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Autonomic Modulation

2012; Lippincott Williams & Wilkins; Volume: 5; Issue: 2 Linguagem: Romeno

10.1161/circep.112.972307

1941-3149

Stavros Stavrakis, Benjamin J. Scherlag, Sunny S. Po,

Cardiovascular Syncope and Autonomic Disorders

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 5, No. 2Autonomic Modulation Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessEditorialPDF/EPUBAutonomic ModulationAn Emerging Paradigm for the Treatment of Cardiovascular Diseases Stavros Stavrakis, MD, PhD, Benjamin J. Scherlag, PhD and Sunny S. Po, MD, PhD Stavros StavrakisStavros Stavrakis From the Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK. , Benjamin J. ScherlagBenjamin J. Scherlag From the Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK. and Sunny S. PoSunny S. Po From the Heart Rhythm Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK. Originally published1 Apr 2012https://doi.org/10.1161/CIRCEP.112.972307Circulation: Arrhythmia and Electrophysiology. 2012;5:247–248A variety of experimental and clinical reports have engendered a different approach to cardiac arrhythmias as well as other cardiovascular conditions. The focus of a new paradigm is the autonomic nervous system and its important role in various pathological states. From an overall standpoint, this new paradigm can be encompassed by the term "autonomic modulation," which would include autonomic nerve stimulation or autonomic denervation to modulate the autonomic activity in physiological or pathophysiological functions of the heart as well as other visceral organ systems.Article see p 279Vaso-vagal syncope is the most common form of neurally mediated syncope.1 The pathophysiology of vaso-vagal syncope is still controversial, but it is thought to be related to prolonged orthostatic stress, which causes increased peripheral venous pooling with a subsequent fall in venous return to the heart. This in turn causes a hypercontractile state, which leads to activation of ventricular mechanoreceptors and a sudden increase in the afferent neural traffic to the brain. The result is sympathetic withdrawal and parasympathetic enhancement that manifests as hypotension (vasodepressor type), bradycardia (cardioinhibitory type), and syncope.1 In other words, vaso-vagal syncope is a disorder caused by an abnormally amplified autonomic reflex involving both sympathetic and parasympathetic components. Over the past 2 decades, β-blockers, α-agonists, mineralocorticoids, selective serotonin reuptake inhibitors, and dual-chamber pacemaker implantation all produced initial promising but later disappointing results.1–3 Vaso-vagal syncope continues to be a vexing clinical arrhythmia.In this issue of Circulation Arrhythmia and Electrophysiology, Yao et al4 reported 10 patients who had drug-refractory, frequent, and highly symptomatic vaso-vagal syncope. Based on the hypothesis that vaso-vagal syncope is related to enhanced parasympathetic activity, the authors performed autonomic denervation by targeting the 4 major atrial ganglionated plexi (GP), guided by high-frequency stimulation as described by the Oklahoma group (Po et al5). The left superior GP, right anterior GP and left inferior GP were identified and ablated in 10 (100%), 5 (50%), and 3 (30%) patients, respectively. Surprisingly, the right inferior GP, often referred to as the atrioventricular nodal GP, did not respond to high-frequency stimulation in any patient and was therefore not ablated. The authors did not show the presumed right inferior GP area where high-frequency stimulation was delivered. However, location of the right anterior GP as shown in Figure 1 in the article is not the typical location of the right anterior GP (at the left atrial septum, near the carina of the right pulmonary veins).5 It is possible that high-frequency stimulation might not have been delivered to the correct location of the right inferior GP. Another technical problem is that ablation was performed using an 8-mm, nonirrigated catheter, which carries a significant risk for thromboembolism. We would prefer an irrigated catheter.Regardless of the technical issues, the long-term (30±16 months) results were impressive, in which the number of prodromes of syncope was markedly attenuated and none of the 10 patients had recurrence of syncope. The therapeutic effects were attributed to parasympathetic denervation evidenced by an increase in the mean heart rate and decrease in the high-frequency component of the heart rate variability 3 and 12 months after ablation. It cannot be overemphasized that all of the 10 patients received "partial denervation" in which 3 patients received 1 GP (left superior GP) ablation and 6 patients received 2 GP ablations. Three GP were ablated in only 1 patient. This is in sharp contrast to another report by Pachon et al,6 in which extensive right and left atrial ablation guided by spectral analysis for "atrial fibrillation (AF) nests" rendered similar successes in treating vaso-vagal syncope (40 of 43 patients free of syncope after 45.1±22 months). The high success of both approaches raises the question, "how much autonomic denervation is needed to treat vaso-vagal syncope?" Although autonomic innervation has been shown to return in 3 to 6 months after GP ablation7 in patients with AF, the changes in heart rate variability were maintained at 1 year, and there was no evidence of loss of efficacy at a mean of 30 months in the present study in which only limited GP ablation was performed. This paradox—that limited GP ablation produced more sustained suppression