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Device-Based Autonomic Modulation in Arrhythmia Patients: the Role of Vagal Nerve Stimulation

  • Arrhythmia (D Spragg, Section Editor)
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Opinion statement

Vagal nerve stimulation (VNS) has shown promise as an adjunctive therapy for management of cardiac arrhythmias by targeting the cardiac parasympathetic nervous system. VNS has been evaluated in the setting of ischemia-driven ventricular arrhythmias and atrial arrhythmias, as well as a treatment option for heart failure. As better understanding of the complexities of the cardiac autonomic nervous system is obtained, vagal nerve stimulation will likely become a powerful tool in the current cardiovascular therapeutic armamentarium.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Farrell TG, Bashir Y, Cripps T, et al. Risk stratification for arrhythmic events in postinfarction patients based on heart rate variability, ambulatory electrocardiographic variables and the signal-averaged electrocardiogram. J Am Coll Cardiol. 1991;18:687–97.

    CAS  PubMed  Google Scholar 

  2. Farrell TG, Paul V, Cripps TR, et al. Baroreflex sensitivity and electrophysiological correlates in patients after acute myocardial infarction. Circulation. 1991;83:945–52.

    CAS  PubMed  Google Scholar 

  3. Hull Jr SS, Evans AR, Vanoli E, et al. Heart rate variability before and after myocardial infarction in conscious dogs at high and low risk of sudden death. J Am Coll Cardiol. 1990;16:978–85.

    PubMed  Google Scholar 

  4. Kleiger RE, Miller JP, Bigger Jr JT, et al. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59:256–62.

    CAS  PubMed  Google Scholar 

  5. La Rovere MT, Bigger Jr JT, Marcus FI, et al. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998;351:478–84.

    PubMed  Google Scholar 

  6. Vanoli E, Schwartz PJ. Sympathetic–parasympathetic interaction and sudden death. Basic Res Cardiol. 1990;85 Suppl 1:305–21.

    PubMed  Google Scholar 

  7. Schwartz PJ, Billman GE, Stone HL. Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with healed myocardial infarction. An experimental preparation for sudden cardiac death. Circulation. 1984;69:790–800.

    CAS  PubMed  Google Scholar 

  8. Vaseghi M, Shivkumar K. The role of autonomic nervous system in sudden cardiac death. Prog Cardiovasc Dis. 2008;50:404–419.

  9. Waxman SG. Clinical neuroanatomy. 27e ed: Mc-Graw Hill Medical, 2013.

  10. Randall WC, Priola DV, Pace JB. Responses of individual cardiac chambers to stimulation of the cervical vagosympathetic trunk in atropinized dogs. Circ Res. 1967;20:534–44.

    CAS  PubMed  Google Scholar 

  11. Seki A, Green HR, Lee TD, et al. Sympathetic nerve fibers in human cervical and thoracic vagus nerves. Heart Rhythm. 2014;11:1411–7.

    PubMed  Google Scholar 

  12. Armour JA. The little brain on the heart. Cleve Clin J Med. 2007;74 Suppl 1:S48–51.

    PubMed  Google Scholar 

  13. Armour JA, Murphy DA, Yuan BX, et al. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec. 1997;247:289–98.

    CAS  PubMed  Google Scholar 

  14. Shen MJ, Zipes DP. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res. 2014;114:1004–21.

    CAS  PubMed  Google Scholar 

  15. Takahashi N, Zipes DP. Vagal modulation of adrenergic effects on canine sinus and atrioventricular nodes. Am J Physiol. 1983;244:H775–81.

    CAS  PubMed  Google Scholar 

  16. Naggar I, Nakase K, Lazar J, et al. Vagal control of cardiac electrical activity and wall motion during ventricular fibrillation in large animals. Auton Neurosci. 2014;183:12–22.

    PubMed  Google Scholar 

  17. Stavrakis S, Scherlag BJ, Fan Y, et al. Inhibition of atrial fibrillation by low-level vagus nerve stimulation: the role of the nitric oxide signaling pathway. J Interv Card Electrophysiol. 2013;36:199–208.

