The Problem: The atria beat very rapidly and irregularly during AF. If each of the atrial beats were transmitted to the ventricles, ventricular fibrillation would be initiated. This seldom happens because of the filtering properties of the AV node, a small structure located between the atria and the ventricles. However, many impulses still manage to reach the ventricles and cause abnormally high ventricular rate, which if left untreated can lead to heart failure.
Conventional Therapy: Clinically, slowing of ventricular rate is now achieved either by prescribing drugs such as beta-adrenergic antagonists or calcium channel blockers, or by irreversible destruction (ablation) of the AV node by application of strong radiofrequency energy. By disrupting the electrical connection between the atria and the ventricles, AV nodal ablation frees the ventricles from high-rate atrial bombardment. However, left on their own, the ventricles beat so slowly that the resulting hemodynamic situation is even worse than during untreated AF, thus permanent ventricular pacemaker implantation is required. Ventricular pacing results in activation of ventricular contraction in a sequence opposite to the normal, i.e. "from the bottom to the top," which may have long-term undesirable consequences.
Our Approach: We are analyzing the mechanisms by which the AV node fulfills its filtering role during AF and testing a new method for nondestructive modulation of this filtering. We hypothesized that by selectively stimulating vagal (parasympathetic) innervation of the AV node, conduction through the node would be slowed, and the conduction of the rapidly bombarding atrial impulses would be depressed within the node. This "selective AV nodal vagal stimulation" should yield a slower ventricular rate while the functional and anatomical integrity of the AV node would be preserved. In early studies, we have shown that the working hypothesis is valid.
In ongoing studies, we are evaluating the efficacy of this approach as a long-term therapy. Preliminary results, with 6 month results available, are quite encouraging. The procedures are well tolerated by the animals and no side effects have thus far been observed.
Relevance to AF patients: The proposed studies have specific importance for patients in which the AF is irreversible. This may include cases with drug resistance or those in which ablation or surgical intervention is impractical. In these cases vagally induced local depression of AV nodal conduction would provide the benefits of better hemodynamic function, due to the improved ventricular rate control and a normal anterograde sequence of ventricular contraction. We are confident that the results of these studies will provide the solid theoretical and practical basis that is needed in order to pursue the ultimate goal of discovering new methods for ventricular rate control during atrial fibrillation.
Todor N. Mazgalev, Siew Yen Ho, Robert H Anderson Anatomic-electrophysiologic correlations concerning the pathways for atrioventricular conduction. Circulation, 2001, 22:2660-2667
Don W. Wallick, Youhua Zhang, Tomotsugu Tabata, Shaowei Zhuang, Kent A. Mowrey, Junko Watanabe, Neil L. Greenberg, Richard A. Grimm, and Todor N. Mazgalev. Selective AV Nodal Vagal Stimulation in-vivo Improves Cardiac Hemodynamics During Atrial Fibrillation in Dogs. Am J Physiol Heart Circ Physiol, 2001, 281: H1490-H1497.
Youhua Zhang, Kent A. Mowrey, Shaowei Zhuang, Don W. Wallick, and Todor N. Mazgalev. Optimal Ventricular Rate Slowing During Atrial Fibrillation by Feedback AV Nodal-Selective Vagal Stimulation, Am J Physiol Heart Circ Physiol, 282, H1102-H1110, 2002.
T. N. Mazgalev. The AV node during atrial fibrillation: is it worth saving? J Cardiovasc. Electrophysiol. 2002, 13; 7: 724-726.
Popovic ZB, Mowrey KA, Zhang Y, Zhuang S, Tabata T, Wallick DW, Grimm RA, Thomas JD, and Mazgalev TN. Slow Rate During AF Improves Ventricular Performance by Reducing Sensitivity to Cycle Length Irregularity. Am J Physiol Heart Circ Physiol 283:H2706-H2713, 2002.
Zhuang S, Zhang Y, Mowrey KA, Tabata T, Wallick DW, Popovic ZB, Natale A, and Mazgalev TN. Ventricular Rate Control by Selective Vagal Stimulation is Superior to Rhythm Regularization by AVN Ablation and Pacing During AF. Circulation, 2002; 106:1853-1858.
Wallick DW, Zhuang S, Zhang Y, Mazgalev TN, Tabata T, Mowrey KA, Wilkoff B, McVenes R. Does bi-ventricular pacing improve cardiac performance during HF in ventricles that have normal conduction? MESPE (Mediterr J Pacing and Electrophysiol), 5, 2:59-65, 2003.
Y. Zhang, S. Bharati, Rabi Sulayman, K. A. Mowrey, P. J. Tchou, and Todor N. Mazgalev. Atrioventricular nodal fast pathway modification: mechanism for lack of ventricular rate slowing in atrial fibrillation. Cardiovasc Research. Vol 61/1 pp 45-55, 2004.
