(Circulation. 1997;95:2573.)
© 1997 American Heart Association, Inc.
Articles |
Efferent Vagal Innervation of the Canine Atria and Sinus and Atrioventricular Nodes
The Third Fat Pad
the Krannert Institute of Cardiology, Indiana University School of Medicine, and the Roudebush Veterans Administration Medical Center, Department of Pathology (J.N.E.), Indianapolis, Ind.
Correspondence to Douglas P. Zipes, MD, Krannert Institute of Cardiology, 1111 W 10th St, Indianapolis, IN 46402-4800.
Abstract
Background The purpose of this study was to investigate the functional pathways of efferent vagal innervation to the atrial myocardium and sinus and atrioventricular (AV) nodes.
Methods and Results Using vagally induced atrial effective refractory period shortening, slowing of spontaneous sinus rate, and prolongation of AV nodal conduction time as end points of vagal effects, we determined the actions of phenol and epicardial radiofrequency catheter ablation (RFCA) applied to different sites at or near the atrial myocardium to inhibit these responses. We found that efferent vagal fibers to the atria are located both subepicardially and intramurally or subendocardially. Most efferent vagal fibers to the atria appear to travel through a newly described fat pad located between the medial superior vena cava and aortic root (SVC-Ao fat pad), superior to the right pulmonary artery, and then project onto two previously noted fat pads at the inferior vena cava–left atrial junction (IVC-LA fat pad) and the right pulmonary vein–atrial junction (RPV fat pad) and to both atria. A few vagal fibers may bypass the SVC-Ao fat pad and go directly to the IVC-LA or RPV fat pad and then innervate the atrial myocardium. Vagal fibers to the sinus and AV nodes also converge at the SVC-Ao fat pad (a few fibers to the sinus node go directly to the RPV fat pad) before projecting to the RPV and IVC-LA fat pads. Long-term vagal denervation of the atria and sinus and AV nodes can be produced by RFCA of these fat pads and results in vagal denervation supersensitivity. Vagal denervation prevents induction of atrial fibrillation in this model.
Conclusions The newly described SVC-Ao fat pad receives most of the vagal fibers to the atria and sinus and AV nodes. Elimination of the fat pads with RFCA selectively vagally denervated the atria and sinus and AV nodes.
Key Words: atrioventricular node • atrium • vagus nerve • sinoatrial node
The vagal pathways to the sinus and AV nodes have been extensively studied.1 2 3 4 5 6 7 8 9 10 11 12 Vagal postganglionic neurons to the sinus node are located in a fat pad adjacent to the RPV-atrial junction (RPV fat pad), while the vagal postganglionic neurons to the AV node are located in a fat pad at the junction of the IVC and LA (IVC-LA fat pad)3 4 5 6 (Fig 1
). The atria receive much greater cholinergic innervation than the ventricles13 and contain more acetylcholine, choline acetyltransferase, and cholinesterase.14 15 16 But little information exists about the specific distribution of efferent vagal pathways to atrial myocardium.17 18 19
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The purpose of the present study was to identify the functional pathways of efferent vagal innervation to the atria by measuring ERP, heart rate, and AV nodal conduction changes during vagal stimulation before and after the application of phenol or RFCA to selected areas of the heart to interrupt efferent vagal fibers that may travel through that site.
Methods
Surgical Preparation for Acute Study
For groups 1 through 9, 56 mongrel dogs of either sex weighing 25 to 35 kg were anesthetized with pentobarbital (30 mg/kg IV). Additional amounts were given as necessary to maintain anesthesia during the study. Dogs were ventilated with room air by use of a cuffed endotracheal tube and a constant volume-cycled respirator (model 607, Harvard apparatus). A fluid-filled cannula was placed in the left femoral artery and connected to a transducer (Statham p-23 Db, Gould) to monitor arterial blood pressure, and the left femoral vein was cannulated to infuse normal saline at 100 to 200 mL/h to replace spontaneous fluid losses. An ECG lead II was monitored throughout the study. A His bundle electrogram was recorded in all dogs by using a 7F bipolar electrode catheter (USCI) introduced through the left carotid artery and advanced in a retrograde manner into the noncoronary cusp of the aortic valve. The signals were amplified, filtered between 30 to 500 Hz, and recorded simultaneously (model 2800, Gould Brush).
After the chest was opened through a median sternotomy, the pericardium was opened and sewn to the chest wall to cradle the heart. Eight plunge electrodes made from polytetrafluoroethylene-coated wires, insulated except for their tips, were inserted 3 to 4 mm beneath the epicardium in the atrial myocardium. Two electrodes in the high lateral RA (near the sulcus terminalis) and two electrodes in the high lateral LA (near the superior left pulmonary vein) were used to record RA and LA electrograms. Unipolar electrodes in the low lateral RAF (20 to 50 mm above the junction of the RA and IVC), the RAA, the low lateral LAF (near the inferior left pulmonary vein), and the LAA served as cathodes to determine atrial ERPs. An anodal electrode was placed in the abdominal wall. A thermistor (model 430, series 400, Yellow Springs Instruments) was used to monitor epicardial temperature, which was maintained between 36°C and 38°C by use of an operating-room table lamp and a heating pad.
