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PRECLINICAL STUDY

Ganglionated Plexi Modulate Extrinsic Cardiac Autonomic Nerve Input

Effects on Sinus Rate, Atrioventricular Conduction, Refractoriness, and Inducibility of Atrial Fibrillation

Yinglong Hou, MD^_*, Benjamin J. Scherlag, PhD, Jiaxiong Lin, MD, Ying Zhang, MD, PhD, Zhibing Lu, MD, Kim Truong, DO, Eugene Patterson, PhD, Ralph Lazzara, MD, Warren M. Jackman, MD and Sunny S. Po, MD, PhD^,_*

^_* Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Clinical Medical College of Shandong University, Jinan City, Shandong, China
Cardiac Arrhythmia Research Institute, College of Medicine
Center for American Indian Health Research, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Manuscript received October 10, 2006; revised manuscript received February 12, 2007, accepted February 27, 2007.

^_* Reprint requests and correspondence: Dr. Sunny S. Po, 1200 Everett Drive, Room TUH6E103, Oklahoma City, Oklahoma 73104. (Email: sunny-po{at}ouhsc.edu).

	Abstract

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Objectives: 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.

Background: Systematic ganglionated plexi (GP) ablation to evaluate the extrinsic and intrinsic cardiac ANS relationship has not been detailed.

Methods: 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.

Results: 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.

Conclusions: 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.

Abbreviations and Acronyms   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

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.

	Methods

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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).

Autonomic stimulation.   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).

View larger version (52K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Schematic and Photographic Representation of the Right and Left Thoracotomy Approach 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 LSPV indicate 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.

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.

Programmed stimulation.   Programmed stimulation of myocardium was performed using a stimulator (model 5328, Medtronic, Minneapolis, Minnesota). Atrial pacing at a cycle length of 330 ms (2x 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.

Statistical analysis.   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).

	Results

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Effects of right vagosympathetic stimulation on SR..   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).

	Discussion

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Figure 2A depicts 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.

View larger version (9K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Interactions Among Vagosympathetic Trunks, ARGP, IRGP, and SLGP on SAN and AVN Function (A) Modulation of sinus rate by vagosympathetic stimulation. (B) Modulation of ventricular rate during atrial fibrillation by vagosympathetic stimulation. Thick lines and thin lines indicate 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.

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 2 are 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.

Right and left vagosympathetic stimulation and effects on ERP and AF inducibility.   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).

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.

Clinical implications.   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).

Study limitations.   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.

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.

	Conclusions

Top Abstract Methods Results Discussion Conclusions References

 
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.

	Footnotes

 
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).

	References

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