Stimulation of the intra-cardiac vagal nerves innervating the AV-node to control ventricular rate during AF: specificity, parameter optimization and chronic use up to 3 months

  • Lilian Kornet
  • Arne van Hunnik
  • Koen Michels
  • Sander Verheule
  • Alberto Della Scala
  • Teena West
  • Roger Kessels
  • Richard Cornelussen



Stimulation of the intra-cardiac vagal nerves innervating the AV-node (AVNS) is a promising approach to slow down ventricular rate (VR) during atrial fibrillation (AF). Our purpose was to demonstrate that effects on R-R-interval during stable AF can be maintained for several months once optimized and that AVNS affects specifically the nerves innervating the AV-node.


Our study included both an acute and chronic phase. Fifteen goats were implanted with a pacemaker connected to an atrial and ventricular lead and a neurostimulator connected to an atrial lead placed at a certain septal site, to induce an AV prolongation. In the chronic experiments (n = 9), after assessment of optimal AVNS parameters, the effect of continuous AVNS on VR was studied during stable AF for up to 3 months. The mechanism of AVNS was studied using atropine and esmolol. Next, the effects of AVNS during the atrial refractory period on electrophysiological and hemodynamic parameters were investigated acutely (n = 7).


The maximal effect was found at a stimulation frequency of 40 Hz, and increased with increasing pulse width (at lower voltages) and increasing voltage. After 0, 1, and 3 months of AVNS during stable AF, AVNS decreased average VR, respectively, 55% (n = 9), 48% (n = 8), and 28% (n = 6). The AVNS effect appeared to be dominantly parasympathetic. AVNS did not influence (1) the sinus node, (2) the refractory period of the atrial, ventricular tissue, and His and (3) hemodynamic parameters.


AVNS is efficient in reducing ventricular rate for at least 3 months using optimized parameters and specifically affects the parasympathetic nerves innervating the AV-node.


Atrial fibrillation AV-node AV-node stimulation Neurostimulation Parasympathetic Ventricular rate reduction 


Conflict of interest

Lilian Kornet, Roger Kessels, Teena West and Richard Cornelussen are employees of Medtronic. Alberto Della Scala and Koen Michels have worked for Medtronic during the time this study was performed


