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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 65, NO. 9, 2015 ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC. ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2014.12.025 EDITORIAL COMMENT Looking Beyond the Ablation Shore, Treating Atrial Fibrillation From Afar Integrating Anatomic, Physiologic, Neurologic, and Cardiovascular Principles Into Novel Therapies* Suraj Kapa, MD,y David J. Callans, MDz One doesn’t discover new lands without consenting to lose sight, for a very long time, of the shore. I —André Gide, Les faux-monnayeurs (1) t is certainly difficult to be a patient with atrial fibrillation (AF) or an electrophysiologist caring for this patient. We live with the frustration related to the seemingly capricious nature of ablation success for AF, trapped in the hope that constructing a slightly altered lesion set, using a newer catheter, or processing signals differently will allow for a major scientific breakthrough. In fact, the last 20 years of research in AF have been characterized by a preponderance of work on potentials and pulmonary veins. More recently, however, we have come to again appreciate the role of the autonomic nervous system in cardiac arrhythmias—a role that has been well recognized since the 1970s, starting with pioneering work by Kapa et al. (2) and Coumel et al. (3). Though initially considered a sympathetically mediated phenomenon, further study led to the understanding that parasympathetic effects on atrial dispersion as well as sympathetic effects may be involved in AF pathogenesis (4–6). In fact, the higher incidence of AF during sleep has been felt to be due to a profound parasympathetic dominance and, in turn, perhaps an increased sympathetic drive converting to a vagal predominance and AF onset (7,8). Decades of large animal work by the University of Oklahoma group has demonstrated a relationship between the autonomic nervous system and phenomena related to AF initiation and maintenance (9–11). This relationship is borne out by simple anatomy: the highest density of nerve endings in the human atria occur at the pulmonary vein/atrial interface; the usual response of ablation at the pulmonary veins is bradycardia rather than tachycardia; and ganglionated plexi that relay vagal and sympathetic efferents to myocardial cells are principally distributed around the heart’s posterior surface including in proximity to the pulmonary veins. This has led to the assumption that ablation of such ganglia and nerve endings may facilitate AF treatment, though this has not been demonstrated consistently in patient studies, potentially due to the difficulty of identifying ganglia, the limitations of existing ablation technology, and the potential for reinnervation or nerve regrowth at the site of successful ablation (12–14). Alternative therapies were then proposed to not just destroy autonomic inputs but to modulate their activity through stimulation or ablation of extracardiac structures. For example, low-level vagus nerve stimulation (LLVNS) makes AF more difficult to *Editorials published in the Journal of the American College of Cardiology induce by lengthening AF cycle length and prevent- reflect the views of the authors and do not necessarily represent the ing electrical (shortening of the atrial refractory views of JACC or the American College of Cardiology. period and dispersion of refractoriness) and auto- From the ySection of Cardiac Electrophysiology, Division of Cardiology, nomic remodeling (through burst firing of cardiac Mayo Clinic College of Medicine, Rochester, Minnesota; and the zSection ganglionated plexi) caused by rapid atrial pacing of Cardiac Electrophysiology, Division of Cardiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Both (15,16). These observations form the basis of the authors have reported that they have no relationships relevant to the “autonomic hypothesis”: hyperactivity of the cardiac contents of this paper to disclose. autonomic nervous system causes/maintains AF; in Kapa and Callans JACC VOL. 65, NO. 9, 2015 MARCH 10, 2015:876–8 Novel Therapies for Atrial Fibrillation turn, modulating the autonomic nervous system may auricular portion of the vagus nerve on cardiac effectively treat AF. Supportive evidence comes from contractility animal studies as well as from human studies of spi- described since the 1970s, where features such as nal cord stimulation, renal denervation, and vagal hypotension, increased ventricular ectopy, and even stimulation (2,17,18). right bundle branch block were associated with and electrical function has been manipulation and sectioning of the upper vagal SEE PAGE 867 rootlets in patients (22). Thus, we must consider the The study by Stavrakis et al. (19) in this issue of subtleties of this novel therapy because a simple the Journal furthers this understanding via a novel, paradigm of stimulation on/off or high energy/low elegant approach that allows for a noninvasive, non- energy may not offer a comprehensive enough un- ablative, nonpharmacological therapy for AF. Study- derstanding of its correct application. Therefore, ing low-level transcutaneous electrical stimulation of clinical studies of LLVNS must continue to be paired the auricular branch of the vagus nerve at the level of with physiological studies to avoid getting caught in the tragus, they demonstrated that AF inducible by the trap of advancing a therapy without first ensuring rapid atrial pacing could be suppressed. Furthermore, the structural integrity of its foundation. such stimulation decreased levels of inflammatory We hope that Stavrakis et al. (19) are correct and cytokines in patients with paroxysmal AF, whereas these lines of investigation will eventually lead to a having minimal effects on sinus rate, atrioventricular successful nonpharmacological, nonablative therapy nodal properties, or blood pressure. These