Elsevier

Journal of the American College of Cardiology
美国心脏病学会杂志

Volume 50, Issue 1, 3 July 2007, Pages 61-68
第50卷,第1期,2007年7月3日,61-68页
Journal of the American College of Cardiology

Preclinical Study 临床前研究
Ganglionated Plexi Modulate Extrinsic Cardiac Autonomic Nerve Input: Effects on Sinus Rate, Atrioventricular Conduction, Refractoriness, and Inducibility of Atrial Fibrillation
神经节丛调节外源性心脏自主神经输入:对窦率、房室传导、房颤难治性和诱发性的影响

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Objectives 目标

This study sought to systematically investigate the interactions between the extrinsic and intrinsic cardiac autonomic nervous system (ANS) in modulating electrophysiological properties and atrial fibrillation (AF) initiation.
本研究旨在系统地探讨外源性和内源性心脏自主神经系统(ANS)在调节电生理特性和心房颤动(AF)起始过程中的相互作用。

Background 背景

Systematic ganglionated plexi (GP) ablation to evaluate the extrinsic and intrinsic cardiac ANS relationship has not been detailed.
系统神经节丛(GP)消融术评估心脏外源性和内源性ANS的关系尚未详细报道。

Methods 方法

The following GP were exposed in 28 dogs: anterior right GP (ARGP) near the sinoatrial node, inferior right ganglionated plexi (IRGP) at the junction of the inferior vena cava and atria, and superior left ganglionated plexi (SLGP) near the junction of left superior pulmonary vein and left pulmonary artery. With unilateral vagosympathetic trunk stimulation (0.6 to 8.0 V, 20 Hz, 0.1 ms in duration), sinus rate (SR), and ventricular rate (VR) during AF were compared before and after sequential ablation of SLGP, ARGP, and IRGP.
28只犬的右侧前GP (ARGP),下腔静脉与心房交界处的右侧下神经节丛(IRGP),左侧上肺静脉与左肺动脉交界处的左侧上神经节丛(SLGP)。在单侧迷走交感干刺激(0.6 ~ 8.0 V, 20 Hz,持续时间0.1 ms)下,比较SLGP、ARGP和IRGP序贯消融前后房颤期间的窦率(SR)和心室率(VR)。

Results 结果

The SLGP ablation significantly attenuated the SR and VR slowing responses with right or left vagosympathetic trunk stimulation. Subsequent ARGP ablation produced additional effects on SR slowing but not VR slowing. After SLGP + ARGP ablation, IRGP ablation eliminated VR slowing but did not further attenuate SR slowing with vagosympathetic trunk stimulation. Unilateral right and left vagosympathetic trunk stimulation shortened the effective refractory period and increased AF inducibility of atrium and pulmonary vein near the ARGP and SLGP, respectively. The ARGP ablation eliminated ERP shortening and AF inducibility with right vagosympathetic trunk stimulation, whereas SLGP ablation eliminated ERP shortening but not AF inducibility with left vagosympathetic trunk stimulation.
SLGP消融术显著减弱右、左迷走交感干刺激的SR和VR慢化反应。随后的ARGP消融对SR减慢产生了额外的影响,但对VR减慢没有影响。SLGP + ARGP消融后,IRGP消融消除了VR减慢,但没有进一步减弱迷走交感干刺激下的SR减慢。单侧左右迷走交感干刺激分别缩短了ARGP和SLGP附近心房和肺静脉的有效不应期,增加了AF诱导力。在右侧迷走交感干刺激下,ARGP消融术可消除ERP缩短和AF诱导,而在左侧迷走交感干刺激下,SLGP消融术可消除ERP缩短,但不能消除AF诱导。

Conclusions 结论

The GP function as the “integration centers” that modulate the autonomic interactions between the extrinsic and intrinsic cardiac ANS. This interaction is substantially more intricate than previously thought.
GP作为“整合中心”,调节心脏外源性和内源性ANS之间的自主相互作用,这种相互作用比以前认为的要复杂得多。

Abbreviations and Acronyms
缩写和缩略语

AF
atrial fibrillation
ANS
autonomic nervous system
ARGP
anterior right ganglionated plexi
ERP
effective refractory period
GP
ganglionated plexi
IRGP
inferior right ganglionated plexi
LSPV
left superior pulmonary vein
RSPV
right superior pulmonary vein
SA
sinoatrial
SLGP
superior left ganglionated plexi
SR
sinus rate
VR
ventricular rate

房颤、自主神经系统、右侧神经节丛、右侧神经节丛、右侧神经节丛、右侧神经节丛、左侧上肺静脉、右侧上肺静脉、左心房、左上神经节丛、左窦率、心室率

Autonomic innervation of the heart involves both the extrinsic and the intrinsic cardiac autonomic nervous system (ANS). The former collectively includes the ganglia in the brain or along the spinal cord and their axons (e.g., the vagosympathetic trunk) en route to the heart; the latter consists of the autonomic ganglia and axons located on the heart itself or along the great vessels in the thorax (1). Ample structural and functional evidence indicates that the intrinsic cardiac ANS forms a complex neural network composed of ganglionated plexi (GP) concentrated within epicardial fat pads and the interconnecting ganglia and axons (2, 3, 4, 5).
心脏的自主神经支配包括外源性和内源性心脏自主神经系统。前者包括大脑中的神经节或沿脊髓及其轴突(如迷走交感干)到达心脏;后者由位于心脏本身或胸腔大血管上的自主神经节和轴突组成(1)。大量的结构和功能证据表明,心脏内在ANS形成了一个复杂的神经网络,由集中在心外膜脂肪垫内的神经节丛(GP)和相互连接的神经节和轴突组成(2,3,4,5)。

Basic and clinical studies on atrial fibrillation (AF) resulting from changes in the ANS have underscored the contributions from the extrinsic cardiac ANS, mainly by stimulating the vagosympathetic trunk in animals (5, 6) or by observing the pattern of AF initiation in patients (7). Recently, stimulation of the intrinsic cardiac ANS by applying high-frequency electrical stimulation to the GP (8) or by injecting parasympathomimetics into the GP (9) has drawn attention to the critical role of the intrinsic cardiac ANS in the dynamics of AF initiation and maintenance. How the extrinsic and intrinsic cardiac ANS operate cooperatively in regard to these aspects has not been detailed. The purpose of this study was to systemically investigate the interactions between the extrinsic and intrinsic cardiac ANS in the context of modulating sinus and atrioventricular (AV) nodal function and facilitating AF inducibility.
由ANS改变引起的心房颤动(AF)的基础和临床研究强调了外源性心脏ANS的作用,主要是通过刺激动物的迷走交感干(5,6)或观察患者心房颤动的起始模式(7)。通过对GP施加高频电刺激(8)或向GP注射副交感神经模拟剂(9)来刺激心脏内源性ANS,引起了人们对心脏内源性ANS在房颤发生和维持动力学中的关键作用的关注。外在和内在的心脏ANS如何在这些方面协同工作还没有详细说明。本研究的目的是系统地研究在调节窦房室(AV)结功能和促进AF诱导的背景下,外源性和内源性心脏ANS之间的相互作用。

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. Twenty-eight adult mongrel dogs weighing 20 to 25 kg were anesthetized with sodium pentobarbital, 50 mg/kg, and ventilated with room air by a positive pressure respirator. Standard electrocardiographic leads II and aVR were continuously monitored. Core body temperature was maintained at 36.5°C ± 1.5°C. All recordings were displayed on a Bard Computerized Electrophysiology system (Bard, Billerica, Massachusetts).
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。用戊巴比妥钠50 mg/kg麻醉28只体重20 ~ 25 kg的成年杂种犬,用正压呼吸器呼吸室内空气。连续监测标准心电图导联II和aVR。核心体温维持在36.5℃±1.5℃。所有记录都显示在巴德计算机电生理系统(巴德,比勒埃里卡,马萨诸塞州)上。