    PubMed  Google Scholar 

  18. Peiss CN, Spurgeon HA. Origin of initial escape beat during graded vagal stimulation. J Electrocardiol. 1975;8:25–9.

    CAS  PubMed  Google Scholar 

  19. Brack KE, Patel VH, Coote JH, et al. Nitric oxide mediates the vagal protective effect on ventricular fibrillation via effects on action potential duration restitution in the rabbit heart. J Physiol. 2007;583:695–704.

    PubMed Central  CAS  PubMed  Google Scholar 

  20. Martins JB, Zipes DP. Effects of sympathetic and vagal nerves on recovery properties of the endocardium and epicardium of the canine left ventricle. Circ Res. 1980;46:100–10.

    CAS  PubMed  Google Scholar 

  21. Martins JB, Zipes DP, Lund DD. Distribution of local repolarization changes produced by efferent vagal stimulation in the canine ventricles. J Am Coll Cardiol. 1983;2:1191–9.

    CAS  PubMed  Google Scholar 

  22. Scherlag BJ, Kabell G, Harrison L, et al. Mechanisms of bradycardia-induced ventricular arrhythmias in myocardial ischemia and infarction. Circulation. 1982;65:1429–34.

    CAS  PubMed  Google Scholar 

  23. Yamakawa K, So EL, Rajendran PS, et al. Electrophysiological effects of right and left vagal nerve stimulation on the ventricular myocardium. Am J Physiol Heart Circ Physiol. 2014;307:H722–31.

    CAS  PubMed  Google Scholar 

  24. Opthof T, Dekker LR, Coronel R, et al. Interaction of sympathetic and parasympathetic nervous system on ventricular refractoriness assessed by local fibrillation intervals in the canine heart. Cardiovasc Res. 1993;27:753–9.

    CAS  PubMed  Google Scholar 

  25. Scherlag BJ, Helfant RH, Haft JI, et al. Electrophysiology underlying ventricular arrhythmias due to coronary ligation. Am J Physiol. 1970;219:1665–71.

    CAS  PubMed  Google Scholar 

  26. Kent KM, Smith ER, Redwood DR, et al. Electrical stability of acutely ischemic myocardium: influences of heart rate and vagal stimulation. Circulation. 1973;47:291–8.

    CAS  PubMed  Google Scholar 

  27. Myers RW, Pearlman AS, Hyman RM, et al. Beneficial effects of vagal stimulation and bradycardia during experimental acute myocardial ischemia. Circulation. 1974;49:943–7.

    CAS  PubMed  Google Scholar 

  28. Kolman BS, Verrier RL, Lown B. The effect of vagus nerve stimulation upon vulnerability of the canine ventricle: role of sympathetic-parasympathetic interactions. Circulation. 1975;52:578–85.

    CAS  PubMed  Google Scholar 

  29. Yoon MS, Han J, Tse WW, et al. Effects of vagal stimulation, atropine, and propranolol on fibrillation threshold of normal and ischemic ventricles. Am Heart J. 1977;93:60–5.

    CAS  PubMed  Google Scholar 

  30. Takahashi N, Ito M, Iwao T, et al. Vagal modulation of ventricular tachyarrhythmias induced by left ansae subclaviae stimulation in rabbits. Jpn Heart J. 1998;39:503–11.

    CAS  PubMed  Google Scholar 

  31. Zuanetti G, De Ferrari GM, Priori SG, et al. Protective effect of vagal stimulation on reperfusion arrhythmias in cats. Circ Res. 1987;61:429–35.

    CAS  PubMed  Google Scholar 

  32. Vanoli E, De Ferrari GM, Stramba-Badiale M, et al. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res. 1991;68:1471–81.

    CAS  PubMed  Google Scholar 

  33. Rosenshtraukh L, Danilo P, Anyukhovsky EP, et al. Mechanisms for vagal modulation of ventricular repolarization and of coronary occlusion-induced lethal arrhythmias in cats. Circ Res. 1994;75:722–32.

    CAS  PubMed  Google Scholar 

  34. Ando M, Katare RG, Kakinuma Y, et al. Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein. Circulation. 2005;112:164–70.

    CAS  PubMed  Google Scholar 

  35. Ng GA, Brack KE, Patel VH, et al. Autonomic modulation of electrical restitution, alternans and ventricular fibrillation initiation in the isolated heart. Cardiovasc Res. 2007;73:750–60.

