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Disease modification by autonomic nerve stimulation
EDITORIAL COMMENTARY
Disease modification by autonomic nerve stimulation Seil Oh, MD, PhD, FHRS Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea. One of the arrhythmogenic mechanisms in the pathophysiology of atrial fibrillation (AF) is autonomic influence. The activation of cardiac autonomic nerves results in electrophysiological changes, causing shortening of the atrial effective refractory period and action potential duration, and spatial heterogeneity of refractoriness.1 Such conditions favor the initiation and maintenance of atrial tachyarrhythmias such as AF. Coumel et al2 reported that vagus nerve might be associated with paroxysmal AF. Studies using heart rate variability analysis have confirmed that paroxysmal AF occurrence is associated with a primary increase in adrenergic tone followed by a marked modulation toward vagal predominance.3 Recently, direct recording of intrinsic cardiac nerve activities in ambulatory animals revealed that the nerve activities are invariable triggers of paroxysmal AF.4 Neural remodeling in atrial tachyarrhythmias has been introduced by several studies. Sympathetic hyperinnervation and nerve sprouting were observed in a canine AF model.5 Increased atrial sympathetic innervation has also been found in patients with persistent AF.6 In this issue of HeartRhythm, Yu et al7 demonstrate the effects of low-level superior vena cava (SVC) stimulation on neural remodeling and AF inducibility in an acute canine model of atrial tachyarrhythmia. They placed a 10-pole circular catheter in the SVC just below the entrance of the innominate vein. High-frequency stimulation (20 Hz, 0.1 ms of pulse duration) was applied for 3 hours with a voltage that was 50% lower than the threshold. They found that low-level SVC stimulation restored the neural activities at the anterior right ganglionated plexus to the baseline level and suppressed AF inducibility.
Is SVC an appropriate site for autonomic nerve stimulation? The conventional site for preganglionic stimulation is the cervical vagus nerve, and cervical vagus nerve stimulation (VNS) has been used for AF induction in numerous experimental models because vagal activation is arrhythmogenic. However, “suprathreshold” VNS may not be always arAddress reprint requests and correspondence: Dr. Seil Oh, MD, PhD, FHRS, Department of Internal Medicine, College of Medicine, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul 110-744, South Korea. E-mail address: [email protected].
rhythmogenic. Zhang et al8 demonstrated that AF inducibility by right cervical VNS was intensity dependent; thus, moderate or weak intensity of neural stimulation can be used for therapeutic purposes without increasing arrhythmogenic risk. Shen et al9 showed that low-level (subthreshold) left cervical VNS suppressed stellate ganglion nerve activities and paradoxically reduced the incidences of paroxysmal atrial tachyarrhythmias in ambulatory animals. The authors’ group had also reported similar data by using low-level VNS, bilateral or right cervical vagus nerve, in acute models.10 –13 In the present work, the authors tested a variant method of preganglionic VNS. They stimulated the SVC just below the entrance of the innominate vein (⫽brachiocephalic vein). The right vagus nerve descends through the superior mediastinum, at first behind the right brachiocephalic vein and then to the right of the trachea and posteromedial to the right brachiocephalic vein and SVC. Therefore, the authors’ method seems to stimulate the mediastinal part of the right vagus nerve or its cardiac branch. One of the major issues of transvenous SVC stimulation would be lead instability. In this respect, cervical VNS would be a more secure method, although lead implantation for cervical VNS is more invasive. In addition, nonselective stimulation may be a problem in all preganglionic stimulation because the vagus nerve has many branches to other organs, such as lung, trachea, esophagus, and stomach, causing extracardiac side effects. According to the report of Shen et al9 (subthreshold left cervical VNS), transient cough and drooling were observed in 4 of 6 dogs and nausea occurred in 2 of 6 dogs. The history of VNS in clinical use is longer in the field of epilepsy management. Only the left vagus nerve is used for this purpose because the left vagus is mainly afferent and, in particular, contains less cardiac efferent fibers than does the right vagus.14 Unfortunately, hoarseness or voice changes are frequently observed in patients with VNS device.14 We still do not have enough data on the superiority of SVC stimulation as compared with cervical VNS in terms of selectivity, although SVC has more proximity to the heart than does the cervical vagus nerve. Theoretically, postganglionic stimulation is applicable15 and can minimize such adverse effects. However, there is a limitation in that postganglionic stimulation may need more invasive procedures such as open-chest surgery.
