Experimental 实验Interactions between atrial electrical remodeling and autonomic remodeling: How to break the vicious cycle
心房电重构与自主神经重构的相互作用:如何打破恶性循环
心脏节律,第九卷,第5期,2012年5月,810-811页
Keywords 关键字
心房颤动自主神经系统迷走神经刺激
Abbreviations 缩写
AFatrial fibrillationAVatrioventricularARGPanterior正确ganglionated plexiCANScardiac autonomic紧张systemGPganglionated plexiLL -SVCSlow入门级上腔静脉stimulationPVpulmonary veinRAPrapid pacingSVCsuperior心房腔静脉ΣWOVcumulative我们之窗
Introduction 介绍
For more than a decade, clinical electrophysiologists have applied catheter ablation procedures to treat drug-refractory atrial fibrillation (AF).1, 2 However, several recent reports found that the long-term success of catheter ablation for paroxysmal AF, the earliest stage of AF, was lower than 50%.3, 4 Moreover, iatrogenic left atrial tachycardias produced by ablation remain a difficult problem, and the long-term effects of extensive collateral damage to atrial myocardium, autonomic neurons, and nerves are yet to be determined. While the ablation technology has rapidly evolved in the past decade, understanding of the mechanisms responsible for the initiation and maintenance of AF continues to lag behind. Consequently, the ablation therapy for drug-refractory AF remains to be a “one-size-fits-all” approach.
十多年来,临床电生理学家已经应用导管消融治疗药物难治性心房颤动(AF)。1,2然而,最近的一些报道发现,导管消融治疗阵发性房颤(房颤的早期阶段)的长期成功率低于50%。3,4此外,消融引起的医源性左房性心动过速仍然是一个难题,对心房心肌、自主神经元和神经的广泛附带损害的长期影响尚未确定。虽然消融技术在过去十年中迅速发展,但对AF发生和维持机制的理解仍然落后。因此,对于药物难治性房颤的消融治疗仍然是一种“一刀切”的方法。
Using obesity as an analogy, an individual would not have gained 200 lbs of weight if he or she has not gained the first 2 lb. If the mechanisms responsible for the maintenance of AF within the first few hours after it was initiated are elucidated, therapies can be customized to terminate AF before it progresses to more persistent forms of AF.5 Hence, the present study was designed to investigate the roles of the intrinsic cardiac autonomic nervous system (CANS) in the maintenance of AF shortly after it was initiated. We also intended to develop a clinically feasible approach by using a multielectrode catheter in the superior vena cava (SVC) to transvenously stimulate the right vagal input to the heart to inhibit the function of the CANS with less permanent damage to the myocardium and neural elements.
以肥胖为例,如果一个人没有增加最初的2磅体重,他或她就不会增加200磅体重。如果在房颤开始后的最初几个小时内负责维持房颤的机制得到阐明,则可以定制治疗方法,在房颤发展为更持久的房颤形式之前终止房颤。 5 因此,本研究旨在探讨内在心脏自主神经系统(can)在房颤开始后不久的维持中的作用。我们还打算开发一种临床可行的方法,通过在上腔静脉(SVC)中使用多电极导管,经静脉刺激右迷走神经输入心脏,以抑制can的功能,同时减少对心肌和神经元件的永久性损伤。
Methods 方法
All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Oklahoma Health Sciences Center. Fourteen adult mongrel dogs weighing between 20 and 30 kg were anesthetized with 50 mg/kg of sodium pentobarbital and ventilated with room air by a positive pressure respirator. Core body temperature was maintained at (36.5 ± 0.5)°C by a sensor-controlled heating pad placed under the dog. Both femoral arteries and veins were cannulated and were used for catheter insertion (His bundle recording from the aortic root), blood pressure recording, and drug and saline administration. Standard electrocardiographic lead II and blood pressure were continuously monitored.
