Neural Activity and Atrial Tachyarrhythmias

Neural Activity and Atrial Tachyarrhythmias

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Peng-Sheng Chen, Lan S. Chen, and Shien-Fong Lin

CHAPTER OUTLINE Cardiac Nerves

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Neural Activity and Atrial Tachyarrhythmias

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Persistent Atrial Fibrillation

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Neural Activity and Ventricular Rate Control During Persistent Atrial Fibrillation

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Neuromodulation for Atrial Tachyarrhythmia Control

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Conclusions

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Atrial tachyarrhythmia, including atrial fibrillation (AF), is a major public health problem. Many studies in animal models and in human patients have suggested that the activities of the autonomic nervous system has an important role in the generation and maintenance of atrial tachyarrhythmias. However, the mechanisms by which autonomic activation induce atrial tachyarrhythmias remain poorly understood. This gap in knowledge is in part due to the limited availability of information on the anatomical structures of the autonomic nerves that innervate the heart, the general absence of information on spontaneous autonomic nerve discharges in ambulatory animals or humans and a limited availability of animal model of spontaneous atrial tachyarrhythmias. The latter limitations have prevented the investigators from studying the temporal relationship between autonomic nerve discharges and spontaneous atrial tachyarrhythmias. This chapter summarizes the data obtained over the past few years in the understanding of the anatomy and physiology of the autonomic nerves, and attempts to relate the neural activities to the generation and maintenance of atrial tachyarrhythmias. There will also be a brief discussion of the use of neuromodulation in the prevention and treatment of atrial arrhythmias.

Cardiac Nerves Extrinsic cardiac nerves The preganglionic sympathetic nerves that innervate the heart arise in the upper four or five segments of thoracic spinal cord. These preganglionic sympathetic nerves pass through white rami communicantes, enter the sympathetic trunk, and terminate in the superior cervical ganglion, the middle cervical ganglion (if present), and the cervicothoracic (stellate) ganglion. These ganglia give off cardiac nerves that join with the cardiac branches of the vagus nerve and form cardiac plexus. The cardiac plexus, which is divided into a superficial (ventral) and deep (dorsal) cardiac plexus, then gives branches of the coronary and atrial plexuses to innervate the heart. The sympathetic nerves are distributed in the superficial epicardial layer throughout most surfaces and penetrate into myocardium along coronary arterial

pathways. Sympathetic nerves are located primarily around blood vessels and between myocytes. The nerve fibers are oriented along the long axis of myocytes. The cardiac branches of the vagus nerve, which are preganglionic fibers, make synaptic connections with ganglion cells in the ganglionated plexi (the intrinsic cardiac nervous system). Cardiac nerves can be demonstrated by labeling nerve-specific markers such as S100 protein (marker of Schwann cells), neurofilament, synaptophysin, protein gene product 9.5, and various regulatory neuropeptides (e.g., neuropeptide-Y) using immunohistochemistry techniques. Sympathetic nerves can be identified by immune-labeling tyrosine hydroxylase (TH) and parasympathetic nerves by acetylcholinesterase or cholineacetyltransferase (ChAT).

Intrinsic Cardiac Nerves In addition to the extrinsic cardiac nerves, the heart is also richly innervated by an extensive intrinsic cardiac nervous system.1,2 The intrinsic cardiac nervous system includes sensory, interconnecting, and autonomic neurons that communicate with each other and with the extrinsic cardiac nervous system. The nerve structures of the intrinsic cardiac nerves are found in various parts of the heart, but mostly in the ganglionated plexi within epicardial fat pads. Among the ganglionated plexi, the right-atrial ganglionated plexi innervates the sinus node, whereas the inferior vena cava–inferior atrial ganglionated plexi (at the junction of inferior vena cava and the left atrium) innervates the atrioventricular node. Another region that is richly innervated is located at the pulmonary vein (PV)-left atrium (LA) junction. Radiofrequency catheter ablation at these sites can potentially result in successful denervation and prevent the inducibility of AF.3 However, preserving (rather than ablating) the anterior epicardial fat pad during coronary arterial bypass surgery decreases incidence of postoperative atrial fibrillation.