Autonomic stimulation 自主的刺激

Both cervical vagosympathetic trunks were exposed by dissections. A pair of Teflon-coated silver wires (0.1-mm diameter) was inserted into the cervical vagosympathetic trunks for stimulation. Vagosympathetic stimulation was performed by applying high-frequency electrical stimulation (20 Hz, 0.1 ms duration, square waves, 0.6 to 8.0 V) to each of the vagosympathetic trunk via a stimulator (Grass-S88, Astro-Med; West Warwick, Rhode Island). A right thoracotomy at the 4th intercostal space was performed to expose the fat pad containing the anterior right GP (ARGP) situated between the caudal end of the sinoatrial (SA) node and the right superior pulmonary vein (RSPV)–atrial junction (10) (Fig. 1A).The inferior right GP (IRGP) located at the junction of the inferior vena cava and both atria was visualized by gently reflecting the inferior vena cava. A left thoracotomy at the 4th intercostal space was used to expose the superior left GP (SLGP) located adjacent to the left superior pulmonary vein (LSPV)–atrial junction between the left atrial appendage and left pulmonary artery (10) (Fig. 1B).
解剖显示两条颈迷走交感神经干。将一对直径为0.1 mm的teflon涂层银丝插入颈迷走交感神经干进行刺激。通过刺激器(Grass-S88, Astro-Med;西沃里克,罗德岛)。在第4肋间隙行右开胸术,暴露位于窦房结(SA)尾端和右上肺静脉(RSPV) -心房交界处之间包含右前GP (ARGP)的脂肪垫(10)(图1A)。右下腔静脉(IRGP)位于下腔静脉与双心房交界处,通过轻反射下腔静脉可见。在第4肋间隙处进行左开胸,暴露位于左上肺静脉(LSPV) -左心房附件和左肺动脉之间的心房连接处附近的左上GP (SLGP)(10)(图1B)。

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Figure 1. Schematic and Photographic Representation of the Right and Left Thoracotomy Approach
图1所示。左、右开胸入路示意图及摄影表现

Schematic and photographic representation of the right (A, C)and left (B, D)atria and associated ganglionated plexi (GP). The labels RA, RSPV, LA, and LSPVindicate cardiac structures or multielectrode catheters positioned on the epicardial surface of the right atrium, right superior pulmonary veins, left atrium, and left superior pulmonary vein, respectively. For all catheters, the distal electrode pair (D,2) was positioned adjacent to the GP (hatched area)near the pulmonary vein–atrial junction. ARGP = anterior right ganglionated plexi; CS = coronary sinus; IRGP = inferior right ganglionated plexi; IVC = inferior vena cava; LAA = left atrial appendage; LIPV = left inferior plumonary vein; LOM = ligament of Marshall; LPA = left pulmonary artery; RAA = right atrial appendage; RIPV = right inferior pulmonary vein; SLGP = superior left ganglionated plexi; SVC = superior vena cava.
右心房(A、C)和左心房(B、D)及相关神经节丛(GP)的示意图和照片。标记RA、RSPV、LA、lspv分别表示放置在右心房、右上肺静脉、左心房、左上肺静脉心外膜表面的心脏结构或多电极导管。对于所有导管,远端电极对(D,2)被放置在靠近肺静脉-心房连接处的GP(阴影区)附近。ARGP =右前神经节丛;CS =冠状窦;IRGP =右下神经节丛;下腔静脉;LAA =左心耳;LIPV =左下垂体静脉;LOM =马歇尔韧带;LPA =左肺动脉;RAA =右心耳;RIPV =右下肺静脉;SLGP =左上神经节丛;SVC =上腔静脉。

The GP were identified by applying high-frequency stimulation using a bipolar electrode probe (AtriCure, West Chester, Ohio) through a Grass stimulator as described above. The effects of vagosympathetic stimulation at various voltage levels on the sinus rate (SR) were determined as well as the averaged ventricular rate (VR) during induced AF. The average SR at each stimulation level was determined by averaging the last 10 sinus cycle lengths. The AF was induced and maintained by rapid atrial pacing (600 to 800 beats/min). During induced AF, the average VR was determined from the ventricular cycle lengths over the last 20 beats at each stimulation level.
通过上述Grass刺激器,使用双极电极探头(AtriCure, West Chester, Ohio)施加高频刺激来识别GP。测定不同电压水平迷走交感神经刺激对诱发心房颤动时窦率(SR)和平均心室率(VR)的影响。各刺激水平下的平均室率取最近10个窦周期长度的平均值。心房快速起搏(600 ~ 800次/分)诱发并维持心房颤动。在诱发性心房颤动期间,根据每个刺激水平下最后20次心跳的心室周期长度确定平均VR。

To determine the interactions between extrinsic and intrinsic cardiac ANS, the SLGP, ARGP, and IRGP were ablated sequentially using the stimulation/ablation device (radiofrequency current at 460 kHz; <32.5 W; AtriCure, West Chester, Ohio). The voltages reported in this study were the delivered voltages across the catheter electrode. Completeness of GP ablation was verified by eliminating the responses (slowing of SR and VR) induced by applying maximal voltage to the GP so that positive responses were attained at much lower voltages before ablation. Identical vagosympathetic stimulation protocols as described above were applied to each vagosympathetic trunk before and after ablation of each GP.
为了确定外源性和内源性心脏ANS之间的相互作用,使用刺激/消融装置(射频电流为460 kHz;< 32.5 W;AtriCure,西切斯特,俄亥俄州)。本研究中报告的电压是通过导管电极传递的电压。通过消除在GP上施加最大电压引起的响应(SR和VR的减慢),验证GP消融的完整性,以便在消融前以低得多的电压获得正响应。上述相同的迷走交感刺激方案应用于每个GP消融前后的每个迷走交感干。

Programmed stimulation 编程的刺激

Programmed stimulation of myocardium was performed using a stimulator (model 5328, Medtronic, Minneapolis, Minnesota). Atrial pacing at a cycle length of 330 ms (2× diastolic threshold; threshold = 0.6 to 1.5 mA) was performed at each electrode pair of the multielectrode catheters on RA, RSPV (Fig. 1A), LA, or LSPV (Fig. 1B). Programmed electrical stimulation (starting at S1–S2 = 150 ms) was applied to each electrode pair with or without concurrent vagosympathetic stimulation (at a voltage level that reduced SR by 50%) until AF was induced or no AF was induced at maximal voltage (8.0 V). The effective refractory period (ERP) was determined at each electrode pair along the catheters positioned at RA, RSPV, LA, or LSPV before and during vagosympathetic stimulation. As the S1–S2 intervals were decreased from 150 ms to refractoriness, the longest and shortest S1–S2 interval (in ms) at which AF was induced was determined. The difference between the two was designated as the window of vulnerability (10). Thus, the mean window of vulnerability at each bipolar pair with and without served as a quantitative measure of AF inducibility.
使用刺激器(5328型,Medtronic, Minneapolis, Minnesota)对心肌进行程序性刺激。周期长度为330 ms(2倍舒张阈值)时心房起搏;阈值= 0.6至1.5 mA)在RA, RSPV(图1A), LA或LSPV(图1B)上的多电极导管的每个电极对上进行。将程序电刺激(从S1-S2 = 150 ms开始)施加于每对电极上,同时施加或不施加迷走交感刺激(电压水平使SR降低50%),直到在最大电压(8.0 V)下诱发AF或不诱发AF。在迷走交感刺激之前和期间,沿着位于RA、RSPV、LA或LSPV的导线测定每对电极上的有效不应期(ERP)。随着S1-S2时间间隔从150 ms减少到耐火度,确定了诱发AF的最长和最短S1-S2时间间隔(ms)。将两者之差指定为漏洞窗口(10)。因此,在每双极对的脆弱性的平均窗口有和没有作为AF诱导的定量措施。