所有动物研究均由俄克拉何马大学健康科学中心的机构动物护理和使用委员会审查和批准。用50 mg/kg戊巴比妥钠麻醉14只体重在20 ~ 30 kg之间的成年杂种狗,并通过正压呼吸器进行室内空气通气。通过放置在狗身下的传感器控制的加热垫,将核心体温维持在(36.5±0.5)°C。将股动脉和股静脉插管,用于导管插入(从主动脉根部记录他的束)、血压记录、给药和生理盐水。连续监测标准心电图导联II和血压。
A left-sided thoracotomy was performed at the fourth intercostal space. Multielectrode catheters were sutured to the left superior and left inferior pulmonary veins and the left atrium to record pulmonary vein (PV) and atrial potentials (Figure 1A). After a right thoracotomy, multielectrode catheters were secured to the right superior and right inferior pulmonary veins and the right atrium (Figure 1B). The fat pad containing the anterior right ganglionated plexi (ARGP) was visualized to the left of the sulcus terminalis between the entrances of the right superior and right inferior pulmonary veins. The exact location of the ARGP was then verified by applying high-frequency stimulation (20 Hz, 0.1 ms) to induce sinus bradycardia or atrioventricular (AV) block. All recordings were displayed on a computerized Bard Electrophysiology System (CR Bard Inc, Billerica, MA). Electrocardiographic recordings were made with filter settings 0.1–250 Hz, whereas electrograms were filtered between 30 and 250 Hz.
在第四肋间隙行左侧开胸术。在左上肺静脉、左下肺静脉和左心房缝合多电极导管,记录肺静脉(PV)和心房电位(图1A)。右开胸后,将多电极导管固定在右上肺静脉、右下肺静脉和右心房(图1B)。右上肺静脉和右下肺静脉入口之间的末梢沟左侧可见含有右前神经节丛(ARGP)的脂肪垫。然后通过应用高频刺激(20 Hz, 0.1 ms)诱导窦性心动过缓或房室传导阻滞来验证ARGP的确切位置。所有的记录都显示在电脑巴德电生理系统(CR巴德公司,Billerica, MA)上。心电图记录在0.1-250 Hz的滤波器设置下进行,而心电图在30 - 250 Hz之间进行滤波。
Determination of ERP and ΣWOV in response to 6-hour rapid atrial pacing
6小时快速心房起搏后ERP和ΣWOV的测定
A 2-channel Grass stimulator (S88, Astro-Med, Warwick, MA) was used to deliver rapid atrial pacing (RAP) to the left atrial appendage (1200 beats/min, 2× diastolic threshold) to simulate AF.5, 6 After each pacing hour, RAP was temporarily stopped for 5−10 minutes to measure the effective refractory period (ERP) and window of vulnerability (WOV), which is a surrogate for AF inducibility.6 Programmed stimulation of the atrial or PV myocardium was performed by using another stimulator (model 5328, Medtronic, Inc, Minneapolis, MN). ERP was determined by using programmed pacing that consisted of 8 consecutive stimuli (S1–S1 interval = 330 ms) followed by a premature stimulus (S1–S2 interval), which was progressively decremented until refractoriness was achieved. Pacing was performed at 10× threshold. The difference between the longest and the shortest S1–S2 interval (in milliseconds) at which AF was induced at each bipolar pair was defined as the window of vulnerability (WOV), which serves as a quantitative measure of AF inducibility.6, 7, 8 The cumulative WOV (ΣWOV) was calculated as the sum of WOV from all sites in each dog. ERP dispersion was calculated as the coefficient of variation (=standard deviation/mean) of the ERP at all recording sites.6 AF was defined as irregular atrial rates faster than 500 beats/min associated with irregular atrioventricular conduction lasting for more than 5 seconds.