Surgical Preparation for Chronic Study
For group 10, five mongrel dogs were premedicated with antibiotics (cefazoline 500 mg IM) and a muscle relaxant (pancuronium bromide 2 mg IV) and anesthetized initially with sodium thiopental 20 mg/kg IV. Anesthesia was maintained by ventilation with 1% to 3% isoflurane gas mixed with oxygen at a rate of 1.0 to 2.0 L/min. By use of a sterile surgical technique, a right lateral intercostal thoracotomy was performed, the ribs and lungs were retracted, and the pericardium was incised. A right pericardial window was created to expose the RA. Serum electrolytes, pH, base excess, and blood gases were monitored during the surgical procedures and were obtained daily for 3 days after surgery. After RFCA (described below), the chest was closed in layers, and negative pressure was reestablished in the pleural cavity. Antibiotics were administered for 5 days after surgery, and analgesics were given as needed.
Neural Stimulation
Autonomic decentralization was performed in dogs assigned to the acute studies (groups 1 through 7 and 9), while dogs in the chronic study (group 10) were autonomically decentralized during the follow-up electrophysiological studies 7 to 10 days after surgery. The heart was autonomically decentralized by isolating, doubly ligating, and transecting both cervical vagi and ansae subclaviae as they exited from the stellate ganglia. Both cervical vagi were stimulated through two polytetrafluoroethylene-coated wire electrodes embedded in the cardiac end of each vagal nerve. Rectangular 4-ms pulses were delivered through a constant voltage stimulator at a frequency of 8 to 20 Hz and at 3 to 10 V by use of a programmable stimulator (model SD-88, Grass Instrument Co). The voltage for vagal stimulation was 0.5 V greater than that required to produce sinus arrest lasting longer than 3 seconds for the right vagus and to produce complete AV block for the left vagus. The conditions of neural stimulation were kept constant in each experiment.
Phenol or Radiofrequency Energy Application
Phenol or RFCA was used epicardially to selectively interrupt the vagal fibers as they entered the heart. Strips of 88% phenol were applied to the epicardial surface of the heart with a wooden applicator stick in groups 2 and 7. The radiofrequency energy was delivered to different sites of the atria through a 7F deflectable quadripolar catheter with a 4-mm-tip electrode (EP Technologies or Mansfield). The catheter tips were positioned manually on the epicardial surface of the heart under direct visualization to ensure optimal tissue contact and energy delivery. Continuous unmodulated radiofrequency current (300 to 750 kHz) with a power output setting of 30 to 35 W was delivered from a radiofrequency generator (EP Technologies) with a duration of 60 seconds. To avoid an impedance rise,20 21 22 23 the catheter tip was flushed with small amounts of saline during epicardial radiofrequency energy delivery. Fig 2 shows the location of epicardial RFCA or phenol application.
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Measurement of Spontaneous Cycle Length, AV Nodal Conduction Time, and Atrial ERPs
Five consecutive SCLs immediately before bilateral vagal stimulation were measured and averaged to obtain the spontaneous SCL. Five consecutive AH intervals were measured during constant RA pacing at a cycle length of 400 ms and averaged to obtain AV nodal conduction times. The atrial ERP was determined at each electrode site by using the extrastimulus technique with a programmable stimulator (Krannert Medical Engineering) and a constant-current isolator.24
Efferent Vagal Innervation of the Atria
In 4 of the 56 dogs in groups 1 through 9, AF lasting >1 hour occurred during measurement of baseline ERP; these 4 dogs were excluded from the study. Table 1 shows the different groups of animals studied.
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To investigate the vagal innervation of the atria, baseline ERPs and ERPs during bilateral vagal stimulation were determined before (during control) and 10 to 20 minutes after each application of phenol or RFCA delivered to different sites at or near the atrial myocardium. Once complete vagal denervation of both atria (described below) was obtained, the electrodes for vagal stimulation were repositioned to another site in the cervical vagus; the output for vagal stimulation was set at a frequency of 20 Hz, a voltage of 10 V, and a pulse duration of 4 ms, and the ERP at each test site was repeatedly measured to exclude the possibility that failure to obtain ERP shortening was due to malfunction of vagal stimulation and not vagal denervation. In addition, if ERP shortening induced by bilateral vagal stimulation at each test site (RAF, RAA, LAF, and LAA) was eliminated, the other plunge electrodes in the RA and LA myocardium, which were used for atrial electrogram recordings, were then used as cathodes for ERP measurement to determine whether these atrial sites were also completely vagally denervated.
Group 1
In group 1 dogs (n=5), RFCA was applied to the fat tissue located between the medial SVC and aortic root (superior to the right pulmonary artery) (SVC-Ao fat pad; Fig 1A
) and the sinus transversus and to encircle the RA (Fig 2) in order to test the effects of RFCA of these areas on vagally induced ERP shortening in both atria. RFCA was performed step by step. In 2 of the 5 dogs, RFCA was first applied to the lateral, inferior, and medial borders of the RA. Baseline ERP and ERP during bilateral vagal stimulation were determined before and after RFCA. Subsequent RFCA was applied to the superior border of the RA, SVA-Ao fat pad, and sinus transversus. The same measurements were repeated after the final RFCA. In the other 3 dogs, RFCA was performed in reverse direction (superior border of the RA, SVC-Ao fat pad, and sinus transversus, followed by the lateral, inferior, and medial borders of the RA). Since both atria were completely vagally denervated after RFCA was applied to the RA, SVC-Ao fat pad, and sinus transversus (described below), RFCA was not applied to the LA.