    CAS  PubMed  Google Scholar 

  36. Brack KE, Coote JH, Ng GA. Vagus nerve stimulation protects against ventricular fibrillation independent of muscarinic receptor activation. Cardiovasc Res. 2011;91:437–46. This paper highlights the potential role of NO released with VNS in reducing ventricular arrhythmias.

    CAS  PubMed  Google Scholar 

  37. Wu W, Lu Z. Loss of anti-arrhythmic effect of vagal nerve stimulation on ischemia-induced ventricular tachyarrhythmia in aged rats. Tohoku J Exp Med. 2011;223:27–33. This paper exemplifies that VNS reduces VF and mechanisms include connexin-43 regulation.

    PubMed  Google Scholar 

  38. Matta RJ, Verrier RL, Lown B. Repetitive extrasystole as an index of vulnerability to ventricular fibrillation. Am J Physiol. 1976;230:1469–73.

    CAS  PubMed  Google Scholar 

  39. Brooks WW, Verrier RL, Lown B. Influence of vagal tone on stellectomy-induced changes in ventricular electrical stability. Am J Physiol. 1978;234:H503–7.

    CAS  PubMed  Google Scholar 

  40. Zheng C, Li M, Inagaki M, et al. Vagal stimulation markedly suppresses arrhythmias in conscious rats with chronic heart failure after myocardial infarction. Conf Proc IEEE Eng Med Biol Soc. 2005;7:7072–5.

    PubMed  Google Scholar 

  41. Takahashi N, Ito M, Ishida S, et al. Effects of vagal stimulation on cesium-induced early afterdepolarizations and ventricular arrhythmias in rabbits. Circulation. 1992;86:1987–92.

    CAS  PubMed  Google Scholar 

  42. Weiss JN, Karma A, Shiferaw Y, et al. From pulsus to pulseless: the saga of cardiac alternans. Circ Res. 2006;98:1244–53.

    CAS  PubMed  Google Scholar 

  43. James R, Arnold J, Allen JD, et al. The effects of heart rate, myocardial ischemia and vagal stimulation on the threshold for ventricular fibrillation. Circulation. 1977;55:311–7.

    CAS  PubMed  Google Scholar 

  44. Herre JM, Thames MD. Responses of sympathetic nerves to programmed ventricular stimulation. J Am Coll Cardiol. 1987;9:147–53.

    CAS  PubMed  Google Scholar 

  45. Smith ML, Hamdan MH, Wasmund SL, et al. High-frequency ventricular ectopy can increase sympathetic neural activity in humans. Heart Rhythm. 2010;7:497–503.

    PubMed  Google Scholar 

  46. Rajendran PS, Vaseghi M, Armour JA, et al. Abstract 12655: cardiac pacing alters neural information processing in the intrinsic cardiac nervous system. Circ J. 2014;130:A12655.

    Google Scholar 

  47. Del Rio CL, Dawson TA, Clymer BD, et al. Effects of acute vagal nerve stimulation on the early passive electrical changes induced by myocardial ischaemia in dogs: heart rate-mediated attenuation. Exp Physiol. 2008;93:931–44.

    PubMed  Google Scholar 

  48. Vaseghi M, Yagishita D, Yamakawa K, et al. Abstract 16272: intermittent vagal nerve stimulation reduces VT inducibility and dispersion of repolarization in a chronic infarct model. Circ J. 2013;128:A16272.

    Google Scholar 

  49. Waxman MB, Sharma AD, Asta J, et al. The protective effect of vagus nerve stimulation on catecholamine-halothane-induced ventricular fibrillation in dogs. Can J Physiol Pharmacol. 1989;67:801–9.

    CAS  PubMed  Google Scholar 

  50. Harvey RD. Muscarinic receptor agonists and antagonists: effects on cardiovascular function. Handb Exp Pharmacol 2012:299–316

  51. Zhao M, He X, Bi XY, et al. Vagal stimulation triggers peripheral vascular protection through the cholinergic anti-inflammatory pathway in a rat model of myocardial ischemia/reperfusion. Basic Res Cardiol. 2013;108:345.

    PubMed  Google Scholar 

  52. Remo BF, Giovannone S, Fishman GI. Connexin43 cardiac gap junction remodeling: lessons from genetically engineered murine models. J Membr Biol. 2012;245:275–81.