使用2通道Grass刺激器(S88, astroo - med, Warwick, MA)向左心耳(1200次/分钟,2倍舒张阈值)提供快速心房起搏(RAP)来模拟心房颤动。5,6每起搏1小时后,RAP暂时停止5 - 10分钟,以测量有效不应期(ERP)和易感窗(WOV),这是心房颤动诱导的替代指标。 6 使用另一种刺激器(型号5328,Medtronic, Inc, Minneapolis, MN)对心房或PV心肌进行程序性刺激。ERP的测定采用程序化起搏,包括8个连续刺激(S1-S1间隔= 330 ms),随后是一个过早刺激(S1-S2间隔),刺激逐渐减少,直到达到不可逆性。以10倍阈值起搏。每个双极对诱发AF的最长和最短的S1-S2间隔(毫秒)之差被定义为脆弱窗口(window of vulnerability, WOV),作为AF诱发性的定量度量。6,7,8累积WOV (ΣWOV)计算为每只狗所有部位的WOV之和。ERP离散度计算为所有记录点ERP的变异系数(=标准差/平均值)。 6 房颤定义为心律失常超过500次/分,并伴有房室传导不规律持续超过5秒。
Recording of the ARGP neural activity
记录ARGP神经活动
Three tungsten-coated microelectrodes (2 cm in length, 50 μm exposed tip, 9−12-mΩ impedance; F Haer, Co, Bowdoin, ME) were aligned and attached to a lightweight holder. The approximate distance between the tips was 2−3 mm. The tips were inserted into the ARGP to contact multiple neuronal sites within the fat pad. Stability of the impalements was maintained since the electrodes moved in sync with each cardiac and respiratory cycle.7 Leads from each microelectrode were connected to a single input to a stainless steel holder whose output was fed into a preamplifier (model 113, Princeton Applied Research, Princeton, NJ). This composite neural recording was band-pass filtered between 300 Hz and 10 kHz, amplification ranging from 100× to 500×. Further amplification (from 50× to 200×) was obtained by use of a hardwired amplifier (Spike 2, CED, Ltd, Cambridge, England). The neural activity was continuously recorded from the ARGP in 4 dogs during 6 hours of RAP to observe the trend of neural activity changes. In 6 other animals, ARGP neural activity was also recorded continuously but low-level vagus nerve stimulation was applied from 4–6 hours of RAP (see descriptions below). In all experiments, after RAP was temporarily stopped at the end of each hour, 1 minute of neural recording was acquired. The neural activity was characterized by the recorded amplitude and frequency. Neural activity was defined as deflections with a signal-to-noise ratio greater than 3:1.
三个钨包覆微电极(2 cm长,50 μm暴露尖端,9−12-mΩ阻抗;F Haer, Co, Bowdoin, ME)将其对准并连接到轻型支架上。针尖之间的距离约为2 ~ 3mm。这些尖端被插入ARGP以接触脂肪垫内的多个神经元部位。由于电极与每个心脏和呼吸周期同步移动,因此维持了穿刺的稳定性。 7 每个微电极的引线连接到一个不锈钢支架的单一输入,其输出被馈送到前置放大器(113型,普林斯顿应用研究,普林斯顿,新泽西州)。该复合神经记录在300 Hz和10 kHz之间进行带通滤波,放大范围从100倍到500倍。通过使用硬线放大器(Spike 2, CED, Ltd, Cambridge, England)获得进一步的放大(从50倍到200倍)。连续记录4只狗在RAP 6小时内的ARGP神经活动,观察神经活动变化趋势。在其他6只动物中,也连续记录ARGP神经活动,但在4-6小时的RAP中施加低水平的迷走神经刺激(见下文)。在所有实验中,在每小时结束时暂时停止RAP后,获得1分钟的神经记录。神经活动的特征是记录振幅和频率。神经活动定义为信噪比大于3:1的偏转。
Low-level vagal stimulation at the SVC
上下丘脑受到低水平迷走神经刺激
The right external jugular vein was dissected in the neck and a 9-F sheath inserted, through which a 10-pole circular catheter (Biosense/Webster, Diamond Bar, CA) was placed (visually via the right thoracotomy) in the SVC just below the entrance of the innominate vein. Vagal stimulation was performed by applying high-frequency electrical stimulation (20 Hz, 0.1-ms duration, square waves) to the preganglionic vagus nerves at the lateral wall of the SVC via a Grass stimulator. The lowest voltage level of vagal stimulation that induced any slowing of the sinus rate or AV conduction (measured by the A-H interval) was considered the threshold.7, 8, 9, 10 If the average sinus rate over 30 seconds was slowed by more than 5 beats/min, low-level vagal stimulation in the superior vena cava (LL-SVCS) at that voltage was considered above the threshold. The voltage that was 50% lower than the threshold was then chosen as the voltage for LL-SVCS. Prior to each hour of LL-SVCS, the stimulation threshold was again determined to adjust the voltage for LL-SVCS for the next hour. During LL-SVCS, the heart rate and the AH interval were monitored to ensure that the stimulation voltage was approximately below the threshold.
