低強度迷走神經(jīng)刺激抑制阻塞性睡眠呼吸暫停兔模型心房顫動的研究
發(fā)布時間：2018-08-17 13:58
【摘要】：心房顫動(Atrial Fibrillation,AF)是臨床上最常見的持續(xù)性心律失常,可引起心力衰竭和動脈栓塞等并發(fā)癥,導(dǎo)致病人病殘率和病死率增加,從而成為一個耗資巨大的公共健康問題。阻塞性睡眠呼吸暫停綜合征(Obstructive Sleep Apnea Sydrome, OSAS)是一種常見的慢性呼吸系統(tǒng)疾病,以睡眠時出現(xiàn)反復(fù)呼吸暫停、嚴(yán)重打鼾、白天嗜睡為特征。據(jù)統(tǒng)計,4%中年男性和2%中年女性患有OSAS。其危險因素諸如年齡、性別、高血壓、肥胖等,均與AF相同。近年來越來越多的證據(jù)證實阻塞性睡眠呼吸暫停(Obstructive Sleep Apnea,OSA)與AF的發(fā)生和維持有重要相關(guān)性,并發(fā)現(xiàn)伴有OSA的AF病人治療的成功率明顯降低。因此及早發(fā)現(xiàn)并積極治療OSA,對心律失常危險因素的識別和治療方案的選擇提出了新的挑戰(zhàn)。然而目前的AF動物模型大多是心房快速起搏、自主神經(jīng)介導(dǎo)以及左房壓力或容積增大導(dǎo)致的AF等,尚缺乏理想的OSA介導(dǎo)的AF模型,本研究第一部分旨在建立一種模擬臨床OSA相關(guān)的AF的動物模型并研究其特點,為進一步研究OSA并發(fā)AF的機制及探索新的治療方案提供基礎(chǔ)。 經(jīng)導(dǎo)管射頻消融術(shù)是目前治療AF的主要方法,然而其復(fù)發(fā)率高達20%-50%。以往認為,AF消融術(shù)后復(fù)發(fā)率升高與高血壓、肥胖、左房增大、持續(xù)性AF等因素有關(guān)。但近期研究發(fā)現(xiàn),在行導(dǎo)管射頻消融術(shù)的AF患者中,如果合并OSAS,其復(fù)發(fā)率要明顯高于單純AF患者,這提示OSAS可能為AF射頻消融術(shù)后高復(fù)發(fā)率的另一項危險因素。因此,在合并OSAS和AF患者中導(dǎo)管射頻消融的應(yīng)用受到了一定限制。所以國內(nèi)外學(xué)者一直在試圖尋找除消融之外其他治療AF的非藥物方法。自上世紀(jì)早期以來,頸部迷走神經(jīng)干刺激一直被公認為是AF誘發(fā)和持續(xù)的重要因素之一,其可能的發(fā)生機制是使心房有效不應(yīng)期(Effective Refractory Period, ERP)縮短并增加心房ERP離散度,從而進一步加速多重折返環(huán)的形成。但最近一系列相關(guān)研究結(jié)果表明,低強度迷走神經(jīng)刺激(Low level vagus nerve stimulation,LLVNS)與閾上刺激不同,有可能是一種預(yù)防和治療AF的有效手段。本研究第二部分旨在研究LLVNS是否能夠抑制OSA誘導(dǎo)的AF的發(fā)生,并可能為OSA誘導(dǎo)的AF提供一條新的治療途徑。 1. OSAS并發(fā)AF的動物模型的建立目的：構(gòu)建模擬臨床OSA相關(guān)的AF的動物模型并研究其特點,為進一步研究OSA并發(fā)AF的機制及探索新的治療方案提供基礎(chǔ)。 方法：成年新西蘭大白兔6只,麻醉后行氣管切開并給予氣管插管,在呼氣末夾閉氣管插管1分鐘模擬OSA。每間隔5分鐘給予一次OSA,6分鐘為一個周期,共持續(xù)4小時。在OSA之前、之后分別測量ERP、血壓、食管內(nèi)壓(ITP)、動脈血氣分析(PaO2、PaCO2、PH),在給予OSA的1分鐘內(nèi)通過程序刺激測量ERP和房顫持續(xù)時間(Atrial Fibrillation Duration,、AFD)。 結(jié)果：每次呼吸暫停1分鐘末動脈血二氧化碳分壓(PaCO2)較呼吸暫停前即刻明顯增加,PH值、動脈血氧分壓(Pa02)較呼吸暫停前即刻明顯降低,ITP也明顯降低。