Group 2
To examine the depth of efferent vagal fibers in the atrial myocardium, we compared the effects of phenol application, which destroys tissue to a depth of <0.5 mm,25 26 with RFCA, which produces transmural necrosis,24 on interrupting vagal fibers to the atria in group 2 dogs (n=6). Baseline ERP and ERP during bilateral vagal stimulation were determined before and after phenol application, followed by RFCA, in the same areas as outlined for group 1 dogs.
Groups 3 and 4
To determine whether some vagal fibers to the atria traveled first to one atrium and then projected to the other atrium, we applied RFCA first to encircle the LA and then to encircle the RA (Fig 2) in group 3 dogs (n=4) and to encircle the RA in group 4 dogs (n=4). To determine whether remaining vagal fibers in group 4 dogs traveled through the SVC-Ao fat pad, the latter received RFCA after applying RFCA to encircle the RA. Baseline ERP and ERP during bilateral vagal stimulation were determined before and after each RFCA session.
Group 5
From groups 1 through 4, we found that the SVC-Ao fat pad played a crucial role in vagal innervation of the atria (described below). To determine whether the RPV and IVC-LA fat pads, known to provide vagal innervation to the sinus and AV nodes, respectively, also played a role in vagal innervation of atrial myocardium, we applied RFCA to the RPV, IVC-LA, and SVC-Ao fat pads in group 5 dogs (n=12) (Figs 1 and 2). Six dogs underwent sequential RFCA of the RPV, IVC-LA, and SVC-Ao fat pads. The other 6 dogs underwent RFCA of the IVC-LA fat pad first, followed by RFCA of the RPV fat pad and then the SVC-Ao fat pad. Baseline ERP and ERP during bilateral vagal stimulation were determined before and after RFCA.
Group 6
To test whether vagal fibers traveled from the SVC-Ao fat pad to the other fat pads, RFCA was first applied to the SVC-Ao fat pad, followed by RFCA of the IVC-LA and then the RPV fat pad in the 7 dogs.
Group 7
To examine the depth of efferent vagal fibers in these three fat pads, in these 4 dogs we applied phenol to each of the fat pads, followed by phenol strips to encircle both atria, to test whether phenol application to the three fat pads and around both atria could vagally denervate both atria. If both atria were not vagally denervated, RFCA was then applied to the three fat pads.
Efferent Vagal Innervation of the Sinus and AV Nodes
SCL and AV nodal conduction time were determined in the baseline setting and during bilateral vagal stimulation, before and after RFCA, to each fat pad in group 5 dogs. In group 6 dogs, SCL and AV nodal conduction times were determined in the baseline setting and during bilateral vagal stimulation before and after RFCA of the SVC-Ao fat pad, after RFCA of the IVC-LA fat pad, and after RFCA of the RPV fat pad. For group 7 dogs, SCL and AV nodal conduction times were determined in the baseline setting and during bilateral vagal stimulation before and after phenol application to the RPV fat pad, after phenol application to the IVC-LA fat pad, and after RFCA of the RPV and IVC-LA fat pads.
Inducibility of Vagally Induced Sustained AF
An attempt to induce sustained AF lasting >30 minutes was made by using burst atrial pacing (10-mA pulse amplitude, 2-ms pulse duration, and 50-ms cycle length) for 2 to 10 seconds. AF was perpetuated by bilateral vagal stimulation before and 10 to 20 minutes after application of phenol or RFCA in acute-study dogs (groups 1 through 7). The same pacing protocols were repeated three to five times if sustained AF was not inducible. Vagally induced sustained AF was also tested during the electrophysiological study in the chronic study group (group 10).
Fat Pad Stimulation: Group 8
In these 5 dogs, three bipolar silver electrodes (2-mm interelectrode distance) were placed on the three fat pads and used to stimulate the ganglia and nerves located there by using continuous stimulation for >10 minutes (Grass SD-88) with a 10-V pulse amplitude, a pulse duration of 0.03 to 0.09 ms, and a frequency of 12 to 20 Hz. This stimulation intensity was subthreshold for direct cardiac activation. SCL, AV nodal conduction time, inducibility of sustained AF, and atrial ERPs at RAF, RAA, LAF, and LAA were measured in the baseline setting and during stimulation of each fat pad.
Effects of Methacholine on Sinus and AV Nodes and Atrial ERPs Before and After Acute Vagal Denervation: Group 9
To test for cholinergic responsiveness acutely after RFCA, the effects of administering continuous infusions of a low (1.5 µg·kg-1·min-1 IV) and high (3.6 µg·kg-1·min-1 IV) dose of methacholine on sinus node automaticity, AV nodal conduction time, atrial ERPs, and AF inducibility were examined before and 30 minutes after RFCA of the SVC-Ao, IVC-LA, and RPV fat pads in these 5 dogs.
Long-term Effectiveness of Chronic Vagal Denervation: Group 10
To determine the safety of long-term selective vagal denervation of the atria and the development of supersensitivity, sterile open-chest RFCA of the RPV, IVC-LA, and SVC-Ao fat pads was performed, and 7 to 10 days later all 5 dogs underwent open-chest electrophysiological testing. At that time, the effects of bilateral vagal stimulation and infusion of low and high doses of methacholine on sinus node automaticity, AV nodal conduction time, atrial ERPs, and inducibility of sustained AF were tested.
