Interactions between atrial electrical remodeling and autonomic remodeling: How to break the vicious cycle

doi:10.1016/j.hrthm.2011.12.023

Heart Rhythm 心脏的节奏

Volume 9, Issue 5, May 2012, Pages 804-809
第9卷，第5期，2012年5月，804-809页

, , , , , , , , Hong Jiang MD ^⁎,
，姜洪博士 ^⁎ ，

https://doi.org/10.1016/j.hrthm.2011.12.023 Get rights and content 获取权利和内容

Referred to by 由

Disease modification by autonomic nerve stimulation
通过自主神经刺激改变疾病

Heart Rhythm, Volume 9, Issue 5, May 2012, Pages 810-811
心脏节律，第九卷，第5期，2012年5月，810-811页

Seil Oh Seil哦

View PDF 查看PDF

Background 背景

The mechanism(s) underlying the maintenance of atrial fibrillation (AF) during the first few hours after AF was initiated remains poorly understood.
心房颤动(AF)发生后最初几个小时内维持的机制尚不清楚。

Objective 客观的

To investigate the roles of the intrinsic cardiac autonomic nervous system in the maintenance of AF at the early stage.
目的探讨心脏自主神经系统在房颤早期维持中的作用。

Methods 方法

In 10 anesthetized dogs, we attached multielectrode catheters on atria and pulmonary veins. Microelectrodes inserted into the anterior right ganglionated plexi recorded neural activity. At baseline, programmed stimulation determined the effective refractory period (ERP) and window of vulnerability (WOV), a measure of AF inducibility. For the next 6 hours, AF was simulated by rapid atrial pacing (RAP) and the same parameters were measured hourly during sinus rhythm. A circular catheter was positioned in the superior vena cava for high-frequency stimulation (20 Hz) of the adjacent vagal preganglionics. During 4−6 hours of RAP, we delivered low-level vagal stimulation in the superior vena cava (LL-SVCS), 50% below that which induced slowing of the sinus rate.
我们在10只麻醉犬的心房和肺静脉上放置了多电极导管。微电极插入右前神经节丛记录神经活动。在基线，程序性刺激确定了有效不应期(ERP)和易损窗口(WOV)，这是AF诱发性的衡量标准。在接下来的6小时内，通过快速心房起搏(RAP)模拟心房颤动，并在窦性心律期间每小时测量相同的参数。在上腔静脉放置一根圆形导管，对邻近的迷走神经节前神经进行高频刺激(20hz)。在4 - 6小时的RAP中，我们对上腔静脉(LL-SVCS)进行了低水平的迷走神经刺激，比引起窦率减慢的低50%。

Results 结果

During the 6-hour RAP, there was a progressive decrease in the ERP and an increase in ERP dispersion, WOV, and neural activity. With LL-SVCS during 4−6-hour RAP, ERP, WOV, and neural activity returned toward baseline levels (all P <.05, compared with the third-hour RAP values).
在6小时的RAP中，ERP逐渐下降，ERP弥散度、WOV和神经活动增加。在4 ~ 6小时的RAP中，LL-SVCS组，ERP、WOV和神经活动恢复到基线水平(P均< 0.05)。05，与第三小时RAP值相比)。

Conclusions 结论

RAP not only induces atrial electrical remodeling but also promotes autonomic remodeling. These 2 remodeling processes may form a vicious cycle and each may perpetuate the other. These findings may help to explain how AF maintains itself in its very early stage. LL-SVCS both reversed remodeling processes and can potentially break the vicious cycle of “AF begets AF” in the first few hours of AF.
RAP不仅诱导心房电重构，而且促进自主神经重构。这两种重塑过程可能形成一个恶性循环，每一个都可能使另一个永久化。这些发现可能有助于解释AF如何维持在其早期阶段。LL-SVCS既逆转了重构过程，也可能在房颤发生的最初几个小时内打破“房颤诱发房颤”的恶性循环。

