International Journal of Cardiology 187 (2015) 637–638
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Noninvasive vagal nerve stimulation for heart failure: Was it practical or just a stunt? Zhuo Wang a,1, Xiaoya Zhou a,1, Xia Sheng b, Lilei Yu a,⁎, Hong Jiang a,⁎⁎ a b
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China Department of Cardiology, Sir Run Run Shaw Hospital Affiliated to Medical College of Zhejiang University, Hangzhou, China
a r t i c l e
i n f o
Article history: Received 30 March 2015 Accepted 31 March 2015 Available online 1 April 2015 Keywords: Auricular branch of vagus nerve Transcutaneous electrical stimulation Heart failure
Heart failure (HF) has been a public health problem with an estimated prevalence of 38 million patients worldwide, and the number is still increasing with the aging of the population [1]. Besides, the risk of mortality in HF remains high, and lots of patients remain very symptomatic, as evidenced by frequent hospitalizations, reduced exercise tolerance, and degraded quality of life [2]. Pharmacological therapy and invasive device-based therapies including implantable cardioverterdefibrillator for primary prevention and cardiac resynchronization therapy for improving cardiac function have changed little during the past decades. The imbalance of the autonomic nervous system (ANS) and the HF create a vicious cycle, the excess of sympathetic activity and the withdrawal of vagal activity clearly contribute to the progression of ventricular remodeling and worsening of heart failure, and vice versa, the progression of HF could augment the imbalance between sympathetic and vagal activity [3]. The enhanced sympathetic activity can be regulated by drugs of beta-adrenergic blockade or inhibitors of the renin–angiotensin–aldosterone system, and reduced parasympathetic activity can be maintained by physical training and low dose digoxin. However, the pace of new drug therapies has declined significantly. Several relatively new and experimental non-pharmacological interventions, which target specific aspects
⁎ Corresponding author. ⁎⁎ Correspondence to: H. Jiang, Department of Cardiology, Renmin Hospital of Wuhan University, No. 99 Zhangzhi Dong Road, Wuchang District, Wuhan City, Hubei Province 430060, China. E-mail addresses: [email protected] (L. Yu), [email protected] (H. Jiang). 1 Wang and Zhou contributed equally to this work.
http://dx.doi.org/10.1016/j.ijcard.2015.03.430 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
of autonomic imbalance (cervical vagus nerve stimulation, renal denervation, spinal cord stimulation, and carotid sinus nerve stimulation) are being actively investigated nowadays. All in all, the autonomic neuromodulation was the key target in HF treatment and device therapy to achieve autonomic modulation has garnered significant interest. Invasive chronic vagus nerve stimulation had been used for HF treatment in patients since 2008 [4] and at present there were mainly three clinical trials undergoing at the Neural Cardiac TherApy foR Heart Failure (NECTARHF) randomized controlled trial, the INNOVATE-HF (INcrease Of VAgal TonE in Heart Failure) trial and the ANTHEM-AF (Autonomic Neural regulation THerapy to Enhance Myocardial function in Heart Failure) trial. Although the results of these trials were not completely satisfied, the regulation of sympathovagal balance in HF is feasible and should be advantageous [5–7]. However, all VNS treatment had to implant stimulators and electrodes by surgery and some side effects including neck pain, coughing, difficulty swallowing, and voice alteration along with nausea and indigestion may be induced sometimes. Besides, the operation under anesthetization restrains it from extensive application. In recent years, noninvasive vagal nerve stimulation emerged as an alternative treatment. Our previous study identified that low-level transcutaneous electrical stimulation of auricular branch of vagus nerve was an effective modality for noninvasive autonomic neuromodulation in beagle dog post-myocardial infarction model [8] and other studies suggested that this noninvasive VNS therapy could be used in humans for suppressing atrial fibrillation, treating epilepsy and depression [9–11]. And it could activate the afferent and efferent vagal nerve, and modulate intrinsic cardiac autonomic nervous system to attain cardio-protective effect [12–14]. What is more, low-level transcutaneous electrical stimulation of auricular branch of vagus nerve treatment was tolerated and convenient for ambulatory patients and especially for patients who could not have pharmacological therapies. It was feasible that noninvasive VNS may be useful for a large population of HF patients. Although the improvements from the noninvasive vagal nerve stimulation treatment were not significant in the recent clinical trials, the autonomic neuromodulation by low-level transcutaneous electrical stimulation of auricular branch of the vagus nerve builds a new hope for HF treatment. Conflict of interest The authors report no relationships that could be construed as a conflict of interest.