Histopathological Examination of the Fat Pads
The hearts from 4 other dogs were used for histological examination of the RPV, IVC-LA, and SVC-Ao fat pads. Each fat pad and underlying tissue were excised and fixed in buffered neutral formalin. Serial sections were taken and stained with hematoxylin and eosin for microscopic examination of the presence and distribution of neural elements in each fat pad.
Data Analysis
The effect of vagally induced slowing of sinus node automaticity or prolongation of AV nodal conduction time was expressed as the percent prolongation of the SCL or AV nodal conduction time (prolongation of AH interval or the degree of AV block during atrial pacing) during bilateral vagal stimulation compared with the value obtained before vagal stimulation. Vagal denervation of the sinus node was defined as being present when the prolongation of the SCL was <10%. Vagal denervation of the AV node was defined as being present when bilateral vagal stimulation failed to produce second- or third-degree AV block and the prolongation of the AH interval was <10%. Atrial sites were considered to be vagally denervated if bilateral vagal stimulation shortened ERP <2 ms. Vagal attenuation was present when ERP shortening induced by bilateral vagal stimulation was reduced significantly compared with the control value after phenol or RFCA but was still >2 ms.
Data are presented as mean±SD. Comparisons of changes in ERP shortening induced by bilateral vagal stimulation before and after phenol or stepwise RFCA were done by using one-way ANOVA for repeated measures. When this procedure was significant, Fisher's protected least significant difference test was used to determine where the difference occurred. For group 9, changes in ERP shortening during low and high doses of methacholine infusion before and after RFCA were compared by two-way ANOVA for repeated measures. Comparisons of the ERP, AV nodal conduction time, and SCL with and without vagal stimulation in chronically denervated dogs (group 10) and comparisons of changes in AV nodal conduction time and SCL during methacholine infusion before and immediately after RFCA in group 9 dogs were done by using a paired t test. Unpaired t tests were used to compare the differences in prolongation of the AV nodal conduction time and SCL and in atrial ERP shortening by infusion of methacholine between groups 9 and 10. Differences were considered significant at P<.05.
Results
Vagal Innervation of the Atria: Groups 1 Through 7
Fig 1A illustrates the location of the SVC-Ao fat pad, not previously characterized, between the medial SVC and aortic root, superior to the right pulmonary artery. Fig 1B shows the RPV and IVC-LA fat pads demonstrated by Randall and coworkers.3 4 5 6 7 8 9
In group 1 dogs, the application of RFCA to the lateral, inferior, and medial borders of the RA or application of RFCA to the superior border of the RA, SVC-Ao fat pad, and sinus transversus only attenuated ERP shortening in both atria (Fig 3 and Table 2). Both atria were completely denervated in all dogs after RFCA to encircle the RA, SVC-Ao fat pad, and sinus transversus. Since the LA was not manipulated directly, these results indicated that vagal fibers to the LA traveled through the RA, SVC-Ao fat pad, and sinus transversus.
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In group 2 dogs, the phenol that encircled the RA, SVC-Ao fat pad, and sinus transversus only attenuated the ERP shortening in both atria (Table 2). Any remaining ERP shortening was completely eliminated after subsequent RFCA to the same areas, indicating that both atria were completely vagally denervated. These results suggested that vagal fibers to the RA are located both subepicardially and intramurally or subendocardially.
In group 3 dogs, RFCA that encircled the LA completely vagally denervated the LA and did not significantly affect ERP shortening in the RA (Table 2). The RA was vagally denervated after subsequent RFCA to encircle the RA. These results showed that vagal fibers to the RA do not travel through the LA.
For groups 1 through 3, once the ERP shortening at each test site was eliminated, the ERP shortening in the areas of atrial electrogram recordings was also abolished. Therefore, we did not test vagally induced ERP shortening in the areas of atrial electrogram recordings in the subsequent groups.
In group 4 dogs, RFCA that encircled the RA completely denervated the RA and attenuated the ERP shortening in the LA (Table 2). The LA was completely vagally denervated after subsequent RFCA to the SVC-Ao fat pad. These results indicated that vagal fibers to the LA travel through the RA and SVC-Ao fat pad.
In group 5 dogs, RFCA to the RPV and IVC-LA fat pads only attenuated the ERP shortening in both atria (Table 2). Both atria were completely vagally denervated after subsequent RFCA to the SVC-Ao fat pad. These data showed that the three fat pads provide vagal innervation to both atria.
In group 6 dogs, RFCA of the SVC-Ao fat pad alone led to complete vagal denervation of the RA in 3 of 7 dogs and of the LA in 5 of 7 dogs and vagal attenuation of the RA in 4 of 7 dogs and of the LA in 2 of 7 dogs (Fig 4 and Table 2). Subsequent RFCA to the IVC-LA fat pad completely vagally denervated the RA in 5 of 7 dogs and the LA in all 7 dogs and partially denervated the RA in 2 of 7 dogs. The RA was completely denervated after final RFCA of the RPV fat pad in the 2 remaining dogs. These results suggested that most vagal fibers to the atria go through the SVC-Ao fat pad and then project onto the IVC-LA and RPV fat pads and to both atria. A few vagal fibers may go directly to the IVC-LA or RPV fat pad and then innervate atrial myocardium.
