| ObjectiveAbove a half of patients with acute myocardial infarction (MI) in all survivals always dead of fatal ventricular arrhythmia. The patients with MI frequently suffered ventricular arrhythmia or sudden death during restoration period. Nowadays, it was presumed that sudden cardiac death is correlated to ventricular arrhythmia after MI and considered to be focal point and nodus of clinical works for the prophylaxis constantly. For the mechanism of sudden cardiac death after MI, it was considered to be correlated to the cardiac muscle remodel and the electricity remodel in recent years. In 2000, Doctor Jimin Cao made correlation analysis for 53 cases of heartmans about cardiac nerve innervation density, ventricular arrhythmia and sudden cardiac death, and discovered that there were very glomerately regenerate sympathetic nerve innervation those in positive groups of ventricular arrhythmia- sudden cardiac death were obviously heavier than those in negative groups. From then he proposed boldly that ventricular arrhythmia and sudden cardiac death with MI or other myocardial damage during restoration period were correlated to excess regeneration of sympathetic nerve in heart named as nerve reconstitution. After this a new concept as nerve remodel were recognised gradually and became a hot spot for study. If energetic means was adopted in early step to interfere in nerves remodel and made regeneration and hyperplasia of cardiac nerve to achieve a suitable level other than exceptional reconstitution. it could make active effect to ventricular arrhythmia even sudden cardiac death after MI.Infracted border zone (IBZ) that encasements filament scar make a important role in the mechanism developing ventricular arrhythmia and ventricular fibrillation. There is phenomenon of sympathetic nerve reconstitution after acute MI that represents regeneration of sympathetic nerve and excess regeneration of sympathetic nerve and present most manifestly at IBZ. The sympathetic remodeling and electrical remodeling promote the development of ventricular arrhythmia and ventricular fibrillation. In common because the nerves controlling heart suffer damage during acute MI. Under the effect of multiplicative neurotrophic factor such as nerve growth factor (NGF) in myocardium region or circulation, the impaired nerves develop reconstitution and present most manifestly at IBZ through acute stage. Measurable regeneration of sympathetic nerve serve as reasonable renovation result for organism damage at early MI, but the regeneration at chronic phase frequently presents helewglnouo vaccine excess regeneration. Sympathetic nerve remodel with a characteristic of excess regeneration of nerve fiber is correlated to the development of ventricular arrhythmia and sudden cardiac death after MI. The excess regeneration of sympathetic nerve bring about the accentuation of sympathesis activity. The disadvantageous factors such as ischemia and oxygen deficiency and myocardial cell at IBZ affected by high level of noradrenalin (NE) induce the alteration of electrophysiological characteristics of myocardium region in common. Apart from inherent electrophysiological heterogeneity of three-tier myocardium and direct effect resulted from MI, the confused distribution of sympathetic nerve with excess regeneration and different sensitivity to NE all could make a important role. The comprehensive effect of above factors change the character of ion channel such as transient outward current (Ito), the delayed rectifier (IKr and IKs, respectively) and L-type Ca2+ current (Ica-L) further more change repolarization process that Ito,Ik and Ica-L all obviously lessen among them there are most obvious variation in midmyocardial (Mid). The relation between the alteration of ion current and sympathetic nerve remodel needed to be further studied. The sympathetic stimulation could induce the change of electrophysiological characteristics of myocardium. The sympathetic nerve under the heart include almost regenerative sympathetic fiber. For the normal cardiac muscle, the effectiveness of increasing IKs and IC1 exceed that of increasing ICa during sympathetic stimulation that induce repolarization to quicken. Thus effective refractory period ( ERP) of every layer shorten and transmural dispersion of repolarization ( TDR) diminish. But at IBZ with apparente sympathetic nerve remodel, sympathetic stimulation could increase TDR significantly and the most induce torsades de pointes ventricular arrhythmia. It was suppose that could be relevant to the electrophysiological characteristics of the Mid cadiocyte line in which the inherent tiny IKs further grow downwards, the effect of increasing ICa enhance relatively during sympathetic stimulation and repolarization retard relatively, and as a result, the extent of ERP abbreviation is inferior to that of endocardial (Endo) and epicardial (Epi) layer to lead to augmentation of TDR. The above hypothesis was supported by apparente after-depolarization in Mid cadiocyte observed during sympathetic stimulation.The mortality of angiocardiopathy is highest of grave diseas threatening mankind health, of which about 17million global peoples died yearly. Although coronary artery bypass graft(CABG) for acute MI was not advocated nowadays because of high mortality, above a half of patients with acute MI in all survivals always dead of fatal ventricular arrhythmia during chronic restoration period. We have already carried out CABG for acute MI and got good therapeutic outcome. Hibernating myocardium surrounding IBZ would develop necrosis myocardium along with the lasting of ischemia time and the aggravation of ischemia degree but no wholly scar cause heart function to cut down. For these patients the result of revascularization is better than that of purely medication. The sympathetic remodeling and electrical remodeling promote the development of ventricular arrhythmia and ventricular fibrillation collectively. For the large clinical significance of nerves remodeling study, if energetic means was adopted in early step to interfere in nerves remodel and made regeneration