Coexistence of Sympathetic and Parasympathetic Nerves in the Same Structure A common misunderstanding of the autonomic nervous system is that the nerve structures are either sympathetic or parasympathetic. For example, the term vagal tone is generally used to describe the level of activity in the parasympathetic nervous system. Vagal denervation was used to describe the successful elimination of bradycardiac responses during catheter ablation of AF. The fact, however, is that the vagus nerves and almost all other cardiac nerve structures contain both sympathetic (adrenergic) and parasympathetic (cholinergic) components. It is not possible to stimulate or ablate one branch of the autonomic nervous system without affecting the other. Tan et al4 performed immunostaining of tissues from the human PV-LA junction. The authors found that adrenergic and cholinergic nerves coexist in all ganglionated plexi. It is also possible for the same neuron to express both TH and ChAT. These findings indicate that it is impossible to target either sympathetic or parasympathetic nerves 399

400  NEURAL CONTROL OF CARDIAC ELECTRICAL ACTIVITY

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Figure 40-1.  Immunocytochemical staining of the cervical vagus nerve. A and C, Examples of the nerves sectioned transversely. Other panels show nerves sectioned longitudinally (craniocaudal). Each cervical vagus nerve contains multiple parallel nerve bundles, most staining positively (brown) for cholineacetyltransferase (ChAT), as shown in A and B. However, a small percentage of the nerve bundles, primarily at the periphery of the nerves, stained positively for tyrosine hydroxylase (TH; arrows in C and D). E, In addition, TH-positive ganglion cells are also present in the nerves. F, These cells were ChAT negative. These findings indicate that bundles of sympathetic nerves are present within the cervical vagus nerves. The presence of sympathetic ganglion cells in the vagus nerve suggests that the cervical vagus nerve is also an important source of sympathetic innervation. A to C, Original magnification ×100. D to F, Original magnification ×40. (From Park HW, Shen MJ, Han S, et al: Neural control of ventricular rate in ambulatory dogs with pacing induced sustained atrial fibrillation. Circ Arrhythm Electrophysiol 5:571–580, 2012.)

selectively during radiofrequency catheter-ablation procedures. Sympathetic nerve fibers are also present in the thoracic vagus nerve.5 More recently, Park et al.6 performed TH and ChAT staining of the left cervical vagus nerve (Figure 40-1). ChAT positive nerve structures formed a majority of the cervical vagus nerve (see Figure 40-1, A, B). However, a small amount of TH-positive nerves were also present at the edge of the nerve bundles (see Figure 40-1, C, D). Unexpectedly, the authors identified sympathetic neurons in the vagus nerve (see Figure 40-1, E), indicating that the cervical vagus nerve was a source of sympathetic innervation. The same neurons stained negative for ChAT (see Figure 40-1, F). The presence of both TH-positive neurons and TH-positive nerve fibers is consistent with the notion that the vagus nerve is a mixed sympathetic and

parasympathetic nerve structure. Therefore, vagal tone includes both sympathetic and parasympathetic components.

Neural Activity and Atrial Tachyarrhythmias Recording Neural Activities in Ambulatory Animals Jung et al7 continuously recorded the activity of stellate ganglia in healthy dogs for an average of 41.5 days and documented that both the heart rate and the stellate ganglion nerve activity (SGNA) showed a circadian variation. Ogawa et al5 and Tan et al8 then applied the same methods to record vagus nerve activity