呼吸暫停后心率下降,血壓有降低趨勢,待呼吸暫停終止后即刻起心率血壓明顯增加,心率基本恢復(fù)至呼吸暫停前狀態(tài),而血壓較呼吸暫停前明顯升高。隨著反復(fù)OSA的時間延長,ERP逐漸縮短,AFD逐漸延長。 結(jié)論：(1)本實驗成功構(gòu)建了一種新的OSAS動物模型。該模型顯示了與臨床OSAS患者相似的病理生理和電生理特點。 (2)本研究成功模擬了臨床OSA相關(guān)的AF的動物模型,為進一步研究OSA并發(fā)AF的機制及探索新的治療方案提供了基礎(chǔ)。 2. LLVNS抑制OSA兔模型AF的研究 目的：研究LLVNS是否能夠抑制OSA誘導(dǎo)的AF的發(fā)生,可能為OSA誘導(dǎo)的AF提供一條新的治療途徑。 方法：成年新西蘭大白兔22只,麻醉后行氣管切開并給予氣管插管,在呼氣末夾閉氣管插管1分鐘模擬OSA。每間隔5分鐘給予一次OSA,6分鐘為一個周期,共持續(xù)4小時。在OSA之前、之后分別測量ERP、血壓、ITP、PaO2、 PaCO2和PH值,在給予OSA的1分鐘內(nèi)通過程序刺激測量ERP和AFD。實驗動物隨機分為兩組,對照組(control,n=11)只給予呼吸暫停4小時,實驗組(LLVNS, n=11)除呼吸暫停外,在起始3小時內(nèi)同時給予LLVNS,第4小時停止LLVNS,只給予OSA。 結(jié)果：本研究發(fā)現(xiàn),對照組隨著反復(fù)OSA時間的延長,ERP逐漸縮短,AFD逐漸延長。與對照組相比,從第二小時起LLVNS組明顯抑制了反復(fù)呼吸暫停引起的ERP的縮短(P0.0001),并且還可以使ERP較基線時延長。同時LLVNS可以顯著縮短OSA誘發(fā)的AFD。2倍起搏閾值時,LLVNS抑制了由OSA誘發(fā)的AF發(fā)生,為OSA誘發(fā)AF的預(yù)防提供了證據(jù)。10倍起搏閾值時,在LLVNS組,LLVNS和反復(fù)呼吸暫停同步進行1.5小時時,AFD出現(xiàn)明顯縮短,至2小時時,LLVNS完全抑制了OSA誘導(dǎo)的AF發(fā)作,為OSA誘發(fā)AF的治療提供了證據(jù)。LLVNS和OSA同步進行3小時后,停止LLVNS,繼續(xù)給予反復(fù)OSA1小時,ERP仍處于延長狀態(tài),且未出現(xiàn)AF發(fā)作,這表明3小時LLVNS引起的抗心律失常作用至少可以持續(xù)1小時以上。PaO2、PaCO2、PH值、ITP及動脈收縮壓(SBP)的變化在兩組間無變化。 結(jié)論：(1)本研究從設(shè)計上高度模擬了臨床OSAS的特征,成功構(gòu)建了OSA誘導(dǎo)的AF模型,并證實LLVNS能夠抑制OSA誘導(dǎo)的心房急性電重構(gòu),既可以預(yù)防也可以治療OSA引發(fā)的AF的發(fā)生,為OSA誘發(fā)AF的預(yù)防和治療提供了證據(jù)。 (2)隨著研究的完善,LLVNS完全有潛力運用到臨床,成為安全有效治療AF的方法,為臨床治療AF尤其是OSA誘發(fā)的AF提供一種新的治療選擇。
[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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R541.75;R766
本文編號：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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R541.75;R766
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，本文編號：2187856
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