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In group 7 dogs, phenol application to the RPV, IVC-LA, and SVC-Ao fat pads and to encircle both atria only attenuated ERP shortening in both atria (Table 2). Both atria were completely vagally denervated after subsequent RFCA to the three fat pads. These data demonstrated that vagal fibers to the RA and LA are located both subepicardially and intramurally or subendocardially and suggested that some ganglia or vagal fibers are located deep in these fat pads.
Inducibility of Vagally Induced Sustained AF: Groups 1 Through 7
The effects of RFCA or phenol application on inducibility of vagally induced sustained AF are shown in Table 3. Whenever the RA (group 4) or both atria (groups 1 through 7) were completely vagally denervated by RFCA, sustained AF could not be induced by burst atrial pacing and bilateral vagal stimulation. However, when the RA and LA were incompletely denervated following phenol applications (groups 2 and 7) or when only the LA was completely denervated by RFCA (group 3), sustained AF was still inducible. In group 6, sustained AF was not inducible after RFCA of the SVC-Ao fat pad in 6 of 7 dogs. Sustained AF became noninducible in all 7 dogs after subsequent RFCA of the IVC-LA fat pad.
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Vagal Innervation of the Sinus and AV Nodes: Groups 5 Through 7
Table 4 shows that RFCA of the RPV fat pad led to complete vagal denervation of the sinus node without interfering with vagal effects on AV nodal conduction in 6 of 6 dogs, confirming the observations of Randall et al.5 6 7 The AV node was completely denervated after subsequent RFCA to the IVC-LA fat pad. RFCA of the IVC-LA fat pad alone led to complete vagal denervation of the AV node in 6 of 6 dogs without affecting vagal effects on sinus node automaticity, as Randall et al have shown5 6 7 (Table 4). The sinus node was completely vagally denervated after subsequent RFCA to the RPV fat pad. RFCA of the SVC-Ao fat pad alone led to complete vagal denervation of the AV node and markedly attenuated vagally induced sinus node slowing in all 7 dogs in group 6 (Table 4). Subsequent RFCA to the IVC-LA fat pad did not significantly affect the vagally induced sinus node slowing, which was completely abolished after the final RFCA of the RPV fat pad. Phenol application to the RPV fat pad markedly attenuated vagally induced sinus node slowing without affecting the vagal effects on AV nodal conduction time in all 4 dogs in group 7 (Table 4). The AV node was completely vagally denervated after subsequent phenol application to the IVC-LA fat pad, which did not significantly affect the vagally induced sinus node slowing. The sinus node was completely vagally denervated after subsequent RFCA to the RPV fat pad. These data suggested that some ganglia or vagal fibers to the sinus node are located deep in the RPV fat pad and that those to the AV node are located superficially in the IVC-LA fat pad. The SVC-Ao fat pad contains most of the vagal ganglia and/or fibers that innervate the sinus and AV nodes.
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Fat Pad Stimulation: Group 8
Fig 5A shows that stimulation of the RPV fat pad induced ERP shortening in the RA in each of 5 dogs and in the LA in 3 of 5 dogs. Fig 5B shows that stimulation of the IVC-LA fat pad induced ERP shortening in both atria in 3 of 5 dogs. Fig 5C shows that stimulation of the SVC-Ao fat pad induced ERP shortening at each test site in all 5 dogs. Fig 5D shows that stimulation of the RPV or SVC-Ao fat pad prolonged the SCL. There was no sinus node slowing during IVC-LA stimulation. Fig 5E shows that stimulation of the RPV fat pad did not affect AV nodal conduction time. Stimulation of the IVC-LA fat pad produced first-degree AV block in 2, second-degree AV block in 2, and third-degree AV block in 1 of 5 dogs. Stimulation of the SVC-Ao fat pad induced first-degree AV block in 1 and second-degree AV block in 4 of the 5 dogs. Sustained AF was not inducible during stimulation of either the RPV or IVC-LA fat pad, but it was inducible with burst atrial pacing and perpetuated by stimulating the SVC-Ao fat pad.
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1°AVB indicates normal AV conduction or first-degree AV block; 2°AVB, second-degree AV block; and 3°AVB, complete AV block. See text for details.
Long-term Effectiveness of Chronic Vagal Denervation: Group 10
There was no disturbance of gastrointestinal motility nor aspiration of regurgitated fluid into the lungs following RFCA of the RPV, IVC-LA, and SVC-Ao fat pads. All 5 dogs recovered promptly and were capable of mild exercise within 24 to 48 hours. Table 5 shows the results of electrophysiological studies 7 to 10 days after RFCA of the three fat pads. There was no significant slowing of sinus node automaticity or AV nodal conduction time and no significant shortening of atrial ERP during bilateral vagal stimulation, indicating that the sinus and AV nodes and both atria were completely vagally denervated.
