Nerve Regeneration Induced Cardiac Sudden Death Potassium Channel Mechanism

Background and Objective Sudden cardiac death(SCD) refers to sudden and unexpected death caused by various cardiac diseases,which mostly is the result of life-threatening arrhythmias such as ventricular fibrillation(VF).SCD occurs mainly among patients with coronary artery diseases,especially in those with myocardial infarction(MI).The underlying mechanism of SCD in chronic MI is poorly understood. Recently,it is reported that cardiac sympathetic nerve sprouting in chronic MI induced VT, VF and SCD.Furthermore,sympathetic nerve sprouting in left ventricle resulted in long QT syndrome(LQTS).It is well known that LQT is a critical risk factor of SCD,and is mainly caused by prolongation of action potential duration(APD),we hypothesize that down-regulation of the key potassium channels which are responsible for the repolarization of action poteltial and the mantinence of resting potential,such as transient outward potassium current(Ito) and inward rectifier potassium current(I_K1),is one of the leading mechanisms accounts for the induction of arrhythmias and SCD by nerve sprouting.The purpose of the present study is to test this hypothesis.Methods Adult Wistar rats weighing 200～250g were used in this study.To induce cardiac nerve sprouting,4-methylcatechol(4-MC,10μg/kg body weight),a potent stimulator of endogenous NGF synthesis,was injected intraperitoneally daily for 4 weeks. MI was induced by liquid nitrogen freeze-thaw injury.The current densities of Ito and Ik1 was analyzed by whole cell recording technique.The protein levels of membrane Kv4.2 and Kir2.1 were evaluated by Western blotting and normalized to the level ofβ-actin. HRV perameters,such as mean RR intervals,SDNN of RR intervals,RMSSD of RR intervals,ApEn of RR intervals and Poincaréplot of RR intervals,were analysized based on the ECG recording.The animals were devided into five groups:(1) 4-MC group,served to observe the effect of nerve sprouting on the expression and function of Ito and I_k1.(2) MI group,to observe the effect of MI on the expression and function oflto and I_k1.(3) MI+4-MC group,to observe the effect of a combination of MI and nerve sprouting on the expression and function of Ito and I_k1.(4) Sham surgery group(normal control group).(4) Acute 4-MC group,to observe the direct effect of 4-MC on Itol and Ik1 currents.An extra of 18 rats were devided into three groups(n=6 for each group) to observe the HRV changes at the conditions of acute 4-MC,chronic 4-MC and normal control,respectively.Results(1) Cardiac sympathetic nerves densities significally increased in 4-MC and MI+4-MC groups compared with sham group;(2) the current densities of Ito and Ik1 of the left ventricular(LV) myocytes decreased significantly in groups of 4-MC,MI and MI+4-MC compared with control group(P＜0.01),with the lowerest values found in the MI+4-MC group;(3) there was no difference in the current dynamics of Ito and I_k1 among these groups;(4) acute injection of 4-MC did not affect any of these potassium currents in LV myocytes;(5) the membrane protein levels of Kv4.2(αsubunit of Ito channel) and Kir2.1(αsubunit of Ik1 channel) significantly decreased in the LV myocytes from 4-MC group,MI group and MI+4-MC group compared with sham sugery group(P＜0.01),with the lowerest values found in MI+4-MC group;(5) The HRV decreased in animals treated with chronic 4-MC injection but not in animals received acute 4-MC injection,as shown by the values of mean RR intervals,SDNN,RMSSD,ApEn and Poincaréplot of RR intervals.Conclusion Chronic 4-MC injection induces cardiac sympathetic nerve sprouting, remodeling and hyperinnervation and downregulates both the membrane protein levels and current densities of Ito and Ik1 in LV myocytes.MI facilitates the downregulation of Ito and Ik1.Cardiac sympathetic nerve sprouting also decreases HRV.Acute 4-MC did not affect the current density and HRV,suggesting that the decreases in both the expression and function of Ito and Ik1 channels and HRV are related with nerve sprouting but not with the acute pharmacological effect of 4-MC.These results suggest that downregulation of Ito and Ik1 may be one of the leading mechanisms by which cardiac nerve sprouting induces ventricular arrhythmias ans SCD in chronic MI.