Statistical analysis 统计分析

All data are expressed as mean ± SD. The mean values of the parameters acquired during different levels of vagosympathetic stimulation were compared to the baseline state, i.e., no stimulation, using 2-way analysis of variance with time (before and after vagosympathetic stimulation) as repeated measures. The mean values of individual parameters acquired at individual level of vagosympathetic stimulation before and after GP ablation also were compared using the same statistical method. Probability values <0.05 were considered statistically significant. All analyses were conducted using SAS version 8.1 (SAS Institute Inc., Cary, North Carolina).
所有数据均以mean±SD表示。将不同迷走交感刺激水平下获得的参数均值与基线状态(即无刺激)进行比较,采用随时间(迷走交感刺激前后)的双向方差分析作为重复测量。采用相同的统计方法比较GP消融前后个体迷走交感神经刺激水平下个体参数的平均值。概率值<0.05认为有统计学意义。所有分析均使用SAS 8.1版本(SAS Institute Inc., Cary, North Carolina)进行。

Results 结果

Effects of right vagosympathetic stimulation on SR
右迷走交感神经刺激对SR的影响

Right vagosympathetic stimulation suppressed SR at voltage levels ≥0.6 V with a maximal effect of 90% reduction in SR (147 ± 16 beats/min baseline vs. 15 ± 19 beats/min, 8.0 V) (Table 1).We elected to ablate the SLGP first to investigate whether GP at a distance from the SA node also modulate the SR. After SLGP ablation, SR still could be slowed by right vagosympathetic stimulation (≥1.5 V) but the maximal effect was significantly attenuated to 59% (154 ± 15 beats/min baseline vs. 63 ± 35 beats/min, 8.0 V) (Table 1). The difference of SR slowing before and after SLGP ablation was statistically significant at voltage levels ≥1.5 V (P1, Table 1). After SLGP ablation, ARGP ablation produced further attenuation of SR slowing induced by right vagosympathetic stimulation. The maximal effect was reduced to 20% (158 ± 19 beats/min baseline vs. 126 ± 16 beats/min, 8.0 V) and the differences before and after ARGP ablation also reached statistical significance at voltage levels ≥1.5 V (P2, Table 1). Subsequent ablation of the IRGP after SLGP + ARGP ablation did not further attenuate the SR slowing effect (P3, Table 1). Right vagosympathetic stimulation still slowed SR at voltage levels ≥1.5 V. To further examine the direction of autonomic innervation from right vagosympathetic trunk to SA node (right vagosympathetic trunk → ARGP → SLGP → SA node vs. right vagosympathetic trunk → SLGP → ARGP → SA node), only the ARGP was ablated in another 7 animals. After ARGP ablation, the magnitude of SR slowing at 8.0 V was diminished to 17% (data not shown in Tables), similar to the effects after ablation of both SLGP and ARGP (20%) (Table 1).
右侧迷走交感神经刺激在电压水平≥0.6 V时抑制SR,最大效果为SR降低90%(基线147±16次/分钟vs. 15±19次/分钟,8.0 V)(表1)。我们选择先切除SLGP,以研究距离窦房结的GP是否也调节SR。右侧迷走交感刺激(≥1.5 V)仍能减缓SR,但最大效果显著减弱至59%(基线154±15次/分钟vs. 63±35次/分钟,8.0 V)(表1)。电压水平≥1.5 V时,SLGP消融前后SR减慢的差异具有统计学意义(P 1 ,表1)。SLGP消融后,ARGP消融进一步减弱右侧迷走交感刺激引起的SR减慢。最大效果降至20%(基线158±19次/分钟vs 126±16次/分钟,8.0 V),电压水平≥1.5 V时,ARGP消融前后的差异也具有统计学意义(P 2 ,表1)。SLGP + ARGP消融后的IRGP后续消融并未进一步减弱SR减缓效果(P 3 ,表1)。为了进一步研究右侧迷走交感干到窦房结的自主神经支配方向(右侧迷走交感干→ARGP→SLGP→SA结vs右侧迷走交感干→SLGP→ARGP→SA结),另外7只动物仅切除ARGP。ARGP消融后,8.0 V SR减慢幅度减少至17%(数据未在表中显示),与SLGP和ARGP消融后的效果相似(20%)(表1)。

Table 1. Effects of Right Vagosympathetic Trunk Stimulation on Sinus Rate (beats/min) Before and After SLGP, ARGP, and IRGP Were Sequentially Ablated
表1。右迷走交感干刺激对SLGP、ARGP和IRGP前后窦率(次/分)的影响

Empty CellBaseline 基线0.3 V0.6 V1.5 V2.4 V3.2 V4.5 V8.0 V
Control, n = 10 对照组,n = 10147 ± 16146 ± 17113 ± 54 113±54 37 ± 38 37±38 __25 ± 30 25±30 __20 ± 21 20±21 __15 ± 20 15±20 __15 ± 19 15±19 __
SLGP ablation, n = 10
SLGP消融,n = 10
154 ± 15154 ± 16137 ± 2692 ± 39 92±39 __81 ± 39 81±39 __71 ± 41 71±41 __71 ± 40 71±40 __63 ± 35 63±35 __
 P1NSNSNS<0.001 < 0.001<0.001 < 0.001<0.001 < 0.001<0.001 < 0.001<0.01 < 0.01
SLGP + ARGP ablation, n = 10
SLGP + ARGP消融,n = 10
158 ± 19158 ± 8148 ± 22131 ± 17 131±17 __127 ± 16 127±16 __127 ± 17 127±17 __126 ± 16 126±16 __126 ± 16 126±16 __
 P2NSNSNS<0.01 < 0.01<0.001 < 0.001<0.001 < 0.001<0.001 < 0.001<0.01 < 0.01
SLGP + ARGP + IRGP ablation, n = 8
SLGP + ARGP + IRGP消融,n = 8
149 ± 17149 ± 16147 ± 17135 ± 14 135±14 133 ± 12 133±12 133 ± 11 133±11 133 ± 11 133±11 133 ± 12 133±12
 P3NSNSNSNSNSNSNSNS

ARGP = anterior right ganglionated plexi; baseline = no vagosympathetic stimulation; control = before ablation; IRGP = inferior right ganglionated plexi; NS = not statistically significant; P1= p value for comparison at each voltage level before and after SLGP ablation; P2= p value for comparison at each voltage level between SLGP + ARGP ablation and SLGP ablation; P3= p value for comparison at each voltage level between SLGP + ARGP + IRGP ablation and SLGP + ARGP ablation; SLGP = superior left ganglionated plexi.
ARGP =右前神经节丛;基线=没有迷走交感神经刺激;控制=消融前;IRGP =右下神经节丛;NS =无统计学意义;P 1 = SLGP消融前后各电压水平比较的P值;P 2 = SLGP + ARGP消融与SLGP消融在各电压水平下比较的P值;P 3 = SLGP + ARGP + IRGP消融与SLGP + ARGP消融在各电压水平下的比较P值;左上神经节神经丛。