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Effects of Methacholine on the Sinus and AV Nodes and the Atria Before and After Acute and Chronic Vagal Denervation: Groups 9 and 10
In group 9 dogs, the sinus and AV nodes and both atria were completely vagally denervated after RFCA of the three fat pads in all 5 dogs (data not shown). No significant slowing of SCL or prolongation of AV nodal conduction time occurred during infusion of a low or high dose of methacholine before and 30 minutes after the sinus and AV nodes were denervated (Table 6). Atrial ERP shortening induced by a low or high dose of methacholine was not significantly different before and after acute denervation of both atria in group 9 dogs (Fig 6). However, in chronically denervated dogs (group 10), infusion of a low or high dose of methacholine shortened atrial ERPs and prolonged SCL and AV nodal conduction time more than in acutely denervated dogs (group 9), consistent with denervation supersensitivity. Sustained AF was still inducible after either acute or chronic vagal denervation of both atria during infusion of a low or high dose of methacholine that also induced sustained AF before vagal denervation.
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Histopathological Findings
In the IVC-LA fat pad, ganglion cells were present in small clusters of 2 to 25 cells that were often embedded in nerve branches. The ganglion cell clusters were approximately evenly divided between the periphery of the myocardium and the more remote areas of the fat pad. The larger clusters were near the myocardium. The small clusters farther from the myocardium were less conspicuously associated with nerve branches. Some clusters of ganglion cells that were present within the myocardium were associated with tendrils of epicardial fat.
In the SVC-Ao fat pad (Fig 7), clusters of ganglion cells were small (2 to 18 cells) and seemed less numerous than in the IVC-LA fat pad. Most were deep in the fat pad, away from other structures. The larger ones were associated with small nerve branches.
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2 mm from the myocardium (hematoxylin-eosin, magnification x40). B, Cluster of 18 ganglion cells with associated nerve fibers in epicardial fat. Ganglion cells have granula cytoplasm, eccentrically located nuclei, and large nucleoli (hematoxylin-eosin, magnification x200).In the RPV fat pad, the clusters of ganglion cells were closely associated with the periphery of the myocardium and were present in tendrils of epicardial fat between bundles of myocardial cells. There were more large clusters of 20 or more ganglion cells than there were in the IVC-LA and SVC-Ao fat pads.
Discussion
Efferent Vagal Innervation of the Atria and Sinus and AV Nodes
The major conclusions from this study are that most efferent vagal fibers to the atria appear to travel through the newly described SVC-Ao fat pad, which is located between the medial SVC and aortic root, superior to the right pulmonary artery, and then project onto the IVC-LA and RPV fat pads and to both atria. A few vagal fibers may bypass the SVC-Ao fat pad and go directly to the IVC-LA or RPV fat pads to innervate atrial myocardium. The vagal fibers to both atria are located in the subepicardium as well as intramurally or subendocardially. Bilateral vagal fibers to the sinus and AV nodes also converge first at the SVC-Ao fat pad (a few fibers to the sinus node go directly to the RPV fat pad) and then project to the RPV and IVC-LA fat pads, which provide vagal innervation to the sinus and AV nodes, respectively.
Thus, the SVC-Ao fat pad appears to be the "head station" of vagal fibers traveling to both atria and to the sinus and AV nodes in the dog. Total efferent vagal denervation of these structures is accomplished easily by RFCA of all three fat pads. Furthermore, we found that vagal denervation of the RA partially denervated the LA, but not vice versa, and that vagal denervation of the RA or both atria eliminated the induction of AF in dogs with atrial pacing and perpetuation of AF by bilateral vagal stimulation. Vagal denervation of the LA did not prevent vagally induced sustained AF. The inducibility and duration of AF during infusion of either a low or high dose of methacholine were not affected by efferent vagal denervation of the atria.
Vagal Denervation Supersensitivity of the Sinus and AV Nodes and the Atria
Slowing of sinus node automaticity, prolongation of AV nodal conduction time, and ERP shortening in the atria produced by infusion of a low (1.5 µg·kg-1·min-1 IV) or high (3.6 µg·kg-1·min-1 IV) dose of methacholine were significantly greater 7 to 10 days after vagal denervation than at baseline and immediately after vagal denervation due to denervation supersensitivity.27 28 29 30 31 32 33 Parasympathetic denervation supersensitivity of atrial myocardium has not been found in previous studies,28 34 35 36 37 38 39 40 41 42 43 perhaps because denervation was performed at a preganglionic level, which may result in vagal decentralization of the heart without direct denervation of the effector cells.
Methodological Considerations and Study Limitations
Our laboratory has shown24 that an RFCA procedure patterned after the surgical maze operation41 attenuates vagally induced ERP shortening in both atria and that RFCA can create contiguous transmural lesions. Therefore, in the present study stepwise RFCA was used epicardially to interrupt vagal fibers to the atria. Phenol application alone was insufficient because it only destroyed superficial tissue,25 26 and we found that some efferent vagal nerves are located intramyocardially or subendocardially. Thus, transmural lesions produced by RFCA were necessary. Because we did not assess sympathetic innervation to the atria and sinus and AV nodes, we cannot state whether the sympathetic supply was still preserved after complete efferent vagal denervation. Randall and coworkers5 have demonstrated that selective vagal denervation of sinus and AV nodes by surgical dissection of the RPV and IVC-LA fat pads does not affect the sympathetic supply to both tissues. Further studies are needed to establish whether our vagal denervation procedure eliminating the three fat pads affected the sympathetic inputs to those tissues and the vagal inputs to the ventricles.