    PubMed Central  CAS  PubMed  Google Scholar 

  53. Shen MJ, Hao-Che C, Park HW, et al. Low-level vagus nerve stimulation upregulates small conductance calcium-activated potassium channels in the stellate ganglion. Heart Rhythm. 2013;10:910–5.

    PubMed Central  PubMed  Google Scholar 

  54. Hill MR, Wallick DW, Mongeon LR, et al. Vasoactive intestinal polypeptide antagonists attenuate vagally induced tachycardia in the anesthetized dog. Am J Physiol. 1995;269:H1467–72.

    CAS  PubMed  Google Scholar 

  55. Scherf D, Blumenfeld S, Yildiz M. Experimental study on ventricular extrasystoles provoked by vagal stimulation. Am Heart J. 1961;62:670–5.

    CAS  PubMed  Google Scholar 

  56. Takato T, Ashida T, Seko Y, et al. Ventricular tachyarrhythmia-related basal cardiomyopathy in rabbits with vagal stimulation—a novel experimental model for inverted Takotsubo-like cardiomyopathy. J Cardiol. 2010;56:85–90.

    PubMed  Google Scholar 

  57. Manning JW, Cotten MDV. Mechanism of cardiac arrhythmias induced by diencephalic stimulation. Am J Physiol. 1962;203:1120–4.

    Google Scholar 

  58. Ashida T, Ono C, Sugiyama T, et al. Mitral valve hemorrhage and mitral annulus shrinkage in rabbits with transient ventricular bigeminies induced by vagal stimulation. J Heart Valve Dis. 2004;13:779–83.

    PubMed  Google Scholar 

  59. Kerzner J, Wolf M, Kosowsky BD, et al. Ventricular ectopic rhythms following vagal stimulation in dogs with acute myocardial infarction. Circulation. 1973;47:44–50.

    CAS  PubMed  Google Scholar 

  60. Buchholz B, Donato M, Perez V, et al. Changes in the loading conditions induced by vagal stimulation modify the myocardial infarct size through sympathetic-parasympathetic interactions. Pflugers Arch 2014.This paper highlights sympathetic and parasympathetic interactions that can occur, particularly in the setting of continuous vagal nerve stimulation where bradycardia and changes in loading conditions can cause sympathetic activation.

  61. Koncz I, Gurabi Z, Patocskai B, et al. Mechanisms underlying the development of the electrocardiographic and arrhythmic manifestations of early repolarization syndrome. J Mol Cell Cardiol. 2014;68:20–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  62. Antzelevitch C. Brugada syndrome. Pacing Clin Electrophysiol. 2006;29:1130–59.

    PubMed Central  PubMed  Google Scholar 

  63. Flaim SN, McCulloch AD. Acetylcholine-induced shortening of the epicardial action potential duration may increase repolarization gradients and LQT3 arrhythmic risk. J Electrocardiol. 2007;40:S66–9.

    PubMed  Google Scholar 

  64. Kasanuki H, Ohnishi S, Ohtuka M, et al. Idiopathic ventricular fibrillation induced with vagal activity in patients without obvious heart disease. Circulation. 1997;95:2277–85.

    CAS  PubMed  Google Scholar 

  65. Shalaby AA, El-Saed A, Nemec J, Moossy JJ, Balzer JR. Exacerbation of electrical storm subsequent to implantation of a right vagal stimulator. Clin Aut Res. 2007;17:385–90.

  66. Katsouras G, Sakabe M, Comtois P, et al. Differences in atrial fibrillation properties under vagal nerve stimulation versus atrial tachycardia remodeling. Heart Rhythm. 2009;6:1465–72.

    PubMed  Google Scholar 

  67. Burn JH, Williams EM, Walker JM. The effects of acetylcholine in the heart-lung preparation including the production of auricular fibrillation. J Physiol. 1955;128:277–93.

    PubMed Central  CAS  PubMed  Google Scholar 

  68. Wang Z, Page P, Nattel S. Mechanism of flecainide’s antiarrhythmic action in experimental atrial fibrillation. Circ Res. 1992;71:271–87.

    CAS  PubMed  Google Scholar 

  69. Goldberger AL, Pavelec RS. Vagally-mediated atrial fibrillation in dogs: conversion with bretylium tosylate. Int J Cardiol. 1986;13:47–55.

