Effects Of Neural Remodeling On Cardiac Electrophysiology In Rabbits With Artificial Myocardial Infarction And Captopril Intervention Study

Background and objectsVentricular arrhythmias (VAs) is one of the major complications of myocardial infarction, and 50% of patients with healed myocardial infarction were dead of fatal VAs, mainly including ventricular tachycardia (VT) and ventricular fibrillation( Vf). The studies of mechanism and prevention of these malignant arrhythmias are always of great importance in clinical performances. Previous studies mainly focused on ventricular remodeling and electrical remodeling, while recent researches had demonstrated that myocardial infarction might result in sympathetic and parasympathetic neural remodeling, which played an important role in the mechanism of VAs and sudden cardiac death(SCD). To improve neural remodeling and make the regeneration of sympathetic and parasympathetic nerve reach a suitable balanced state again may reduce the incidence of VAs and SCD after MI.Several studies had showed that β-blocker could reduce the incidence of SCD and improve sympathetic innervation of infarct border after MI. It is known to all angiotensin converting enzyme inhibitor (ACEI) is a kind of medicine that is important in acute myocardial infarction (AMI) management. Previous study demonstrated that chronic ACEI intervention can attenuate the reduction of tyrosine hydroxylase ( TH ) immunostained nerve terminal and catecholaminergic histofluorescence profiles in pacing-induced heart failure. However, until now there is no research of its probable effect on neural remodeling after MI and what role the effect plays in cardiac electrophysiology. For this reason, the main objects of this study are: 1) Immunohistochemistry RT-PCR and electrophysiological study were used in healed animal MI model to investigate the character of neural remodeling and the relationship between neural remodeling and incidence of inducible ventricular arrhythmias. 2) To investigate the probable effect of ACEI on neural remodeling and cardiac electrophysiology after MI. MethodsForty-two rabbits were randomly assigned to three groups. Captopril group (n=15) were ligated with coronary artery for MI induction and administrated with oral captopril (10mg·kg^-1·d^-1 ). Control group (n=15) were also ligated with coronary artery and administrated with sodium chloride solution of 0.9% (5ml·kg^-1·d^-1 ). Sham group (n=12) did not have coronary artery ligated, and only underwent thoracotomy and pericardiotomy. 8 weeks after operation, programmed electrical stimulation (PES) was applied to detect the incidence of VA and effective refractory period (ERP) of the periphery of infarct. Then the expressions of S100 protein growth associated protein 43 (GAP43) TH and neurofilament (NF) were studied by immunohistochemistry or RT-PCR. Results1. Animal ModelDuring the procedure, 3 rabbits in control group and 4 in captopril group died, while no rabbit died in sham group. Eight weeks after operation, there are abnormal Q waves in lead I aVL detected by the surface electrocardiogram in captopril group and control group, and the myocardium below the ligated level were pallescence. No changes of the surface electrocardiogram and myocardium were found in sham group.2. Electrophysiological StudyDuring electrophysiological study, significant prolongation of ERP was demonstrated in control group compared that in the sham group (120.4±8.1ms vs. 92.5±5.0ms, p<0.01 ) . However, ERP was restored significantly after the treatment with captopril (102.2±8.7ms vs. 92.5±5.0ms, p<0.01) . Programmed ventricular stimulation induced Vf in 2 of 12 rabbits (16.7%) in sham group. VAs were induced in 7 of 12 (58.3%)control group rabbits. Among these rabbits, monomorphic ventricular tachycardia (MVT) occurred in 3 rabbits (25.0%), and 1 rabbit (8.3%) had polymorphic ventricular tachycardia (PVT); and others 3 rabbits (25.0%) were induced to Vf. Furthermore, prolonged captopril treatment could decrease the incidence of the inducible VAs in healed myocardial infarction. Only 1 of 11 rabbits (9.1%) was induced to PVT and 2(18.2%) were induced to Vf was 18.1%. No MVT was observed in captopril group. The incidence of inducible VAs had significant statistical significance between captopril group and control group control group and sham group.3. ImmunohistochemistryIn sham group, S100 immunopositive slender nerve fibers distributed evenly among cardiac muscle bundles. However, they took a gross look in control group, and nerve fibers were mainly distributed at the periphery of infarcted tissues and the perivascular regions. Inhomogeneous distribution of nerve fibers was easily seen in the infarct border. Some nerve fibers clustered together around the infarct border or perivascular regions. GAP 43 immunopositive nerve fibers were rarely found or even couldn't be found in sham group, while they were easily found in control group. The densities of GAP 43 and S100 positive nerve fibers were significantly high (p<0.01 p<0.01) in infarct border of control rabbits compared with sham group. After 8 weeks of captopril treatment, nerve fibers became slender and were largely parallel to the orientation of myocardial fibers, which got close to the distribution and appearance of nerve fibers in sham group. However, the densities of GAP 43 and S100 positive nerve fibers decreased after prolonged captopril therapy in infarct border by the number. But there was no statistical significance (p =0.13 and p =0.07 respectively) compared with that in the placebo rabbits. In the non-infarct left ventricle free wall (LVFW) , the densities of GAP 43 and S100 positive nerve fibers of control group were significantly high (p<0.01 p<0.01) compared with that of sham group, but no statistical significance was found between control group and captopril group (p>0.05 p>0.05) .4. RT-PCR MI resulted in the increased expressions of TH and NF comparing to the sham group both at the infarct border and non-infarct LVFW(p < 0.01 p<0.01). Furthermore, prolonged treatment with captopril did not decreased the expression of TH and NF mRNA significantly (p =0.09 p =0.11) in healed myocardial infarction. Conclusion1. MI results in cardiac autonomic neural remodeling, which mainly shows the increased densities inhomogeneous distribution and paramorphia of nerve fibers.2. Neural remodeling can increase the incidence of inducible ventricular arrhythmias.3. Prolonged captopril treatment is effective to reduce the occurrence of VAs in healed MI, partly by attenuating the heterogeneity of cardiac innervation and normalizing the appearance of cardiac nerve fibers.