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Z. Wang et al. / International Journal of Cardiology 187 (2015) 637–638
Acknowledgment This work was supported by the grants from National Natural Science Foundation of China No. 81270339 and No. 81300182, grant from the Science and Technology Research Project of Wuhan No. 201306060201010271, grant from the Natural Science Foundation of Hubei Province No. 2013CFB302, grant from the Natural Science Foundation of Zhejiang Province No. LY13H020003, and grant from the Fundamental Research Funds for the Central Universities No. 2042014kf0110. References [1] E. Braunwald, The war against heart failure: the Lancet lecture, Lancet 385 (2015) 812–824. [2] A.J. Camm, I. Savelieva, Vagal nerve stimulation in heart failure, Eur. Heart J. 36 (2015) 404–406. [3] H.C. Patel, S.D. Rosen, A. Lindsay, C. Hayward, A.R. Lyon, C. di Mario, Targeting the autonomic nervous system: measuring autonomic function and novel devices for heart failure management, Int. J. Cardiol. 170 (2013) 107–117. [4] P.J. Schwartz, G.M. De Ferrari, A. Sanzo, M. Landolina, R. Rordorf, C. Raineri, et al., Long term vagal stimulation in patients with advanced heart failure: first experience in man, Eur. J. Heart Fail. 10 (2008) 884–891. [5] L. Dicarlo, I. Libbus, B. Amurthur, B.H. Kenknight, I.S. Anand, Autonomic regulation therapy for the improvement of left ventricular function and heart failure symptoms: the ANTHEM-HF study, J. Card. Fail. 19 (2013) 655–660.
[6] P.J. Hauptman, P.J. Schwartz, M.R. Gold, M. Borggrefe, D.J. Van Veldhuisen, R.C. Starling, et al., Rationale and study design of the increase of vagal tone in heart failure study: INOVATE-HF, Am. Heart J. 163 (2012) 954–962. [7] F. Zannad, G.M. De Ferrari, A.E. Tuinenburg, D. Wright, J. Brugada, C. Butter, et al., Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial, Eur. Heart J. 36 (2015) 425–433. [8] 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 (2014) 1014–1021. [9] W. He, X. Jing, X. Wang, P. Rong, L. Li, H. Shi, et al., Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial, Epilepsy Behav. 28 (2013) 343–346. [10] E. Hein, M. Nowak, O. Kiess, T. Biermann, K. Bayerlein, J. Kornhuber, et al., Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study, J. Neural Transm. 120 (2013) 821–827. [11] S. Stavrakis, M.B. Humphrey, B.J. Scherlag, Y. Hu, W.M. Jackman, H. Nakagawa, et al., Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation, J. Am. Coll. Cardiol. 65 (2015) 867–875. [12] 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. [13] 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. [14] 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 (2014) 676–677.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Noninvasive vagal nerve stimulation for heart failure: Was it practical or just a stunt? Zhuo Wang a,1, Xiaoya Zhou a,1, Xia Sheng b, Lilei Yu a,⁎, Hong Jiang a,⁎⁎ a b
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China Department of Cardiology, Sir Run Run Shaw Hospital Affiliated to Medical College of Zhejiang University, Hangzhou, China
a r t i c l e
i n f o
Article history: Received 30 March 2015 Accepted 31 March 2015 Available online 1 April 2015 Keywords: Auricular branch of vagus nerve Transcutaneous electrical stimulation Heart failure
Heart failure (HF) has been a public health problem with an estimated prevalence of 38 million patients worldwide, and the number is still increasing with the aging of the population [1]. Besides, the risk of mortality in HF remains high, and lots of patients remain very symptomatic, as evidenced by frequent hospitalizations, reduced exercise tolerance, and degraded quality of life [2]. Pharmacological therapy and invasive device-based therapies including implantable cardioverterdefibrillator for primary prevention and cardiac resynchronization therapy for improving cardiac function have changed little during the past decades. The imbalance of the autonomic nervous system (ANS) and the HF create a vicious cycle, the excess of sympathetic activity and the withdrawal of vagal activity clearly contribute to the progression of ventricular remodeling and worsening of heart failure, and vice versa, the progression of HF could augment the imbalance between sympathetic and vagal activity [3]. The enhanced sympathetic activity can be regulated by drugs of beta-adrenergic blockade or inhibitors of the renin–angiotensin–aldosterone system, and reduced parasympathetic activity can be maintained by physical training and low dose digoxin. However, the pace of new drug therapies has declined significantly. Several relatively new and experimental non-pharmacological interventions, which target specific aspects
⁎ Corresponding author. ⁎⁎ Correspondence to: H. Jiang, Department of Cardiology, Renmin Hospital of Wuhan University, No. 99 Zhangzhi Dong Road, Wuchang District, Wuhan City, Hubei Province 430060, China. E-mail addresses: [email protected] (L. Yu), [email protected] (H. Jiang). 1 Wang and Zhou contributed equally to this work.
