低强度迷走神经刺激抑制阻塞性睡眠呼吸暂停兔模型心房颤动的研究
发布时间：2018-08-17 13:58
【摘要】：心房颤动(Atrial Fibrillation,AF)是临床上最常见的持续性心律失常,可引起心力衰竭和动脉栓塞等并发症,导致病人病残率和病死率增加,从而成为一个耗资巨大的公共健康问题。阻塞性睡眠呼吸暂停综合征(Obstructive Sleep Apnea Sydrome, OSAS)是一种常见的慢性呼吸系统疾病,以睡眠时出现反复呼吸暂停、严重打鼾、白天嗜睡为特征。据统计,4%中年男性和2%中年女性患有OSAS。其危险因素诸如年龄、性别、高血压、肥胖等,均与AF相同。近年来越来越多的证据证实阻塞性睡眠呼吸暂停(Obstructive Sleep Apnea,OSA)与AF的发生和维持有重要相关性,并发现伴有OSA的AF病人治疗的成功率明显降低。因此及早发现并积极治疗OSA,对心律失常危险因素的识别和治疗方案的选择提出了新的挑战。然而目前的AF动物模型大多是心房快速起搏、自主神经介导以及左房压力或容积增大导致的AF等,尚缺乏理想的OSA介导的AF模型,本研究第一部分旨在建立一种模拟临床OSA相关的AF的动物模型并研究其特点,为进一步研究OSA并发AF的机制及探索新的治疗方案提供基础。 经导管射频消融术是目前治疗AF的主要方法,然而其复发率高达20%-50%。以往认为,AF消融术后复发率升高与高血压、肥胖、左房增大、持续性AF等因素有关。但近期研究发现,在行导管射频消融术的AF患者中,如果合并OSAS,其复发率要明显高于单纯AF患者,这提示OSAS可能为AF射频消融术后高复发率的另一项危险因素。因此,在合并OSAS和AF患者中导管射频消融的应用受到了一定限制。所以国内外学者一直在试图寻找除消融之外其他治疗AF的非药物方法。自上世纪早期以来,颈部迷走神经干刺激一直被公认为是AF诱发和持续的重要因素之一,其可能的发生机制是使心房有效不应期(Effective Refractory Period, ERP)缩短并增加心房ERP离散度,从而进一步加速多重折返环的形成。但最近一系列相关研究结果表明,低强度迷走神经刺激(Low level vagus nerve stimulation,LLVNS)与阈上刺激不同,有可能是一种预防和治疗AF的有效手段。本研究第二部分旨在研究LLVNS是否能够抑制OSA诱导的AF的发生,并可能为OSA诱导的AF提供一条新的治疗途径。 1. OSAS并发AF的动物模型的建立目的：构建模拟临床OSA相关的AF的动物模型并研究其特点,为进一步研究OSA并发AF的机制及探索新的治疗方案提供基础。 方法：成年新西兰大白兔6只,麻醉后行气管切开并给予气管插管,在呼气末夹闭气管插管1分钟模拟OSA。每间隔5分钟给予一次OSA,6分钟为一个周期,共持续4小时。在OSA之前、之后分别测量ERP、血压、食管内压(ITP)、动脉血气分析(PaO2、PaCO2、PH),在给予OSA的1分钟内通过程序刺激测量ERP和房颤持续时间(Atrial Fibrillation Duration,、AFD)。 结果：每次呼吸暂停1分钟末动脉血二氧化碳分压(PaCO2)较呼吸暂停前即刻明显增加,PH值、动脉血氧分压(Pa02)较呼吸暂停前即刻明显降低,ITP也明显降低。呼吸暂停后心率下降,血压有降低趋势,待呼吸暂停终止后即刻起心率血压明显增加,心率基本恢复至呼吸暂停前状态,而血压较呼吸暂停前明显升高。随着反复OSA的时间延长,ERP逐渐缩短,AFD逐渐延长。 结论：(1)本实验成功构建了一种新的OSAS动物模型。该模型显示了与临床OSAS患者相似的病理生理和电生理特点。 (2)本研究成功模拟了临床OSA相关的AF的动物模型,为进一步研究OSA并发AF的机制及探索新的治疗方案提供了基础。 2. LLVNS抑制OSA兔模型AF的研究 目的：研究LLVNS是否能够抑制OSA诱导的AF的发生,可能为OSA诱导的AF提供一条新的治疗途径。 方法：成年新西兰大白兔22只,麻醉后行气管切开并给予气管插管,在呼气末夹闭气管插管1分钟模拟OSA。每间隔5分钟给予一次OSA,6分钟为一个周期,共持续4小时。在OSA之前、之后分别测量ERP、血压、ITP、PaO2、 PaCO2和PH值,在给予OSA的1分钟内通过程序刺激测量ERP和AFD。实验动物随机分为两组,对照组(control,n=11)只给予呼吸暂停4小时,实验组(LLVNS, n=11)除呼吸暂停外,在起始3小时内同时给予LLVNS,第4小时停止LLVNS,只给予OSA。 结果：本研究发现,对照组随着反复OSA时间的延长,ERP逐渐缩短,AFD逐渐延长。与对照组相比,从第二小时起LLVNS组明显抑制了反复呼吸暂停引起的ERP的缩短(P0.0001),并且还可以使ERP较基线时延长。同时LLVNS可以显著缩短OSA诱发的AFD。2倍起搏阈值时,LLVNS抑制了由OSA诱发的AF发生,为OSA诱发AF的预防提供了证据。10倍起搏阈值时,在LLVNS组,LLVNS和反复呼吸暂停同步进行1.5小时时,AFD出现明显缩短,至2小时时,LLVNS完全抑制了OSA诱导的AF发作,为OSA诱发AF的治疗提供了证据。LLVNS和OSA同步进行3小时后,停止LLVNS,继续给予反复OSA1小时,ERP仍处于延长状态,且未出现AF发作,这表明3小时LLVNS引起的抗心律失常作用至少可以持续1小时以上。PaO2、PaCO2、PH值、ITP及动脉收缩压(SBP)的变化在两组间无变化。 结论：(1)本研究从设计上高度模拟了临床OSAS的特征,成功构建了OSA诱导的AF模型,并证实LLVNS能够抑制OSA诱导的心房急性电重构,既可以预防也可以治疗OSA引发的AF的发生,为OSA诱发AF的预防和治疗提供了证据。 (2)随着研究的完善,LLVNS完全有潜力运用到临床,成为安全有效治疗AF的方法,为临床治疗AF尤其是OSA诱发的AF提供一种新的治疗选择。
[Abstract]:Atrial Fibrillation (AF) is the most common persistent arrhythmia in clinical practice, which can cause complications such as heart failure and arterial embolism, resulting in increased disability and mortality, thus becoming a costly public health problem. Obstructive Sleep Apnea Sydrome (OSAS) It is a common chronic respiratory disease characterized by recurrent apnea during sleep, severe snoring, and daytime sleepiness. According to statistics, 4% of middle-aged men and 2% of middle-aged women have OSAS. Risk factors