patients for AF. More importantly, this study aims at under- were studied under general anesthesia, so one must standing the fundamental nature of AF and its patho- wonder whether the “type” of AF reflected by physiology. Many have argued that electrophysiology, inducibility under general anesthesia necessarily re- once a mostly intellectual pursuit firmly grounded flects what is seen clinically; inducibility or lack in our understanding of physiology, has lost its way. thereof at the end of traditional ablation does not By rediscovering our past to help innovate our future, correlate with risk of clinical recurrence (20). Whether we may be able to again harness the elegance of LLVNS is effective for patients with discrete subtypes the neural-cardiac interface to better manage our of AF remains to be determined. patients—more safely, effectively, and thoughtfully. Much work remains, as Stavrakis et al. (19) Ultimately, the effectiveness of interventions on the mentioned. First, analysis of ambulatory patients is basis of this knowledge remains to be determined. necessary. This new study of LLVNS was done using What is clear, however, is that there may be value to general anesthesia, meaning the comfort factor for electrophysiologists sometimes losing “sight of the patients must be considered. Furthermore, it will be shore” of ablation therapy to discover new and critical to determine the level of stimulation required potentially more effective options for patient care. to achieve the desired suppressive effect. In other mammalian hearts, there is a parabolic effect on the REPRINT REQUESTS AND CORRESPONDENCE: Dr. cardiac response, with low-level stimulation affecting David J. Callans, Section of Cardiac Electrophysi- features of cardiac contractility differently than ology, Division of Cardiology, Perelman School of higher outputs would (21). Whether this applies to Medicine, University of Pennsylvania, 3400 Spruce the heart’s electrical properties is less clear. In turn, Street, Philadelphia, Pennsylvania 19104. E-mail: the relationship of injury to, or stimulation of, the [email protected]. REFERENCES 1. Gide A. Les faux-monnayeurs. New York, NY: 5. Scherlag BJ, Patterson E, Po SS. The neural fibrillation after coronary artery bypass grafting. Knopf Doubleday, 1927. basis of atrial fibrillation. J Electrocardiol 2006;39 Suppl 4:S180–3. Am J Cardiol 1998;82:22–5. autonomic nervous system in cardiac electrophysiology: an elegant interaction and emerging concepts. Cardiol Rev 2010;18:275–84. 6. Scherlag BJ, Po S. The intrinsic cardiac nervous system and atrial fibrillation. Curr Opin Cardiol 2006;21:51–4. 3. Coumel P, Attuel P, Lavallee J, Flammang D, Leclercq JF, Slama R. [The atrial arrhythmia syndrome of vagal origin]. Arch Mal Coeur Vaiss 1978; 71:645–56. 7. Ghias M, Scherlag BJ, Lu Z, et al. The role of ganglionated plexi in apnea-related atrial fibrillation. J Am Coll Cardiol 2009;54: 2075–83. plexi modulate extrinsic cardiac autonomic nerve input: effects on sinus rate, atrioventricular conduction, refractoriness, and inducibility of atrial fibrillation. J Am Coll Cardiol 2007;50:61–8. 4. Chen PS, Tan AY. Autonomic nerve activity and atrial fibrillation. Heart Rhythm 2007;4 Suppl 3: S61–4. 8. Dimmer C, Tavernier R, Gjorgov N, Van Nooten G, Clement DL, Jordaens L. Variations of autonomic tone preceding onset of atrial 2. Kapa S, Venkatachalam KL, Asirvatham SJ. The 9. Hou Y, Scherlag BJ, Lin J, et al. Ganglionated 10. Yu L, Scherlag BJ, Sha Y, et al. Interactions between atrial electrical remodeling and autonomic remodeling: how to break the vicious cycle. Heart Rhythm 2012;9:804–9. 11. Li S, Scherlag BJ, Yu L, et al. Low-level vagosympathetic stimulation: a paradox and potential 877 878 Kapa and Callans JACC VOL. 65, NO. 9, 2015 MARCH 10, 2015:876–8 Novel Therapies for Atrial Fibrillation new modality for the treatment of focal atrial fibrillation. Circ Arrhythm Electrophysiol 2009;2: 645–51. 12. Katritsis DG, Pokushalov E, Romanov A, et al. Autonomic denervation added to pulmonary vein isolation for paroxysmal atrial fibrillation: a randomized clinical trial. J Am Coll Cardiol 2013; 62:2318–25. 13. Buendia-Fuentes F, Almenar L, Ruiz C, et al. Sympathetic reinnervation 1 year after heart transplantion, assessed using iodine-123 metaiodobenzylguanidine imaging. Transplant Proc 2011;43:2247–8. 14. Madhavan M, Gard JJ, Swale MJ, et al. Percutaneous epicardial ablation of cardiac ganglionated plexi without myocardial injury in the canine: a novel treatment strategy for atrial fibrillation S331–2. (abstr.). Heart Rhythm 2012;9: 15. Sheng X, Scherlag BJ, Yu L, et al. Prevention and reversal of atrial fibrillation inducibility and autonomic remodeling by low-level vagosympathetic nerve stimulation. J Am Coll Cardiol 2011; 19. Stavrakis S, Humphrey MB, Scherlag BJ, et al. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol 2015;65:867–75. 57:563–71. 20. Leong-Sit P, Robinson M, Zado ES, et al. Inducibility of atrial fibrillation and flutter 16. 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. 17. Pokushalov E, Romanov A, Katritsis DG, et al. Renal denervation for improving outcomes of catheter ablation in patients with atrial fibrillation and hypertension: early experience. Heart Rhythm 2014;11:1131–8. 18. Bernstein SA, Wong B, Vasquez C, et al. Spinal cord stimulation protects against atrial fibrillation induced by tachypacing. Heart Rhythm 2012;9: 1426–33. following pulmonary vein ablation. J Cardiovasc Electrophysiol 2013;24:617–23. 21. O’Shea JE, Evans BK. Innervation of bat heart: cholinergic and adrenergic nerves innervate all chambers. Am J Physiol 1985;249:H876–82. 22. Nagashima C, Sakaguchi A, Kamisasa A, Kawanuma S. Cardiovascular complications on upper vagal rootlet section for glossopharyngeal neuralgia. J Neurosurg 1976;44:248–53. KEY WORDS atrial fibrillation, autonomic nervous system, catheter ablation, electrophysiology