Keywords 关键字

Atrial fibrillation

Autonomic nervous system

Vagal stimulation

心房颤动自主神经系统迷走神经刺激

Abbreviations 缩写

atrial fibrillation

atrioventricular

ARGP

anterior right ganglionated plexi

CANS

cardiac autonomic nervous system

ganglionated plexi

LL-SVCS

low-level superior vena cava stimulation

pulmonary vein

RAP

rapid atrial pacing

SVC

superior vena cava

ΣWOV

cumulative window of vulnerability

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。

References

1
M. Haissaguerre, P. Jais, D.C. Shah, et al.
Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins
N Engl J Med, 339 (1998), pp. 659-666
View in Scopus Google Scholar
2
R. Cappato, H. Calkins, S.A. Chen, et al.
Up-dated worldwide survey on the methods, efficacy and safety of catheter ablation for human atrial fibrillation
Circ Arrhythm Electrophysiol, 3 (2010), pp. 32-38
View in Scopus Google Scholar
3
F. Ouyang, R. Tilz, J. Chun, et al.
Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up
Circulation, 122 (2010), pp. 2368-2377
View in Scopus Google Scholar
4
R. Weerasooriya, P. Khairy, J. Litalien, et al.
Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up?
J Am Coll Cardiol, 57 (2011), pp. 160-166
View PDF View article View in Scopus Google Scholar
5
M.C. Wijffels, C.J. Kirchhoff, R. Dorland, et al.
Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats
Circulation, 92 (1995), pp. 1954-1968
View in Scopus Google Scholar
6
Z. Lu, B.J. Scherlag, J. Lin, et al.
Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing
Circ Arrhythm Electrophysiol, 1 (2008), pp. 184-192
View in Scopus Google Scholar
7
L. Yu, B.J. Scherlag, S. Li, et al.
Low level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia
J Cardiovasc Electrophysiol, 22 (2011), pp. 455-463
Crossref View in Scopus Google Scholar
8
Y. Sha, B.J. Scherlag, L. Yu, et al.
Low-level right vagal stimulation: anticholinergic and antiadrenergic effects
J Cardiovasc Electrophysiol, 22 (2011), pp. 1147-1153
Crossref View in Scopus Google Scholar
9
S. Li, B.J. Scherlag, L. Yu, et al.
Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of focal atrial fibrillation
Circ Arrhythm Electrophysiol, 2 (2009), pp. 645-651
Google Scholar
10
X. Sheng, B.J. Scherlag, L. Yu, et al.
Prevention and reversal of atrial fibrillation inducibility and autonomic remodeling by low-level vagosympathetic nerve stimulation
J Am Coll Cardiol, 57 (2011), pp. 563-571
View PDF View article View in Scopus Google Scholar
11
L. Yue, P. Melnyk, R. Gaspo, Z. Wang, S. Nattel
Molecular mechanisms underlying ionic remodeling in a dog model of atrial fibrillation
Circ Res, 84 (1999), pp. 776-784
View in Scopus Google Scholar
12
A.Y. Tan, S. Zhou, M. Ogawa, et al.
Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines
Circulation, 118 (2008), pp. 916-925
26
View in Scopus Google Scholar
13
R.N. Doshi, T.J. Wu, M. Yashima, et al.
Relation between ligament of Marshall and adrenergic atrial tachyarrhythmia
Circulation, 100 (1999), pp. 876-883
View in Scopus Google Scholar
14
E. Patterson, S.S. Po, B.J. Scherlag, R. Lazzara
Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation
Heart Rhythm, 2 (2005), pp. 624-631
View PDF View article View in Scopus Google Scholar
15
E.K. Choi, M.J. Shen, S. Han, et al.
Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs
Circulation, 121 (2010), pp. 2615-2623
View in Scopus Google Scholar
16
A. Burashnikov, C. Antzelevitch
Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase 3 early afterdepolarization-induced triggered activity
Circulation, 107 (2003), pp. 2355-2360
View in Scopus Google Scholar
17
M. Bettoni, M. Zimmermann
Autonomic tone variations before the onset of paroxysmal atrial fibrillation
Circulation, 105 (2002), pp. 2753-2759
View in Scopus Google Scholar
18
D. Amar, H. Zhang, S. Miodownik, A.H. Kadish
Competing autonomic mechanisms precede the onset of postoperative atrial fibrillation
J Am Coll Cardiol, 42 (2003), pp. 1262-1268
View PDF View article View in Scopus Google Scholar
19
C.T. Tai, C.W. Chiou, Z.C. Wen, et al.
Effect of phenylephrine on focal atrial fibrillation originating in the pulmonary veins and superior vena cava
J Am Coll Cardiol, 36 (2000), pp. 788-793
View PDF View article View in Scopus Google Scholar
20
F. Markos, H.M. Snow
Vagal postganglionic origin of vasoactive intestinal polypeptide (VIP) mediating the vagal tachycardia
Eur J Appl Physiol, 98 (2006), pp. 419-422
Crossref View in Scopus Google Scholar
21
S. Manta, J. Dong, G. Debonnel, P. Blier
Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation
J Psychiatry Neurosci, 34 (2009), pp. 272-280
View in Scopus Google Scholar
22
S. Stavrakis, B.J. Scherlag, Y. Fan, et al.
Suppression of atrial fibrillation inducibility by vasostatin-1 [abstract]
Heart Rhythm, 8 (2011), p. S265
Google Scholar
23
A. Ilebekk, J.A. Björkman, M. Nordlander
Influence of endogenous neuropeptide Y (NPY) on the sympathetic-parasympathetic interaction in the canine heart
J Cardiovasc Pharmacol, 46 (2005), pp. 474-480
Crossref View in Scopus Google Scholar
24
M.P. Gallo, R. Levi, R. Ramella, et al.
Endothelium-derived nitric oxide mediates the anti-adrenergic effect of human vasostatin-1 in rat ventricular myocardium
Am J Physiol Heart Circ Physiol, 292 (2007), pp. H2906-H2912
Crossref View in Scopus Google Scholar
25
M. Lynn, K. James, J. Cawthra, R. Westlund
Chronic feasibility of transvenous phrenic nerve stimulation in canines [abstract]
Heart Rhythm, 7 (2010), p. S303
View in Scopus Google Scholar
26
P. Ponikowski, S. Zhang, T. Witkowski, et al.
Central sleep apnea events are terminated by phrenic nerve stimulation [abstract]
J Am Coll Cardiol, 55 (2010), p. A30
E289
Google Scholar
27
K. Fan, R. Yee, L. Gula, et al.
Transvenous vagus nerve stimulation: a potential heart failure therapy is feasible in humans [abstract]
J Am Coll Cardiol, 55 (2010), p. A16
E152
Google Scholar