Neural Activity and Atrial Tachyarrhythmias  401

contractions and nonsustained ventricular tachycardia.9 A second important observation is that, in ambulatory animals, the nerve structures often activate either simultaneously or alternatively, suggesting a close coordination among the nerve activities from different parts of the autonomic nervous system. For example, the left and right stellate ganglion usually activate together.7 Similarly, the VNA can activate with SGNA.5,8 The VNA can also activate simultaneously with the ganglionated plexi.11-13 Figure 40-3, A, shows simultaneous discharges of the right and left stellate ganglion in a normal dog. Figure 40-3, B, shows simultaneous recording of both extrinsic and intrinsic nerve activities in a dog with intermittent rapid atrial pacing. Note that both extrinsic nerve activities (SGNA and VNA) activated together with one of the intrinsic nerve structure (superior left ganglionated plexus, SLGPNA), but not the ligament of Marshall ganglionated plexus. The VNA and SLGPNA activation patterns were almost mirror images of each other, suggesting that these two structures closely coordinate with each other. Another important finding is that the SGNA in Figure 40-3, A, resulted in less apparent heart rate acceleration than that shown in Figure 40-2, whereas in Figure 40-3, B, there was sinus rate acceleration associated with SGNA. Subsequent studies showed that right

(VNA). These earlier studies showed several findings about nerve discharges that were previously unknown. First of all, there are fundamentally two different types of nerve activities (Figure 40-2). The vast majority of the nerve activities were the lowamplitude burst discharge activities (LABDA), with an amplitude less than 0.2 mV and variable duration. A second type of nerve activity is the high-amplitude spike discharge activity (HASDA) with amplitude of greater than 0.2 mV (average, 1.4 mV). There is usually a nearly isoelectric interval between the spikes, with obvious depolarization shifts in some of the episodes. The HASDA has a frequency of approximately 6.6 Hz, and there is an average of 6.7 spikes per run.5 HASDA episodes were rare, with an average of approximately 15 episodes per 24 hours. However, when they were observed, there was a high likelihood of both atrial and ventricular arrhythmias.5,9,10 Figure 40-2, A, shows examples of LABDA and HASDA in a normal dog. Note that LABDA in the SGNA can accelerate the heart rate. HASDA usually occurs during LABDA and can further accelerate the heart rate. Figure 40-2, B, shows that a HASDA episode immediately precedes the premature atrial contraction in a dog with pacing-induced heart failure.5 In another study, we have observed multiple episodes of HASDA-induced premature ventricular

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Figure 40-2.  Two types of nerve activities in ambulatory dogs. A, Patterns of nerve activities form a normal dog. The upper panel shows low-amplitude burst discharge activity (LABDA), which accounts for the vast majority of nerve activities in all nerve structures. In this example, LABDA accelerated the heart rate. The lower panel shows high-amplitude spike discharge activity (HASDA), which further accelerated the heart rate. Units for stellate ganglion nerve activity and electrocardiogram (ECG) are given in millivolts (mV) in this and all other figures. B, Patterns of nerve activities from a dog with pacing-induced heart failure. The premature atrial contraction (arrow on ECG channel) was preceded immediately by simultaneous sympathovagal discharges. The sympathetic nerve activity show spiky discharges (HASDA). (A, From Zhou S, Jung BC, Tan AY, et al: Spontaneous stellate ganglion nerve activity and ventricular arrhythmia in a canine model of sudden death. Heart Rhythm 5:131–139, 2008. B, From Ogawa M, Tan AY, Song J, et al: Cryoablation of extrinsic cardiac sympathetic nerves markedly reduces atrial arrhythmias in ambulatory dogs with pacing-induced heart failure. Heart Rhythm 5:S54, 2008.)

