International Journal of Cardiology 187 (2015) 44–45
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
The right side or left side of noninvasive transcutaneous vagus nerve stimulation: Based on conventional wisdom or scientific evidence? Mingxian Chen a,1, Lilei Yu b,1, Fan Ouyang a, Qiming Liu a, Zhuo Wang b, Songyun Wang b, Liping Zhou b, Hong Jiang b, Shenghua Zhou a,⁎ a b
Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
a r t i c l e
i n f o
Article history: Received 20 March 2015 Accepted 21 March 2015 Available online 23 March 2015 Keywords: Autonomic nerve system Vagus nerve stimulation Transcutaneous tragus nerve stimulation Cardiac disease
Vagus nerve stimulation (VNS) has been considered as an effective approach for drug-resistant cardiac diseases with autonomic tone dysfunction [1]. Because of surgical implantation of the neurostimulator system, surgical complication and the side effects are usually inevitable to take place on patients [2,3]. Transcutaneous tragus nerve stimulation (TNS), the noninvasive vagus nerve stimulation, has been proven to have the similar effect on cardiac diseases induced by autonomic dysfunction in the heart, and would be a promising modulation for cardiac autonomic tone disorder presented as sympathetic hyper-function and parasympathetic hypo-function [4–7]. Conventionally, the left-sided cervical vagus nerve instead of the right-sided was mostly selected as the site for stimulation because of safety concerns. Early studies found that exogenous cardiac autonomic nerve system efferent projects to the heart presented as “sidedness” because of asymmetric cardiac innervation. The right-sided cervical vagus nerve predominantly innervated the sinus-atrial node (SAN), whereas the left-sided vagus nerve predominantly innervated the atrial–ventricular node (AVN). The right-sided VNS would be likely to result in significant cardiac side effects great bradycardia, whereas the
⁎ Corresponding author at: Department of Cardiology, the Second Xiangya Hospital of Central South University, No. 139 middle Renmin Road, Furong District, Changsha City, Hunan Province 410011, China. E-mail address: [email protected] (S. Zhou). 1 These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.ijcard.2015.03.351 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
left-sided causes no such effects [8,9]. We previously showed that the right-sided low-level tragus nerve stimulation (LL-TNS) could effectively and safely suppress AF via preventing the loss of atrial connexin expression [4]. Whether the left-sided LL-TNS would be as equally safe as the right-sided remains unknown. Currently, there is no direct evidence to be proven which side of LL-TNS would be much more safe when ear-clips are placed on tragus for stimulation. Should we choose the LL-TNS side based more on conventional wisdom than on sound scientific evidence? To explain this question, the neurocircuitry of TNS underlying cardiac autonomic tone modulation needs further elucidation (Fig. 1). The auricular branch of vagus nerve (ABVN) is the only peripheral branch of vagus nerve that locates on skin. The afferent vagal nerve fibers of ABVN enter the main vagal trunk through the jugular ganglions and project to the nucleus tractus solitaries (NTS) [10]. As the central
Fig. 1. Shows the pathway of tragus nerve stimulation and vagus nerve stimulation. TNS = tragus nerve stimulation; ABVN = auricular branch of vagus nerve; NTS = nucleus tractus solitaries; DMV = dorsal motor nucleus.
M. Chen et al. / International Journal of Cardiology 187 (2015) 44–45
45
Fig. 2. Represents the detail pathway of different side stimulation. TNS = tragus nerve stimulation; SA = sino-atrial; AV = atrio-ventricular.
integration of autonomic neurons, NTS collects afferent information, and activates caudal ventrolateral medulla (CVM) and dorsal motor nucleus (DMN) to modulate autonomic central neurons activity [11]. The hyper-activity of DMN delivered electrochemical signals through bilateral cervical vagal nerve to epicardial ganglion plexus and enhanced cardiac vagal tone. That is to say, the unilateral side of TNS, the rightsided or the left-sided stimulation, activates tragus nerve of ABVN and then the afferent fibers deliver stimulating signals to NTS for information integration. Then NTS projects processed signals to heart surface through the efferent of bilateral cervical vagal nerves (Fig. 2A, B). Unlike unilateral TNS, unilateral VNS directly delivers electrical signals to the asymmetric side of the heart and may cause different cardiac responses (Fig. 2C, D). It would be significantly safe to stimulate one side of the tragus if the other side of tragus region suffers from surgery in patients with cardiac diseases induced by cardiac autonomic dysfunction. Therefore, we think that the left-sided TNS against cardiac diseases with cardiac autonomic dysfunction will be as equally safe and efficacious as the right-sided TNS. All authors contributing to manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. This work was supported by the grants from the National Natural Science Foundation of China No. 81270257.
Conflicts of interest No.