Cited by (102) 引自(102)

Pathophysiologic Mechanisms in Cardiac Autonomic Nervous System and Arrhythmias
心脏自主神经系统和心律失常的病理生理机制
2024, Cardiac Electrophysiology Clinics
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
The mechanisms underlying atrial fibrillation are yet to be elucidated. We sought to investigate the interactions among autonomic remodeling, epicardial adipose tissue, inflammation, and atrial fibrillation.
Myocardium and adjacent epicardial adipose tissue of the left atrial appendage, right atrial appendage, and pulmonary vein muscle sleeves were obtained from 61 consecutive patients (35 with atrial fibrillation, 26 with no atrial fibrillation) during mitral valve surgeries. Patients were divided into the atrial fibrillation group and no atrial fibrillation group according to the history and Holter monitoring before surgery. Sympathetic and parasympathetic innervation were evaluated by tyrosine hydroxylase and choline acetyltransferase staining, respectively. Atrial fibrosis as well as cytokines/adipokines and related inflammatory proteins and signaling pathways in the epicardial adipose tissue were examined.
Immunohistochemical studies revealed significantly increased tyrosine hydroxylase (+) and choline acetyltransferase (+) neural elements in the left atrial appendage and pulmonary vein muscle sleeve myocardium, as well as adjacent epicardial adipose tissue in the atrial fibrillation group, particularly the pulmonary vein muscle sleeve sites. The receiver operating curve identified a threshold ratio (tyrosine hydroxylase/choline acetyltransferase) of 0.8986 in the epicardial adipose tissue (sensitivity = 82.86%; specificity = 80.77%; area under the curve = 0.85, 95% confidence interval = 0.76-0.95, P < .0001). More patients with a higher tyrosine hydroxylase/choline acetyltransferase ratio (≥0.8986) had atrial fibrillation. Expression levels of the genes and related proteins of the β1 adrenergic, mitogen-activated protein kinase, and nuclear factor kappa B signaling pathways were higher in patients with a higher tyrosine hydroxylase/choline acetyltransferase ratio. The tyrosine hydroxylase/choline acetyltransferase ratio also correlated with fibrosis.
Differentially enhanced autonomic remodeling and proinflammatory and profibrotic cytokines/adipokines in the epicardial adipose tissue adjacent to the pulmonary vein muscle sleeve site may work synergistically to promote atrial fibrillation.
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。
The cardiac autonomic nervous system (CANS) plays an important role in the pathophysiology of atrial fibrillation (AF). Cardiovascular disease can cause an imbalance within the CANS, which may contribute to the initiation and maintenance of AF. Increased understanding of neuromodulation of the CANS has resulted in novel emerging therapies to treat cardiac arrhythmias by targeting different circuits of the CANS. Regarding AF, neuromodulation therapies targeting the vagus nerve have yielded promising outcomes. However, targeting the vagus nerve can be both pro-arrhythmogenic and anti-arrhythmogenic. Currently, these opposing effects of vagus nerve stimulation (VNS) have not been clearly described. The aim of this review is therefore to discuss both pro-arrhythmogenic and anti-arrhythmogenic effects of VNS and recent advances in clinical practice and to provide future perspectives for VNS to treat AF.
A comprehensive review of current literature on VNS and its pro-arrhythmogenic and anti-arrhythmogenic effects on atrial tissue was performed. Both experimental and clinical studies are reviewed and discussed separately.
VNS exhibits both pro-arrhythmogenic and anti-arrhythmogenic effects. The anatomical site and stimulation settings during VNS play a crucial role in determining its effect on cardiac electrophysiology. Since the last decade, there is accumulating evidence from experimental studies and randomized clinical studies that low-level VNS (LLVNS), below the bradycardia threshold, is an effective treatment for AF.
LLVNS is a promising novel therapeutic modality to treat AF and further research will further elucidate the underlying anti-arrhythmogenic mechanisms, optimal stimulation settings, and site to apply LLVNS.
Dietary ω-3 fatty acids reduced atrial fibrillation vulnerability via attenuating myocardial endoplasmic reticulum stress and inflammation in a canine model of atrial fibrillation
在犬房颤模型中，膳食ω-3脂肪酸通过减轻心肌内质网应激和炎症来降低房颤易感性
2022, Journal of Cardiology
Dietary consumption of ω-3 fatty acids is correlated with a reduced incidence of cardiovascular events. Here, we investigated the effect of dietary ω-3 fatty acids on atrial fibrillation (AF) vulnerability in a canine model of AF and explored the related mechanisms.