在颈部切开右颈外静脉,插入9-F鞘,通过鞘将一根10极圆形导管(Biosense/Webster, Diamond Bar, CA)(视觉上通过右开胸)置入无名静脉入口正下方的SVC。迷走神经刺激是通过Grass刺激器对SVC外侧壁的节前迷走神经施加高频电刺激(20 Hz, 0.1 ms持续时间,方波)。迷走神经刺激引起窦率或房室传导减慢(通过A-H间隔测量)的最低电压水平被认为是阈值。7,8,9,10如果超过30秒的平均窦率减慢超过5次/分,则认为在该电压下上腔静脉(lv - svcs)的低水平迷走神经刺激高于阈值。然后选择低于阈值50%的电压作为LL-SVCS的电压。在进行每小时的低压svcs之前,再次确定刺激阈值,以调整下一小时的低压svcs电压。在LL-SVCS期间,监测心率和AH间隔,以确保刺激电压大致低于阈值。
Statistical analysis 统计分析
Data were expressed as mean ± standard error. Repeated-measures analysis of variance was used for the comparison of repeated measures for data points acquired at different time intervals. Post hoc analysis was done to compare the following parameters measured hourly to the values in the baseline state or the values at the end of the third hour of RAP before the initiation of LL-SVCS: (a) the frequency and amplitude of the ARGP neural activity (Figure 2, Figure 3), (b) PV and atrial ERPs (Figure 4), and (c) ΣWOV and ERP dispersion (Figure 5). P values of ≤.05 were considered statistically significant.
数据以均数±标准误差表示。重复测量方差分析用于比较在不同时间间隔获得的数据点的重复测量。进行事后分析,将每小时测量的以下参数与基线状态或LL-SVCS开始前第3小时RAP结束时的值进行比较:(a) ARGP神经活动的频率和幅度(图2、图3),(b) PV和心房ERP(图4),(c) ΣWOV和ERP离散度(图5)。P值≤。0.05认为有统计学意义。
Results 结果
ARGP neural activity in response to RAP
RAP对ARGP神经活动的反应
In the 4 dogs subjected to 6 hours of RAP without LL-SVCS, there was a sequence of a progressive increase of both the frequency and the amplitude of the neural activity recorded from the ARGP after each hour when RAP stopped and sinus rhythm was restored (Figure 2A). The bar graphs (Figures 2B and 2C) show the changes in the mean values of frequency and amplitude of the recorded neural activity at baseline (23 ± 5 impulses/min, 0.06 ± 0.02 mV), the end of 3 hours of RAP (121 ± 9 impulses/min, 0.50 ± 0.04 mV; P <.001 compared with the baseline values), and the end of 6 hours of RAP (196 ± 6 impulses/min, 0.93 ± 0.01 mV; P <.001, compared with the third-hour RAP values). Figure 3 illustrates a similar sequence of progressive changes in the first 3 hours of RAP. From the fourth to the sixth hour of RAP, LL-SVCS was applied. Note the reversal of the changes in the frequency and amplitude of the neural activity. The bar graphs (Figures 3B and 3C) show the changes in the mean values of frequency and amplitude of the recorded neural activity at baseline (25 ± 6 impulses/min, 0.08 ± 0.02 mV), during the first 3 hours of RAP (123 ± 10 impulses/min, 0.48 ± 0.04 mV; P <.001, compared with the baseline values), and after 3 hours of LL-SVCS+RAP (23 ± 5 impulses/min, 0.07 ± 0.01 mV; P <.001, compared with the third-hour RAP values). There was no significant difference between the mean values of frequency and amplitude of the neural activity at the baseline and after 3 hours of LL-SVCS+RAP.