p < 0.05 p < 0.05

p < 0.01 (compared with baseline).
P <0.01(与基线比较)。

Effects of left vagosympathetic stimulation on SR
左迷走交感神经刺激对SR的影响

Left vagosympathetic stimulation produced similar but smaller effects on SR slowing compared with right vagosympathetic stimulation, with a maximal effect of 57% reduction of SR (145 ± 18 beats/min baseline vs. 63 ± 36 beats/min, 8.0 V) (Table 2).After SLGP ablation, stimulation levels ≥2.4 V still slowed SR but the maximal effect was reduced to 22% (156 ± 16 beats/min baseline vs. 122 ± 29 beats/min, 8.0 V) (Table 2). It required ≥2.4 V to slow the SR, and the differences before and after SLGP ablation were statistically significant at voltage levels ≥0.3 V (P1, Table 2). After SLGP ablation, subsequent ablation of ARGP diminished the maximal effect to 9% (153 ± 16 beats/min baseline vs. 139 ± 11 beats/min, 8.0 V) (Table 2). However, the differences before and after ARGP ablation failed to achieve statistical significance at all voltage levels (P2, Table 2). No additional effect on SR suppression was observed after subsequent ablation of IRGP. To further investigate the direction of innervation (e.g., left vagosympathetic trunk → SLGP → ARGP → SA node vs. left vagosympathetic trunk → ARGP → SLGP → SA node), only ARGP was ablated in 7 animals, which diminished the maximal effect of left vagosympathetic stimulation on SR to 8% (data not shown in Tables). The residual effect (8%) was similar to that after ablation of SLGP and ARGP (9%) (Table 2).
老左vagosympathetic刺激产生相似但较小影响而放缓对vagosympathetic刺激,减少57%的最大效应的SR(145±18胜/分钟基线vs 63±36胜/分钟,8.0 V)(表2)经过SLGP消融,刺激水平仍然≥2.4 V SR放缓但最大影响降低到22%(156±16胜/分钟基线vs 122±29胜/分钟,8.0 V)(表2)。它要求≥2.4 V SR缓慢,在电压水平≥0.3 V时,SLGP消融前后的差异具有统计学意义(P 1 ,表2)。SLGP消融后,后续的ARGP消融将最大效果降低至9%(基线153±16次/分钟vs. 139±11次/分钟,8.0 V)(表2)。然而,在所有电压水平下,ARGP消融前后的差异均未达到统计学意义(P 2 ,表2)。随后IRGP消融后未观察到对SR抑制的额外影响。为了进一步研究神经支配方向(如左侧迷走交感干→SLGP→ARGP→SA结vs左侧迷走交感干→ARGP→SLGP→SA结),7只动物仅切除ARGP,使左侧迷走交感刺激对SR的最大影响降低至8%(数据未见表)。残余效应(8%)与SLGP和ARGP消融后(9%)相似(表2)。

Table 2. Effects of Left Vagosympathetic Trunk Stimulation on Sinus Rate (beats/min) Before and After SLGP, ARGP, and IRGP Were Sequentially Ablated
表2。左迷走交感干刺激对SLGP、ARGP和IRGP前后窦率(次/分)的影响

Empty CellBaseline 基线0.3 V0.6 V1.5 V2.4 V3.2 V4.5 V8.0 V
Control, n = 10 对照组,n = 10145 ± 18137 ± 23118 ± 3178 ± 33 78±33 __71 ± 37 71±37 __66 ± 39 66±39 __65 ± 37 65±37 __63 ± 36 63±36 __
SLGP ablation, n = 10
SLGP消融,n = 10
156 ± 16155 ± 16149 ± 16138 ± 26131 ± 25 131±25 128 ± 26 128±26 __126 ± 27 126±27 __122 ± 29 122±29 __
 P1NS<0.05 < 0.05<0.01 < 0.01<0.001 < 0.001<0.001 < 0.001<0.001 < 0.001<0.001 < 0.001<0.001 < 0.001
SLGP + ARGP ablation, n = 10
SLGP + ARGP消融,n = 10
153 ± 16153 ± 9149 ± 14145 ± 14143 ± 14142 ± 13141 ± 12139 ± 11 139±11
 P2NSNSNSNSNSNSNSNS
SLGP + ARGP + IRGP ablation, n = 8
SLGP + ARGP + IRGP消融,n = 8
157 ± 17157 ± 4156 ± 17152 ± 18151 ± 17149 ± 17148 ± 17146 ± 16
 P3NSNSNSNSNSNSNSNS

Abbreviations as in Table 1.
缩写如表1所示。

p < 0.05 p < 0.05

p < 0.01 (compared with baseline).
P <0.01(与基线比较)。

Effects of right vagosympathetic stimulation on VR during AF
右迷走交感刺激对房颤时VR的影响

Right vagosympathetic stimulation significantly slowed the VR during AF at voltages ≥1.5 V with a maximal effect of 69% (243 ± 27 beats/min baseline vs. 75 ± 86 beats/min, 8.0 V) (Table 3).The SLGP ablation attenuated the maximal effect to 23% (236 ± 28 beats/min baseline vs. 182 ± 59 beats/min, 8.0 V) (Table 3). The differences before and after ablation were statistically significant at voltages ≥1.5 V (P1, Table 3). Subsequent ablation of the ARGP induced nonsignificant changes (P2, Table 3), whereas ablation of IRGP eliminated the VR slowing effects, suggesting that the neural pathways followed a direction such as right vagosympathetic trunk → SLGP → ARGP → IRGP or right vagosympathetic trunk → ARGP → SLGP → IRGP. To differentiate which of the 2 pathways was involved, only the ARGP was ablated in 7 other animals. The maximal response was reduced from 67% (264 ± 31 beats/min baseline vs. 87 ± 85 beats/min, 8.0 V) to 26% (249 ± 27 beats/min baseline vs. 185 ± 66 beats/min, 8.0 V) (data not shown in tables), similar to the magnitude of attenuation after SLGP + ARGP ablation (23%) (Table 3). Subsequent ablation of the IRGP also completely eliminated the VR slowing response.
在电压≥1.5 V时,右侧迷走交感神经刺激显著减缓房颤期间的VR,最大效应为69%(基线243±27次/分钟vs. 75±86次/分钟,8.0 V)(表3)。SLGP消融将最大效应减弱至23%(基线236±28次/分钟vs. 182±59次/分钟,8.0 V)(表3)。在电压≥1.5 V时,消融前后差异具有统计学意义(P 1 ,表3)。随后消融ARGP诱导的无明显变化(P 2 ,表3),而消融IRGP消除了VR减缓效应,提示神经通路遵循右侧迷走交感干→SLGP→ARGP→IRGP或右侧迷走交感干→ARGP→SLGP→IRGP的方向。为了区分两种通路中哪一种参与,在其他7只动物中只切除了ARGP。最大反应从67%(基线264±31次/分钟vs. 87±85次/分钟,8.0 V)降低到26%(基线249±27次/分钟vs. 185±66次/分钟,8.0 V)(数据未在表中显示),与SLGP + ARGP消融后的衰减幅度相似(23%)(表3)。随后的IRGP消融也完全消除了VR减慢反应。

Table 3. Effects of Right Vagosympathetic Trunk Stimulation on Ventricular Rate (beats/min) During Induced AF Before and After SLGP, ARGP, and IRGP Were Sequentially Ablated
表3。在SLGP、ARGP和IRGP前后依次消融右侧迷走交感干刺激对诱发AF时心室率(次/分)的影响

Empty CellBaseline 基线0.3 V0.6 V1.5 V2.4 V3.2 V4.5 V8.0 V
Control, n = 10 对照组,n = 10243 ± 27242 ± 27214 ± 6198 ± 77 98±77 __81 ± 86 81±86 __78 ± 85 78±85 __81 ± 84 81±84 __75 ± 86 75±86 __
SLGP ablation, n = 10
SLGP消融,n = 10
236 ± 28236 ± 28233 ± 28200 ± 66198 ± 60200 ± 60188 ± 61 188±61 182 ± 59 182±59
 P1NSNSNS<0.01 < 0.01<0.001 < 0.001<0.001 < 0.001<0.001 < 0.001<0.001 < 0.001
SLGP + ARGP ablation, n = 10
SLGP + ARGP消融,n = 10
244 ± 26240 ± 25240 ± 28212 ± 65213 ± 63203 ± 70202 ± 62195 ± 64 195±64
 P2NSNSNSNSNSNSNSNS
SLGP + ARGP + IRGP ablation, n = 8
SLGP + ARGP + IRGP消融,n = 8
239 ± 33239 ± 4238 ± 32233 ± 31224 ± 39221 ± 33225 ± 31224 ± 28
 P3NSNSNSNSNSNSNSNS

Abbreviations as in Table 1.
缩写如表1所示。

p < 0.05 p < 0.05

p < 0.01 (compared with baseline).
P <0.01(与基线比较)。

Effects of left vagosympathetic stimulation on ventricular rate during AF
左迷走交感神经刺激对房颤时心室率的影响