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402  NEURAL CONTROL OF CARDIAC ELECTRICAL ACTIVITY ECG 0 –8 Left SGNA 0 –5

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Figure 40-3.  Coordinated activation among different nerve structures. A, An ambulatory dog with simultaneous recording of left and right stellate ganglion nerve activity (SGNA). The arrow points to the onset of right SGNA, which slightly preceded onset of left SGNA. B, Simultaneous recording of both extrinsic and intrinsic nerve activities. Note the similarities between the nerve activities recorded by the superior left ganglionated plexus nerve activity (SLGPNA) and the vagus nerve activity (VNA). LOMNA, Ligament of Marshall nerve activity. (A, From Jung BC, Dave AS, Tan AY, et al: Circadian variations of stellate ganglion nerve activity in ambulatory dogs. Heart Rhythm 3:78–85, 2006. B, From Choi E-K, Shen MJ, Han S, et al: Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs. Circulation 121:2615–2623, 2010.)

anterior ganglionated plexus has an important role in heart rate control.13 Therefore, recording extrinsic nerve activity alone might not be sufficient in determining the mechanisms of heart rate control in ambulatory animals. The complex interactions among different autonomic nerve structures is one of the mechanisms by which heart rate variability measurements in general fail to accurately predict the instantaneous sympathetic and parasympathetic nerve activities. In dogs with heart failure, the relationship between nerve discharge and heart rate control is further uncoupled because of the sinus node dysfunction.13 Therefore, there is little relationship between the heart rate variability parameters and the actual autonomic nerve discharge patterns in heart failure.14

Canine Models of Atrial Tachyarrhythmias We used two different canine models to study the spontaneous atrial arrhythmias. One is rapid ventricular pacing to induce heart failure. A significant amount of spontaneous atrial tachyarrhythmias are observed in this heart failure model.5 The second model uses intermittent rapid atrial pacing to cause electrical remodeling and paroxysmal atrial tachyarrhythmias. This model is particularly suitable for the study of neural activation because it is associated with a heterogeneous increase of sympathetic

innervations and extensive atrial nerve sprouting. Such neural remodeling could, in turn, promote the electrical remodeling caused by rapid atrial pacing.15 However, because human AF is not induced by electrical stimulations, it is not known whether this model adequately simulates human AF remains.

Simultaneous Sympathovagal Discharges and Paroxysmal Atrial Tachyarrhythmias To determine whether autonomic nerve discharges preceded paroxysmal AF and other atrial tachyarrhythmias, Tan et al8 implanted a pacemaker and a radiotransmitter in dogs to simultaneously record nerve activities of the left stellate ganglion and left vagal nerve as well as a surface electrocardiogram (ECG) over a period of several weeks. The authors then performed intermittent rapid atrial pacing and monitored the nerve activity when the pacemaker was turned off. They found that there is a circadian variation of the frequencies of atrial tachyarrhythmias (Figure 40-4, A), similar to that found in human patients with symptomatic paroxysmal AF. They found that simultaneous sympathovagal discharges are a common trigger for premature atrial contractions (see Figure 40-4, B) and the most frequent trigger of paroxysmal atrial tachyarrhythmias (see Figure 40-4, C).8 Cryoablation of bilateral stellate ganglia and of the superior

Neural Activity and Atrial Tachyarrhythmias  403

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Figure 40-4.  Paroxysmal atrial arrhythmias in dogs with intermittent rapid atrial pacing. A, Circadian incidence of paroxysmal arrhythmias (PAC, PAT, and PAF combined) over a 24-hour period. B, The arrow points to the PAC. C, PAT induced by simultaneous sympathovagal discharge. PAC, premature atrial contraction; PAF, paroxysmal atrial fibrillation; PAT, paroxysmal atrial tachycardia. (From Tan AY, Zhou S, Ogawa M, et al: Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines. Circulation 118:916–925, 2008.)