1547-5271/$ -see front matter © 2012 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2012.01.016
Oh
Editorial Commentary
Appropriate recording method of autonomic nerve activity The study of Yu et al7 in this issue of HeartRhythm has limitations in assessing the neural activity. First, the investigators used Na-pentobarbital for general anesthesia. In general, autonomic nerve activity is suppressed under the anesthesia with this agent. Therefore, to assess autonomic nerve activities in an acute study, it is usually recommended to use alpha-chloralose as an anesthetic drug. One of the problems in alpha-chloralose use is that some Institutional Animal Care and Use Committees do not permit its use for the purpose of general anesthesia, because it may be considered as a paralytic agent rather than an anesthetic. Second, the acute study can reveal only the autonomic nerve status of the supine position during the sedative state. Although acute study data per se have some clinical implications, those cannot fully support real clinical situations. Therefore, the ambulatory animal model would be the best one for the autonomic nerve study. This is able to not only remove concerns of various drug actions on autonomic tone but also provide nerve activity information during real life. If the present study is performed in ambulatory animals, we will be able to get more clinically relevant data as well as those of SVC catheter stability.
Neural stimulation for AF seems to be good rather than bad or ugly Some may wonder why weak-intensity stimulation is antiarrhythmic, although autonomic stimulation is arrhythmogenic. What can be considered is that the action of neural stimulation may not be dichotomous. For example, numerous pharmacological agents have their own pharmacological favorable effects and adverse effects, and each effect is usually dose-dependent linearly or nonlinearly. Neural stimulation may work similarly on the cardiac tissue: dosedependent favorable and adverse effects. Some action will be manifest at a specific level of stimulation intensity. Therefore, we can choose the intensity of neural stimulation, according to the appropriate purpose (eg, AF model development, rate control, or reverse remodeling), in a way similar to how we choose an optimal dose of a pharmacological agent for disease control without toxic effect. According to the current knowledge, appropriate autonomic stimulation affects electrical properties of the atria and reverses neural remodeling. These effects may be favorable especially for the management of patients with both
811 heart failure and AF. Exact mechanisms of low-level neural stimulation have not been elucidated yet. Inflammation is important in AF pathophysiology;16 thus, cholinergic antiinflammatory pathway may also be related to this favorable effect.17 To get more robust information, following issues should be resolved in the future studies: mechanism of subthreshold stimulation on neural remodeling, effects of subthreshold ganglionated plexus stimulation, reliable stimulation methods/sites for neural stimulation for clinical use, and so on.
References 1. Tai CT, Chiou CW, Chen SA. Interaction between the autonomic nervous system and atrial tachyarrhythmias. J Cardiovasc Electrophysiol 2002;13: 83– 87. 2. Coumel P, Attuel P, Lavallee J, Flammang D, Leclercq JF, Slama R. [The atrial arrhythmia syndrome of vagal origin]. Arch Mal Coeur Vaiss 1978;71:645– 656. 3. Bettoni M, Zimmermann M. Autonomic tone variations before the onset of paroxysmal atrial fibrillation. Circulation 2002;105:2753–2759. 4. Choi EK, Shen MJ, Han S, et al. Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs. Circulation 2010;121:2615–2623. 5. Chang CM, Wu TJ, Zhou S, et al. Nerve sprouting and sympathetic hyperinnervation in a canine model of atrial fibrillation produced by prolonged right atrial pacing. Circulation 2001;103:22–25. 6. Gould PA, Yii M, McLean C, et al. Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation. Pacing Clin Electrophysiol 2006;29:821– 829. 7. Yu L, Scherlag BJ, Sha Y, et al. Interactions between atrial electrical remodeling and autonomic remodeling: how to break the vicious cycle. Heart Rhythm 2012;9:804 – 809. 8. Zhang Y, Ilsar I, Sabbah HN, Ben David T, Mazgalev TN. Relationship between right cervical vagus nerve stimulation and atrial fibrillation inducibility: therapeutic intensities do not increase arrhythmogenesis. Heart Rhythm 2009;6:244 – 250. 9. 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 2011;123:2204 –2212. 10. Li S, Scherlag BJ, Yu L, et al. Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of focal atrial fibrillation. Circ Arrhythm Electrophysiol 2009;2:645– 651. 11. Sha Y, Scherlag BJ, Yu L, et al. Low-level right vagal stimulation: anticholinergic and antiadrenergic effects. J Cardiovasc Electrophysiol 2011;22:1147– 1153. 12. Yu L, Scherlag BJ, Li S, et al. Low-level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia. J Cardiovasc Electrophysiol 2011;22:455– 463. 13. Sheng X, Scherlag BJ, Yu L, et al. Prevention and reversal of atrial fibrillation inducibility and autonomic remodeling by low-level vagosympathetic nerve stimulation. J Am Coll Cardiol 2011;57:563–571. 14. Binnie CD. Vagus nerve stimulation for epilepsy: a review. Seizure 2000;9: 161–169. 15. Zhang Y, Yamada H, Bibevski S, et al. Chronic atrioventricular nodal vagal stimulation: first evidence for long-term ventricular rate control in canine atrial fibrillation model. Circulation 2005;112:2904 –2911. 16. Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003;108:3006 –3010. 17. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007;117:289 –296.