Left vagosympathetic stimulation significantly reduced VR at voltage ≥1.5 V, and VR was reduced by 70% at 8.0 V (235 ± 25 beats/min baseline vs. 66 ± 80 beats/min, 8.0 V) (Table 4).The SLGP ablation attenuated the response, and the maximal effect was only 27% (229 ± 25 beats/min baseline vs. 163 ± 84 beats/min, 8.0 V) (Table 4). Ablation of the ARGP after SLGP ablation produced no additional effect, whereas subsequent ablation of IRGP completely abolished the effects of left vagosympathetic stimulation. To examine the direction of innervation (e.g., left vagosympathetic trunk → SLGP → ARGP → IRGP vs. left vagosympathetic trunk → ARGP → SLGP → IRGP), only ARGP was ablated in 7 other animals, which moderately reduced the maximal effect of VR slowing from 72% (260 ± 27 beats/min baseline vs. 73 ± 54 beats/min, 8.0 V, before ARGP ablation) to 39% (239 ± 22 beats/min baseline vs. 146 ± 82 beats/min, 8.0 V, after ARGP ablation) (data not shown in Tables). Subsequent ablation of the IRGP in these 7 animals further attenuated but did not eliminate the VR response elicited by left vagosympathetic stimulation (16% reduction in VR at 8.0 V, data not shown in Tables). This residual effect (16%) was larger than that of SLGP + ARGP + IRGP ablation (5% reduction in VR at 8.0 V) (Table 4).
左迷走交感神经刺激在电压≥1.5 V时显著降低VR,在8.0 V时VR降低70%(基线235±25次/分钟vs 66±80次/分钟,8.0 V)(表4)。SLGP消融术减弱反应,最大效果仅为27%(基线229±25次/分钟vs 163±84次/分钟,8.0 V)(表4)。SLGP消融术后对ARGP的消融术没有额外的影响。而随后的IRGP消融完全消除了左侧迷走交感神经刺激的影响。检查神经支配的方向(例如,左vagosympathetic主干→SLGP→ARGP→IRGP与左vagosympathetic主干→ARGP→SLGP→IRGP),只有ARGP切除7的其他动物,适度降低VR的最大效果从72%放缓(260±27胜/分钟基线与73±54胜/分钟,8.0 V, ARGP消融前)到39%(239±22次/分钟基线与146±82次/分钟,8.0 V, ARGP消融后)(数据表中没有显示)。随后对这7只动物的IRGP进行消融,进一步减弱但没有消除左迷走交感刺激引起的VR反应(8.0 V时VR降低16%,数据未在表中显示)。这一残余效应(16%)大于SLGP + ARGP + IRGP消融(在8.0 V时VR降低5%)(表4)。

Table 4. Effects of Left Vagosympathetic Trunk Stimulation on Ventricular Rate (beats/min) During Induced AF Before and After SLGP, ARGP, and IRGP Were Sequentially Ablated
表4。在SLGP、ARGP和IRGP前后依次消融左迷走交感干刺激对诱发AF时心室率(次/分)的影响

Empty CellBaseline 基线0.3 V0.6 V1.5 V2.4 V3.2 V4.5 V8.0 V
Control, n = 10 对照组,n = 10235 ± 25218 ± 55174 ± 7595 ± 88 95±88 __88 ± 87 88±87 __83 ± 74 83±74 __76 ± 77 76±77 __66 ± 80 66±80 __
SLGP ablation, n = 10
SLGP消融,n = 10
229 ± 25229 ± 24223 ± 29176 ± 84182 ± 83176 ± 82179 ± 82163 ± 84 163±84
 P1NSNS<0.05 < 0.05<0.05 < 0.05<0.05 < 0.05<0.05 < 0.05<0.01 < 0.01<0.01 < 0.01
SLGP + ARGP ablation, n = 10
SLGP + ARGP消融,n = 10
235 ± 28231 ± 20216 ± 50167 ± 85162 ± 92 162±92 161 ± 94163 ± 91158 ± 96 158±96 __
 P2NSNSNSNSNSNSNSNS
SLGP + ARGP + IRGP ablation, n = 8
SLGP + ARGP + IRGP消融,n = 8
240 ± 33238 ± 20237 ± 33233 ± 28235 ± 29229 ± 28228 ± 29229 ± 28
 P3NSNSNSNSNS<0.05 < 0.05<0.05 < 0.05<0.05 < 0.05

Abbreviations as in Table 1.
缩写如表1所示。

p < 0.05 p < 0.05

p < 0.01 (compared with baseline).
P <0.01(与基线比较)。

Right and left vagosympathetic stimulation on ERP and AF inducibility
左右迷走交感刺激对ERP和AF诱发性的影响

Unilateral right and left vagosympathetic stimulation at a voltage level that slowed the SR by 50% in individual animal was selected and applied to the left or right vagosympathetic trunk before and after GP ablation. Right vagosympathetic stimulation shortened the ERP recorded from the right atrium (RA-D,2: 110 ± 24 ms baseline vs. 82 ± 27 ms stimulation; RA-3,4: 112 ± 20 ms baseline vs. 78 ± 32 ms stimulation) (Table 5,top left). The ERPs along the RSPV recording sites also were shortened by right vagosympathetic stimulation (RSPV-D,2: 113 ± 17 ms baseline vs. 80 ± 31 ms stimulation) (Table 5, top left). The window of vulnerability on the right atrium was widened by right vagosympathetic stimulation (RA-D,2: 6 ± 20 ms baseline vs. 38 ± 31 ms stimulation, RA-3,4: 5 ± 20 ms baseline vs. 46 ± 35 ms stimulation) (Table 5, top right), so did the window of vulnerability on RSPV-D,2 (5 ± 16 baseline vs. 32 ± 36 stimulation) (Table 5, top right). Both ERP shortening and window of vulnerability widening of the right atrium and RSPV were eliminated by ARGP ablation. Left vagosympathetic stimulation elicited ERP shortening of the left atrium and LSPV (Table 5, bottom left), which was eliminated by SLGP ablation. Left vagosympathetic stimulation failed to widen the window of vulnerability of the LA and LSPV sites (Table 5, bottom right).
选择单侧左右迷走交感电刺激,使个体动物的SR减慢50%,并在GP消融前后分别施加于左右迷走交感干。右侧迷走交感刺激缩短了右心房记录的ERP (RA-D,基线值110±24 ms vs刺激值82±27 ms;ra -3,4:基线112±20 ms vs刺激78±32 ms)(表5,左上)。右迷走交感刺激也缩短了RSPV记录部位的erp (RSPV- d,2: 113±17 ms基线vs 80±31 ms刺激)(表5,左上)。右迷走交感神经刺激(RA-D, 2:6±20 ms基线vs. 38±31 ms刺激,RA-3, 4:5±20 ms基线vs. 46±35 ms刺激)可拓宽右心房易损窗口(表5,右上),RSPV-D,2(5±16基线vs. 32±36刺激)易损窗口也可拓宽(表5,右上)。ARGP消融消除了右心房和RSPV的ERP缩短和易损性窗口扩大。左侧迷走交感刺激引起左心房和LSPV的ERP缩短(表5,左下),SLGP消融消除了这一现象。左侧迷走交感刺激未能扩大LA和LSPV部位的易损性窗口(表5,右下)。

Table 5. Effects of Right or Left Vagosympathetic Trunk Stimulation on ERP (in ms) and WOV (in ms) of Atria and Pulmonary Veins Before and After ARGP or SLGP Ablation (n = 11)
表5所示。左右迷走交感干刺激对ARGP或SLGP消融前后心房肺静脉ERP(单位ms)和WOV(单位ms)的影响(n = 11)