cardiac branches of the left vagus nerve eliminated all episodes of paroxysmal AF and atrial tachycardias, indicating a causal relationship between ANS activity and the generation of paroxysmal atrial tachyarrhythmias. Similarly, in a canine model of pacing-induced heart failure, simultaneous sympathovagal discharge was the most frequent trigger of atrial tachyarrhythmias,5 which could be prevented by cryoablation of the stellate ganglion and the T2-T4 thoracic sympathetic ganglia.16 Choi et al11 recorded both left extrinsic nervous system activity (SGNA and VNA) and intrinsic nerve activity (the superior left ganglionated plexi and the ligament of Marshall). They found that the vast majority of atrial tachyarrhythmia episodes were preceded by simultaneous discharges of both extrinsic and intrinsic nervous systems, whereas a small percentage (10% to 20%) of episodes was preceded by intrinsic nerve activity alone without the participation of the extrinsic nervous system. In all dog studies, intrinsic cardiac nerve activities invariably preceded atrial tachyarrhythmia episodes. An example is shown in Figure 40-5. The importance of intrinsic cardiac nervous system in generating paroxysmal atrial tachyarrhythmias is further supported by Nishida et al,17 who reported that ganglionated plexi ablation reduced the inducibility of AF in dogs with rapid atrial pacing. Another interesting observation in this study11 is that the activities of intrinsic cardiac nerves might contaminate local atrial electrograms, resulting in recordings similar to that of complex fractionated atrial electrograms. These findings might explain the clinical efficacy of ablative therapy that targets those intrinsic cardiac ganglia18 or sites with complex fractionated atrial electrograms.

Persistent Atrial Fibrillation The mechanism by which some patients develop persistent (sustained) AF remains unclear. For patients with paroxysmal AF, approximately half of them progress to sustained AF after 25 years of follow-up.19 However, the time-to-progression varies considerably among individuals who progress from paroxysmal to sustained AF. Furthermore, many patients with chronic AF do not have documented paroxysmal AF before diagnosis. It is apparent that there are large individual variations in the susceptibility to progression of AF. Intermittent rapid atrial pacing in large animals can initially induce paroxysmal AF. However, if pacing continues, sustained AF is induced.8, 11 Rapid pacing causes shortening of the effective refractory periods. However, the time course of changes in atrial refractoriness did not exactly parallel the development of sustained AF, indicating that other factors might also be important in the progression to sustained AF. We analyzed long-term recordings of nerve activities in ambulatory dogs to determine the duration of intermittent rapid atrial pacing needed to induce sustained AF (>48 hours).12 We found that there are two differential patterns of interactions among cardiac autonomic structures (Figure 40-6, A). Among them, dogs with a linear sympathovagal correlation (group 1) nerves are associated with a faster development of sustained AF than those with L-shaped sympathovagal correlation (see Figure 40-6, B). Figure 40-6, C and D, shows the correlation between VNA and SLGPNA for group 1 and group 2 dogs, respectively. Figure 40-6, E and F, shows examples of nerve activities that correspond to Figure

404  NEURAL CONTROL OF CARDIAC ELECTRICAL ACTIVITY

ECG LA LOMNA SLGPNA SGNA VNA

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Figure 40-5.  Induction of PAT by extrinsic and intrinsic cardiac nerve activities. A, An example in which ICNA occurred before ECNA and a PAT episode. The magnified pseudo-electrocardiogram shows the different P wave morphologies during sinus rhythm (Aa) and PAT (Ab). B, Simultaneous ICNA and SGNA leading to the onset of PAT. ECNA, Extrinsic cardiac nerve activity; ICNA, intrinsic cardiac nerve activity; PAT, paroxysmal atrial tachycardia; SGNA, stellate ganglion nerve activity.

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Figure 40-6.  Patterns of autonomic interactions. A, Representative SGNA-VNA scatter plot of a group 1 dog. Each dot represents an SGNA-VNA pair of nerve activity integrated over 1 minute. The entire plot has 1440 data points to cover in a 24-hour period. B, Representative SGNA-VNA scatter plot from a group 2 dog. C, Representative VNA-SLGPNA scatter plot from a group 1 dog. D, Representative VNA-SLGPNA scatter plot from a group 2 dog. E, An example of simultaneous sympathovagal coactivation (black arrows) observed in a group 1 dog that led to heart rate acceleration. The arrowhead shows independent SLGPNA. F, An example of a recording from a group 2 dog showing that simultaneously increased VNA and SLGPNA (black arrows) resulted in heart rate deceleration. ECG, Electrocardiogram; SGNA, stellate ganglion nerve activity; VNA, vagal nerve activity; SLGPNA, superior left ganglionated plexus nerve activity. (From Shen MJ, Choi EK, Tan AY, et al: Patterns of baseline autonomic nerve activity and the development of pacing-induced sustained atrial fibrillation. Heart Rhythm 8:583–589, 2011.)

