自主神经系统与心房颤动的关系及房颤诊疗策略的研究

发布时间：2018-05-12 14:31

本文选题：自主神经系统 + 心房颤动　；参考：《上海交通大学》2015年博士论文

【摘要】：本课题我们拟通过观察皮肤神经活性与星状神经节活性的关系、低强度迷走神经刺激对心房颤动的影响以及环左房消融对心房颤动及心脏电生理的影响,来探讨心房颤动与自主神经系统的关系,同时进一步研究心房颤动诊疗的策略。本课题的研究内容主要包括以下三个部分:(1)观察胸部皮肤神经活性与星状神经节活性关系,探讨应用胸部皮肤神经活性间接评估星状神经节活性的可行性及其与心率变化的关系。(2)观察低强度迷走神经刺激对心房颤动的影响,研究自主神经干预治疗房颤的新方法,探讨心房颤动与自主神经系统的关系及迷走神经刺激抑制心房颤动的作用机制。(3)观察环左房消融对心房颤动及心脏电生理的影响,评价心外膜环左房消融联合肺静脉消融治疗心房颤动的有效性和安全性,进一步完善外科治疗心房颤动的策略。研究结果表明:(1)胸部皮肤神经活性可用于间接评估犬星状神经节活性,与心率变化存在很好的相关性,可用来预测心律失常的发生。(2)低强度迷走神经刺激可以减慢房颤时的快速心室率,其作用机制可能是通过:(1)增加下腔静脉-心房下部神经节丛活性(inferior vena cava-inferior atrial ganglionated plexus nerve activity,IVC-IAGPNA),减慢房室结的传导;(2)诱导星状神经节(stellate ganglion,SG)内神经节细胞凋亡,减弱SG的交感神经活性。(3)心外膜环左房消融联合肺静脉消融可以安全、有效的隔离消融左房顶部及后壁。与单纯肺静脉消融相比,环左房消融联合肺静脉消融可以更有效的终止房颤的维持、抑制房颤的复发,提高房颤的治疗效果。第一部分胸部皮肤神经活性与星状神经节活性的关系目的:星状神经节活性与心律失常的发生密切相关,被认为是心律失常发生的重要基础。直接记录星状神经节活性需要开胸手术,不仅操作复杂,而且创伤较大。相关研究,已证实上胸部的皮肤主要受来自星状神经节的交感神经的支配。本研究拟通过观察胸部皮肤神经活性与星状神经节活性的关系,来探讨应用胸部皮肤神经活性间接评估星状神经节活性的可行性。方法:实验用杂种犬9只,体重22~30Kg,5只用于急性实验研究,4只用于慢性实验研究。急性实验:麻醉状态下,将蜂毒明肽直接注射到犬的右侧星状神经节,同时记录10分钟犬右侧星状神经节活性、胸部皮肤神经活性及心电图。慢性实验:左侧开胸,将神经活性记录仪植入犬体内记录左侧星状神经节活性;待犬恢复2周后,在犬清醒状态下,同时记录30分钟犬左侧星状神经节活性、胸部皮肤神经活性及心电图。结果:急性实验结果表明,胸部皮肤神经活性与右侧星状神经节活性呈明显正相关(r=0.877,95%CI[0.732,1.000],P0.05);胸部皮肤神经活性与心率也呈明显的正相关(r=0.837,95%CI[0.752,0.923],P0.05)。慢性实验结果表明,胸部皮肤神经活性与左侧星状神经节活性呈明显正相关(r=0.746,95%CI[0.527,0.964],P0.05);胸部皮肤神经活性与心率也呈明显的正相关(r=0.706,95%CI[0.484,0.927],P0.05)。结论:胸部皮肤神经活性可用于间接评估犬星状神经节活性,与心率变化存在很好的相关性,可用来预测心律失常的发生。第二部分低强度迷走神经刺激抑制犬心房颤动的作用机制研究目的:目前,大量研究已证实低强度迷走神经刺激(low-level vagal nerve stimulation,LL-VNS)可以有效抑制心房颤动的触发,但迷走神经刺激(vagal nerve stimulation,VNS)对房颤维持的影响目前研究仍较少,而且迷走神经刺激抑制心房颤动的具体作用机制仍不清楚。本实验拟通过观察迷走神经刺激对犬心房颤动的影响,研究迷走神经刺激抑制心房颤动的作用机制。方法:实验用杂种犬6只,体重23~28Kg。全麻下,右侧开胸,在右心耳上安装植入型复律除颤器;安装神经活性记录仪记录下腔静脉-心房下部神经节丛活性(inferior vena cava-inferior atrial ganglionated plexus nerve activity,IVC-IAGPNA)、右侧迷走神经活性(right vagal nerve activity,RVNA)和左侧迷走神经活性(left vagal nerve activity,LVNA);在犬左侧颈部迷走神经上安装迷走神经刺激器。犬恢复2周后,打开复律除颤器进行右心耳快速起搏(600bpm),构建犬持续的心房颤动模型。模型构建成功后,打开迷走神经刺激器,刺激模式为(14s ON,1.1min OFF或3min OFF)观察迷走神经刺激对犬心房颤动的影响,并对比观察不同时间点犬左房右下GP及左、右迷走神经活性的变化情况。病理研究,分别应用酪氨酸羟化酶染色和TUNEL检测观察星状神经节(stellate ganglion,SG)的病理变化情况,探究其可能的机制。结果:快速起搏2~6周(平均4.00±1.79周)后,6只犬均构建成持续的房颤模型。与房颤基线(142.04±7.93 bpm[95%CI,133.72 to 150.37])相比,犬的心室率在VNS 1.1min OFF(123.29±6.29 bpm[95%CI,116.69 to 129.89])(P=0.001)和VNS 3min OFF(120.01±4.93 bpm[95%CI,114.84 to 125.18])(P=0.001)时均有明显减慢。IVC-IAGPNA在VNS 1.1min OFF(40.98±11.27m V-s[95%CI,29.16 to 52.80])(P=0.002)和VNS 3min OFF(39.78±10.14m V-s[95%CI,29.14 to 50.42])(P=0.001)时均较房颤基线(35.68±10.99 m V-s[95%CI,24.15 to 47.21])有明显提高。酪氨酸羟化酶染色发现,在成功取到双侧星状神经节的5只犬中,左侧的星状神经节中均可见明显的坏死区,而右侧未见明显坏死区。左侧坏死区的面积约占左侧星状神经节面积的38.6±19.3%[95%CI,14.7%to 62.5%]。坏死区内TH阴性神经节细胞的百分比约为8.4±4.1%[95%CI,3.3%to 13.6%],较正常区内TH阴性神经节细胞的百分比(3.0±1.3%[95%CI,0%to 6.5%])明显升高(P=0.04)。TUNEL检测发现,5只犬双侧星状神经节内均可见到TUNEL阳性的神经节细胞,左侧星状神经节内TUNEL阳性细胞的比例约为22.2±17.2%[95%CI,0.9%to 43.5%],右侧星状神经节内TUNEL阳性细胞的比例约为12.8±8.4%[95%CI,2.4%to 23.2%]。结论:迷走神经刺激可以减慢房颤时的快速心室率,其作用机制可能是通过:(1)增加IVC-IAGPNA,减慢房室结的传导;(2)诱导SG内神经节细胞凋亡,减弱SG的交感神经活性。第三部分心外膜环左房消融联合肺静脉消融对心房颤动的影响目的:本研究的目的是评价心外膜环左房消融(circumferential left atrial ablation,CLAA)联合肺静脉隔离(pulmonary vein isolation,PVI)治疗心房颤动(atrial fibrillation,AF)的有效性和安全性。