Empty CellERPWOV
RA-D,2RA-3,4 RA-3 4RSPV-D,2 RSPV-D 2RSPV-3,4 RSPV-3 4RA-D,2 RA-D 2RA-3,4 RA-3 4RSPV-D,2 RSPV-D 2RSPV-3,4 RSPV-3 4
BSRVG-StimBSRVG-StimBSRVG-StimBSRVG-StimBSRVG-StimBSRVG-StimBSRVG-StimBSRVG-Stim
ARGP ablation
 Before110 ± 2482 ± 27112 ± 2078 ± 32 78±32 __113 ± 1780 ± 31 80±31 __113 ± 1499 ± 266 ± 2038 ± 31 38±31 __5 ± 2046 ± 35 46±35 __5 ± 1632 ± 36 32±36 __0 ± 011 ± 26
 After127 ± 22120 ± 24115 ± 2399 ± 25109 ± 1496 ± 29109 ± 11104 ± 180 ± 03 ± 100 ± 015 ± 25 15 25± 2 ± 816 ± 310 ± 05 ± 19
 pNS0.01NSNSNSNSNSNSNS0.001NS0.011NSNSNSNS
Empty CellLA-D,2LA-3,4 洛杉矶3、4LSPV-D,2 LSPV-D 2LSPV-3,4 LSPV-3 4LA-D,2 d、2LA-3,4 洛杉矶3、4LSPV-D,2 LSPV-D 2LSPV-3,4 LSPV-3 4
BSLVG-StimBSLVG-StimBSLVG-StimBSLVG-StimBSLVG-StimBSLVG-StimBSLVG-StimBSLVG-Stim
SLGP ablation
 Before107 ± 2386 ± 24105 ± 1384 ± 22 84±22 108 ± 1986 ± 25 86±25 __94 ± 1177 ± 20 77±20 4 ± 1310 ± 222 ± 88 ± 200 ± 08 ± 180 ± 014 ± 23
 After111 ± 17108 ± 15106 ± 20105 ± 16108 ± 1497 ± 2491 ± 1085 ± 180 ± 00 ± 04 ± 140 ± 00 ± 07 ± 240 ± 09 ± 22
 pNS0.013NS0.015NSNSNSNSNSNSNSNSNSNSNSNS

BS = baseline without stimulation; D,2 = electrode pair in close proximity to ARGP (RA-D,2, RSPV-D,2) or SLGP (LA-D,2, LSPV-D,2); ERP = effective refractory period; LA = multielectrode catheters sewn to the left atrium; LSPV = multielectrode catheters sewn to the left superior pulmonary vein; LVG-Stim = left vagosympathetic stimulation; RA = multielectrode catheters sewn to the right atrium; RSPV = multielectrode catheters sewn to the right superior pulmonary vein; RVG-Stim = right vagosympathetic stimulation; WOV = window of vulnerability; other abbreviations as in Table 1.
BS =无刺激的基线;D,2 =靠近ARGP (RA-D,2, RSPV-D,2)或SLGP (LA-D,2, LSPV-D,2)的电极对;ERP =有效不应期;LA =缝合在左心房的多电极导管;LSPV =多电极导管缝在左上肺静脉;左迷走交感神经刺激;RA =缝合在右心房的多电极导管;RSPV =多电极导管缝在右上肺静脉;RVG-Stim =右侧迷走交感神经刺激;WOV =漏洞窗口;其他缩写如表1所示。

p < 0.05 p < 0.05

p < 0.01 (compared with baseline)
P <0.01(与基线比较)

comparison before and after ARGP or SLGP ablation.
ARGP或SLGP消融前后的比较。

Discussion 讨论

In the present study, a stepwise approach was used to systematically investigate the interactions between vagosympathetic trunk (extrinsic cardiac ANS) and GP (intrinsic cardiac ANS). We found that GP function as “integration centers” (1) that integrate the autonomic innervation between extrinsic and intrinsic cardiac ANS because they affect atrial electrophysiology and pathophysiology as indicated by AF inducibility. For instance, IRGP seems to be the integration center for the extrinsic ANS to innervate the AV node as ablation of IRGP completely eliminated the VR slowing response induced by vagosympathetic stimulation. Other investigators have shown that the ARGP and IRGP play a selective role in regulating SA and AV nodal function, respectively (11, 12, 13, 14). Our findings do not support these observations, possibly because we implemented a more systematic approach (e.g., multiple stimulation voltages at multiple GP) to explore the autonomic neural network. Moreover, we found that the integration between the extrinsic and intrinsic cardiac ANS is substantially more complicated than previously thought (15). For instance, vagal innervation often travels through multiple GP before reaching the SA and AV node and GP also modulate the contralateral vagosympathetic inputs.
在本研究中,采用逐步方法系统地研究迷走交感干(心脏外源性ANS)和GP(心脏内源性ANS)之间的相互作用。我们发现GP作为“整合中心”(1)的功能,整合了外源性和内在心脏ANS之间的自主神经支配,因为它们影响心房电生理和病理生理,如心房颤动诱导性所示。例如,IRGP似乎是外源性ANS支配房室结的整合中心,因为IRGP的消融完全消除了迷走交感刺激引起的VR减慢反应。其他研究者已经表明ARGP和IRGP分别在调节SA和AV节点功能中发挥选择性作用(11,12,13,14)。我们的研究结果不支持这些观察结果,可能是因为我们采用了更系统的方法(例如,在多个GP处使用多重刺激电压)来探索自主神经网络。此外,我们发现外在和内在心脏ANS之间的整合比以前认为的要复杂得多(15)。例如,迷走神经支配在到达窦房结和房室结之前经常经过多个GP, GP也调节对侧迷走交感神经输入。

Figure 2Adepicts the proposed interactions between vagosympathetic trunks and SA node. The neural pathway (right vagosympathetic trunk → ARGP → SA node) seems to be the main connection between right vagosympathetic trunk and SA node because after SLGP ablation subsequent ablation of ARGP produced further attenuation of SR slowing induced by right vagosympathetic stimulation (Table 1). Ablation of ARGP alone produced similar effect as sequential ablation of SLGP and ARGP. These results also suggest the presence of another neural pathway (right vagosympathetic trunk → SLGP → ARGP → SA node) with the ARGP being the convergent gate before proceeding to the SA node. Similarly, left vagosympathetic trunk modulates the SA nodal function through both SLGP and ARGP (Table 2). The main neural pathway between the left vagosympathetic trunk and the SA node traverses the SLGP and ARGP sequentially before proceeding to the SA node (left vagosympathetic trunk → SLGP → ARGP → SA node) because subsequent ablation of ARGP after SLGP ablation produced minimal additional effects (Table 2) and ablating only the ARGP produced similar effects as sequential ablation of SLGP and ARGP. These data also suggest that ARGP serves as the integration center for both the right and the left vagosympathetic trunks to modulate SR, and IRGP seems to play a trivial role in this process. Because SLGP + ARGP + IRGP ablation failed to eliminate the SR slowing response induced by right or left vagosympathetic stimulation, it indicates the presence of other neural pathways between the vagosympathetic trunk and the SA node that bypass these GP.
图2描述了迷走交感神经干与窦房结之间的相互作用。右侧迷走交感干→ARGP→窦房结的神经通路似乎是右侧迷走交感干与窦房结之间的主要联系,因为在SLGP消融后,后续的ARGP消融会进一步减弱右侧迷走交感刺激引起的SR减慢(表1)。单独消融ARGP与连续消融SLGP和ARGP的效果相似。这些结果也提示存在另一条神经通路(右迷走交感干→SLGP→ARGP→窦房结),其中ARGP是进入窦房结前的收敛门。同样的,左vagosympathetic树干调节SA节点功能通过SLGP和ARGP(表2)。左vagosympathetic树干之间的主要神经通路和SA节点遍历SLGP ARGP顺序之前SA节点(左vagosympathetic主干→SLGP→ARGP→SA节点),因为后续消融后的ARGP SLGP消融产生最小的额外的影响(表2)和去除只有ARGP产生类似的影响顺序消融SLGP ARGP。这些数据还表明,ARGP作为左右迷走交感干的整合中心来调节SR,而IRGP似乎在这一过程中起着微不足道的作用。由于SLGP + ARGP + IRGP消融术不能消除左右迷走交感刺激引起的SR减慢反应,提示迷走交感干与窦房结之间存在绕过GP的其他神经通路。