    CAS  PubMed  Google Scholar 

  70. Zhang Y, Ilsar I, Sabbah HN, et al. Relationship between right cervical vagus nerve stimulation and atrial fibrillation inducibility: therapeutic intensities do not increase arrhythmogenesis. Heart Rhythm. 2009;6:244–50.

    PubMed  Google Scholar 

  71. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation. 2000;102:2774–80.

    CAS  PubMed  Google Scholar 

  72. Furukawa T, Hirao K, Horikawa-Tanami T, et al. Influence of autonomic stimulation on the genesis of atrial fibrillation in remodeled canine atria not the same as in normal atria. Circ J. 2009;73:468–75.

    PubMed  Google Scholar 

  73. Alessi R, Nusynowitz M, Abildskov JA, et al. Nonuniform distribution of vagal effects on the atrial refractory period. Am J Physiol. 1958;194:406–10.

    CAS  PubMed  Google Scholar 

  74. Liu L, Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol. 1997;273:H805–16.

    CAS  PubMed  Google Scholar 

  75. Page PL, Hassanalizadeh H, Cardinal R. Transitions among atrial fibrillation, atrial flutter, and sinus rhythm during procainamide infusion and vagal stimulation in dogs with sterile pericarditis. Can J Physiol Pharmacol. 1991;69:15–24.

    CAS  PubMed  Google Scholar 

  76. Ninomiya I. Direct evidence of nonuniform distribution of vagal effects on dog atria. Circ Res. 1966;19:576–83.

    CAS  PubMed  Google Scholar 

  77. Liu Y, Scherlag BJ, Fan Y, et al. Inducibility of atrial fibrillation after GP ablations and “autonomic blockade”: evidence for the pathophysiological role of the nonadrenergic and noncholinergic neurotransmitters. J Cardiovasc Electrophysiol. 2013;24:188–95.

    CAS  PubMed  Google Scholar 

  78. 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;123:2204–12.

    PubMed Central  PubMed  Google Scholar 

  79. Stavrakis S, Scherlag BJ, Fan Y, et al. Antiarrhythmic effects of vasostatin-1 in a canine model of atrial fibrillation. J Cardiovasc Electrophysiol. 2012;23:771–7.

    PubMed  Google Scholar 

  80. 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;22:455–63.

    PubMed  Google Scholar 

  81. 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;2:645–51.

    PubMed  Google Scholar 

  82. Sha Y, Scherlag BJ, Yu L, et al. Low-level right vagal stimulation: anticholinergic and antiadrenergic effects. J Cardiovasc Electrophysiol. 2011;22:1147–53.

    PubMed  Google Scholar 

  83. Gao M, Zhang L, Scherlag BJ, et al. Low-level vago-sympathetic trunk stimulation inhibits atrial fibrillation in a rabbit model of obstructive sleep apnea. Heart Rhythm 2014; In Press.This experimental canine model of atrial fibrillation highlights the role of low level VNS in protecting against atrial arrhythmias and demonstrates a mechanism for its beneficial effects via modulating stellate ganglion nerve activity.

  84. Coumel P, Friocourt P, Mugica J, et al. Long-term prevention of vagal atrial arrhythmias by atrial pacing at 90/minute: experience with 6 cases. Pacing Clin Electrophysiol. 1983;6:552–60.

    CAS  PubMed  Google Scholar 

  85. Brack KE, Coote JH, Ng GA. Vagus nerve stimulation inhibits the increase in Ca2+ transient and left ventricular force caused by sympathetic nerve stimulation but has no direct effects alone—epicardial Ca2+ fluorescence studies using fura-2 AM in the isolated innervated beating rabbit heart. Exp Physiol. 2010;95:80–92.

    CAS  PubMed  Google Scholar 

  86. Ng GA, Brack KE, Coote JH. Effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart—a novel model of isolated Langendorff perfused rabbit heart with intact dual autonomic innervation. Exp Physiol. 2001;86:319–29.

    CAS  PubMed  Google Scholar 

  87. Lewis ME, Al-Khalidi AH, Bonser RS, et al. Vagus nerve stimulation decreases left ventricular contractility in vivo in the human and pig heart. J Physiol. 2001;534:547–52.