在4只接受6小时无LL-SVCS的RAP的狗中,当RAP停止并恢复窦性心律时,每小时ARGP记录的神经活动频率和幅度都有一个循序渐进的增加序列(图2A)。柱状图(图2B和2C)显示了基线时(23±5个脉冲/min, 0.06±0.02 mV)、3小时RAP结束时(121±9个脉冲/min, 0.50±0.04 mV;P <。6小时RAP结束时(196±6个脉冲/min, 0.93±0.01 mV;P <。001,与第三小时的RAP值相比)。图3显示了在RAP的前3个小时中类似的渐进式变化序列。在RAP的第4 ~ 6小时,应用LL-SVCS。注意神经活动的频率和幅度变化的反转。柱状图(图3B和图3C)显示了在基线(25±6个脉冲/min, 0.08±0.02 mV)记录的神经活动频率和振幅平均值在RAP前3小时(123±10个脉冲/min, 0.48±0.04 mV)的变化;P <。0.001,与基线值相比),而LL-SVCS+RAP 3小时后(23±5脉冲/min, 0.07±0.01 mV;P <。001,与第三小时的RAP值相比)。基线时与LL-SVCS+RAP治疗3小时后的神经活动频率和振幅平均值无显著差异。
LL-SVCS effects on ERP and ΣWOV in response to 6-hour RAP
l - svcs对6小时RAP对ERP和ΣWOV的影响
No phrenic nerve capture was observed in any of the experiments. During the first 3 hours of RAP, PV and atrial ERPs showed a significant decrease compared with the baseline values and the effects appeared not to be further enhanced by RAP from the fourth to the sixth hour (Figure 4A). In contrast, after the initiation of LL-SVCS during the fourth to the sixth hour of RAP, ERP shortening at all sites was reversed from the third hour on and returned toward the baseline values at the end of the sixth hour of RAP (Figure 4B).
在所有实验中均未观察到膈神经捕获。在RAP的前3小时,PV和心房erp与基线值相比显着下降,并且从第4小时到第6小时RAP的效果似乎没有进一步增强(图4A)。相反,在RAP的第4 ~ 6小时启动LL-SVCS后,所有位点的ERP缩短从第3小时开始逆转,并在RAP的第6小时结束时向基线值恢复(图4B)。
Throughout the 6 hours of RAP, there was a progressive increase in the ΣWOV (sum of the WOVs at each recording site) (Figure 5A). On the other hand, dispersion of ERP during the first 3 hours of RAP was significantly increased compared with the baseline values but not further increased by RAP from the fourth to the sixth hour (Figure 5B). No spontaneous firing was noted in any dog when RAP was temporarily discontinued every hour. During 3 hours of LL-SVCS+RAP, there was a return toward baseline values in both these parameters (P <.01, compared with the end of the third-hour RAP values; Figures 5C and 5D).
在整个6小时的RAP过程中,ΣWOV(各记录部位WOVs的总和)呈渐进式增加(图5A)。另一方面,与基线值相比,在RAP的前3小时,ERP的离散度显著增加,但从第4小时到第6小时,RAP没有进一步增加(图5B)。当RAP每小时暂时停止时,没有发现任何狗自发射击。在LL-SVCS+RAP治疗的3小时内,这两个参数都恢复到基线值(P < 0.05)。01,与第三小时结束时的RAP值比较;图5C和5D)。
Discussion 讨论
Major findings 主要发现
In the present study, we demonstrated the closely related interactions between autonomic remodeling and atrial electrical remodeling induced by RAP. We also demonstrated the feasibility of transvenous stimulation of the preganglionic fibers of the vagal trunks in effectively suppressing AF by inhibiting the activity of the ganglionated plexi (GP) (intrinsic CANS). LL-SVCS may provide an alternative treatment for AF, particularly within the first few hours after AF was initiated.