Twenty four male beagle dogs (weight, 8-10 kg) were randomly divided into four groups: (a) sham-operated group (normal chow); (b) AF+FO [AF and normal chow supplemented with fish oil (FO): 0.6 g n-3 polyunsaturated fatty acids (ω-3 PUFA) /kg/day]; (c) AF group (normal chow); (d) sham-operated FO group (chow supplemented with FO: 0.6 g ω-3 PUFA/kg/day). AF was induced by rapid atrial pacing (RAP: 400 bpm for 4 weeks). Daily oral administration of FO was initiated 1 week before surgery and continued for 4 weeks post operation.
Atrial electric remodeling was significantly attenuated and AF vulnerability were significantly reduced in AF+FO group compared to AF group. Endoplasmic reticulum (ER) stress-related protein expression levels of glucose-regulated protein78, C/EBP homologous protein, cleaved-Caspase12, and phosphorylation of protein kinase R-like ER kinase as well as inflammatory cytokines interleukin-1β, interleukin-6, tumor necrosis factor-α in left atrium (LA) were significantly downregulated in AF+FO group than in AF group (all p<0.05). In addition, Masson staining revealed lower extent of LA interstitial fibrosis in AF+FO group than in AF group (p<0.01). Myocardial apoptosis was also significantly reduced in AF+FO group than in AF group (p<0.05).
Dietary ω-3 fatty acids could significantly reduce RAP-induced AF vulnerability, possibly via attenuating myocardial ER stress, inflammation, and apoptosis in this canine model of AF.
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
Autonomic nervous system (ANS) dysfunction is a well-known feature of cardiovascular diseases (CVDs). Studies on heart rate variability (HRV), a non-invasive method useful in investigating the status of cardiovascular autonomic control, have shown that a predominance of sympathetic modulation not only contributes to the progression of CVDs but has a pivotal role in their onset. Current therapies focus more on inhibition of sympathetic activity, but the presence of drug-resistant conditions and the invasiveness of some surgical procedures are an obstacle to complete therapeutic success. On the other hand, targeting the parasympathetic branch of the autonomic nervous system through invasive vagus nerve stimulation (VNS) has shown interesting results as alternative therapeutic approach for CVDs. However, the invasiveness and cost of the surgical procedure limit the clinical applicability of VNS and hinder the research on the physiological pathway involved.
Transcutaneous stimulation of the auricular branch of the vagus nerve (tVNS) seems to represent an important non-invasive alternative with effects comparable to those of VNS with surgical implant. Thus, in the present narrative review, we illustrate the main studies on tVNS performed in healthy subjects and in three key examples of CVDs, namely heart failure, hypertension and atrial fibrillation, highlighting the neuromodulatory effects of this technique.
Impact of low-level electromagnetic fields on the inducibility of atrial fibrillation in the electrophysiology laboratory
低强度电磁场对电生理实验室心房颤动诱发性的影响
2021, Heart Rhythm O2 2021，心律O2
Atrial fibrillation (AF) is the most common sustained arrhythmia in adults. Research suggests that autonomic nervous (ANS) system dysfunction contributes to AF pathophysiology. Animal studies have shown that low-level electromagnetic fields (LL-EMF) are potentially capable of AF suppression. This study evaluated the safety and efficacy of LL-EMF in suppressing AF in humans.
To investigate the impact of LL-EMF on AF inducibility in humans.
Patients presenting for ablation of paroxysmal AF were randomized to a sham protocol or LL-EMF (3.2 × 10^-8 G at 0.89 Hz) applied via a Helmholtz coil around the head. AF was induced via atrial pacing, and was cardioverted if duration was greater than 15 minutes. The protocol was then run for 60 minutes, followed by reinduction of AF. The primary endpoint was the duration of pacing-induced AF after protocol completion compared between groups.
Eighteen patients completed the study protocol (n = 10 sham, n = 8 LL-EMF). Pacing-induced AF duration in the LL-EMF group was 11.0 ± 3.43 minutes shorter than control after protocol completion (CI 3.72–18.28 minutes, P = .03). A smaller proportion of LL-EMF patients experienced spontaneous firing initiating an AF episode (0/7 vs 5/6, P = .0047). A significantly greater proportion of patients in the control group required direct current cardioversion after 1 hour (0.78 vs 0.13, P = .02).
In patients with paroxysmal AF, LL-EMF stimulation results in shorter episodes of pacing-induced AF and a reduced likelihood of spontaneous firing initiating an episode of AF.