    PubMed Central  CAS  PubMed  Google Scholar 

  88. Nakayama Y, Miyano H, Shishido T, et al. Heart rate-independent vagal effect on end-systolic elastance of the canine left ventricle under various levels of sympathetic tone. Circulation. 2001;104:2277–9.

    CAS  PubMed  Google Scholar 

  89. Takahashi H, Maehara K, Onuki N, et al. Decreased contractility of the left ventricle is induced by the neurotransmitter acetylcholine, but not by vagal stimulation in rats. Jpn Heart J. 2003;44:257–70.

    CAS  PubMed  Google Scholar 

  90. Brack KE, Coote JH, Ng GA. The effect of direct autonomic nerve stimulation on left ventricular force in the isolated innervated Langendorff perfused rabbit heart. Auton Neurosci. 2006;124:69–80.

    PubMed  Google Scholar 

  91. Matsuura W, Sugimachi M, Kawada T, et al. Vagal stimulation decreases left ventricular contractility mainly through negative chronotropic effect. Am J Physiol. 1997;273:H534–9.

    CAS  PubMed  Google Scholar 

  92. Henning RJ, Feliciano L, Coers CM. Vagal nerve stimulation increases right ventricular contraction and relaxation and heart rate. Cardiovasc Res. 1996;32:846–53.

    CAS  PubMed  Google Scholar 

  93. Sabbah HN. Electrical vagus nerve stimulation for the treatment of chronic heart failure. Cleve Clin J Med. 2011;78 Suppl 1:S24–9.

    PubMed  Google Scholar 

  94. Zhang Y, Popovic ZB, Bibevski S, et al. Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model. Circ Heart Fail. 2009;2:692–9.

    CAS  PubMed  Google Scholar 

  95. Hamann JJ, Ruble SB, Stolen C, et al. Vagus nerve stimulation improves left ventricular function in a canine model of chronic heart failure. Eur J Heart Fail. 2013;15:1319–26.

    PubMed Central  PubMed  Google Scholar 

  96. Uemura K, Zheng C, Li M, et al. Early short-term vagal nerve stimulation attenuates cardiac remodeling after reperfused myocardial infarction. J Card Fail. 2010;16:689–99.

    PubMed  Google Scholar 

  97. Shinlapawittayatorn K, Chinda K, Palee S, et al. Vagus nerve stimulation initiated late during ischemia, but not reperfusion, exerts cardioprotection via amelioration of cardiac mitochondrial dysfunction. Heart Rhythm 2014

  98. Shinlapawittayatorn K, Chinda K, Palee S, et al. Low-amplitude, left vagus nerve stimulation significantly attenuates ventricular dysfunction and infarct size through prevention of mitochondrial dysfunction during acute ischemia-reperfusion injury. Heart Rhythm. 2013;10:1700–7.

    PubMed  Google Scholar 

  99. Li M, Zheng C, Sato T, et al. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation. 2004;109:120–4.

    PubMed  Google Scholar 

  100. Muscholl E. Peripheral muscarinic control of norepinephrine release in the cardiovascular system. Am J Physiol. 1980;239:H713–20.

    CAS  PubMed  Google Scholar 

  101. Feigl EO. Parasympathetic control of coronary blood flow in dogs. Circ Res. 1969;25:509–19.

    CAS  PubMed  Google Scholar 

  102. Henning RJ, Sawmiller DR. Vasoactive intestinal peptide: cardiovascular effects. Cardiovasc Res. 2001;49:27–37.

    CAS  PubMed  Google Scholar 

  103. Zhao G, Shen W, Xu X, et al. Selective impairment of vagally mediated, nitric oxide-dependent coronary vasodilation in conscious dogs after pacing-induced heart failure. Circulation. 1995;91:2655–63.

    CAS  PubMed  Google Scholar 

  104. Sawmiller DR, Henning RJ, Cuevas J, et al. Coronary vascular effects of vasoactive intestinal peptide in the isolated perfused rat heart. Neuropeptides. 2004;38:289–97.

    CAS  PubMed  Google Scholar 

  105. Kelly RA, Balligand JL, Smith TW. Nitric oxide and cardiac function. Circ Res. 1996;79:363–80.

    CAS  PubMed  Google Scholar 

  106. Feng Q, Song W, Lu X, et al. Development of heart failure and congenital septal defects in mice lacking endothelial nitric oxide synthase. Circulation. 2002;106:873–9.