方法:实验用猪30只,随机分为3组,每组各10只:房颤对照组(AF组)、肺静脉消融组(PVI组)、环左房消融联合肺静脉消融组(CLAA+PVI组)。通过心房快速起搏构建持续的心房颤动模型。房颤构建成功后,AF组不做消融处理;PVI组应用双极射频消融钳做肺静脉隔离消融;CLAA+PVI组应用双极射频消融钳先做肺静脉隔离消融,再做环左房消融。消融后,应用电复律将所有房颤猪恢复窦性心律,再次检测比较各组猪的房颤易感性及房颤维持时间的差异。结果:起搏6.27±0.69周后,所有猪均成功构建成稳定的持续的房颤模型。PVI组和CLAA+PVI组的猪顺利在心脏不停跳下实施心外膜消融术。2组中,单纯肺静脉消融使3只(3/20,15%)猪终止房颤,环左房消融联合肺静脉消融使5只(5/8,62.5%)猪终止房颤(P=0.022)。全部猪恢复窦性心律后,burst起搏可使AF组10只(10/10)猪全都诱发成持续的房颤;PVI组仅有3只(3/10,P=0.003)诱发成持续的房颤,CLAA+PVI组(0/10,P0.001)无持续的房颤诱发成功,均明显低于AF组;而PVI组与CLAA+PVI组无明显差异(P=0.211)。AF组诱导的房颤平均维持时间为1800s;PVI组的房颤平均维持时间为1217.90±444.10s[95%CI,900.21-1535.59],CLAA+PVI组的房颤平均维持时间为734.70±177.81s[95%CI,607.51-861.89],较AF组明显缩短(P0.05);与PVI组相比,CLAA+PVI组的房颤平均维持时间也明显缩短(P0.05)。结论:心外膜环左房消融联合肺静脉消融可以安全、有效的隔离消融左房顶部及后壁。与单纯肺静脉消融相比,环左房消融联合肺静脉消融可以更有效的终止房颤的维持、抑制房颤的复发,提高房颤的治疗效果。
[Abstract]:We intend to investigate the relationship between the activity of the cutaneous nerve and the stellate ganglion, the influence of the low intensity vagus nerve stimulation on atrial fibrillation and the effect of the left atrial ablation on atrial fibrillation and the electrophysiology of the heart, to explore the relationship between atrial fibrillation and the autonomic nervous system, and to further study the strategy of the diagnosis and treatment of atrial fibrillation. The main contents of this study include the following three parts: (1) observe the relationship between the activity of the thoracic skin nerve and the activity of the stellate ganglion, and discuss the feasibility of indirect evaluation of the activity of stellate ganglion with the activity of the skin of the chest and the relationship between the activity of the stellate ganglion and the change of heart rate. (2) observe the effect of the low intensity vagus nerve stimulation on the atrial fibrillation. A new method of autonomic nerve intervention in the treatment of atrial fibrillation. The relationship between atrial fibrillation and autonomic nervous system and the mechanism of vagus stimulation to inhibit atrial fibrillation. (3) observe the effect of left atrial ablation on atrial fibrillation and cardiac electrophysiology, and evaluate the effectiveness of left atrial ablation combined with pulmonary vein ablation in the treatment of atrial fibrillation. Safety, further improving the strategy of surgical treatment of atrial fibrillation. The results show: (1) the activity of the chest skin nerve can be used to indirectly evaluate the activity of the dog stellate ganglion, and there is a good correlation with the change of heart rate, which can be used to predict the occurrence of arrhythmia. (2) the low intensity vagus nerve stimulation can slow the rapid ventricular rate of atrial fibrillation. Its mechanism may be through: (1) increasing the activity of the inferior vena cava subatrium ganglion plexus (inferior vena cava-inferior atrial ganglionated plexus nerve activity, IVC-IAGPNA), slowing the conduction of atrioventricular node; (2) inducing the apoptosis of the ganglion cells in the stellate ganglion (stellate ganglion, SG) and reducing the sympathetic activity of the ganglion. (3) the heart. Epicardial left