The Mechanism Of Slow Frequency-dependent Arrhythmia And The Mechanism Of Action Of Stable Particles

Background:Slowrate-dependent Long QT Syndrome,not acquired from drugs,is characterized by sudden decreased heart rate followed by QTc prolongation andleads to ventricular fibrillation(VF)or torsade de pointes(TdP).Increasing heart rate by rapidly pacing can shorten QTc and terminate the arrhythmia.This arrhythmia has been reported to be caused by ’loss-of function’ of potassium channels(IKs or IKr),and the molecular mechanism is not fully understood.Objectives:The aim of the present study was to identify the genetic mutation underlying slowrate-dependent Long QT Syndrome with torsade de pointes,and tentatively analyze the mechanism of SCN5A mutation underlying the electrocardiogram(ECG)phenotype.Methods:The clinical and genetic background of 5 patientswith rate-dependent long QT syndrome was studied.Peripheral blood was collected and genetic testing was conducted to the subjects.Mutational SCN5A plasmid was constructed and transfected human embryonic kidney 293(HEK-293)cells respectively with wide type plasmid.The whole cell patch clamp was performed and the electrophysiological characteristics of sodium channel were analyzed between these two groups.Results:After analyzing the clinical information of these patients,we found that they were all between 52±22 years and 4 were females.In all patients the TdP or VF occurred spontaneously after atrioventricular block(4 patients)or sinus bradycardia(1 patient).The arrhythmia was inhibited after a pacemaker or ICD was implanted.Faster pacing(>70bpm)shortened QTc interval(583±60ms before vs.470±37ms after pacing)and eliminated TdP.Sixty-one arrhythmia related genes(including KCNQ1,KCNH2,SCN5A,ANK2,KCNE1,KCNE2,CAV3)were sequenced,ten heterozygous missense mutations of SCN5A(p.S705F)、HCN4(p.R666Q)、Titin(p.R12053W、P.T16515M、p.R4770Q、p.A1868T、p.R18427C、p.I9550M,)、DMD(p.E440K)和 SGCD(p.Q283R)in 5 patients were identified.The functional consequences of SCN5A S705F mutation were analyzed.Whole-cell configuration of patch-clamp analysis revealed that the mutation(-247±90 pA/pF,n=11)did not influence the peak sodium current(INa)density compared to WT(-241±54 pA/pF,n=7,P>0.05),but shifted the steady-state activation curve of INa to a more negative potential(V1/2mutation vs.V1/2wT,-43.10±1.49 mV vs.-34.97±3.11mV,P<0.05;Kmutation vs.KwT,4.86±0.49mV vs.6.97±1.40mV,P>0.05).INa/peak ratio were analyzed at pacing rate of 0.5Hz,1Hz,2Hz.In mutant channels,0.5Hz pacing increased INa/peak ratio by 6.8%compared with that in 2Hz pacing(P<0.05).However,INa/peak ratio remained the same during three pacing rate in WT channels.Conclusion:Rate-dependent Long QT Syndrome may relate with different genes.The ’gain-of function’ of the sodium channel at slower heart rate may account for one of the arrhythmogenic mechanism of rate-dependent long QT syndrome.BackgroundThe occurrence of acute myocardial infarction is increasing year by year.The concomitant ventricular remodeling is the important reason for heart failure after myocardial infarction.Even though early reperfusion therapy timely opened the criminal coronary artery and saved numerous lives,its influence on heart functions after myocardial infarction is still unkown.Researches showed that ventricular remodeling is a kind of restoration behaviors after myocardial infarction and is closely related to the scope of infarction,inflammatory reaction and nuro-humoral regulation.Therefore it became a noteworthy question that how to reduce the the scope of infarction,reverse ventricular remodeling and slower the process of heart failure.As we all know,WenxinKeli(WXKL)is a Chinese herb extract composed of 5 agents and usually used to treat arrhythmia.Its influence on heart failure after myocardial infarction is worth to be explored.ObjectiveThere is little evidence proving the molecular mechanism of WenxinKeli.This study tried to explore the gene expression profile and pathology alteration of WXKL treated rabbits with myocardial infarction.MethodsTwenty male adult rabbits were randomly divided into 4 groups:sham,model,WXKL and captoprilgroups.Model,WXKL and captoprilgroups underwent the ligation of the left anterior descending coronary artery while sham group went through an identical procedure without ligation.WXKL(817mg/kg/d),captopril(8mg/kg/d)and distilled water(model and sham)were administered orally to the rabbits.4 weeks later,hearts were taken out for expression chip and pathological staining(H&E,Masson and Tunel)after echocardiography.ResultsWXKL could down-regulate genes associated with inflammation(CX3CR1,MRC1,and FPR1),apoptosis(CTSC and TTC5),neuro-humoral system(ACE and EDN1)and up-regulate angiogenesis promoting gene like RSP03,which explained why WXKL group represented with better cardiac function,less histopathological injury and slighter apoptosis.ConclusionThe present study showed that WXKL hadplayed an important role in suppressing inflammation,inhibiting renin-angiotensin system,alleviating apoptosis and might be a promising Chinese medicine in treating patients with myocardial infarction.