such as age, sex, hypertension, obesity, etc. are the same as AF. In recent years, more and more evidence has confirmed obstructive sleep apnea. Obstructive Sleep Apnea (OSA) is associated with the occurrence and maintenance of AF, and the success rate of treatment for AF patients with OSA is significantly reduced. Therefore, early detection and active treatment of OSA pose new challenges to the identification of risk factors for arrhythmia and the choice of treatment options. However, most of the current AF animal models are atrial. There is no ideal OSA-mediated AF model for rapid pacing, autonomic nerve-mediated AF and left atrial pressure or volume enlargement. In the first part of this study, we aimed to establish an animal model of OSA-related AF and study its characteristics, so as to provide a basis for further study of the mechanism of OSA complicated with AF and explore new treatment options.
Radiofrequency catheter ablation is the main treatment for AF, but its recurrence rate is as high as 20% - 50%. Previous studies have shown that the increased recurrence rate after AF is associated with hypertension, obesity, enlarged left atrium, persistent AF and other factors. However, recent studies have found that in AF patients undergoing catheter radiofrequency ablation, if combined with OSAS, the recurrence rate is significantly higher. This suggests that OSAS may be another risk factor for high recurrence rate of AF after radiofrequency ablation. Therefore, the use of catheter radiofrequency ablation in patients with OSAS and AF has been limited to some extent. Therefore, scholars at home and abroad have been trying to find other non-drug treatments for AF besides ablation. Vagus trunk stimulation has long been recognized as one of the important factors inducing and sustaining AF. Its possible mechanism is to shorten the effective refractory period (ERP) and increase the dispersion of atrial ERP, thus further accelerating the formation of multiple reentry loops. Unlike suprathreshold stimulation, low level vagus nerve stimulation (LLVNS) may be an effective means to prevent and treat AF. The second part of this study was to investigate whether LLVNS can inhibit OSA-induced AF and may provide a new therapeutic approach for OSA-induced AF.
1. Establishment of an animal model of OSAS complicated with AF. Objective: To construct an animal model of OSA-related AF and study its characteristics, so as to provide a basis for further study of the mechanism of OSA complicated with AF and explore new treatment options.
Methods: Six adult New Zealand rabbits were given tracheotomy and tracheal intubation after anesthesia, and OSA was simulated by clipping tracheal intubation at the end of expiration for 1 minute. OSA was given once every 5 minutes for a period of 6 minutes for 4 hours. ERP, blood pressure, intraesophageal pressure (ITP), arterial blood gas analysis (PaO2, PaCO2, PH) were measured before and after OSA. ERP and AFD were measured by programmed stimulation within one minute of OSA administration.