  1. 1.
    Wyse, D. G., Waldo, A. L., DiMarco, J. P., Domanski, M. J., Rosenberg, Y., Schron, E. B., et al. (2002). A comparison of rate control and rhythm control in patients with atrial fibrillation. The New England Journal of Medicine, 347, 1825–1833.PubMedCrossRefGoogle Scholar
  2. 2.
    Pürerfellner, H., Ruiter, J. H., Widdershoven, J. W., Van Gelder, I. C., Urban, L., Kirchhof, C. J., et al. (2006). Reduction of atrial tachyarrhythmia episodes during the overdrive pacing period using the post-mode switch overdrive pacing (PMOP) algorithm. Heart Rhythm, 3, 1164–1171.PubMedCrossRefGoogle Scholar
  3. 3.
    Pürerfellner, H., Urban, L., de Weerd, G., Ruiter, J., Brandt, J., Havlicek, A., et al. (2009). Reduction of atrial fibrillation burden by atrial overdrive pacing: experience with an improved algorithm to reduce early recurrences of atrial fibrillation. Europace, 11, 62–69.PubMedCrossRefGoogle Scholar
  4. 4.
    Lee, M. A., Weachter, R., Pollak, S., Kremers, M. S., Naik, A. M., Silverman, R., et al. (2003). The effect of atrial pacing therapies on atrial tachyarrhythmia burden and frequency: Results of a randomized trial in patients with bradycardia and atrial tachyarrhythmias. Journal of the American College of Cardiology, 41, 1926–1932.PubMedCrossRefGoogle Scholar
  5. 5.
    Bradley, D. J., & Shen, W. K. (2007). Overview of management of atrial fibrillation in symptomatic elderly patients: pharmacologic therapy versus AV node ablation. Clinical Pharmacology and Therapeutics, 81, 284–287.PubMedCrossRefGoogle Scholar
  6. 6.
    Garrigue, S., Mowrey, K. A., Fahy, G., Tchou, P. J., & Mazgalev, T. N. (1999). Atrioventricular nodal conduction during atrial fibrillation: Role of atrial input modification. Circulation, 99, 2323–2333.PubMedGoogle Scholar
  7. 7.
    Mazgalev, T. N., Garrigue, S., Mowrey, K. A., Yamanouchi, Y., & Tchou, P. J. (1999). Autonomic modification of the atrioventricular node during atrial fibrillation: role in the slowing of ventricular rate. Circulation, 99, 2806–2814.PubMedGoogle Scholar
  8. 8.
    Zhang, Y., Mowrey, K. A., Zhuang, S., Wallick, D. W., Popovic, Z. B., & Mazgalev, T. N. (2002). Optimal ventricular rate slowing during atrial fibrillation by feedback AV nodal-selective vagal stimulation. American Journal of Physiology Heart Circ Physiol, 282, H1102–H1110.Google Scholar
  9. 9.
    Zhang, Y., Zhuang, S., Mowrey, K. A., Jianbo, L., Tabata, T., Wallick, D. W., et al. (2002). Ventricular rate control by selective vagal stimulation is superior to rhythm regularization by AVN ablation and pacing during AF. Circulation, 106, 1853–1858.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang, Y., & Mazgalev, T. N. (2004). Achieving regular slow rhythm during atrial fibrillation without atrioventricular nodal ablation: Selective vagal stimulation plus ventricular pacing. Heart Rhythm, 1, 469–475.PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang, Y., Yamada, H., Bibevski, S., Zhuang, S., Mowrey, K. A., Wallick, D. W., et al. (2005). Chronic atrioventricular nodal vagal stimulation: First evidence for long-term ventricular rate control in canine atrial fibrillation model. Circulation, 112, 2904–2911.PubMedGoogle Scholar
  12. 12.
    Chen, S. A., Chiang, C. E., Tai, C. T., Wen, Z. C., Lee, S. H., Chiou, C. W., et al. (1998). Intracardiac stimulation of human parasympathetic nerve fibers induces negative dromotropic effects: Implication with the lesions of radiofrequency catheter ablation. Journal of Cardiovascular Electrophysiology, 9, 245–252.PubMedCrossRefGoogle Scholar
  13. 13.
    Quan, K. J., Van Hare, G. F., Biblo, L. A., Mackall, J. A., & Carlson, M. D. (2001). Endocardial stimulation of efferent parasympathetic nerves to the atrioventricular node in humans: Optimal stimulation sites and the effects of digoxin. Journal of Interventional Cardiology and Electrophysiology, 5, 145–152.CrossRefGoogle Scholar
  14. 14.
    Bianchi, S., Rossi, P., Della, S. A., Kornet, L., Pulvirenti, R., Monari, G., et al. (2009). Atrioventricular (AV) node vagal stimulation by transvenous permanent lead implantation to modulate AV node function: Safety and feasibility in humans. Heart Rhythm, 6, 1282–1286.PubMedCrossRefGoogle Scholar
  15. 15.