View all citing articles on Scopus
查看Scopus上的所有引用文章

: 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)。

View Abstract 视图抽象

[1] 1
M. Haissaguerre, P. Jais, D.C. Shah, et al.
Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins
N Engl J Med, 339 (1998), pp. 659-666
View in Scopus Google Scholar

[2] 2
R. Cappato, H. Calkins, S.A. Chen, et al.
Up-dated worldwide survey on the methods, efficacy and safety of catheter ablation for human atrial fibrillation
Circ Arrhythm Electrophysiol, 3 (2010), pp. 32-38
View in Scopus Google Scholar

[3] 3
F. Ouyang, R. Tilz, J. Chun, et al.
Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up
Circulation, 122 (2010), pp. 2368-2377
View in Scopus Google Scholar

[4] 4
R. Weerasooriya, P. Khairy, J. Litalien, et al.
Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up?
J Am Coll Cardiol, 57 (2011), pp. 160-166
View PDF View article View in Scopus Google Scholar

[5] 5
M.C. Wijffels, C.J. Kirchhoff, R. Dorland, et al.
Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats
Circulation, 92 (1995), pp. 1954-1968
View in Scopus Google Scholar

[6] 6
Z. Lu, B.J. Scherlag, J. Lin, et al.
Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing
Circ Arrhythm Electrophysiol, 1 (2008), pp. 184-192
View in Scopus Google Scholar

[7] 7
L. Yu, B.J. Scherlag, S. Li, et al.
Low level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia
J Cardiovasc Electrophysiol, 22 (2011), pp. 455-463
Crossref View in Scopus Google Scholar

[8] 8
Y. Sha, B.J. Scherlag, L. Yu, et al.
Low-level right vagal stimulation: anticholinergic and antiadrenergic effects
J Cardiovasc Electrophysiol, 22 (2011), pp. 1147-1153
Crossref View in Scopus Google Scholar

[9] 9
S. Li, B.J. Scherlag, L. Yu, et al.
Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of focal atrial fibrillation
Circ Arrhythm Electrophysiol, 2 (2009), pp. 645-651
Google Scholar

[10] 10
X. Sheng, B.J. Scherlag, L. Yu, et al.
Prevention and reversal of atrial fibrillation inducibility and autonomic remodeling by low-level vagosympathetic nerve stimulation
J Am Coll Cardiol, 57 (2011), pp. 563-571
View PDF View article View in Scopus Google Scholar