http://dx.doi.org/10.1016/j.ijcard.2015.03.430 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
of autonomic imbalance (cervical vagus nerve stimulation, renal denervation, spinal cord stimulation, and carotid sinus nerve stimulation) are being actively investigated nowadays. All in all, the autonomic neuromodulation was the key target in HF treatment and device therapy to achieve autonomic modulation has garnered significant interest. Invasive chronic vagus nerve stimulation had been used for HF treatment in patients since 2008 [4] and at present there were mainly three clinical trials undergoing at the Neural Cardiac TherApy foR Heart Failure (NECTARHF) randomized controlled trial, the INNOVATE-HF (INcrease Of VAgal TonE in Heart Failure) trial and the ANTHEM-AF (Autonomic Neural regulation THerapy to Enhance Myocardial function in Heart Failure) trial. Although the results of these trials were not completely satisfied, the regulation of sympathovagal balance in HF is feasible and should be advantageous [5–7]. However, all VNS treatment had to implant stimulators and electrodes by surgery and some side effects including neck pain, coughing, difficulty swallowing, and voice alteration along with nausea and indigestion may be induced sometimes. Besides, the operation under anesthetization restrains it from extensive application. In recent years, noninvasive vagal nerve stimulation emerged as an alternative treatment. Our previous study identified that low-level transcutaneous electrical stimulation of auricular branch of vagus nerve was an effective modality for noninvasive autonomic neuromodulation in beagle dog post-myocardial infarction model [8] and other studies suggested that this noninvasive VNS therapy could be used in humans for suppressing atrial fibrillation, treating epilepsy and depression [9–11]. And it could activate the afferent and efferent vagal nerve, and modulate intrinsic cardiac autonomic nervous system to attain cardio-protective effect [12–14]. What is more, low-level transcutaneous electrical stimulation of auricular branch of vagus nerve treatment was tolerated and convenient for ambulatory patients and especially for patients who could not have pharmacological therapies. It was feasible that noninvasive VNS may be useful for a large population of HF patients. Although the improvements from the noninvasive vagal nerve stimulation treatment were not significant in the recent clinical trials, the autonomic neuromodulation by low-level transcutaneous electrical stimulation of auricular branch of the vagus nerve builds a new hope for HF treatment. Conflict of interest The authors report no relationships that could be construed as a conflict of interest.
638
Z. Wang et al. / International Journal of Cardiology 187 (2015) 637–638
Acknowledgment This work was supported by the grants from National Natural Science Foundation of China No. 81270339 and No. 81300182, grant from the Science and Technology Research Project of Wuhan No. 201306060201010271, grant from the Natural Science Foundation of Hubei Province No. 2013CFB302, grant from the Natural Science Foundation of Zhejiang Province No. LY13H020003, and grant from the Fundamental Research Funds for the Central Universities No. 2042014kf0110. References [1] E. Braunwald, The war against heart failure: the Lancet lecture, Lancet 385 (2015) 812–824. [2] A.J. Camm, I. Savelieva, Vagal nerve stimulation in heart failure, Eur. Heart J. 36 (2015) 404–406. [3] H.C. Patel, S.D. Rosen, A. Lindsay, C. Hayward, A.R. Lyon, C. di Mario, Targeting the autonomic nervous system: measuring autonomic function and novel devices for heart failure management, Int. J. Cardiol. 170 (2013) 107–117. [4] P.J. Schwartz, G.M. De Ferrari, A. Sanzo, M. Landolina, R. Rordorf, C. Raineri, et al., Long term vagal stimulation in patients with advanced heart failure: first experience in man, Eur. J. Heart Fail. 10 (2008) 884–891. [5] L. Dicarlo, I. Libbus, B. Amurthur, B.H. Kenknight, I.S. Anand, Autonomic regulation therapy for the improvement of left ventricular function and heart failure symptoms: the ANTHEM-HF study, J. Card. Fail. 19 (2013) 655–660.
[6] P.J. Hauptman, P.J. Schwartz, M.R. Gold, M. Borggrefe, D.J. Van Veldhuisen, R.C. Starling, et al., Rationale and study design of the increase of vagal tone in heart failure study: INOVATE-HF, Am. Heart J. 163 (2012) 954–962. [7] F. Zannad, G.M. De Ferrari, A.E. Tuinenburg, D. Wright, J. Brugada, C. Butter, et al., Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial, Eur. Heart J. 36 (2015) 425–433. [8] 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 (2014) 1014–1021. [9] W. He, X. Jing, X. Wang, P. Rong, L. Li, H. Shi, et al., Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial, Epilepsy Behav. 28 (2013) 343–346. [10] E. Hein, M. Nowak, O. Kiess, T. Biermann, K. Bayerlein, J. Kornhuber, et al., Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study, J. Neural Transm. 120 (2013) 821–827. [11] S. Stavrakis, M.B. Humphrey, B.J. Scherlag, Y. Hu, W.M. Jackman, H. Nakagawa, et al., Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation, J. Am. Coll. Cardiol. 65 (2015) 867–875. [12] 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. [13] 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. [14] 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 (2014) 676–677.