Clinical Implications
Denervation supersensitivity has been proposed as a mechanism for induction of ventricular arrhythmias by the sympathetic nervous system.29 30 42 43 This study provides the first evidence that parasympathetic denervation supersensitivity of the atrial myocardium exists. In diseased atria there may be areas of regional fibrosis that interrupt parasympathetic fibers and create localized areas of denervation and subsequently denervation supersensitivity, which might play a role in the genesis of some atrial arrhythmias. An atrium that is more homogeneous electrically would have a reduced propensity to fibrillate. Therefore, total efferent vagal denervation of the atria might reduce the possibility of regional parasympathetic supersensitivity and might be an antifibrillatory maneuver. This could easily be accomplished by RFCA of the RPV, IVC-LA, and SVC-Ao fat pads.
Selected Abbreviations and Acronyms
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Acknowledgments
This work was supported in part by the Herman C. Krannert Fund and by grant No. HL-52323 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The authors thank Claude J. Arnett and Dzung Nguyen for technical assistance and Naomi S. Fineberg, PhD, for statistical analysis of the data.
Received October 23, 1996; revision received December 5, 1996; accepted January 2, 1997.
References
- Geis WP, Kaye MP, Randall WC. Major autonomic pathways to the atria and S-A and A-V nodes of the canine heart. Am J Physiol. 1973;224:202-208.
[Free Full Text]
- Lazzara R, Scherlag BJ, Robison MJ, Samet P. Selective in situ parasympathetic control of the canine sinoatrial and atrioventricular nodes. Circ Res. 1973;32:393-401.
[Abstract/Free Full Text]
- Randall WC, Ardell JL. Selective parasympathectomy of automatic and conductible tissues of the canine heart. Am J Physiol. 1985;248:H61-H68.[Medline]
[Order article via Infotrieve]
- Randall WC, Milosavljevic M, Wurster RD, Geis GS, Ardell JL. Selective vagal innervation of the heart. Ann Clin Lab Sci. 1986;16:198-208.[Abstract]
- Randall WC, Ardell JL, Wurster RD, Milosavljevic M. Vagal postganglionic innervation of the canine sinoatrial node. J Auton Nerv Syst. 1987;20:13-23.[Medline]
[Order article via Infotrieve]
- Randall WC, Ardell JL, Calderwood D, Milosavljevic M, Goyal SC. Parasympathetic ganglia innervating the canine atrioventricular nodal region. J Auton Nerv Syst. 1986;16:311-323.[Medline]
[Order article via Infotrieve]
- O'Toole MF, Ardell JL, Randall WC. Functional interdependence of discrete vagal projections to SA and AV nodes. Am J Physiol. 1986;251:H398-H404.[Medline]
[Order article via Infotrieve]
- Ardell JL, Randall WC. Selective vagal innervation of sinoatrial and atrioventricular nodes in canine heart. Am J Physiol. 1986;251:H764-H773.[Medline]
[Order article via Infotrieve]
- Billman GE, Hoskins RS, Randall DC, Randall WC, Hamlin RL, Lin YC. Selective vagal postganglionic innervation of the sinoatrial and atrioventricular nodes in the non-human primate. J Auton Nerv Syst. 1989;26:27-36.[Medline]
[Order article via Infotrieve]
- Furukawa Y, Wallick DW, Carlson MD, Martin PL. Cardiac electrical responses to vagal stimulation of fibers to discrete cardiac regions. Am J Physiol. 1990;258:H1112-H1118.[Medline]
[Order article via Infotrieve]
- Wallick DW, Martin PL. Separate parasympathetic control of heart rate and atrioventricular conduction of dogs. Am J Physiol. 1990;259:H536-H542.[Medline]
[Order article via Infotrieve]
- Prystowsky EN, Grant AO, Wallace AG, Strauss HC. An analysis of the effects of acetylcholine on conduction and refractoriness in the rabbit sinus node. Circ Res. 1979;44:112-120.
[Abstract/Free Full Text]
- Randall WC, Armour JA. Gross and microscopic anatomy of cardiac innervation. In: Randall WC, ed. Neural Regulation of the Heart. New York, NY: Oxford University Press; 1977:13-41.
- Slavikova J, Tucek S. Choline acetyltransferase in the heart of adult rats. Pflugers Arch. 1982;392:225-229.[Medline]
[Order article via Infotrieve]
- Schmid PG, Greif BJ, Lund DD, Roskoski R Jr. Regional choline acetyltransferase activity in the guinea pig heart. Circ Res. 1978;42:657-660.
[Abstract/Free Full Text]
- Tucek S. Changes in choline acetyltransferase activity in the cardiac auricles of dogs during postnatal development. Physiol Bohemoslov. 1965;14:530-535.[Medline]
[Order article via Infotrieve]
- Burgen ASV, Terroux KG. On the negative inotropic effect in the cat's auricle. J Physiol. 1953;120:449-464.
[Free Full Text]
- Zipes DP, Mihalick MJ, Robbins GT. Effects of selective vagal and stellate ganglion stimulation on atrial refractoriness. Cardiovasc Res. 1974;8:647-655.[Medline]
[Order article via Infotrieve]
- Allessi R, Nusynowtiz M, Abildskov JA, Moe GK. Nonuniform distribution of vagal effects on the atrial refractory period. Am J Physiol. 1958;194:406-410.