References [1] J.J. Hamann, S.B. Ruble, C. Stolen, M. Wang, R.C. Gupta, S. Rastogi, et al., Vagus nerve stimulation improves left ventricular function in a canine model of chronic heart failure, Eur. J. Heart Fail. 15 (12) (2013) 1319–1326. [2] S. Spuck, V. Tronnier, I. Orosz, R. Schönweiler, A. Sepehrnia, G. Nowak, J. Sperner, Operative and technical complications of vagus nerve stimulator implantation, Neurosurgery 67 (2 Suppl. Operative) (2010) 489–494. [3] R.E. Elliott, A. Morsi, S.P. Kalhorn, J. Marcus, J. Sellin, M. Kang, et al., Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: longterm outcomes and predictors of response, Epilepsy Behav. 20 (1) (2011) 57–63. [4] M. Chen, L. Yu, Q. Liu, Z. Wang, S. Wang, H. Jiang, et al., Low level tragus nerve stimulation is a non-invasive approach for anti-atrial fibrillation via preventing the loss of connexins, Int. J. Cardiol. 179 (2015) 144–145. [5] Z. Wang, L. Yu, S. Wang, B. Huang, K. Liao, G. Saren, et al., Chronic intermittent lowlevel transcutaneous electrical stimulation of auricular branch of vagus nerve improves left ventricular remodeling in conscious dogs with healed myocardial infarction, Circ. Heart Fail. 7 (6) (2014) 1014–1021. [6] Z. Wang, L. Yu, M. Chen, S. Wang, H. Jiang, Transcutaneous electrical stimulation of auricular branch of vagus nerve: a noninvasive therapeutic approach for postischemic heart failure, Int. J. Cardiol. 177 (2) (2014) 676–677 (A). [7] S. Li, X. Zhou, L. Yu, H. Jiang, Low level non-invasive vagus nerve stimulation: a novel feasible therapeutic approach for atrial fibrillation, Int. J. Cardiol. 182C (2015) 189–190. [8] J.L. Ardell, W.C. Randall, Selective vagal innervation of sinoatrial and atrioventricular nodes in canine heart, Am. J. Physiol. 251 (4 Pt 2) (1986) H764–H773. [9] A. Pelleg, C.M. Hurt, J.M. Soler-Baillo, M. Polansky, Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in dogs, Am. J. Physiol. 265 (2 Pt 2) (1993) H681–H690. [10] F.O. Gamboa-Esteves, P.N. McWilliam, T.F. Batten, Substance P (NK1) and somatostatin (sst2A) receptor immunoreactivity in NTS-projecting rat dorsal horn neurones activated by nociceptive afferent input, J. Chem. Neuroanat. 27 (4) (2004) 251–266. [11] J.A. Clancy, D.A. Mary, K.K. Witte, J.P. Greenwood, S.A. Deuchars, J. Deuchars, Noninvasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity, Brain Stimul. 7 (6) (2014) 871–877.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
The right side or left side of noninvasive transcutaneous vagus nerve stimulation: Based on conventional wisdom or scientific evidence? Mingxian Chen a,1, Lilei Yu b,1, Fan Ouyang a, Qiming Liu a, Zhuo Wang b, Songyun Wang b, Liping Zhou b, Hong Jiang b, Shenghua Zhou a,⁎ a b
Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
a r t i c l e
i n f o
Article history: Received 20 March 2015 Accepted 21 March 2015 Available online 23 March 2015 Keywords: Autonomic nerve system Vagus nerve stimulation Transcutaneous tragus nerve stimulation Cardiac disease
Vagus nerve stimulation (VNS) has been considered as an effective approach for drug-resistant cardiac diseases with autonomic tone dysfunction [1]. Because of surgical implantation of the neurostimulator system, surgical complication and the side effects are usually inevitable to take place on patients [2,3]. Transcutaneous tragus nerve stimulation (TNS), the noninvasive vagus nerve stimulation, has been proven to have the similar effect on cardiac diseases induced by autonomic dysfunction in the heart, and would be a promising modulation for cardiac autonomic tone disorder presented as sympathetic hyper-function and parasympathetic hypo-function [4–7]. Conventionally, the left-sided cervical vagus nerve instead of the right-sided was mostly selected as the site for stimulation because of safety concerns. Early studies found that exogenous cardiac autonomic nerve system efferent projects to the heart presented as “sidedness” because of asymmetric cardiac innervation. The right-sided cervical vagus nerve predominantly innervated the sinus-atrial node (SAN), whereas the left-sided vagus nerve predominantly innervated the atrial–ventricular node (AVN). The right-sided VNS would be likely to result in significant cardiac side effects great bradycardia, whereas the
⁎ Corresponding author at: Department of Cardiology, the Second Xiangya Hospital of Central South University, No. 139 middle Renmin Road, Furong District, Changsha City, Hunan Province 410011, China. E-mail address: [email protected] (S. Zhou). 1 These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.ijcard.2015.03.351 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
left-sided causes no such effects [8,9]. We previously showed that the right-sided low-level tragus nerve stimulation (LL-TNS) could effectively and safely suppress AF via preventing the loss of atrial connexin expression [4]. Whether the left-sided LL-TNS would be as equally safe as the right-sided remains unknown. Currently, there is no direct evidence to be proven which side of LL-TNS would be much more safe when ear-clips are placed on tragus for stimulation. Should we choose the LL-TNS side based more on conventional wisdom than on sound scientific evidence? To explain this question, the neurocircuitry of TNS underlying cardiac autonomic tone modulation needs further elucidation (Fig. 1). The auricular branch of vagus nerve (ABVN) is the only peripheral branch of vagus nerve that locates on skin. The afferent vagal nerve fibers of ABVN enter the main vagal trunk through the jugular ganglions and project to the nucleus tractus solitaries (NTS) [10]. As the central
Fig. 1. Shows the pathway of tragus nerve stimulation and vagus nerve stimulation. TNS = tragus nerve stimulation; ABVN = auricular branch of vagus nerve; NTS = nucleus tractus solitaries; DMV = dorsal motor nucleus.