atrial ablation combined with pulmonary vein ablation can safely and effectively isolate the top and posterior wall of the left atrium. Compared with the only pulmonary vein ablation, the left atrial catheter ablation combined with the pulmonary vein ablation can effectively terminate the maintenance of atrial fibrillation, inhibit the recurrence of atrial fibrillation, and improve the treatment effect of atrial fibrillation. The activity of ganglionic ganglion Objective: the activity of stellate ganglion is closely related to the occurrence of arrhythmia, which is considered as an important basis for the occurrence of arrhythmia. Direct recording of stellate ganglion activity requires thoracotomy, not only complicated, but also traumatic. Related research has confirmed that the skin of the upper chest is mainly from the stellate ganglion. This study is to explore the feasibility of indirect evaluation of the activity of stellate ganglia by using the thoracic skin neuroactivity by observing the relationship between the neuroactivity of the chest skin and the activity of the stellate ganglion. Methods: 9 dogs in the experimental hybrid dogs, weight 22~30Kg, 5 were used in the acute experimental study, and 4 were used for chronic experimental study. In a sex experiment, the drug was injected into the right stellate ganglion of the dog by injecting MELITIN directly to the right stellate ganglion of the dog. At the same time, the right stellate ganglion activity, the nerve activity and electrocardiogram of the chest skin were recorded for 10 minutes. The chronic experiment: the left thoracotomy was carried out to record the activity of the left stellate ganglion in the dog. After 2 weeks of recovery, the dog was treated in dogs. At the same time, the left stellate ganglion activity of the dog, the nerve activity of the chest skin and the electrocardiogram were recorded for 30 minutes. Results: the results of acute experiment showed that the activity of the skin of the chest was positively correlated with the activity of the right stellate ganglion (r=0.877,95%CI[0.732,1.000], P0.05), and the neuroactivity of the chest skin and heart rate also showed a positive positive phase. R=0.837,95%CI[0.752,0.923] (P0.05). Chronic experimental results showed that there was a significant positive correlation between the activity of the chest skin and the activity of the left stellate ganglion (r=0.746,95%CI[0.527,0.964], P0.05); the neuroactivity of the chest skin was also positively correlated with the heart rate (r= 0.706,95%CI[0.484,0.927], P0.05). Conclusion: the neuroactivity of the chest skin is available. The activity of the stellate ganglion in dogs was evaluated indirectly, and there was a good correlation with heart rate changes. It could be used to predict the occurrence of arrhythmia. Second the mechanism of the inhibitory effect of low intensity vagus nerve stimulation on atrial fibrillation in dogs was studied. At present, a large number of studies have proved low-level vagal nerve stimulation, LL-V NS) can effectively inhibit the triggering of atrial fibrillation, but the effect of vagal nerve stimulation (VNS) on