[Abstract/Free Full Text]
- Borggrefe M, Hindricks G, Haverkamp W, Budde T, Breidthardt G. Radiofrequency ablation. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. Philadelphia, Pa: WB Saunders Co; 1990:997-1004.
- Haines DE. Determinants of lesion size during radiofrequency catheter ablation: the role of electrode-tissue contact pressure and duration of energy delivery. J Cardiovasc Electrophysiol. 1991;2:509-515.
- Wittkamp FHM, Hauer RNW, Robles de Medina EO. Control of radiofrequency lesion by power regulation. Circulation. 1989;80:962-968.
[Abstract/Free Full Text]
- Haines DE, Verow AF. The impedance rise during radiofrequency ablation in vivo is prevented by maintaining an electrode tip temperature below the boiling point. Circulation. 1989;80(suppl II):II-41. Abstract.
- Elvan A, Pride HP, Eble JN, Zipes DP. Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation. 1995;91:2235-2244.
[Abstract/Free Full Text]
- Geis WP, Kaye MP. Distribution of sympathetic fibers in the left ventricular epicardial plexus of the dog. Circ Res. 1968;23:165-170.
[Abstract/Free Full Text]
- Martins JB, Zipes DP. Epicardial phenol interrupts refractory period responses to sympathetic but not vagal stimulation in canine left ventricular epicardium and endocardium. Circ Res. 1980;47:33-40.
[Free Full Text]
- Dempsey PJ, Cooper T. Supersensitivity of the chronically denervated feline heart. Am J Physiol. 1968;215:1245-1249.
[Free Full Text]
- Hageman GRF, Urthaler F, James TN. Differential sensitivity to neuro-transmitters in denervated canine sinus node. Am J Physiol. 1977;233:H211-H216.[Medline]
[Order article via Infotrieve]
- Inoue H, Zipes DP. Results of sympathetic denervation in the canine heart: supersensitivity that may be arrhythmogenic. Circulation. 1987;75:877-887.
[Abstract/Free Full Text]
- Kammerling JJ, Green FJ, Watanabe AM, Inoue H, Barber MJ, Henry DP, Zipes DP. Denervation supersensitivity of refractoriness in noninfarcted areas apical to transmural myocardial infarction. Circulation. 1987;76:383-393.
[Abstract/Free Full Text]
- Lurie KG, Bristow MR, Reitz BA. Increased beta-adrenergic receptor density in an experimental model of cardiac transplantation. J Thorac Cardiovasc Surg. 1983;86:195-201.[Abstract]
- Vatner DE, Lavallee M, Amano J, Finizola A, Homcy CJ, Vatner SF. Mechanisms of supersensitivity to sympathomimetic amines in the chronically denervated heart of the conscious dog. Circ Res. 1985;57:55-64.
[Abstract/Free Full Text]
- Kaseda S, Zipes DP. Supersensitivity to acetylcholine of canine sinus and AV nodes after parasympathetic denervation. Am J Physiol. 1988;255:H534-H539.[Medline]
[Order article via Infotrieve]
- Blomquist TM, Priola DV, Romero AM. Source of intrinsic innervation of canine ventricle: a functional study. Am J Physiol. 1987;252:H638-H644.[Medline]
[Order article via Infotrieve]
- Priola DV, Curtis MB, Anagnostelis C, Martinez E. Altered nicotinic sensitivity of AV node in surgically denervated canine hearts. Am J Physiol. 1983;245:H27-H32.[Medline]
[Order article via Infotrieve]
- Priola DV, Spurgeon HA. Cholinergic sensitivity of the denervated canine heart. Circ Res. 1977;41:600-606.
[Free Full Text]
- Smith DC, Priola DV, Anagnostelis C. Comparison of in vivo and in vitro cholinergic response of normal and denervated canine hearts. J Pharmacol Exp Ther. 1985;235:37-44.
[Abstract/Free Full Text]
- Inoue Y, Furukawa Y, Nakano H, Sawaki S, Oguchi T, Chiba S. Parasympathetic control of right atrial pressure in anesthetized dogs. Am J Physiol. 1994;266:H861-H866.[Medline]
[Order article via Infotrieve]
- Bluemel KM, Wurster RD, Randall WC, Duff MJ, Ottole MF. Parasympathetic post-ganglionic pathways to the sinoatrial node. Am J Physiol. 1990;259:H1504-H1510.[Medline]
[Order article via Infotrieve]
- Takei M, Furukawa Y, Narita M, Ren LM, Karasawa Y, Murakami M, Chiba S. Synergistic nonuniform shortening of atrial refractory period induced by autonomic stimulation. Am J Physiol. 1991;261:H1988-H1993.[Medline]
[Order article via Infotrieve]
- Cox JL, Boinear JP, Schuessler RB, Ferguson TB, Lindsay BD, Cain ME, Corr PB, Kater RM, Kappas DG. Review of surgery for atrial fibrillation. J Cardiovasc Electrophysiol. 1991;2:541-561.
- Barber MJ, Muller TM, Henry DP, Felten SY, Zipes DP. Transmural myocardial infarction in the dog produces sympathectomy in noninfarcted myocardium. Circulation. 1983;67:787-796.
[Free Full Text]
- Stanton MS, Zipes DP. Modulation of drug effects by regional sympathetic denervation and supersensitivity. Circulation. 1991;84:1709-1714.
[Abstract/Free Full Text]
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