Late Sodium Current Result In Sinus Node And Introcardiac Conduction Dysfunction

The late sodium current (I_Na,L)is a sustained component of the fast Na⁺ current Asrecently appreciated,lots of cardiac diseases including the LQT3 are associated withabnormal INa,L enhancement.We hypothesized that an increase of I_Na,L may induce notonly prolonged QT and ventricular arrhythmia but also play a critical role in thepathophysiology of sinus node dysfunction and depressed intraventricular conductionin the LQT3.Anemone toxinâ…¡(ATX-â…¡) (1-10 nmol/l) was used to enhance I_Na,L whileranolazine (10μm) was applied to block ATX-â…¡-induced I_Na,L.Scn5a+/â–³transgenicmice were also used to verification our hypothesis.The data reveal that an increase ofI_Na,L induced the alterations in sinus node function and intracardiac conduction andpharmacological modulation of ranolazine may be the therapeutic potential. Partâ… Sinus Node Dysfunction and Intracardiac Conduction ina Murine Model of Long QT Syndrome Type 3 Induced byATX-â…¡and Rescue Effect of RanolazineObject:The aim of this study was to characterize the role of the late Na⁺ current (I_Na,L) as amechanism for induction of both tachy- and brady-arrhythmias in murine heart andsino-atrial node tissue.Method:The sea anemone toxin ATX-â…¡and ranolazine were used to evoke and block,respectively,I_Na,L.Result:In sixteen hearts studied,exposure to 1 to 10 nM ATX-â…¡caused a slowing ofintrinsic heart rate and prolongations of the PR and QT intervals,the duration of themonophasic action potential,and the sinus node recovery time,accompanied by frequentoccurrences of early afterdepolarisations,delayed afterdepolarisations and rapid,repetitiveventricular tachycardiac and sino-atrial bradycardic arrhythmias.ATX-â…¡also slowed sinusnode pacemaking,and induced bradycardic arrhythmias in isolated sino-atrial preparations(n=5).The ATX-II-induced alteration of electrophysiological properties and occurrence ofarrhythmic events were significantly attenuated by 10μM ranolazine in intact hearts (n=11)and isolated sino-atrial preparations (n=5).Conclusion:The I_Na,L enhancer ATX-â…¡causes both tachy- and brady-arrhythmias in themurine heart,and these arrhythmias are markedly attenuated by the I_Na,L blocker,ranolazine(10μM).The results suggest that I_Na,L blockade may be the mechanism underlying thereductions of both brady- and tachy-arrhythmias by ranolazine that were observed duringthe MERLIN-TIMI clinical outcomes trial. Partâ…¡Sinus Node Function and Intracardiac Conduction ina Murine Model of Long QT Syndrome Type 3Object:The aim of this study was to characterize the role of the late Na⁺ current (I_Na,L) as amechanism for induction of both tachy- and brady-arrhythmias in murine heart andsino-atrial node tissue.Method:Scn5a +/â–³transgenic mice were used to verification our hypothesis.Result:The present experiments on an established murine,Scn5a+/â–³,model for LQT3extended previous reports of its ventricular arrhythmogenic properties.In addition tosignificant prolongations in QT and QTc intervals in common with human LQT3,Scn5a+/â–³mice showed evidence for significant sino-atrial node (SAN) dysfunction.Although baseline electrocardiographic heart rates in intact Scn5a+/â–³preparations wereindistinguishable from WT,anaesthetised Scn5a+/â–³mice showed episodes of sinusbradycardia,sinus pause or arrest.Isolated Scn5a +/â–³sino-atrial preparations showed lowermean intrinsic heart rates.Furthermore,Scn5a +/â–³mice showed a significant longer SNRTfollowing burst pacing.Both intact animals and isolated Scn5a+/â–³sino-atrial preparationsshowed evidence for depressed intra-atrial,atrioventricular node and intraventricularconduction in the Scn5a +/â–³in the absence of significant sino-atrial exit block.Conclusion:Thus electrocardiographic studies demonstrated episodes of second and thirddegree heart block,as well as prolonged PR intervals and QRS durations in Scn5a+/â–³.Multi-array electrode mapping studies demonstrated significantly greater latencies inconduction of excitation between SA node,and septum and inferior vena cava,but not theright atrium and superior vena cava in isolated Scn5a +/â–³sino-atrial preparations Togetherthese findings demonstrate alterations in sinus node function and intracardiac conductionthereby recapitulating phenotypic characteristics reported in the corresponding clinicalcondition.