在本研究中,我们证明了RAP诱导的自主神经重构和心房电重构之间密切相关的相互作用。我们还证明了经静脉刺激迷走干神经节前纤维通过抑制神经节丛(GP)(内在can)的活性有效抑制房颤的可行性。LL-SVCS可能是房颤的一种替代治疗方法,特别是在房颤开始后的最初几个小时内。
While the concept of atrial electrical remodeling (“AF begets AF”) has been meticulously investigated and the associated ionic and structural changes have been widely accepted,5, 11 the critical elements that facilitate the perpetuation of AF in the first few hours after its onset are yet to be fully elucidated. Changes in the autonomic nervous system such as nerve sprouting12, 13 induced by structural heart abnormalities indicate that the autonomic nervous system also undergoes remodeling processes (autonomic remodeling). Previously, we showed that during 6 hours of RAP, there was a progressive decrease in ERP and a progressive increase in ERP dispersion as well as AF inducibility, consistent with acute electrical remodeling.6 Such changes could be reversed or prevented by ablating the 4 major atrial GP and ligament of Marshall or by administering atropine and propranolol, underscoring the important role of autonomic remodeling in the process of acute atrial electrical remodeling.6 Reduction of atrial tachyarrhythmia by mitigating autonomic remodeling was also observed by other investigators.13 In the present study, we provided direct evidence showing progressive increases in the neural activity recorded from the ARGP as a result of RAP (Figure 2), confirming the presence of autonomic remodeling during RAP. It has been shown in basic and clinical studies that the initiation and maintenance of paroxysmal AF may require simultaneous activation of both the sympathetic and parasympathetic nervous systems.14, 15, 16, 17, 18 Our neural recording data indicate that the activity of the intrinsic CANS is further amplified by rapid atrial rate-simulating AF. Although we could not discern sympathetic from parasympathetic activity with our neural recording technique, RAP-induced increases in the cholinergic activity of the intrinsic CANS can further shorten the ERP and increase the ERP dispersion to help maintain AF while increased sympathetic activity may enhance the Ca2+ transient and early afterdepolarization formation. In other words, acute atrial electrical remodeling and acute autonomic remodeling may form a vicious cycle in which each perpetuates the other, thereby initiating and sustaining AF. This vicious cycle may help to explain how AF maintains itself in its very early stage. Thus, a therapy that suppresses the activity of the intrinsic CANS may not only inhibit the frequency of AF episodes (Figure 4, Figure 5) but also limit its duration8, 10 to avoid the morbidities, such as stroke, dementia, and depressed cardiac function caused by long-standing AF. LL-SVCS reversed the altered neural activity of the intrinsic CANS as well as the ERP, ERP dispersion, and AF inducibility caused by RAP. Such actions can potentially break the vicious cycle of “AF begets AF” in the first few hours of AF.
虽然心房电重构(“房颤导致房颤”)的概念已被仔细研究,相关的离子和结构变化已被广泛接受,但在房颤发作后的最初几个小时内促进房颤持续的关键因素尚未得到充分阐明。由心脏结构异常引起的自主神经系统的变化,如神经萌芽12,13,表明自主神经系统也经历了重塑过程(自主神经重塑)。先前,我们发现在6小时的RAP中,ERP逐渐减少,ERP离散度和AF诱导性逐渐增加,与急性电重构一致。 6 这种改变可以通过消融心房4大GP和马歇尔韧带或给予阿托品和心得安来逆转或预防,强调自主神经重构在急性心房电重构过程中的重要作用。 6 其他研究者也观察到通过减轻自主神经重构来减少房性心动过速。 13 在本研究中,我们提供了直接证据,表明RAP导致ARGP记录的神经活动进行性增加(图2),证实RAP期间存在自主神经重塑。基础和临床研究表明,阵发性房颤的发生和维持可能需要交感和副交感神经系统同时激活。14,15,16,17,18我们的神经记录数据表明,快速心房速模拟心房颤动进一步放大了内在can的活动。 虽然我们的神经记录技术无法区分交感神经和副交感神经的活动,但rap诱导的内在can胆碱能活动的增加可以进一步缩短ERP,增加ERP的分散,以帮助维持AF,而交感神经活动的增加可能会增强Ca 2+ 瞬时和早期后去极化形成。换句话说,急性心房电重构和急性自主神经重构可能形成恶性循环,相互延续,从而引发和维持房颤。这种恶性循环可能有助于解释房颤如何在早期维持自身。因此,抑制内源性can活性的治疗不仅可以抑制房颤发作的频率(图4、图5),还可以限制其持续时间8,10,以避免由长期房颤引起的中风、痴呆和心功能下降等发病率。lc - svcs逆转了内源性can的神经活动改变,以及RAP引起的ERP、ERP离散度和房颤诱发性。这些行为可能会在房颤发生的最初几个小时内打破“房颤引发房颤”的恶性循环。
Vagal stimulation at higher intensity that markedly slows the heart rate and AV conduction has been used for several decades to promote the induction of AF in experimental laboratories. However, recent studies have provided evidence that reflex vagal activation can suppress PV ectopic firing in patients with paroxysmal AF.19 Our results suggest that LL-SVCS may stimulate nerve fibers with a lower threshold that have inhibitory effects on the GP and subsequently suppress AF, while higher stimulation intensity stimulates nerve fibers with higher threshold that activate the GP and promote AF. Suprathreshold vagal stimulation is known to release neurotransmitters or neuropeptides such as serotonin and vasoactive intestinal peptide.20, 21 However, the modulatory effects on these neurotransmitters or peptides exerted by subthreshold vagal stimulation such as LL-SVCS are yet to be discovered. We hypothesize that LL-SVCS may increase the release of vasostatin-122 or neuropeptide-Y,23 which are antiadrenergic and anticholinergic, respectively. In addition, nitric oxide, which is a strong antiadrenergic agent, may be involved.24 As AF initiation and maintenance may require simultaneous activation of both the sympathetic and parasympathetic components, inhibition of either component may suffice to suppress AF.