and hyperplasia of cardiac nerve to achieve a suitable level other than exceptional reconstitution, it could make active effect to ventricular arrhythmia even sudden cardiac death after MI. The nerves remodeling study at IBZ could not illustrate the effect of CABG to sympathetic remodeling and electrical remodeling at IBZ by means of medicine and intervention customarily because these measure got of the possibility of sympathetic nerve and vagus nerve damage. Our study investigate whether CABG could lessen sympathetic remodeling and electrical remodeling at IBZ, and decrease the happen of ventricular arrhythmia even sudden cardiac death, and improve the prognosis of acute MI. All above could provide theory groundwork for early CABG with acute MLIn our study, through early coronary artery bypass graft (CABG) in different time serve as intervention approach, we measured ERP and TDR at IBZ, ERP and TDR during sympathetic nerve stimulation, and ventricular fibrillation threshold (VFT) at eight weeks after surgery to investigate the alteration of electrophysiological characteristics of myocardium. There is redundant express of ionophorous protein Kv4.3 as Ito expression in ventricular myocardium (VM) of dog. Recently, it has been reported that channel subunits encoded by Kv4 genes form heteromeric complexes in vivo withβsubunits encoded by the KChIP gene family. Co-assembly of the KChIP subunits with Kv4 a subunits results in a significant increase in the size of the currents and in an increase in the rate of recovery from inactivation. KChIP2 can account for the transmural gradient of Ito expression in canine heart. In our study, we detected the local expression of ionophorous protein such as Cav1.2,Kv4.3 and KchIP2 mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR) to demonstrated the mechanism of electrical remodeling at IBZ. We detected the local expression of growth associated protein 43 (GAP43) mRNA,NGF mRNA and synaptophysin (SYN) mRNA at IBZ by RT-PCR to investigate the effect of neurotrophic factor to nerves reconstitution.Materials and Methodsthirty healthy mongrels whatever female and male their body weight 16～26kg were provided by animal experiment center of China Medical University. The anterior descending coronary of all thirty dogs randomly assigned into experimental group (n =22) and control group (n =8) were ligated into MI model. The experimental group included 1th week (n =6),2th week (n =4),4th week (n =6) and 6th week (n =6) CABG. and established control group (n =2) for every experimental group. We measured ERP and TDR at IBZ, ERP and TDR during sympathetic nerve stimulation, and VFT at eight weeks after surgery. We detected the local expression level of ionophorous protein such as Cav1.2, Kv4.3 and KchIP2 mRNA, and GAP43 mRNA,NGF mRNA and SYN mRNA at IBZ or corresponding location by RT-PCR at eight weeks after surgery.Results1. Four dogs of every experimental group and all dogs of control group survived to the end of the study.2. The TDR of 1th week,2th week and 4th week CABG at IBZ were significantly shorter than that of all control group at IBZ (P<0.05). The ERP and TDR of the three myocardial layers at IBZ in 4th week and 6th week CABG significantly extended comparing with that in 1th week and 2th week CABG(P<0.05). The ERP of control group in epimyocardium became most short during sympathetic nerve stimulation comparing with that of experimental group and the TDR of control group became augmente rather than short (P<0.05).3. VFT: VF were induced successfully at IBZ of all dogs by strong intensity electric stimulation. VFT in control groups more degraded than that in experiment groups (13.0±3.21V; 24.44±3.98V)(P<0.01).4. The expression level of three kinds of ionophorous protein in all control group downregulated significantly compared with that in all experienmental groups and normal group(P<0.01).The expression level of Cav1.2 mRNA in 4th week and 6th week CABG downregulated significantly compared with that in normal group(P<0.05); The expression level of Kv4.3 and KchIP2 mRNA in 4th week and 6th week CABG downregulated significantly compared with that in 1th week and 2th week CABG and normal group(P<0.05). The change of Cav1.2mRNA in all control group were higher than every experienmental group among them there were not differences obviously(P<0.05). The change of Kv4.3 and KchIP2 mRNA in all control group were higher than every experienmental group (P<0.05), of the total experienmental group the change of Kv4.3 and KchIP2 mRNA in 4th week and 6th week CABG were higher than that in 1th week and 2th week CABG(P<0.05).5. The expression level of GAP43mRNA,NGFmRNA and SYNmRNA in all control group upregulated significantly compared with that in all experienmental group and normal group(P<0.01), The expression level of GAP43mRNA and NGFmRNA in 4th week and 6th week CABG upregulated significantly compared with that in 1th week and 2th week CABG and normal group(P<0.05).There are not obviously discrepancy of SYNmRNA expression level between every experienmental group and normal group.Conclusion1. Early CABG surgery for acute MI could lessen the change of TDR and lessen sensitivity of myocardium at IBZ to sympathetic nerve, and then reduce happen of arrhythmic, and elevate the threshold of VF , deplete the effect of ischemia to electrophysiological characteristics of myocardium.2. CABG surgery among two weeks could lessen the change of electrophysiological characteristics of myocardium, and handled the downregulation of Kv4.3 and KchIP2 mRN maximatily.3. Early CABG surgery for acute MI could lessen the expression level of GAP43mRNA,NGFmRNA and SYNmRNA at IBZ of dog with MI and lessen the neurotization and neurotransmitter releasing at IBZ of dog with acute MI, Especially. CABG surgery for acute MI among two weeks could lessen the sympathetic recommendation maximatily. The densities of sympathetic nerve in 6th week CABG were significantly higher than that at other experienmental group and normal group(P<0.05), but in which there are seldom SYN express possiblely. |
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