    Bianchi, S., Rossi, P., Della, S. A., & Kornet, L. (2009). Endocardial transcatheter stimulation of the AV nodal fat pad: Stabilization of rapid ventricular rate response during atrial fibrillation in left ventricular failure. Journal of Cardiovascular Electrophysiology, 20, 103–105.PubMedCrossRefGoogle Scholar
  16. 16.
    Quan, K. J., Lee, J. H., Van Hare, G. F., Biblo, L. A., Mackall, J. A., & Carlson, M. D. (2002). Identification and characterization of atrioventricular parasympathetic innervation in humans. Journal of Cardiovascular Electrophysiology, 13, 735–739.PubMedCrossRefGoogle Scholar
  17. 17.
    Rossi, P., Bianchi, S., Barretta, A., Della, S. A., Kornet, L., De Paulis, R., et al. (2009). Post-operative atrial fibrillation management by selective epicardial vagal fat pad stimulation. Journal of Interventional Cardiology and Electrophysiology, 24, 37–45.CrossRefGoogle Scholar
  18. 18.
    Wallick, D. W., & Martin, P. J. (1990). Separate parasympathetic control of heart rate and atrioventricular conduction of dogs. American Journal of Physiology, 259, 536–542.Google Scholar
  19. 19.
    Rossi, P., Bianchi, S., Monari, G., Della, S. A., Porcelli, D., Valsecchi, S., et al. (2010). Vagal tone augmentation to the atrioventricular node in humans: Efficacy and safety of burst endocardial stimulation. Heart Rhythm, 7, 683–689.PubMedCrossRefGoogle Scholar
  20. 20.
    Rossi, P., Bianchi, S., Valsecchi, S., Porcelli, D., Sgreccia, F., Lucifiero, A., et al. (2010). Endocardial vagal atrioventricular node stimulation in humans: Reproducibility on 18-month follow-up. Europace, 12, 1719–1724.PubMedCrossRefGoogle Scholar
  21. 21.
    Wijffels, M. C., Kirchhof, C. H., Dorland, R., & Allessie, M. A. (1995). Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation, 92, 1954–1968.PubMedGoogle Scholar
  22. 22.
    Bland, J. M., & Altman, D. G. (2009). Analysis of continuous data from small samples. BMJ, 338, 3166.CrossRefGoogle Scholar
  23. 23.
    Soós, P., Merkely, B., Horvat, P. M., Zima, E., & Schauerte, P. (2005). Determinants and effects of electrical stimulation of the inferior interatrial parasympathetic plexus during atrial fibrillation. Journal of Cardiovascular Electrophysiology, 16, 1362–1367.PubMedCrossRefGoogle Scholar
  24. 24.
    Gardner, T. D., & Potter, E. K. (1988). Dependence of non-adrenergic inhibition of cardiac vagal action on peak frequency of sympathetic stimulation in the dog. The Journal of Physiology, 405, 115–122.PubMedGoogle Scholar
  25. 25.
    Tran, L. V., Somogyi, G. T., & De Groat, W. C. (1994). Inhibitory effect of neuropeptide Y on adrenergic and cholinergic transmission in rat urinary bladder and urethra. American Journal of Physiology, 266, 1411–1417.Google Scholar
  26. 26.
    Mischke, K., Zarse, M., Schmid, M., Gemein, C., Hatam, N., Spillner, J., et al. (2010). Chronic augmentation of the parasympathetic tone to the atrioventricular node: a nonthoracotomy neurostimulation technique for ventricular rate control during atrial fibrillation. Journal of Cardiovascular Electrophysiology, 21, 193–199.PubMedCrossRefGoogle Scholar
  27. 27.
    Gaiarsa, J. L., Caillard, O., & Ben-Ari, Y. (2002). Long-term plasticity at GABAergic and glycinergic synapses: Mechanisms and functional significance. Trends Neuroscience, 25, 564–570.CrossRefGoogle Scholar
  28. 28.
    Johnson, T. A., Gray, A. L., Lauenstein, J. M., Newton, S. S., & Massari, V. J. (2004). Parasympathetic control of the heart. I. An interventriculo-septal ganglion is the major source of the vagal intracardiac innervation of the ventricles. Journal of Applied Physiology, 96, 2265–2272.PubMedCrossRefGoogle Scholar
  29. 29.
    Stein, K. M., Euler, D. E., Mehra, R., Seidl, K., Slotwiner, D. J., Mittal, S., et al. (2002). Do atrial tachyarrhythmias beget ventricular tachyarrhythmias in defibrillator recipients? Journal of the American College of Cardiology, 40, 335–340.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Lilian Kornet
    • 1
  • Arne van Hunnik
    • 2
  • Koen Michels
    • 1
  • Sander Verheule
    • 2
  • Alberto Della Scala
    • 3
  • Teena West
    • 1
  • Roger Kessels
    • 1
  • Richard Cornelussen
    • 1
    • 2
  1. 1.Medtronic, Bakken Research CenterMaastrichtthe Netherlands
  2. 2.Department of PhysiologyMaastricht UniversityMaastrichtthe Netherlands
  3. 3.Medtronic ItalyRomeItaly

Personalised recommendations