Results: At the end of 1 minute after apnea, arterial partial pressure of carbon dioxide (PaCO2) increased significantly, PH value, arterial partial pressure of oxygen (Pa02) decreased significantly, and ITP decreased significantly. After apnea, heart rate decreased, blood pressure decreased, and heart rate and blood pressure increased significantly immediately after apnea. Additionally, the heart rate basically returned to the pre-apnea state, while the blood pressure was significantly higher than that before apnea. With the prolongation of repeated OSA, ERP gradually shortened and AFD gradually prolonged.
CONCLUSION: (1) A new OSAS animal model was successfully constructed, which showed similar pathophysiological and electrophysiological characteristics with clinical OSAS patients.
(2) The animal model of OSA-related AF was successfully simulated in this study, which provides a basis for further study of the mechanism of OSA-associated AF and exploration of new therapeutic regimens.
Inhibitory effect of 2. LLVNS on AF in OSA rabbit model
AIM: To investigate whether LLVNS can inhibit OSA-induced AF and provide a new therapeutic approach for OSA-induced AF.
Methods: 22 adult New Zealand white rabbits were given tracheotomy and tracheal intubation after anesthesia. OSA was simulated by clipping tracheal intubation at the end of expiration for 1 minute. OSA was given at intervals of 5 minutes and 6 minutes for a period of 4 hours. The experimental animals were randomly divided into two groups. The control group (control, n = 11) was given apnea for 4 hours. The experimental group (LLVNS, n = 11) was given LLVNS within 3 hours except apnea. The LLVNS was stopped at 4 hours and only OSA was given.
Results: Compared with the control group, LLVNS significantly inhibited the shortening of ERP (P 0.0001) induced by repeated apnea from the second hour, and also prolonged ERP compared with baseline. Meanwhile, LLVNS significantly shortened the onset of AFD induced by OSA by 2 times. LLVNS inhibited the onset of AF induced by OSA and provided evidence for the prevention of OSA-induced AF. When the pacing threshold was 10 times, AFD was significantly shortened in LLVNS group, when LLVNS and repeated apnea were synchronized for 1.5 hours, and completely inhibited the onset of OSA-induced AF at 2 hours, which provided evidence for the treatment of OSA-induced AF. After 3 hours of synchronization with SA, LLVNS was stopped and repeated OSA1 for 1 hour. ERP was still prolonged and no AF attack was observed. This indicated that the antiarrhythmic effect of LLVNS for 3 hours could last at least for more than 1 hour. The changes of PaO2, PaCO2, PH, ITP and arterial systolic blood pressure (SBP) remained unchanged between the two groups.
CONCLUSIONS: (1) This study simulated the characteristics of clinical OSAS and successfully constructed an OSA-induced AF model. It was confirmed that LLVNS could inhibit OSA-induced atrial electrical remodeling, prevent and treat OSA-induced AF, and provide evidence for the prevention and treatment of OSA-induced AF.
(2) With the improvement of research, LLVNS has the potential to be used in clinic as a safe and effective treatment for AF, providing a new choice for clinical treatment of AF, especially OSA-induced AF.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R541.75;R766
本文编号：2187856
[Abstract]:Atrial Fibrillation (AF) is the most common persistent arrhythmia in clinical practice, which can cause complications such as heart failure and arterial embolism, resulting in increased disability and mortality, thus becoming a costly public health problem. Obstructive Sleep Apnea Sydrome (OSAS) It is a common chronic respiratory disease characterized by recurrent apnea during sleep, severe snoring, and daytime sleepiness. According to statistics, 4% of middle-aged men and 2% of middle-aged women have OSAS. Risk factors such as age, sex, hypertension, obesity, etc. are the same as AF. In recent years, more and more evidence has confirmed obstructive sleep apnea. Obstructive Sleep Apnea (OSA) is associated with the occurrence and maintenance of AF, and the success rate of treatment for AF patients with OSA is significantly reduced. Therefore, early detection and active treatment of OSA pose new challenges to the identification of risk factors for arrhythmia and the choice of treatment options. However, most of the current AF animal models are atrial. There is no ideal OSA-mediated AF model for rapid pacing, autonomic nerve-mediated AF and left atrial pressure or volume enlargement. In the first part of this study, we aimed to establish an animal model of OSA-related AF and study its characteristics, so as to provide a basis for further study of the mechanism of OSA complicated with AF and explore new treatment options.