Neural Activity and Atrial Tachyarrhythmias  405

40-6, A and B, respectively. Group 1 dogs had more paroxysmal atrial tachycardias at baseline and faster induction of sustained AF by rapid atrial pacing compared with group 2 dogs. These findings show that baseline nerve activity patterns can predict the durations needed to induce sustained AF. Different forms of sympathovagal discharge patterns might also be present in human patients, and differential ANS discharge patterns may predetermine which patients will be at greater risks of progression from paroxysmal to sustained AF.

Neural Activity and Ventricular Rate Control during Persistent Atrial Fibrillation In most patients with AF, rate control is not inferior to rhythm control as a management strategy. However, the mechanisms of ventricular rate (VR) control during AF remain unclear. It is also generally accepted that autonomic nervous system inputs, especially the vagal tone, are important in modulating the AV node conduction. Left vagal nerve stimulation has been proposed as a method to control VR during AF. In addition to vagal nerves, it is

also known that the inferior vena cava–inferior atrial ganglionated plexus (IVC-IAGP) is important in modulating AV node conduction, and that direct electrical stimulation of this GP can slow VR during AF in human patients.20 However, none of these studies was performed in the ambulatory state with direct nerve recording. Therefore, the relative importance of right vagal nerve activity (RVNA), left vagal nerve activity (LVNA), and IVC-IAGP nerve activity (IVC-IAGPNA) in VR control during AF in ambulatory animals remains poorly understood. To fill this gap in knowledge, Park et al6 recorded bilateral cervical VNA and IVC-IAGPNA during baseline sinus rhythm and during pacing-induced sustained AF in six ambulatory dogs. Integrated nerve activities and average VR were measured every 10 seconds over 24-hour periods. It was found that that the LVNA was associated with VR reduction during AF in five of six dogs and RVNA in one of six dogs. Figure 40-7 shows typical examples. Figure 40-7, A, shows that five dogs showed VR reduction with combined LVNA and IVC-IAGPNA. Figure 40-7, B, is from one dog showing VR reduction with combined RVNA discharge and IVCIAGPNA discharge. Figure 40-7, C, shows IVC-IAGP discharge alone, without other autonomic nerve activity, is sufficient to cause transient AV conduct delay. Figure 40-7, D, shows that

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Figure 40-7.  Right vagal nerve activity (RVNA), left vagal nerve activity (LVNA), inferior vena cava–inferior atrial ganglionated plexus nerve activity (IVC-IAGPNA), and local electrograms (LEGM) during sustained atrial fibrillation. IVC-IAGPNA with LVNA (A) or RVNA (B) coactivation was associated with reduced VR. C, Independent IVC-IAGP was associated with slow VR. D, RVNA activation after IVC-IAGPNA withdrawal was associated with rapid VR. The LEGM shows ventricular electrograms and T waves. (From Park HW, Shen MJ, Han S, et al: Neural control of ventricular rate in ambulatory dogs with pacing-induced sustained atrial fibrillation. Circ Arrhythm Electrophysiol 5:571–580, 2012.)

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RVNA activation induces rapid heart rates, suggesting selective activation of the sympathetic fibers within the right cervical vagal nerve. When RVNA is not firing, the IVC-IAGP activation slowed the VR. These studies show that IVC-IAGPNA is invariably associated with VR reduction during AF. In comparison, right or left VNA was associated with VR reduction only when it coactivated with the IVC-IAGPNA. These studies also suggest that vagus nerves do not directly innervate the AV node; rather, it activates IVC-IAGP to control the VR during AF.

