The Effect Of IPS Cells Transplantation On Neural Remodeling And Ventricular Arrhythmia After Myocardial Infarction In Swine Model

Background:Ventricular arrhythmias(VAs) is one of the major complications of myocardialinfarction, and50%of patients with healed myocardial infarction were dead of fatalVas, mainly including ventricular tachycardia(VT)and ventricular fibrillation(VF).The studies of mechanism and prevention of these malignant arrhythmias are alwaysof great importance in clinical performances. Previous studies mainly focused onventricular remodeling and electrical remodeling, while recent researches haddemonstrated that myocardial infarction might result in sympathetic andparasympathetic neural remodeling, which played an important role in themechanism of VAs and sudden cardiac death(SCD).To improve neural remodelingand make the regeneration of sympathetic and parasympathetic nerve reach asuitable balanced state again may reduce the incidence of VAs and SCD aider MI.iPS cell is a new type of stem cells similar to embryonic stem cells. iPS cells can betransformed from all sorts of different cells of different animals. In theory, iPS cellsare capable of differentiating into various kinds of cells as needed, of course,including cardiovascular system such as atrial muscle, ventricular muscle, bloodvessels and conducting tissue. iPS cells can be used to treat patients with myocardialinfarction. Because of the simplicity and high efficiency of generating patientspecific pluripotent stem cells, iPS cell was the most promising candidate for cardiacregeneration treatments. Studies have shown that iPS cells transplantation canimprove the heart function and myocardial remodeling after myocardial infarction. However, no one has researched the effect of iPS cells transplantation on nerveregeneration and VAs after MI.Object:1) To investigate the survivorship and plasticity of iPS engrafted inpostinfarcted swine myocardium via intromycardial injection;2) To investigate the effects of ipsc transplantation on Neural remodelingand the possible mechanism;3) To evaluate the risk of ventricular arrhythmias after iPS transplantationin postinfarcted swine myocardium;Methods：1) Culture and preparation of porcine iPS cell;2) Swine models with myocardial infarction were created by intracoronaryballoon occlusion of left anterior descending coronary artery. Followingthe successful establishment of the model, mini-swine (n=18) wererandomly allocated to three groups as follows: Sham Group (n=6); PBSGroup (n=6); iPS Group (n=6).3) At6weeks after MI, the pigs received again anaesthesia and2-hoursDynamic Electrocardiography was obtained. Heart rate variability(HRV) was analysed. Then cardiac electrophysiologic study (EPS) wasperformed to evaluate the ventricular arrhythmic risks after iPStransplantation.4) Histological and immunofluorescence studies were performed aftermyocardial specimens were collected. As for immunofluorescencestudy, tyrosine hydroxylase (TH), acetylcholinesterase enzyme (AChE),growth associated protein43(GAP43) and connexin43(CX43) stainingwere performed.TH, GAP43and connexin43expression were detected by using western blot.Results:1) iPS engrafted intramyocardiom can survive for a long time andparticipate in tissue repairs in the infarct area.2) The abnormal HRV induced by MI can be improved by iPStransplantation.3) iPS transplantation can remarkably promote the formation of capillariesand regeneration of cardiac nerves,and significantly improve theautonomic imbalance induced by MI.4) The risk of ventricular tachyarrhythmias was not found to increase and,incontrast,that of malignant ventricular arrhythmias inclined to reductionafter iPS implantation in the course of cardiac EPS.Conclusions:1) MI results in cardiac autonomic neural remodeling, which mainly showsthe increased densities inhomogeneous distribution and paramorphia ofnerve fibers.2) Neural remodeling can increase the incidence of inducible ventriculararrhythmias.3) IPS cell transplantation is effective to reduce the occurrence of VAs inhealed MI, partly by attenuating the heterogeneity of cardiac innervationand normalizing the appearance of cardiac nerve fibers.4) IPS-based therapy can markedly promote formation of capillary andCX43, improve the arrangement of the CX43disorder after MI, thusreducing arrhythmogenic matrix;...