Radiofrequency catheter ablation is the main treatment for AF, but its recurrence rate is as high as 20% - 50%. Previous studies have shown that the increased recurrence rate after AF is associated with hypertension, obesity, enlarged left atrium, persistent AF and other factors. However, recent studies have found that in AF patients undergoing catheter radiofrequency ablation, if combined with OSAS, the recurrence rate is significantly higher. This suggests that OSAS may be another risk factor for high recurrence rate of AF after radiofrequency ablation. Therefore, the use of catheter radiofrequency ablation in patients with OSAS and AF has been limited to some extent. Therefore, scholars at home and abroad have been trying to find other non-drug treatments for AF besides ablation. Vagus trunk stimulation has long been recognized as one of the important factors inducing and sustaining AF. Its possible mechanism is to shorten the effective refractory period (ERP) and increase the dispersion of atrial ERP, thus further accelerating the formation of multiple reentry loops. Unlike suprathreshold stimulation, low level vagus nerve stimulation (LLVNS) may be an effective means to prevent and treat AF. The second part of this study was to investigate whether LLVNS can inhibit OSA-induced AF and may provide a new therapeutic approach for OSA-induced AF.
1. Establishment of an animal model of OSAS complicated with AF. Objective: To construct an animal model of OSA-related AF and study its characteristics, so as to provide a basis for further study of the mechanism of OSA complicated with AF and explore new treatment options.
Methods: Six adult New Zealand rabbits were given tracheotomy and tracheal intubation after anesthesia, and OSA was simulated by clipping tracheal intubation at the end of expiration for 1 minute. OSA was given once every 5 minutes for a period of 6 minutes for 4 hours. ERP, blood pressure, intraesophageal pressure (ITP), arterial blood gas analysis (PaO2, PaCO2, PH) were measured before and after OSA. ERP and AFD were measured by programmed stimulation within one minute of OSA administration.
Results: At the end of 1 minute after apnea, arterial partial pressure of carbon dioxide (PaCO2) increased significantly, PH value, arterial partial pressure of oxygen (Pa02) decreased significantly, and ITP decreased significantly. After apnea, heart rate decreased, blood pressure decreased, and heart rate and blood pressure increased significantly immediately after apnea. Additionally, the heart rate basically returned to the pre-apnea state, while the blood pressure was significantly higher than that before apnea. With the prolongation of repeated OSA, ERP gradually shortened and AFD gradually prolonged.
CONCLUSION: (1) A new OSAS animal model was successfully constructed, which showed similar pathophysiological and electrophysiological characteristics with clinical OSAS patients.
(2) The animal model of OSA-related AF was successfully simulated in this study, which provides a basis for further study of the mechanism of OSA-associated AF and exploration of new therapeutic regimens.
Inhibitory effect of 2. LLVNS on AF in OSA rabbit model
AIM: To investigate whether LLVNS can inhibit OSA-induced AF and provide a new therapeutic approach for OSA-induced AF.
Methods: 22 adult New Zealand white rabbits were given tracheotomy and tracheal intubation after anesthesia. OSA was simulated by clipping tracheal intubation at the end of expiration for 1 minute. OSA was given at intervals of 5 minutes and 6 minutes for a period of 4 hours. The experimental animals were randomly divided into two groups. The control group (control, n = 11) was given apnea for 4 hours. The experimental group (LLVNS, n = 11) was given LLVNS within 3 hours except apnea. The LLVNS was stopped at 4 hours and only OSA was given.
Results: Compared with the control group, LLVNS significantly inhibited the shortening of ERP (P 0.0001) induced by repeated apnea from the second hour, and also prolonged ERP compared with baseline. Meanwhile, LLVNS significantly shortened the onset of AFD induced by OSA by 2 times. LLVNS inhibited the onset of AF induced by OSA and provided evidence for the prevention of OSA-induced AF. When the pacing threshold was 10 times, AFD was significantly shortened in LLVNS group, when LLVNS and repeated apnea were synchronized for 1.5 hours, and completely inhibited the onset of OSA-induced AF at 2 hours, which provided evidence for the treatment of OSA-induced AF. After 3 hours of synchronization with SA, LLVNS was stopped and repeated OSA1 for 1 hour. ERP was still prolonged and no AF attack was observed. This indicated that the antiarrhythmic effect of LLVNS for 3 hours could last at least for more than 1 hour. The changes of PaO2, PaCO2, PH, ITP and arterial systolic blood pressure (SBP) remained unchanged between the two groups.
CONCLUSIONS: (1) This study simulated the characteristics of clinical OSAS and successfully constructed an OSA-induced AF model. It was confirmed that LLVNS could inhibit OSA-induced atrial electrical remodeling, prevent and treat OSA-induced AF, and provide evidence for the prevention and treatment of OSA-induced AF.
(2) With the improvement of research, LLVNS has the potential to be used in clinic as a safe and effective treatment for AF, providing a new choice for clinical treatment of AF, especially OSA-induced AF.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R541.75;R766
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