胺碘酮与抗心律失常肽合用对陈旧心肌梗死兔心缝隙连接和室性心律失常诱发率的影响
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摘要
陈旧心肌梗死或心力衰竭并发的恶性心律失常是临床最常见的死亡原因之一。目前抗心律失常药物疗效并不能令人满意,而且抗心律失常药物常常带来致心律失常的问题。折返参与了大多数心律失常的发生和维持。折返激动得以维持的条件是心脏激动的波长(传导速度×有效不应期)一定要小于解剖学上的折返路径。因此增快传导速度或延长不应期理论上都能抑制折返的形成。目前延长不应期的药物主要通过Ⅲ类抗心律失常药物延长心肌细胞的动作电位实现,但Ⅲ类抗心律失常药物常常增加心肌的复极离散度而导致尖端扭转型室速的发生。缝隙连接是细胞间特殊的离子通道,对细胞间小分子物质交换和电信号的传导有重要意义。缝隙连接失偶联参与了跨室壁复极离散度的形成。多种器质性心脏病可以出现缝隙连接的重构,表现为缝隙连接蛋白表达减少,缝隙连接从心肌细胞间端端分布转变为侧侧分布,这些情况都造成缝隙连接功能的下降,导致传导的减慢和复极离散度的增加,从而产生致心律失常的基质。缝隙连接增效剂的研发为心律失常的治疗开辟了新的方向。许多研究证实缝隙连接增效剂可以抑制心律失常。我们设想缝隙连接增效剂加快传导,Ⅲ类抗心律失常药物延长不应期,这两种药物优势互补,可以通过抑制折返起到抗心律失常的协同作用。本研究利用陈旧心肌梗死兔楔形心肌块体外灌流制备室性心律失常模型,采用2×2析因设计方法,研究缝隙连接增效剂与Ⅲ类抗心律失常药物胺碘酮合用预防室性心律失常的效果。
第一部分陈旧心肌梗死模型兔的制作
目的制备适用于离体灌流的陈旧心肌梗死模型兔。研究改性壳聚糖防粘连膜预防心脏与周围组织粘连的效果。观察捶击复律对急性心肌梗死兔早期原发性室颤的效果。
方法日本长耳兔200只,随机分为假手术组20只(A组)和心肌梗死模型组180只,假手术组开胸后不结扎冠脉直接关胸,心肌梗死模型组开胸结扎冠脉左旋支的左室支制作心肌梗死模型,对急性心肌梗死造模过程中的原发性心室颤动采取心前区捶击,观察复律效果。实验中随机选择25只兔子术中加用改性壳聚糖防粘连膜以预防心脏与周围组织粘连,三月后分别行磁共振电影和二次开胸评价粘连程度。心肌梗死模型组术后存活160只。术后8周末,再将存活的124只心肌梗死兔随机分为对照组31只(B组)、胺碘酮组31只(C组)、抗心律失常肽组31只(D组)、胺碘酮+抗心律失常肽组31只(E组)。第9周开始给A组、B组及D组口饲生理盐水2ml QD×4周,给C组及E组口饲含胺碘酮100mg／Kg的生理盐水2ml QDx4周。12周末A、B、C、D、E组各存活20、24、26、25、27只。行超声心动图评价心功能。
结果开胸结扎兔左旋支左室主支,制备心肌梗死兔模型成功率高,三月后示心肌梗死兔射血分数较假手术兔明显减低。磁共振电影可以评价心脏与周围组织粘连。术中置入防粘连膜兔心脏与周围组织粘连程度较轻。心前区捶击对急性心肌梗死兔早期原发性室颤有复律效果。
结论开胸结扎兔左旋支的左室主支可制备陈旧心肌梗死兔模型,术后3月心功能明显降低。改性壳聚糖防粘连膜可以防止心脏与周围组织粘连。心前区捶击对急性心肌梗死兔早期原发性室颤有复律效果。
第二部分胺碘酮与抗心律失常肽合用对陈旧心肌梗死兔缝隙连接蛋白Cx43和室性心律失常诱发率的影响
目的研究胺碘酮与心律失常肽合用是否能增强抗心律失常的疗效。
方法麻醉后将各组兔子处死,取左室心肌块动脉插管灌流,A组、B组及C组灌流台氏液,D组及E组灌流加入抗心律失常肽(AAP10)500 nmol／L的台氏液,程序刺激起搏心肌,并记录容积心电图、室性心律失常诱发与否及QT、QRS、ERP、Tpe、等电生理参数,计算Tpe／QT。灌流完成后取心肌组织,利用westernblot和免疫荧光技术检测缝隙连接蛋白Cx43。组间计数资料统计分析采用bonferroni方法校正的卡方检验或精确检验,以P<0.005为差异有统计学意义。A组和其他组间计量资料统计分析采用完全随机设计资料的方差分析。B、C、D、E组间计量资料采用析因设计的方差分析,以评价两种药物之间的交互作用,以P<0.05为差异有统计学意义。
结果A、B、C、D、E组心律失常诱发率分别为0%、62.5%、40%、26.9%、22.2%,E组较B组诱发率减小。B组较A组Tpe／QT增大,E组较B组Tpe／QT减小。B组较A组Cx43表达明显减少。C、E组较B组Cx43表达增加。差异有统计学意义。
结论陈旧心肌梗死兔离体心肌块模型可用于室性心律失常的研究。胺碘酮慢性应用能上调心肌梗死兔心Cx43,与AAP10合用上调心肌梗死兔Cx43作用加强,并进一步减小Tpe／QT,抗心律失常作用进一步加强。
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 classⅢdrugs 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.