[11] 11
L. Yue, P. Melnyk, R. Gaspo, Z. Wang, S. Nattel
Molecular mechanisms underlying ionic remodeling in a dog model of atrial fibrillation
Circ Res, 84 (1999), pp. 776-784
View in Scopus Google Scholar

[12] 12
A.Y. Tan, S. Zhou, M. Ogawa, et al.
Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines
Circulation, 118 (2008), pp. 916-925
26
View in Scopus Google Scholar

[13] 13
R.N. Doshi, T.J. Wu, M. Yashima, et al.
Relation between ligament of Marshall and adrenergic atrial tachyarrhythmia
Circulation, 100 (1999), pp. 876-883
View in Scopus Google Scholar

[14] 14
E. Patterson, S.S. Po, B.J. Scherlag, R. Lazzara
Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation
Heart Rhythm, 2 (2005), pp. 624-631
View PDF View article View in Scopus Google Scholar

[15] 15
E.K. Choi, M.J. Shen, S. Han, et al.
Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs
Circulation, 121 (2010), pp. 2615-2623
View in Scopus Google Scholar

[16] 16
A. Burashnikov, C. Antzelevitch
Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase 3 early afterdepolarization-induced triggered activity
Circulation, 107 (2003), pp. 2355-2360
View in Scopus Google Scholar

[17] 17
M. Bettoni, M. Zimmermann
Autonomic tone variations before the onset of paroxysmal atrial fibrillation
Circulation, 105 (2002), pp. 2753-2759
View in Scopus Google Scholar

[18] 18
D. Amar, H. Zhang, S. Miodownik, A.H. Kadish
Competing autonomic mechanisms precede the onset of postoperative atrial fibrillation
J Am Coll Cardiol, 42 (2003), pp. 1262-1268
View PDF View article View in Scopus Google Scholar

[19] 19
C.T. Tai, C.W. Chiou, Z.C. Wen, et al.
Effect of phenylephrine on focal atrial fibrillation originating in the pulmonary veins and superior vena cava
J Am Coll Cardiol, 36 (2000), pp. 788-793
View PDF View article View in Scopus Google Scholar

[20] 20
F. Markos, H.M. Snow
Vagal postganglionic origin of vasoactive intestinal polypeptide (VIP) mediating the vagal tachycardia
Eur J Appl Physiol, 98 (2006), pp. 419-422
Crossref View in Scopus Google Scholar

[21] 21
S. Manta, J. Dong, G. Debonnel, P. Blier
Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation
J Psychiatry Neurosci, 34 (2009), pp. 272-280
View in Scopus Google Scholar

[22] 22
S. Stavrakis, B.J. Scherlag, Y. Fan, et al.
Suppression of atrial fibrillation inducibility by vasostatin-1 [abstract]
Heart Rhythm, 8 (2011), p. S265
Google Scholar

[23] 23
A. Ilebekk, J.A. Björkman, M. Nordlander
Influence of endogenous neuropeptide Y (NPY) on the sympathetic-parasympathetic interaction in the canine heart
J Cardiovasc Pharmacol, 46 (2005), pp. 474-480
Crossref View in Scopus Google Scholar

[24] 24
M.P. Gallo, R. Levi, R. Ramella, et al.
Endothelium-derived nitric oxide mediates the anti-adrenergic effect of human vasostatin-1 in rat ventricular myocardium
Am J Physiol Heart Circ Physiol, 292 (2007), pp. H2906-H2912
Crossref View in Scopus Google Scholar

[25] 25
M. Lynn, K. James, J. Cawthra, R. Westlund
Chronic feasibility of transvenous phrenic nerve stimulation in canines [abstract]
Heart Rhythm, 7 (2010), p. S303
View in Scopus Google Scholar

[26] 26
P. Ponikowski, S. Zhang, T. Witkowski, et al.
Central sleep apnea events are terminated by phrenic nerve stimulation [abstract]
J Am Coll Cardiol, 55 (2010), p. A30
E289
Google Scholar

[27] 27
K. Fan, R. Yee, L. Gula, et al.
Transvenous vagus nerve stimulation: a potential heart failure therapy is feasible in humans [abstract]
J Am Coll Cardiol, 55 (2010), p. A16
E152
Google Scholar

Outline 大纲

Cited by (102)

Figures (5)