Disease modification by autonomic nerve stimulation Seil Oh, MD, PhD, FHRS Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea. One of the arrhythmogenic mechanisms in the pathophysiology of atrial fibrillation (AF) is autonomic influence. The activation of cardiac autonomic nerves results in electrophysiological changes, causing shortening of the atrial effective refractory period and action potential duration, and spatial heterogeneity of refractoriness.1 Such conditions favor the initiation and maintenance of atrial tachyarrhythmias such as AF. Coumel et al2 reported that vagus nerve might be associated with paroxysmal AF. Studies using heart rate variability analysis have confirmed that paroxysmal AF occurrence is associated with a primary increase in adrenergic tone followed by a marked modulation toward vagal predominance.3 Recently, direct recording of intrinsic cardiac nerve activities in ambulatory animals revealed that the nerve activities are invariable triggers of paroxysmal AF.4 Neural remodeling in atrial tachyarrhythmias has been introduced by several studies. Sympathetic hyperinnervation and nerve sprouting were observed in a canine AF model.5 Increased atrial sympathetic innervation has also been found in patients with persistent AF.6 In this issue of HeartRhythm, Yu et al7 demonstrate the effects of low-level superior vena cava (SVC) stimulation on neural remodeling and AF inducibility in an acute canine model of atrial tachyarrhythmia. They placed a 10-pole circular catheter in the SVC just below the entrance of the innominate vein. High-frequency stimulation (20 Hz, 0.1 ms of pulse duration) was applied for 3 hours with a voltage that was 50% lower than the threshold. They found that low-level SVC stimulation restored the neural activities at the anterior right ganglionated plexus to the baseline level and suppressed AF inducibility.
Is SVC an appropriate site for autonomic nerve stimulation? The conventional site for preganglionic stimulation is the cervical vagus nerve, and cervical vagus nerve stimulation (VNS) has been used for AF induction in numerous experimental models because vagal activation is arrhythmogenic. However, “suprathreshold” VNS may not be always arAddress reprint requests and correspondence: Dr. Seil Oh, MD, PhD, FHRS, Department of Internal Medicine, College of Medicine, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul 110-744, South Korea. E-mail address: [email protected].
rhythmogenic. Zhang et al8 demonstrated that AF inducibility by right cervical VNS was intensity dependent; thus, moderate or weak intensity of neural stimulation can be used for therapeutic purposes without increasing arrhythmogenic risk. Shen et al9 showed that low-level (subthreshold) left cervical VNS suppressed stellate ganglion nerve activities and paradoxically reduced the incidences of paroxysmal atrial tachyarrhythmias in ambulatory animals. The authors’ group had also reported similar data by using low-level VNS, bilateral or right cervical vagus nerve, in acute models.10 –13 In the present work, the authors tested a variant method of preganglionic VNS. They stimulated the SVC just below the entrance of the innominate vein (⫽brachiocephalic vein). The right vagus nerve descends through the superior mediastinum, at first behind the right brachiocephalic vein and then to the right of the trachea and posteromedial to the right brachiocephalic vein and SVC. Therefore, the authors’ method seems to stimulate the mediastinal part of the right vagus nerve or its cardiac branch. One of the major issues of transvenous SVC stimulation would be lead instability. In this respect, cervical VNS would be a more secure method, although lead implantation for cervical VNS is more invasive. In addition, nonselective stimulation may be a problem in all preganglionic stimulation because the vagus nerve has many branches to other organs, such as lung, trachea, esophagus, and stomach, causing extracardiac side effects. According to the report of Shen et al9 (subthreshold left cervical VNS), transient cough and drooling were observed in 4 of 6 dogs and nausea occurred in 2 of 6 dogs. The history of VNS in clinical use is longer in the field of epilepsy management. Only the left vagus nerve is used for this purpose because the left vagus is mainly afferent and, in particular, contains less cardiac efferent fibers than does the right vagus.14 Unfortunately, hoarseness or voice changes are frequently observed in patients with VNS device.14 We still do not have enough data on the superiority of SVC stimulation as compared with cervical VNS in terms of selectivity, although SVC has more proximity to the heart than does the cervical vagus nerve. Theoretically, postganglionic stimulation is applicable15 and can minimize such adverse effects. However, there is a limitation in that postganglionic stimulation may need more invasive procedures such as open-chest surgery.