PartⅠPreparation of healed myocardial infarction rabbit models
Objective 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.
Results
Echocardiogram 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 models
Objective 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.
第一部分陈旧心肌梗死模型兔的制作
目的制备适用于离体灌流的陈旧心肌梗死模型兔。研究改性壳聚糖防粘连膜预防心脏与周围组织粘连的效果。观察捶击复律对急性心肌梗死兔早期原发性室颤的效果。
方法日本长耳兔200只,随机分为假手术组20只(A组)和心肌梗死模型组180只,假手术组开胸后不结扎冠脉直接关胸,心肌梗死模型组开胸结扎冠脉左旋支的左室支制作心肌梗死模型,对急性心肌梗死造模过程中的原发性心室颤动采取心前区捶击,观察复律效果。实验中随机选择25只兔子术中加用改性壳聚糖防粘连膜以预防心脏与周围组织粘连,三月后分别行磁共振电影和二次开胸评价粘连程度。心肌梗死模型组术后存活160只。术后8周末,再将存活的124只心肌梗死兔随机分为对照组31只(B组)、胺碘酮组31只(C组)、抗心律失常肽组31只(D组)、胺碘酮+抗心律失常肽组31只(E组)。第9周开始给A组、B组及D组口饲生理盐水2ml QD×4周,给C组及E组口饲含胺碘酮100mg／Kg的生理盐水2ml QDx4周。12周末A、B、C、D、E组各存活20、24、26、25、27只。行超声心动图评价心功能。
结果开胸结扎兔左旋支左室主支,制备心肌梗死兔模型成功率高,三月后示心肌梗死兔射血分数较假手术兔明显减低。磁共振电影可以评价心脏与周围组织粘连。术中置入防粘连膜兔心脏与周围组织粘连程度较轻。心前区捶击对急性心肌梗死兔早期原发性室颤有复律效果。
结论开胸结扎兔左旋支的左室主支可制备陈旧心肌梗死兔模型,术后3月心功能明显降低。改性壳聚糖防粘连膜可以防止心脏与周围组织粘连。心前区捶击对急性心肌梗死兔早期原发性室颤有复律效果。
第二部分胺碘酮与抗心律失常肽合用对陈旧心肌梗死兔缝隙连接蛋白Cx43和室性心律失常诱发率的影响
目的研究胺碘酮与心律失常肽合用是否能增强抗心律失常的疗效。
方法麻醉后将各组兔子处死,取左室心肌块动脉插管灌流,A组、B组及C组灌流台氏液,D组及E组灌流加入抗心律失常肽(AAP10)500 nmol／L的台氏液,程序刺激起搏心肌,并记录容积心电图、室性心律失常诱发与否及QT、QRS、ERP、Tpe、等电生理参数,计算Tpe／QT。灌流完成后取心肌组织,利用westernblot和免疫荧光技术检测缝隙连接蛋白Cx43。组间计数资料统计分析采用bonferroni方法校正的卡方检验或精确检验,以P<0.005为差异有统计学意义。A组和其他组间计量资料统计分析采用完全随机设计资料的方差分析。B、C、D、E组间计量资料采用析因设计的方差分析,以评价两种药物之间的交互作用,以P<0.05为差异有统计学意义。
结果A、B、C、D、E组心律失常诱发率分别为0%、62.5%、40%、26.9%、22.2%,E组较B组诱发率减小。B组较A组Tpe／QT增大,E组较B组Tpe／QT减小。B组较A组Cx43表达明显减少。C、E组较B组Cx43表达增加。差异有统计学意义。
结论陈旧心肌梗死兔离体心肌块模型可用于室性心律失常的研究。胺碘酮慢性应用能上调心肌梗死兔心Cx43,与AAP10合用上调心肌梗死兔Cx43作用加强,并进一步减小Tpe／QT,抗心律失常作用进一步加强。
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 classⅢdrugs 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.
PartⅠPreparation of healed myocardial infarction rabbit models
Objective 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.
Results
Echocardiogram 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 models
Objective 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.
引文
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