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Figure 2. Interactions Among Vagosympathetic Trunks, ARGP, IRGP, and SLGP on SAN and AVN Function
图2。迷走交感主干、ARGP、IRGP和SLGP在SAN和AVN功能中的相互作用

(A)Modulation of sinus rate by vagosympathetic stimulation. (B)Modulation of ventricular rate during atrial fibrillation by vagosympathetic stimulation. Thick linesand thin linesindicate strong and weak regulatory effects, respectively. See text for details. AVN = atrioventricular node; LVG = left vagosympathetic trunk; RVG = right vagosympathetic trunk; SAN = sinoatrial node; other abbreviations as in Figure 1.
(A)迷走交感神经刺激对窦率的调节。(B)迷走交感神经刺激对房颤期间心室率的调节。粗线和细线分别表示调节效果强和弱。详情请参阅文本。房室结;左迷走交感干;右迷走交感干;SAN =窦房结;其他缩写,如图1所示。

Figure 2B depicts the proposed interactions between vagosympathetic trunks and the AV node. Ablation of ARGP after SLGP ablation produced minimal additional effects on VR slowing induced by left vagosympathetic stimulation, whereas ARGP ablation alone produced smaller effects than sequential ablation of SLGP and ARGP. Ablation of IRGP produced the most dramatic response. These observations suggest the presence of a major neural pathway (left vagosympathetic trunk → SLGP → ARGP → IRGP → AV node) and another pathway (left vagosympathetic trunk → SLGP → IRGP → AV node), both converging at the IRGP before proceeding to the AV node. Moreover, ablation of ARGP followed by IRGP ablation produced more residual effects (16%) than SLGP + ARGP + IRGP ablation, suggesting a neural pathway from SLGP to AV node bypassing the IRGP. This pathway may in part account for the observation that ablating only the ARGP produced smaller effects than sequential ablation of the SLGP and ARGP. The main neural pathway between the right vagosympathetic trunk and the AV node traverses SLGP, ARGP, and IRGP sequentially (right vagosympathetic trunk → SLGP → ARGP → IRGP → AV node), as ablation of ARGP induced similar effects as sequential ablation of SLGP and ARGP. Moreover, sequential ablation of ARGP and IRGP completely eliminated VR slowing induced by right vagosympathetic stimulation (data not shown in Tables), suggesting the absence of a pathway directly connecting ARGP to the AV node. These results also indicate that both ARGP and IRGP are the integration centers for both vagosympathetic trunks to innervate the AV node and IRGP is the final converging point.
图2B描述了迷走交感干和房室结之间的相互作用。SLGP消融后的ARGP消融对左迷走交感刺激引起的VR减缓的额外影响很小,而ARGP单独消融的影响小于SLGP和ARGP的顺序消融。IRGP消融产生了最显著的反应。这些观察结果提示存在一条主要的神经通路(左迷走交感干→SLGP→ARGP→IRGP→房室结)和另一条通路(左迷走交感干→SLGP→IRGP→房室结),这两条通路在进入房室结之前都在IRGP汇合。此外,消融ARGP后再消融IRGP比SLGP + ARGP + IRGP消融产生更多的残留效应(16%),这表明从SLGP到房室结的神经通路绕过IRGP。这一途径可能部分解释了仅消融ARGP产生的效果小于连续消融SLGP和ARGP的观察结果。右侧迷走交感干与房室结之间的主要神经通路依次经过SLGP、ARGP和IRGP(右侧迷走交感干→SLGP→ARGP→IRGP→房室结),ARGP的消融与SLGP和ARGP的消融效果相似。此外,连续消融ARGP和IRGP完全消除了右侧迷走交感刺激引起的VR减慢(数据未在表中显示),表明没有直接连接ARGP和房室结的通路。这些结果也提示ARGP和IRGP是迷走交感神经干支配房室结的整合中心,IRGP是最终的汇合点。

Because the main purpose of this study was to provide functional evidence for the interactions between the extrinsic and intrinsic cardiac ANS, we did not pursue the exact courses of the neural pathways within the extrinsic and intrinsic ANS, with the understanding that the neural interactions proposed in Figure 2are by no means complete. Nevertheless, prior work by other investigators (1–5,11–17) provided a wealth of information showing that the heart itself is richly innervated by the ANS. Although the autonomic ganglia are usually concentrated in several areas covered by epicardial fat pads, the axons and small clusters of autonomic ganglia form an extensive interconnecting neural network. We postulate that these interconnections may constitute the neural pathways elucidated in the present study.
由于本研究的主要目的是为心脏外源性和内源性ANS之间的相互作用提供功能证据,我们没有追求外源性和内源性ANS内神经通路的确切过程,理解图2中提出的神经相互作用绝不是完整的。然而,其他研究者先前的工作(1 - 5,11 - 17)提供了丰富的信息,表明心脏本身具有丰富的ANS神经支配。尽管自主神经节通常集中在被心外膜脂肪垫覆盖的几个区域,但轴突和自主神经节的小簇形成了一个广泛的相互连接的神经网络。我们假设这些相互联系可能构成本研究中阐明的神经通路。

Right and left vagosympathetic stimulation and effects on ERP and AF inducibility
左右迷走交感刺激及其对ERP和AF诱导性的影响

The ERP abbreviation and AF inducibility during vagosympathetic stimulation were also modulated by GP. Right vagosympathetic stimulation shortened the ERP and widened the window of vulnerability at the RSPV and right atrial sites. These responses were eliminated by ARGP ablation. Likewise, left vagosympathetic stimulation induced similar ERP shortening at the LSPV and left atrial sites but failed to widen the window of vulnerability, giving the impression that right vagosympathetic stimulation was more arrhythmogenic than left vagosympathetic stimulation despite similar degrees of ERP shortening. These findings are contrary to a widely accepted notion that shortening of ERP by autonomic stimulation serves as an indicator for AF inducibility. A recent report (10) from our group described a measure of AF inducibility using the window of vulnerability defined as the longest S1–S2 minus the shortest S1–S2 at which AF was induced. Concurrent ARGP stimulation widened the window of vulnerability and allowed both late-coupled and early-coupled premature stimulations to initiate AF. Therefore, the window of vulnerability serves as a better indicator of regional autonomic activity and AF inducibility than the ERP. Although a systematic study of AF inducibility by sequentially ablating individual GP was not performed, we showed that ablating certain critical neural elements (e.g., ARGP) in the intrinsic cardiac ANS can eliminate AF inducibility. We postulate that GP in general may be critical elements that facilitate the occurrence of AF in a hyperactive state of the intrinsic cardiac ANS. Because the ARGP is larger in size and closer to atrial myocardium than the SLGP, we postulate that ARGP may play a more active role than the SLGP in the dynamics of AF initiation because of the larger axonal field extending into both atria. Future studies on the distribution and relative abundance of parasympathetic and sympathetic neural elements in the intrinsic cardiac ANS may provide the anatomical basis for the discrepancies in AF inducibility described in this study and the long-term effects of denervation described by others (16).
GP对迷走交感刺激时的ERP缩短和AF诱导也有调节作用。右侧迷走交感刺激缩短了ERP,扩大了RSPV和右心房的易损窗口。ARGP消融消除了这些反应。同样,左侧迷走交感刺激在LSPV和左心房部位引起类似的ERP缩短,但没有扩大易损窗口,这给人的印象是,尽管ERP缩短程度相似,但右侧迷走交感刺激比左侧迷走交感刺激更容易致心律失常。这些发现与一个广泛接受的概念相反,即通过自主神经刺激缩短ERP可作为心房颤动诱发性的指标。我们小组最近的一份报告(10)描述了一种AF诱导性的测量方法,使用脆弱性窗口定义为最长的S1-S2减去诱发AF的最短的S1-S2。并发的ARGP刺激扩大了脆弱性窗口,并允许晚耦合和早耦合的过早刺激启动心房颤动。因此,脆弱性窗口比ERP更能反映区域自主神经活动和心房颤动诱导性。虽然没有通过顺序消融单个GP对房颤诱导性进行系统研究,但我们发现,消融内在心脏ANS中的某些关键神经元件(如ARGP)可以消除房颤诱导。我们假设GP一般可能是促进心房颤动发生的关键因素,在内在心脏ANS的过度活跃状态。 由于ARGP比SLGP更大,更接近心房心肌,我们推测ARGP可能比SLGP在房颤起始动力学中发挥更积极的作用,因为更大的轴突场延伸到两个心房。未来对心脏内源性ANS中副交感神经和交感神经成分的分布和相对丰度的研究可能为本研究中描述的AF诱导性差异和其他人描述的去神经支配的长期影响提供解剖学基础(16)。