1547-5271/$ -see front matter © 2012 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2012.01.016
Oh
Editorial Commentary
Appropriate recording method of autonomic nerve activity The study of Yu et al7 in this issue of HeartRhythm has limitations in assessing the neural activity. First, the investigators used Na-pentobarbital for general anesthesia. In general, autonomic nerve activity is suppressed under the anesthesia with this agent. Therefore, to assess autonomic nerve activities in an acute study, it is usually recommended to use alpha-chloralose as an anesthetic drug. One of the problems in alpha-chloralose use is that some Institutional Animal Care and Use Committees do not permit its use for the purpose of general anesthesia, because it may be considered as a paralytic agent rather than an anesthetic. Second, the acute study can reveal only the autonomic nerve status of the supine position during the sedative state. Although acute study data per se have some clinical implications, those cannot fully support real clinical situations. Therefore, the ambulatory animal model would be the best one for the autonomic nerve study. This is able to not only remove concerns of various drug actions on autonomic tone but also provide nerve activity information during real life. If the present study is performed in ambulatory animals, we will be able to get more clinically relevant data as well as those of SVC catheter stability.
Neural stimulation for AF seems to be good rather than bad or ugly Some may wonder why weak-intensity stimulation is antiarrhythmic, although autonomic stimulation is arrhythmogenic. What can be considered is that the action of neural stimulation may not be dichotomous. For example, numerous pharmacological agents have their own pharmacological favorable effects and adverse effects, and each effect is usually dose-dependent linearly or nonlinearly. Neural stimulation may work similarly on the cardiac tissue: dosedependent favorable and adverse effects. Some action will be manifest at a specific level of stimulation intensity. Therefore, we can choose the intensity of neural stimulation, according to the appropriate purpose (eg, AF model development, rate control, or reverse remodeling), in a way similar to how we choose an optimal dose of a pharmacological agent for disease control without toxic effect. According to the current knowledge, appropriate autonomic stimulation affects electrical properties of the atria and reverses neural remodeling. These effects may be favorable especially for the management of patients with both
811 heart failure and AF. Exact mechanisms of low-level neural stimulation have not been elucidated yet. Inflammation is important in AF pathophysiology;16 thus, cholinergic antiinflammatory pathway may also be related to this favorable effect.17 To get more robust information, following issues should be resolved in the future studies: mechanism of subthreshold stimulation on neural remodeling, effects of subthreshold ganglionated plexus stimulation, reliable stimulation methods/sites for neural stimulation for clinical use, and so on.
References 1. Tai CT, Chiou CW, Chen SA. Interaction between the autonomic nervous system and atrial tachyarrhythmias. J Cardiovasc Electrophysiol 2002;13: 83– 87. 2. Coumel P, Attuel P, Lavallee J, Flammang D, Leclercq JF, Slama R. [The atrial arrhythmia syndrome of vagal origin]. Arch Mal Coeur Vaiss 1978;71:645– 656. 3. Bettoni M, Zimmermann M. Autonomic tone variations before the onset of paroxysmal atrial fibrillation. Circulation 2002;105:2753–2759. 4. Choi EK, Shen MJ, Han S, et al. Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs. Circulation 2010;121:2615–2623. 5. Chang CM, Wu TJ, Zhou S, et al. Nerve sprouting and sympathetic hyperinnervation in a canine model of atrial fibrillation produced by prolonged right atrial pacing. Circulation 2001;103:22–25. 6. Gould PA, Yii M, McLean C, et al. Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation. Pacing Clin Electrophysiol 2006;29:821– 829. 7. Yu L, Scherlag BJ, Sha Y, et al. Interactions between atrial electrical remodeling and autonomic remodeling: how to break the vicious cycle. Heart Rhythm 2012;9:804 – 809. 8. Zhang Y, Ilsar I, Sabbah HN, Ben David T, Mazgalev TN. Relationship between right cervical vagus nerve stimulation and atrial fibrillation inducibility: therapeutic intensities do not increase arrhythmogenesis. Heart Rhythm 2009;6:244 – 250. 9. 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 2011;123:2204 –2212. 10. Li S, Scherlag BJ, Yu L, et al. Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of focal atrial fibrillation. Circ Arrhythm Electrophysiol 2009;2:645– 651. 11. Sha Y, Scherlag BJ, Yu L, et al. Low-level right vagal stimulation: anticholinergic and antiadrenergic effects. J Cardiovasc Electrophysiol 2011;22:1147– 1153. 12. Yu L, Scherlag BJ, Li S, et al. Low-level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia. J Cardiovasc Electrophysiol 2011;22:455– 463. 13. Sheng X, Scherlag BJ, Yu L, et al. Prevention and reversal of atrial fibrillation inducibility and autonomic remodeling by low-level vagosympathetic nerve stimulation. J Am Coll Cardiol 2011;57:563–571. 14. Binnie CD. Vagus nerve stimulation for epilepsy: a review. Seizure 2000;9: 161–169. 15. Zhang Y, Yamada H, Bibevski S, et al. Chronic atrioventricular nodal vagal stimulation: first evidence for long-term ventricular rate control in canine atrial fibrillation model. Circulation 2005;112:2904 –2911. 16. Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003;108:3006 –3010. 17. Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007;117:289 –296.