高强度的迷走神经刺激可显著减缓心率和房室传导,几十年来在实验实验室中已被用于促进AF的诱导。然而,最近的研究提供了证据,表明迷走神经反射激活可以抑制阵发性房颤患者的PV异位放电。 19 我们的研究结果表明,llsvcs可能刺激具有较低阈值的神经纤维,这些神经纤维对GP具有抑制作用,从而抑制房颤。而更高的刺激强度刺激阈值较高的神经纤维,激活GP,促进AF。阈上迷走神经刺激释放神经递质或神经肽,如血清素和血管活性肠肽。20,21然而,阈下迷走神经刺激(如LL-SVCS)对这些神经递质或肽的调节作用尚未被发现。我们推测,lc - svcs可能增加血管抑素-1 22 或神经肽- y, 23 的释放,这两种物质分别具有抗肾上腺素能和抗胆碱能。此外,一氧化氮是一种强抗肾上腺素能剂,也可能参与其中。 24 由于房颤的发生和维持可能需要同时激活交感神经和副交感神经成分,抑制其中任何一种成分都足以抑制房颤。
Clinical implications 临床意义
Recently, transvenous neural stimulation has been actively investigated as a new therapy to treat diseases such as heart failure and sleep apnea.25, 26, 27 For instance, a neurostimulation unit consisting of a pulse generator and a stimulation electrode implanted at the canine inferior vena cava was capable of stimulating the phrenic nerve with minimal rise of the stimulation threshold over 18 weeks without acute or chronic safety issues.25 In a recent clinical study, 14 patients with heart failure and central sleep apnea underwent phrenic nerve stimulation via a circular (Lasso) catheter positioned at the SVC or right brachiocephalic vein. Transvenous phrenic nerve stimulation was capable of mitigating sleep apnea and was tolerated without acute safety issues.27 Although the long-term safety profile (eg, lead dislodgement and thrombosis) of transvenous vagal stimulation is yet to be investigated, transvenous neurostimulation as proposed in the present study may encourage new pacing technology and open a new venue of therapies that modulates the imbalance of the CANS, treats diseases such as AF, and produces less permanent damage to the myocardium and neural elements.
近年来,经静脉神经刺激作为一种治疗心力衰竭和睡眠呼吸暂停等疾病的新疗法得到了积极的研究。25,26,27例如,一个由脉冲发生器和植入犬下腔静脉的刺激电极组成的神经刺激单元能够在18周内刺激膈神经,刺激阈值的上升很小,没有急性或慢性安全问题。 25 在最近的一项临床研究中,14例心力衰竭和中枢性睡眠呼吸暂停患者通过位于SVC或右侧头臂静脉的环状(Lasso)导管接受膈神经刺激。经静脉膈神经刺激能够缓解睡眠呼吸暂停,并且耐受无急性安全问题。 27 虽然经静脉迷走神经刺激的长期安全性(如铅脱位和血栓形成)尚待研究,但本研究提出的经静脉神经刺激可能会促进新的起搏技术,并开辟新的治疗领域,调节can的不平衡,治疗房颤等疾病,并对心肌和神经元件产生更少的永久性损伤。
Study limitations 研究的局限性
In the present study, we recorded only the neural activity from the ARGP. Whether the activity of other major atrial GP is affected the same way by RAP and LL-SVCS was not investigated. Prior studies from our group showed that the neural activity of both ARGP and SLGP were augmented similarly in response to high-frequency stimulation.7 In addition, similar changes in ERP of all the PV and atrial sites recorded in the present study lead us to hypothesize that all the major atrial GP may respond to RAP and LL-SVCS similarly.