Patterson et al. (18) showed that both parasympathetic and sympathetic components are required to induce rapid-triggered firing to initiate AF. Therefore, no adrenergic blocker was used in conjunction with vagosympathetic stimulation in this study to avoid suppressing the sympathetic activity and artificially altering the window of vulnerability and AF inducibility. It is also known that vagosympathetic trunks contain sympathetic nerve fibers (19) that can be activated by electrical stimulation of the entire trunk. In the present study, the results acquired at a higher level of stimulation might be confounded by sympathetic activation, particularly after GP, which are known to contain predominantly parasympathetic neural elements, were ablated. However, the magnitude of attenuation of SR and VR slowing would have been even greater without concurrent sympathetic activation, further strengthening the conclusions drawn in the present study.
Patterson等人(18)表明,副交感神经和交感神经成分都需要诱导快速触发触发心房颤动。因此,在本研究中,没有将肾上腺素能阻滞剂与迷走交感神经刺激联合使用,以避免抑制交感神经活动,人为地改变易感性和心房颤动诱发的窗口期。我们也知道迷走交感神经干含有交感神经纤维(19),整个躯干的电刺激可以激活这些纤维。在目前的研究中,在更高水平的刺激下获得的结果可能会被交感神经激活所混淆,特别是在GP(已知主要包含副交感神经元素)被切除后。然而,如果没有交感神经同时激活,SR和VR的衰减幅度会更大,这进一步加强了本研究的结论。

Clinical implications 临床意义

Recently, AF ablation targeting the intrinsic cardiac ANS has been shown to improve the success rate for AF ablation (20–22). The intrinsic cardiac ANS, particularly the GP, was ablated either intentionally (20, 21) or inadvertently (22). The capability of axonal regeneration after injury has been known for decades, but regeneration of neurons after injury is rare. Thus, AF ablation aiming at autonomic denervation should selectively target the autonomic ganglia (neurons) located within GP to produce long-term denervation and cause minimal myocardial damage. The data from this study showed that ARGP ablation attenuated ERP shortening and window of vulnerability widening induced by right vagosympathetic stimulation, providing additional support for the clinical efficacy of GP ablation for AF. It is crucial to point out that partial autonomic denervation may increase the incidence of AF as described by Hirose et al. (23). Therefore, an ablation strategy targeting the intrinsic cardiac ANS should be designed so as to avoid partial denervation (mainly the right side) that can accentuate the dispersion of refractoriness across the atria and facilitate AF initiation as shown by the elegant mapping study of Hirose et al. (22) and recently confirmed by Oh et al. (17).
最近,针对心脏内在ANS的房颤消融已被证明可以提高房颤消融的成功率(20-22)。内在心脏ANS,特别是GP,可以有意或无意地消融(20,21)。损伤后轴突的再生能力已经被发现了几十年,但损伤后神经元的再生是罕见的。因此,针对自主神经去神经支配的房颤消融应选择性地靶向GP内的自主神经节(神经元),以产生长期去神经支配并使心肌损伤最小。本研究的数据显示,ARGP消融可减弱右侧迷走交感刺激引起的ERP缩短和易感窗扩大,为GP消融治疗房颤的临床疗效提供了额外的支持。正如Hirose等人所描述的,部分自主神经去支配可能增加房颤的发生率,这一点至关重要(23)。因此,应设计针对内在心脏ANS的消融策略,以避免部分去神经支配(主要是右侧),因为它会加剧难治性在整个心房的分散,并促进房颤的发生,Hirose等人(22)的精细绘图研究表明了这一点,最近也得到了Oh等人的证实(17)。

Study limitations 研究的局限性

This study was not intended to provide a complete body of knowledge about the complicated interaction between the extrinsic and intrinsic cardiac ANS or the interaction within the intrinsic ANS itself. We selected 3 GP whose human equivalents can be identified and ablated in patients with AF (21) to provide experimental evidence for the hypothesis that external cardiac ANS exerts its influences on SA and AV nodal function and AF inducibility through the intrinsic cardiac ANS. Other potentially important GP such as the GP between the superior vena cava and aortic root (15) and the GP near the ligament of Marshall (24) were not studied for the enormous number of permutations that would have generated in stepwise ablation of GP. The results presented herein may assist future researchers in defining the complex interactions between the extrinsic and intrinsic ANS.
本研究的目的不是提供一个完整的知识体系,了解外源性和内源性心脏自动神经系统之间复杂的相互作用,或内在心脏自动神经系统本身内部的相互作用。我们选择3 GP的人类等价物可以识别并切除患者房颤(21)提供实验证据的假设外部心脏ANS施加其影响SA和AV节点通过内在心脏ANS功能和房颤可诱导性。其他潜在重要的医生如上腔静脉之间的GP和主动脉根(15)和附近的GP韧带的马歇尔(24)没有研究大量的排列在GP的逐步消融中产生。本文提出的结果可能有助于未来的研究人员定义外在和内在ANS之间的复杂相互作用。

In the present study, vagosympathetic trunks were not decentralized to maintain a more physiological state. We acknowledge that vagosympathetic stimulation may activate the afferent vagal or sympathetic fibers and initiate reflexes that are difficult to quantify. Therefore, all of the experiments in this study were designed in pairs to estimate the contribution of each GP by analyzing the differences in parameters before and after ablation of that GP. We presume that the reflexes activated by vagosympathetic stimulation before and after GP ablation were very similar and that their impact could be minimized by paired analysis. By the same token, potential confounding effects from stimulating the sympathetic nerves could be minimized by paired analysis.
在本研究中,迷走交感神经干没有分散以维持更生理的状态。我们承认迷走交感刺激可能激活传入迷走神经或交感神经纤维,并引发难以量化的反射。因此,本研究中所有的实验都是成对设计的,通过分析GP消融前后参数的差异来估计每个GP的贡献。我们假设迷走交感刺激在GP消融前后激活的反射非常相似,通过配对分析可以将其影响降到最低。出于同样的原因,刺激交感神经的潜在混淆效应可以通过配对分析最小化。

Conclusions 结论

The GP function as the integration centers that modulate the autonomic innervation between extrinsic and intrinsic cardiac ANS, as ablation of SLGP, ARGP, and IRGP markedly altered SR slowing, VR slowing, and AF inducibility with vagosympathetic stimulation. The integration between extrinsic and intrinsic cardiac ANS is substantially more intricate than previously thought. The present study also provides experimental support for the clinical efficacy of GP ablation for AF.
GP是调节外源性和内源性心脏ANS之间自主神经支配的整合中心,因为SLGP、ARGP和IRGP的消融显著改变了迷走交感刺激下的SR减慢、VR减慢和AF诱导。外在和内在心脏ANS之间的整合比以前认为的要复杂得多。本研究也为GP消融治疗房颤的临床疗效提供了实验支持。

References

Cited by (296) 引自(296)

  • Autonomic Modulation of Atrial Fibrillation
    心房颤动的自主调节

    2023, JACC: Basic to Translational Science
    2023,中国科学院学报(自然科学版)
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Supported by grant 0650077Z from the American Heart Association (to Dr. Po) and grant 5K23HL069972 from the National Heart, Lung, and Blood Institute (to Dr. Po).
由美国心脏协会(Dr. Po)的0650077Z和国家心肺血液研究所(Dr. Po)的5K23HL069972资助。