea.Later,made a longitudinal incision on the chest 3-5 mm to the right of the sternum.Cut the pericardium and ablated the sinus node at the anatomical part of the sinus node slightly inside the junction of the right atrium and the superior vena cava after the lung collapsed and the heart was exposed.Cut the trachea,intubated the ventilator into it,and observed the change in heart rate.Modeling was successful when the heart rate dropped by more than 30%or sinus arrhythmia(sinus arrest,sinus block,etc.)or junctional escape rhythm occurred;(3)Placed the stimulating electrode close to the right atrium,gave electrical stimulation at different pacing intervals(300,400,500ms),and record the body surface electrocardiogram under different pacing intervals;(4)Injected Sotalol,ATX-Ⅱ,mexiletine and a combination of ATX-II and mexiletine into the ear vein according to the groups,observed the electrocardiogram changes after injection and record the body surface electrocardiogram;(5)Comparison:Compared the changes of QT and Tp-Te interval in these rabbit body surface electrocardiogram,which revealed the role of INa-L in the frequency-dependent dispersion of transmural repolarization.Results1.After ablation of the sinus node with formaldehyde,the heart rate of all rabbits was significantly slowed down,and the heart rate generally dropped between 36.3%and 64.1%.The difference in heart rate before and after ablation were statistically significant.2.The changes of QT and Tp-Te interval under different frequency stimulation in body surface electrocardiogram of different groups.(1)Control group:Atrial constant interval stimulation of 300 ms,400 ms and 500 ms was given.As the pacing interval increased,the QT interval gradually increased.The longer the pacing interval(the slower heart rate),the longer the QT interval.The difference between QT intervals under different pacing intervals was statistically significant(P<0.001).And with the extension of pacing interval,Tp-Te,an indicator of TDR on the body surface ECG,also gradually increased.The longer the pacing interval(the slower the heart rate),the longer the Tp-Te interval,and the difference between Tp-Te interval under different pacing intervals was statistically significant(P<0.001).(2)Sotalol group:After Sotalol was injected into the ear-edge vein,the ST segment of the rabbit body surface electrocardiogram showed prolongation,the T wave appeared later,the base became wider,and showed double peaks,appeared electrical alternation,and the amplitude of some leads was significantly increased,QT interval gradually prolonged,and finally showed a wider base and sharp asymmetry changes.Atrial constant pacing interval stimulation of 300 ms,400 ms,and 500 ms was given.As the pacing interval prolonged,the QT interval gradually increased.The longer the pacing interval(the slower frequency),the more obvious the increase in QT interval.The difference between QT interval of the same pacing interval before and after medication was statistically significant(all P<0.001).And with the extension of the pacing interval,the Tp-Te interval,an indicator of TDR on the surface electrocardiogram,also gradually increased.The longer the pacing interval(the slower the frequency),the more obvious the increase in Tp-Te interval.During the same pacing interval,the difference between Tp-Te intervals before and after medication was statistically significant(P<0.001,P=0.010,P<0.001).However,during the pacing intervals of 300ms and 500ms,the increase of QT interval and Tp-Te interval before and after medication was not statistically significant.But before and after medication,the rabbits’ heart rate slowed down,and the contract was statistically significant(P<0.001).(3)ATX-II group:After ATX-II was injected into the ear-edge vein,the body surface electrocardiogram showed that the QT interval gradually prolonged and stabilized at about 10 minutes.The T wave amplitude increased significantly,showing an approximate symmetrical towering and sharp change.Atrial constant pacing interval stimulation of 300 ms,400 ms,and 500 ms was given.With the extension of pacing interval(the frequency slowed down),the QT interval gradually increased.During the same pacing interval,the contract between QT intervals before and after medication was statistically significant(P=0.001,P=0.001,P<0.001).And with the extension of pacing interval,body surface ECG reflected that the Tp-Te interval(an indicator of TDR)was gradually prolonged.The longer the pacing interval(the lower the frequency),the more obvious the increase in Tp-Te interval.During the same pacing interval,the contract between Tp-Te intervals before and after medication was statistically significant(P<0.001).In addition,during the pacing intervals of 300ms and 500ms,the increase of QT interval and Tp-Te interval before and after medication was statistically significant(P=0.032,P=0.002).(4)Mexiletine group:After Mexiletine was injected into the ear-edge vein,the T wave of the body surface electrocardiogram became slightly narrower.Atrial constant pacing interval stimulation of 300 ms,400 ms,and 500 ms was given.With the extension of the pacing interval,QT interval did not change obviously.During the same pacing interval,the contract between QT intervals before and after medication was not statistically significant.And with the extension of pacing interval,body surface ECG reflected that the Tp-Te interval(an indicator of TDR)was gradually shortened.But only the contract of Tp-Te interval before and after medication during the pacing interval was 500ms was statistically significant(P=0.021).It showed that the longer the pacing interval,the more significant the effect of mexiletine in shortening the Tp-Te interval.(5)ATX-Ⅱ plus Mexiletine group:After ATX-II plus Mexiletine was injected into the ear-edge vein,the body surface ECG showed that the base of the T wave became wider,the amplitude of the T wave increased slightly,and the QT interval gradually and slightly extended.Atrial fixed interval stimulation of 300 ms,400 ms and 500 ms was given.With the extension of pacing interval,although the QT interval was slightly prolonged,there was no statistical significance in the contract of QT interval before and after medication during the same pacing interval.The Tp-Te interval did not change obviously after medication.During these three pacing intervals,all the contracts of Tp-Te interval before and after medication were not statistically significant.Conclusions1.The rabbit bradycardia model was successful:after the sinus node was ablated,the rabbit heart rate decreased significantly;2.Sinus node ablation plus right atrium electrical stimulation can be used to measure the frequency-dependent repolarization changes and TDR of the rabbit heart in vivo.3.INa-L is the main ion current that causes slow frequency-dependent TDR.4.Drug blocking INa-L can reduce or eliminate slow frequency-dependent TDR and stop malignant ventricular arrhythmia caused by certain drugs or organic heart disease.