the maintenance of atrial fibrillation is still less, and the specific mechanism of the vagus stimulation inhibition of atrial fibrillation is still unclear. This experiment is to observe the effect of vagus nerve stimulation on atrial fibrillation in dogs and study the vagus The mechanism of the inhibition of atrial fibrillation by nerve stimulation. Methods: 6 dogs were tested in a hybrid dog, under 23~28Kg. general anesthesia, right open chest, and an implantable defibrillator on the right auricle, and a neuroactive recorder was installed to record the activity of inferior vena cava ganglion plexus (inferior vena cava-inferior atrial ganglionated plexus nerve AC) Tivity, IVC-IAGPNA), right vagus nerve activity (right vagal nerve activity, RVNA) and left vagus nerve activity (left vagal nerve activity, LVNA). The vagus nerve stimulator was installed on the vagus nerve in the left neck of the dog. After 2 weeks, the dog opened the cardioversion defibrillator to make the right auricle rapid pacing, and set up the continuous atrial fibrillation of the dog. After the model was built, the vagus stimulator was opened and the stimulation mode was observed (14s ON, 1.1min OFF or 3min OFF) to observe the effect of vagus nerve stimulation on the atrial fibrillation in dogs, and the changes in the activity of left and right vagus nerve in left atrium of dogs at different time points were compared. The pathological study was used to stain the tyrosine hydroxylase, respectively. The pathological changes of stellate ganglion (SG) were detected and observed by TUNEL. Results: after fast pacing 2~6 weeks (average 4 + 1.79 weeks), 6 dogs were constructed to build a continuous atrial fibrillation model. Compared with the baseline of atrial fibrillation (142.04 + 7.93 bpm[95%CI, 133.72 to 150.37]), the ventricular rate of dogs was VNS 1.1min OFF (123.29). When 6.29 bpm[95%CI, 116.69 to 129.89]) (P=0.001) and VNS 3min OFF (120.01 + 4.93 bpm[95%CI, 114.84 to 125.18]) (P=0.001), there was a significant decrease in the baseline of.IVC-IAGPNA. (35. The 68 + 10.99 m V-s[95%CI, 24.15 to 47.21]) was obviously improved. The necrotic area was found in the left stellate ganglion, while the left stellate ganglion had no obvious necrotic zone in the left stellate ganglion, and the area of the left necrotic area was about 38.6 + 19.3%[95%CI in the left stellate ganglion area. The percentage of TH negative ganglion cells in the necrotic area of 14.7%to 62.5%]. was about 8.4 + 4.1%[95%CI, 3.3%to 13.6%], and the percentage of TH negative ganglion cells in the normal area (3 + 1.3%[95%CI, 0%to 6.5%]) increased significantly (P=0.04).TUNEL detection found that 5 dogs could see the positive ganglion cells in the bilateral star shaped divine ganglion, left star The proportion of TUNEL positive cells in the ganglionic ganglion was about 22.2 + 17.2%[95%CI, 0.9%to 43.5%], and the proportion of TUNEL positive cells in the right stellate ganglion was about 12.8 + 8.4%[95%CI. 2.4%to 23.2%]. concluded that vagus nerve stimulation could slow the rapid ventricular rate of atrial fibrillation, and its mechanism may be through: (1) increasing IVC-IAGPNA