Neuromodulation for Atrial Tachyarrhythmia Control Animal studies suggest that increasing the vagal tone may be beneficial for controlling heart failure and ventricular arrhythmias.21,22 Spinal cord stimulation, which enhances parasympathetic activity, improves ventricular function and reduces ventricular arrhythmias in a canine postinfarction heart failure model.23 While most of these previous studies used vagal stimulation with stimulus strength sufficient to reduce heart rate, lowlevel vagus nerve stimulation (LL-VNS) with stimulus strength

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1 V below the threshold needed to reduce heart rate is known to be effective in suppressing AF induction in open-chest–anesthetized dogs.24, 25 We hypothesize that vagal stimulation could achieve its antiarrhythmic effects by suppressing sympathetic outflow to the heart. To test this hypothesis, we implanted a neurostimulator in 12 dogs to stimulate left cervical vagus nerve and a radiotransmitter for continuous recording of left SGNA, left thoracic VNA, and ECGs. Group 1 dogs (n = 6) underwent 1 week of continuous LL-VNS. Group 2 dogs (n = 6) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. We found that integrated SGNA was significantly reduced during LL-VNS in group 1. The reduction was most apparent at 8:00 am, along with a significantly reduced heart rate (Figure 40-8). LL-VNS did not change VNA. We also found that LL-VNS causes structural remodeling of the left stellate ganglion. Normal stellate ganglion naturally contains both TH-positive and TH-negative ganglion cells. The density of TH-negative nerves in the left stellate ganglion 1 week after cessation of LL-VNS were significantly more than that in normal control dogs. The frequencies of paroxysmal atrial fibrillation and tachycardia during active LL-VNS were significantly lower than when the LL-VNS was turned off. These findings show that LL-VNS suppresses SGNA and reduces the incidences

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Figure 40-8.  Effects of low-level vagus nerve stimulation (LL-VNS) on stellate ganglion nerve activity (SGNA) and heart rate (HR). A, Chronic LL-VNS significantly reduced SGNA over 24 hours. The SGNA normalized to baseline level after cessation of LL-VNS. B, Hourly averages of SGNA show that the reduction in integrated SGNA was particularly striking at 8:00 AM. All values are averaged over 5 days and six dogs. C, The administration and cessation of chronic LL-VNS did not change the overall heart rate. D, Hourly averages of HR reveal that the morning surge of HR (arrowhead) was markedly attenuated during LL-VNS. *P < 0.05. (From Shen MJ, Shinohara T, Park HW, et al: Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines. Circulation 123:2204–2212, 2011.)

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of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident 1 week after cessation of chronic LL-VNS.

Conclusions Autonomic nervous system activation invariably precedes the onset of paroxysmal atrial tachyarrhythmias, and the preexisting sympathovagal discharge patterns determines the duration of rapid pacing needed to induce persistent AF in ambulatory dogs. The intrinsic nervous system activation invariably precedes the onset of atrial tachyarrhythmia. Simultaneous discharges from the sympathetic and vagal nerves of the extrinsic nervous system are also commonly observed before the onset of atrial tachyarrhythmias. The extrinsic and intrinsic nervous systems also work together to control the VR during sustained AF. However, vagal nerves do not directly affect the AV conduction. They work through the IVC-IAGP to reduce the ventricular rate during AF.

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Acknowledgments The authors thank Medtronic (Minneapolis, MN), St. Jude Inc. (St. Paul, MN), and Cryocath (Houston, TX) for donating the research equipment to the laboratory. Peng-Sheng Chen was a consultant for Cyberonics, which manufactures and sells cervical vagal nerve stimulators. This work was supported by National Institutes of Health grants P01 HL78931, R01s HL78932, and R01 HL71140 and a Medtronic-Zipes Endowment.

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