Tabata T., Grimm R. A., Asada J., Popovic Z. B., Greenberg N. L., Wallick D. W., Zhang Y., Zhuang S., Mowrey K. A., Thomas J. D., and Mazgalev T. N. Determinants of left ventricular diastolic function during atrial fibrillation: beat-by-beat analysis in acute dog experiments. Am J Physiology, 2004, 286:H145-H152.
Y. Zhang, T.N. Mazgalev. Ventricular rate control during atrial fibrillation and AV node modifications: past, present and future. PACE 2004, 27:382-393.
T.N. Mazgalev. Atrioventricular Nodal Physiology (Review), Cardiac Rhythm Society (NASPE) web-site educational center at http://www.hrsonline.org/professional_education/learning_categories/articles/mazgalev/, 2004.
Z. B. Popovic, H. Yamada, K. A. Mowrey, Y. Zhang, D. W. Wallick, R. A. Grimm, J. D. Thomas, and T. N. Mazgalev. Frank-Starling mechanism contributes modestly to ventricular performance during atrial fibrillation. Heart Rhythm, 2004, 1 (4): 482–489.
Y. Zhang, T. N. Mazgalev. Achieving Regular Slow Rhythm During Atrial Fibrillation Without Atrioventricular Nodal Ablation: Selective Vagal Stimulation Plus Ventricular Pacing. Heart Rhythm, 2004, 4: 469–475.
T. Tabata, R. A. Grimm, F. J. Bauer, K. Fukamachi, M. Takagaki, Y. Ochiai, T. N. Mazgalev, B. L. Wilkoff, P. M. McCarthy, and J. D. Thomas. Giant flow reversal in pulmonary venous flow as a possible mechanism for asynchronous pacing-induced heart failure. J Am Soc Echocardiogr 2005;18:722–728.
Z. B. Popovic, J. P. Sun, H. Yamada, J. Drinko, K. Mauer, N. L. Greenberg, Y. Cheng, C. S. Moravec, M. S. Penn, T. N. Mazgalev, J. D. Thomas. Differences in left ventricular long axis function from mice to humans follow allometric scaling to ventricular size, J Physiol (London), 2005, 568.1, 255-265.
Y. Zhang, H. Yamada, S. Bibevski, S. Zhuang, K. A. Mowrey, D. W. Wallick, S. Oh, T. N. Mazgalev. Chronic Atrioventricular Nodal Vagal Stimulation: First Evidence For Long-Term Ventricular Rate Control In Canine Atrial Fibrillation Model. Circulation, 2005, 112:2904-2911.
S. Oh, Y. Zhang, S. Bibevski, N. F. Marrouche, A. Natale, T. N. Mazgalev. Vagal Denervation and Atrial Fibrillation Inducibility: Epicardial Fat Pad Ablation Does Not Have Long-Term Effects. Heart Rhythm, 2006 3(6):701-708.
Saliba W, et al. Novel robotic catheter remote control system: feasibility and safety of transseptal puncture and endocardial catheter navigation. J Cardiovasc Electrophysiol 2006;17:1102-5.
Zhang Y, Mazgalev T. Role of vagus in atrial fibrillation and therapeutic applications. In Natale A, Jalife J, eds. Atrial Fibrillation: From Bench to Bedside. Ch. 9. New York: Springer/Humana Press, 2008 (in press).
T.N. Mazgalev, Y. Zhang. Optical imaging of the atrioventricular node: are we looking through warped glasses? Heart Rhythm 2008 v5:3: 502-503
Y. Zhang, I. Ilsar, H. N. Sabbah, T. Ben David, T. N. Mazgalev. Relationship between right cervical vagus nerve stimulation and atrial fibrillation inducibility: Therapeutic intensities do not increase arrhythmogenesis. Heart Rhythm, 2009;6 (2):244-250. PMID: 19187919
Y. Zhang, T. N. Mazgalev. Site of Origin of the Monophasic Action Potential: Which Electrode, the “Potassium” or the “Indifferent”, Records MAP? Heart Rhythm, 2009;6(4):561-563. PMID: 19233740
T. N. Mazgalev The Specialized Rings and the Endless Saga of the AV Node Puzzle. Editorial, Heart Rhythm, 2009;6(5):681-683. PMID: 19389654
Y. Zhang, T. N. Mazgalev. Cardiac Vagal Stimulation Eliminates Detrimental Tachycardia Effects of Dobutamine Used for Inotropic Support. Ann Thorac Surg 2009;88:117–23. PMID: 19559207
Y. Zhang, Z.B Popovic, S. Bibevski, I. Fakhry, D. A Sica, D.R Van Wagoner, and T.N. Mazgalev. 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;2:692-699. PMID: 19919995
Asada-Kamiguchi J, Tabata T, Popovic ZB, Greenberg NL, Kim YJ, Garcia MJ, Wallick DW, Mowrey KA, Zhuang S, Zhang Y, Mazgalev TN, Thomas JD, Grimm RA. Non-invasive assessment of left ventricular relaxation during atrial fibrillation using mitral flow propagation velocity. Eur J Echocardiogr 2009;10:826-32. PMID: 19692424