在本研究中,我们只记录了ARGP的神经活动。RAP和LL-SVCS是否以同样的方式影响其他主要心房GP的活动,未作研究。我们小组先前的研究表明,ARGP和SLGP的神经活动在高频刺激下相似地增强。 7 此外,本研究记录的所有PV和心房部位的ERP相似变化使我们假设所有主要心房GP可能对RAP和LL-SVCS有相似的反应。
Conclusions 结论
A hyperactive state of the intrinsic CANS may facilitate the initiation of AF. Sustained AF not only induces acute atrial electrical remodeling but also promotes autonomic remodeling. These 2 remodeling processes may form a vicious cycle, and each may perpetuate the other, thereby maintaining AF. LL-SVCS reversed the altered neural activity of the intrinsic CANS as well as the ERP and ERP dispersion caused by RAP. Such actions can potentially break the vicious cycle of “AF begets AF” in the first few hours of AF.
内源性can的过度活跃状态可能促进房颤的发生。持续性房颤不仅诱发急性心房电重构,还促进自主神经重构。这两种重塑过程可能形成恶性循环,彼此相互延续,从而维持AF。LL-SVCS逆转了RAP引起的内在can的神经活动改变以及ERP和ERP弥散。这些行为可能会在房颤发生的最初几个小时内打破“房颤引发房颤”的恶性循环。
Acknowledgments 致谢
We thank Mrs Andrea Moseley for her technical assistance in the experimental studies cited herein.
我们感谢Andrea Moseley女士在本文引用的实验研究中提供的技术援助。
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Cited by (102) 引自(102)
Pathophysiologic Mechanisms in Cardiac Autonomic Nervous System and Arrhythmias
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2024,心脏电生理诊所Impact of proinflammatory epicardial adipose tissue and differentially enhanced autonomic remodeling on human atrial fibrillation
促炎心外膜脂肪组织和差异增强的自主神经重构对人房颤的影响2023, Journal of Thoracic and Cardiovascular Surgery
2023,心胸外科杂志Vagus Nerve Stimulation and Atrial Fibrillation: Revealing the Paradox
迷走神经刺激与心房颤动:揭示矛盾2022, Neuromodulation 2022年,神经调节Citation Excerpt : 引文摘录:In line with these findings, Beaumont et al71,72 demonstrated that remodeling in the CANS induced by pressure overload or myocardial infarction can be mitigated by chronic VNS. The possibility to suppress autonomic remodeling by LLVNS was further substantiated during HFRAP,57 confirming that LLVNS may indeed be a promising strategy to break the vicious cycle of “AF begets AF.” The various ways through which LLVNS may break this cycle are depicted in Figure 1.
与这些发现一致,Beaumont等人71,72证明,慢性VNS可以减轻压力过载或心肌梗死引起的can重构。在HFRAP期间,LLVNS抑制自主神经重塑的可能性得到了进一步证实,57证实LLVNS确实可能是打破“房颤引发房颤”恶性循环的一种有希望的策略。图1描述了LLVNS打破这一循环的各种方式。Effects of transcutaneous auricular vagus nerve stimulation on cardiovascular autonomic control in health and disease
经皮耳迷走神经刺激对健康和疾病患者心血管自主神经控制的影响2021, Autonomic Neuroscience: Basic and Clinical
2021,自主神经科学:基础与临床
This work was supported in part by a grant from the Heart Rhythm Institute (to S.S.P.) and Webster Arrhythmia Research Fund at the University of Oklahoma and grants (81070143 and 81170195) from the National Natural Science Foundation of China (to H.J.).
这项工作得到了俄克拉何马大学心律研究所(to S.S.P.)和韦伯斯特心律失常研究基金以及中国国家自然科学基金(to H.J.)的资助(81070143和81170195)。
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