and slowing atrioventricular node Conduction; (2) induce apoptosis in SG internal ganglion cells and weaken the sympathetic activity of SG. The purpose of the third part of the epicardial ring left atrial ablation combined with pulmonary vein ablation on atrial fibrillation: the purpose of this study was to evaluate circumferential left atrial ablation, CLAA) combined with pulmonary vein isolation (pulmonary vein isol). The efficacy and safety of ation, PVI) for the treatment of atrial fibrillation (atrial fibrillation, AF). Methods: 30 pigs were randomly divided into 3 groups, 10 rats in each group: atrial fibrillation control group (AF group), pulmonary vein ablation group (group PVI), left atrial ablation combined with pulmonary vein ablation group (group CLAA+PVI). Atrial fibrillation model was constructed by atrial rapid pacing. After the construction of the tremor was successful, the AF group did not do the ablation treatment; the PVI group applied the bipolar radiofrequency ablation forceps to the pulmonary vein isolation ablation; the CLAA+PVI group applied the bipolar radiofrequency ablation forceps to the pulmonary vein isolation ablation and the left atrium ablation. After ablation, all the atrial fibrillation pigs were restored to sinus rhythm and the susceptibility to atrial fibrillation in each group was compared again. Results: after 6.27 + 0.69 weeks of pacing, all pigs were successfully constructed into a stable persistent atrial fibrillation model.PVI and CLAA+PVI in group.2, and 3 (3/20,15%) pig terminated atrial fibrillation, 5 pigs were ablation combined with pulmonary vein ablation. (5/8,62.5%) the pig terminated atrial fibrillation (P=0.022). After all pigs were restored to sinus rhythm, burst pacing could induce 10 (10/10) pigs in the AF group to induce persistent atrial fibrillation; only 3 (3/10, P=0.003) induced persistent atrial fibrillation in group PVI, and the CLAA+PVI group (0/10, P0.001) was successfully induced by no persistent atrial fibrillation, all significantly lower than that in the AF group. The average maintenance time of atrial fibrillation induced by the difference (P=0.211) group.AF was 1800s, and the average maintenance time of atrial fibrillation in group PVI was 1217.90 + 444.10s[95%CI, 900.21-1535.59], and the average maintenance time of atrial fibrillation in group CLAA+PVI was 734.70 + 177.81s[95%CI, 607.51-861.89], and the AF group was significantly shorter (P0.05). Compared with the PVI group, the average maintenance time of atrial fibrillation was compared with the PVI group. Conclusion: the left atrial catheter ablation combined with pulmonary vein ablation can safely and effectively isolate the top and posterior wall of the left atrium. Compared with the pure pulmonary vein ablation, the left atrial catheter ablation combined with pulmonary vein ablation can more effectively terminate the maintenance of atrial fibrillation, inhibit the recurrence of atrial fibrillation and improve the therapeutic effect of atrial fibrillation.

【学位授予单位】：上海交通大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R541.75

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