    CAS  PubMed  Google Scholar 

  107. Mungrue IN, Gros R, You X, et al. Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest. 2002;109:735–43.

    PubMed Central  CAS  PubMed  Google Scholar 

  108. Damy T, Ratajczak P, Shah AM, et al. Increased neuronal nitric oxide synthase-derived NO production in the failing human heart. Lancet. 2004;363:1365–7.

    CAS  PubMed  Google Scholar 

  109. Schwartz PJ, De Ferrari GM, Sanzo A, et al. Long term vagal stimulation in patients with advanced heart failure: first experience in man. Eur J Heart Fail. 2008;10:884–91.

    PubMed  Google Scholar 

  110. Premchand RK, Sharma K, Mittal S, et al. Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF Trial. J Card Fail 2014.

  111. Zannad F, De Ferrari GM, Tuinenburg AE, 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 2014.

  112. Hauptman PJ, Schwartz PJ, Gold MR, et al. Rationale and study design of the increase of vagal tone in heart failure study: INOVATE-HF. Am Heart J. 2012;163:954–62.

    PubMed  Google Scholar 

  113. Tsutsumi T, Ide T, Yamato M, et al. Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction. Cardiovasc Res. 2008;77:713–21.

    CAS  PubMed  Google Scholar 

  114. Kong SS, Liu JJ, Yu XJ, et al. Protection against ischemia-induced oxidative stress conferred by vagal stimulation in the rat heart: involvement of the AMPK-PKC pathway. Int J Mol Sci. 2012;13:14311–25.

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Wang Q, Cheng Y, Xue FS, et al. Postconditioning with vagal stimulation attenuates local and systemic inflammatory responses to myocardial ischemia reperfusion injury in rats. Inflamm Res. 2012;61:1273–82.

    CAS  PubMed  Google Scholar 

  116. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–62.

    CAS  PubMed  Google Scholar 

  117. Yamakawa K, Matsumoto N, Imamura Y, et al. Electrical vagus nerve stimulation attenuates systemic inflammation and improves survival in a rat heatstroke model. PLoS One. 2013;8:e56728.

    PubMed Central  CAS  PubMed  Google Scholar 

  118. Tracey KJ. The inflammatory reflex. Nature. 2002;420:853–9.

    CAS  PubMed  Google Scholar 

  119. Katare RG, Ando M, Kakinuma Y, et al. Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury. J Mol Cell Cardiol. 2010;49:234–44.

    CAS  PubMed  Google Scholar 

  120. Zhang R, Wugeti N, Sun J, et al. Effects of vagus nerve stimulation via cholinergic anti-inflammatory pathway activation on myocardial ischemia/reperfusion injury in canine. Int J Clin Exp Med. 2014;7:2615–23.

    PubMed Central  PubMed  Google Scholar 

  121. Calvillo L, Vanoli E, Andreoli E, et al. Vagal stimulation, through its nicotinic action, limits infarct size and the inflammatory response to myocardial ischemia and reperfusion. J Cardiovasc Pharmacol. 2011;58:500–7.

    CAS  PubMed  Google Scholar 

  122. Imataka K, Yamaoki K, Seki A, et al. Peculiar mitral valve and papillary muscle lesions induced by vagus manipulations in rabbits. An experimental model for nonrheumatic mitral regurgitation. Jpn Heart J. 1986;27:377–86.

    CAS  PubMed  Google Scholar 

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Dr. William A. Huang, Dr. Kalyanam Shivkumar, and Dr. Marmar Vaseghi each declare no potential conflicts of interest.

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  1. UCLA Cardiac Arrhythmia Center, University of California, 100 Medical Plaza, Suite 660, Los Angeles, CA, 90095, USA

    William A. Huang MD, Kalyanam Shivkumar MD, PhD & Marmar Vaseghi MD

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  1. William A. Huang MD
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  2. Kalyanam Shivkumar MD, PhD
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Correspondence to Marmar Vaseghi MD.

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Huang, W.A., Shivkumar, K. & Vaseghi, M. Device-Based Autonomic Modulation in Arrhythmia Patients: the Role of Vagal Nerve Stimulation. Curr Treat Options Cardio Med 17, 22 (2015). https://doi.org/10.1007/s11936-015-0379-9

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