Effects Of Combination Of Amiodarone And Antiarrhythmic Peptide On The Cardiac Gap Junctions And Incidence Of Ventricular Arrhythmias In Healed Myocardial Infarction Rabbit Models

The death due to arrhythmias is one of the leading causes of death in the world, but current antiarrhythmias were limited by unsatisfactory effect and adverse effects such as proarrhythmias. Reentry mechanism play an important role for persistence of arrhythmias. Only reentry can continue when reentry path-length is longer than cardiac wavelength which equal to product of conduction velocity and effective refractory period. Class 3 drugs prolong effective refractory period with a augmented transmural dispersion of repolarization (TDR), so classâ…¢drugs can be proarrhythmic sometimes. Gap junction is very important for the conduction of electrical signals between adjacent myocytes, which provide the electrical coupling channels of low resistance.Gap junction uncoupling associate with proarrhythmic conduction velocity slowing and dispersion of depolarization increasing in many cardiac diseases. Gap junction enhancer antiarrhythmia peptide (AAP10) can improve intercelluar communication and enhances gap junction conductance, so it can augment conduction velocity and diminish TDR. By compensating with each other, gap junction enhancer combined with class 3 drugs may be a promising antiarrhythmic method.In the present study, we used healed myocardial infarction rabbit models to study the effect of combination of AAP10 and Amiodarone on the cardiac gap junctions and incidence of ventricular arrhythmias. Partâ… Preparation of healed myocardial infarction rabbit modelsObjective To preparation of healed myocardial infarction rabbit models with heart failure.To evaluate the efficacy of a chemically modified chitosan anti-adhesion membrane for preventing postoperative pericardial adhesions in rabbit myocardial infarction model. To determine the effect of precordial thumps on terminating early primary ventricular fibrillation in a rabbit model of acute myocardial infarction.Methods 20 Japanese rabbits was performed thoracotomy without coronary artery ligation (A group),180 Japanese rabbits were ligated the middle piece of the left circumflex branch to prepare the myocardial infarction models. Nine weeks after operation,124 survived myocardial infarction rabbitss were divided into four groups:control group 31 (B group), amiodarone group 31 (C group), AAP10 group 31 (D group) and amiodarone combined with AAP10 group 31(E group). The A and B and D groups were treated with saline 2 ml per day at 8 weeks after operation, the C and E groups were treated with saline 2 ml containded with amiodarone 100mg/Kg per day. All rabbits were examined by echocardiogram 12 weeks after operation.The rabbit acute myocardial infarction models with primarily ventricular fibrillation on the surgical bench were divided into two groups. One group was given a sharp precordial thump immediately within two minutes after the onset of ventricular fibrillation. Another group was given heart massage or precordial massage. The effect of precordial thump on ventricular fibrillation were recorded. The statistically significant difference was assessed by Fisher's exact test.Besides,25 Japanese White Rabbits were randomly selected and devided into anti-adhesion membrane group and control group randomly, After thoracotomy and ligation of the middle piece of the left circumflex branch, The treatment group had a chitosan anti-adhesion membrane placed between the heart and retrosternal injured surfaces while control group received nothing. Then Chest was subsequently closed.11 rabbits survived the operation in each group. After a period of 3 months, The alive animals were examined by Cine magnetic resonance imaging then sacrificed under anesthesia, the formation of pericardial adhesions by magnetic resonance cinema and histological anatomy respectively were graded. Data were analyzed by Wilcoxon's rank test.ResultsEchocardiogram showed that in 102 surviving rabbits with healed myocardial infarction, left ventricular internal diastolic diameter (LVIDd) increased significantly,as did left ventricular internal systolic diameter (LVIDs), and the difference between LVIDd and LVIDs. Mean SF decreased, compared with 20 surviving sham operation rabbits. Amiodarone had no effect on heart construction and function.Cine magnetic resonance imaging evaluation of adhesion level, anti-membrane group of mild adhesions, moderate adhesions, severe adhesions, were 2,2,4 respectively; control group were 7,2,0 respectively. The difference was statistically significant (P<0.05). Thoracotomy evaluation of adhesion levels, A group of no adhesions, mild adhesions, moderate adhesions, severe adhesions, were 1,1,2,4 respectively; B group were 3,4,2, 0 respectively. The difference was statistically significant (P<0.05).There were 15 rabbits developed ventricular fibrillation on the bench after ligation of the middle piece of the left circumflex branch.5 rabbits was successfully defibrillated by a sharp precordial thump in 8 rabbits (62.5%).7 rabbits died after heart massage or precordial massage. The difference was statistically significant.Conclusion The healed myocardial infarction rabbit model could be prepared by ligation of the middle piece of the left circumflex branch. Heart function of these models decreased three months after operation. Placement of a chemically modified chitosan anti-adhesion membrane between injured surfaces effectively reduced the formation of postoperative pericardial adhesion in rabbits of myocardial infarction model.Precordial thump was effective on terminating early primary ventricular fibrillation in a rabbit model of acute myocardial infarction. Part II Effects of combination of amiodarone and antiarrhythmic peptide on the gap junctions and incidence of ventricular arrhythmias in healed myocardial infarction modelsObjective the aim of this study is to testify the effect of combination amiodarone with antiarrhythmic peptide (AAP10) on the incidence of ventricular arrhythmiams in healed myocardial infarction rabbits.Methods All rabbits were anesthetized by sodium barbital, then the left wedge ventricular preparations were cannulated and artery perfused by Tyrode's solution in vitro. The volume electrocardiogram, QT Interval, QRS intervial, effective refractory period (ERP), the T-peak to T-end interval (Tp-e), and ventricular tachycardia episodes induced by programmed stimulation was recorded. The Tp-e/QT ratio was calculated. After perfusion, westernblot and immunofluorescence of gap junctions protein connexin 43(Cx43) were performed. The analysis method was bonferroni corrected chi square test or Fisher's exact test, one-way anova, and factorial design analysis.Results The incidence of ventricular tachycardia episodes of E group was less than B group. The Tp-e/QT ratio in B, C, D group were greater than A group, The Tp-e/QT ratio of E group was less than B group. The Cx43 in the heart of B group was downregulated and disorganized compared to A groups. However, The Cx43 in the heart of C, E group was upregulated compared to B group. The Cx43 in the heart of E group was upregulated compared to D group. The Cx43 in the heart of D, E group were well organized than B, C group.Conclusions The artery perfused rabbits wedge preparations with healed myocardial infarction which demonstrated high incidence of induced ventricular tachycardia episodes could be a good platform for research on Ventricular arrhythmias. Amiodarone and AAP10 decreased the Tp-e/QT ratio and the incidence of induced ventricular tachycardia episodes. Amiodarone and AAP10 have synergistic effects on Upregulating Cx43 and prevention of ventricular arrhythmias in a rabbit model of healed myocardial infarction.