M. Chen et al. / International Journal of Cardiology 187 (2015) 44–45
45
Fig. 2. Represents the detail pathway of different side stimulation. TNS = tragus nerve stimulation; SA = sino-atrial; AV = atrio-ventricular.
integration of autonomic neurons, NTS collects afferent information, and activates caudal ventrolateral medulla (CVM) and dorsal motor nucleus (DMN) to modulate autonomic central neurons activity [11]. The hyper-activity of DMN delivered electrochemical signals through bilateral cervical vagal nerve to epicardial ganglion plexus and enhanced cardiac vagal tone. That is to say, the unilateral side of TNS, the rightsided or the left-sided stimulation, activates tragus nerve of ABVN and then the afferent fibers deliver stimulating signals to NTS for information integration. Then NTS projects processed signals to heart surface through the efferent of bilateral cervical vagal nerves (Fig. 2A, B). Unlike unilateral TNS, unilateral VNS directly delivers electrical signals to the asymmetric side of the heart and may cause different cardiac responses (Fig. 2C, D). It would be significantly safe to stimulate one side of the tragus if the other side of tragus region suffers from surgery in patients with cardiac diseases induced by cardiac autonomic dysfunction. Therefore, we think that the left-sided TNS against cardiac diseases with cardiac autonomic dysfunction will be as equally safe and efficacious as the right-sided TNS. All authors contributing to manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. This work was supported by the grants from the National Natural Science Foundation of China No. 81270257.
Conflicts of interest No.
References [1] J.J. Hamann, S.B. Ruble, C. Stolen, M. Wang, R.C. Gupta, S. Rastogi, et al., Vagus nerve stimulation improves left ventricular function in a canine model of chronic heart failure, Eur. J. Heart Fail. 15 (12) (2013) 1319–1326. [2] S. Spuck, V. Tronnier, I. Orosz, R. Schönweiler, A. Sepehrnia, G. Nowak, J. Sperner, Operative and technical complications of vagus nerve stimulator implantation, Neurosurgery 67 (2 Suppl. Operative) (2010) 489–494. [3] R.E. Elliott, A. Morsi, S.P. Kalhorn, J. Marcus, J. Sellin, M. Kang, et al., Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: longterm outcomes and predictors of response, Epilepsy Behav. 20 (1) (2011) 57–63. [4] M. Chen, L. Yu, Q. Liu, Z. Wang, S. Wang, H. Jiang, et al., Low level tragus nerve stimulation is a non-invasive approach for anti-atrial fibrillation via preventing the loss of connexins, Int. J. Cardiol. 179 (2015) 144–145. [5] Z. Wang, L. Yu, S. Wang, B. Huang, K. Liao, G. Saren, et al., Chronic intermittent lowlevel transcutaneous electrical stimulation of auricular branch of vagus nerve improves left ventricular remodeling in conscious dogs with healed myocardial infarction, Circ. Heart Fail. 7 (6) (2014) 1014–1021. [6] Z. Wang, L. Yu, M. Chen, S. Wang, H. Jiang, Transcutaneous electrical stimulation of auricular branch of vagus nerve: a noninvasive therapeutic approach for postischemic heart failure, Int. J. Cardiol. 177 (2) (2014) 676–677 (A). [7] S. Li, X. Zhou, L. Yu, H. Jiang, Low level non-invasive vagus nerve stimulation: a novel feasible therapeutic approach for atrial fibrillation, Int. J. Cardiol. 182C (2015) 189–190. [8] J.L. Ardell, W.C. Randall, Selective vagal innervation of sinoatrial and atrioventricular nodes in canine heart, Am. J. Physiol. 251 (4 Pt 2) (1986) H764–H773. [9] A. Pelleg, C.M. Hurt, J.M. Soler-Baillo, M. Polansky, Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in dogs, Am. J. Physiol. 265 (2 Pt 2) (1993) H681–H690. [10] F.O. Gamboa-Esteves, P.N. McWilliam, T.F. Batten, Substance P (NK1) and somatostatin (sst2A) receptor immunoreactivity in NTS-projecting rat dorsal horn neurones activated by nociceptive afferent input, J. Chem. Neuroanat. 27 (4) (2004) 251–266. [11] J.A. Clancy, D.A. Mary, K.K. Witte, J.P. Greenwood, S.A. Deuchars, J. Deuchars, Noninvasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity, Brain Stimul. 7 (6) (2014) 871–877.