of the parasympathetic tone—may further allude to distinct autonomic bases underlying AF and vaso-vagal syncope. The reasons for this apparent discrepancy remain unclear, but may indicate that heart rate variability may not be an appropriate measure for the intrinsic, as opposed to the extrinsic autonomic innervation to the heart. Another intriguing finding in Yao's study is that left superior GP appears to be the most important GP underlying the enhanced parasympathetic activity in all the 10 patients. A prior experimental study8 demonstrated that the left superior GP controls sinus and atrioventricular nodal function through the right anterior GP and right inferior GP, respectively. In the present study, the right anterior GP and right inferior GP were ablated in 5 of 10 and none of 10 patients, respectively, implying that vaso-vagal syncope might be caused by a unique form of GP hyperactivity.The results of Yao et al4 illustrate another example of the emerging paradigm of autonomic modulation for the treatment of cardiac arrhythmias and other cardiovascular diseases. The conventional wisdom to treat a disease caused by tissue hyperactivity is to injure (eg, ablate) that tissue. GP ablation for AF and vaso-vagal syncope serve as typical examples. Recently, autonomic denervation within the renal arteries has not only been shown to dramatically reduce blood pressure in patients with refractory hypertension,9 but other studies indicate significant reductions in left ventricular mass and improved left ventricular diastolic function.10 These effects may be due to decreased afferent nerve signaling from the kidney to the brain, thereby further decreasing efferent vasoconstriction to the kidney.11 In other words, the "set point" of the global autonomic nervous system might have been reset by focal autonomic denervation.Another novel and potentially better approach of autonomic modulation is to take advantage of the plasticity of the neural tissue to shape it to our advantage without injuring it. For instance, vagus nerve stimulation delivered through an implantable device is being frequently used for the treatment of drug-refractory epilepsy.12 Preliminary studies of the use of vagus nerve stimulation through an implantable device in patients with heart failure showed promising results, including improvement in heart failure functional class, quality of life, left ventricular ejection fraction, and left ventricular end-systolic volume.13 In experimental models, vagal activation protects the heart from ventricular arrhythmia during myocardial infarction14 and limits infarct size.15 More recent experimental studies in acute, anesthetized,16–18 and chronic ambulatory19 dogs have shown that low level vagus nerve stimulation, below the intensity that causes heart rate slowing, can suppress the left stellate ganglion as well as intracardiac GP and thereby prevent or suppress AF without administered drugs or ablation. These experimental studies are highly suggestive of the possibility that autonomic stimulation at levels that are not sensed can be an antifibrillatory therapy. Indeed, a method for the transcutaneous access to the vagal efferent innervation to the heart has now been shown with which low-level stimulation can be achieved in an experimental model of AF to prevent and suppress AF.20The study by Yao et al provides important insight into the complicated cardiac autonomic nervous system that comprises seemingly contradictory responses. It demonstrates that focused GP ablation is as effective as extensive GP ablation in treating vaso-vagal syncope. In contrast to pharmacological therapy and pacemaker implantation, GP ablation was designed to take on the root of the problem: disturbances in the intrinsic cardiac autonomic nervous system. While the dramatic effects of GP ablation must be verified by larger clinical studies, autonomic modulation may be a new paradigm for other cardiac arrhythmias such as inappropriate sinus tachycardia, symptomatic premature ventricular depolarizations, and focal atrial tachycardias that are often related to disturbances of autonomic tone.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Sunny S. Po, MD, PhD, Heart Rhythm Institute, University of Oklahoma Health Sciences Center, 1200 Everett Dr, TCH 6E103, Oklahoma City, OK 73104. E-mail [email protected]eduReferences1. Grubb BP. Clinical practice. Neurocardiogenic syncope. N Engl J Med. 2005; 352:1004–1010.CrossrefMedlineGoogle Scholar2. Brignole M. Randomized clinical trials of neurally mediated syncope. J Cardiovasc Electrophysiol. 2003; 14:S64–S69.CrossrefMedlineGoogle Scholar3. 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J Am Coll Cardiol. 2012; 59:901–909.CrossrefMedlineGoogle Scholar11. Zile MR, Little WC. Effects of autonomic modulation: more than just blood pressure. J Am Coll Cardiol. 2012; 59:910–912.CrossrefMedlineGoogle Scholar12. Uthman BM, Reichl AM, Dean JC, Eisenschenk S, Gilmore R, Reid S, Roper SN, Wilder BJ. Effectiveness of vagus nerve stimulation in epilepsy patients: a 12-year observation. Neurology. 2004; 63:1124–1126.CrossrefMedlineGoogle Scholar13. De Ferrari GM, Crijns HJ, Borggrefe M, Milasinovic G, Smid J, Zabel M, Gavazzi A, Sanzo A, Dennert R, Kuschyk J, Raspopovic S, Klein H, Swedberg K, Schwartz PJ. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J. 2011; 32:847–855.CrossrefMedlineGoogle Scholar14. Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS, foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res. 1991; 68:1471–1481.CrossrefMedlineGoogle Scholar15. Cavillo L, Vanoli E, Andreoli E, Besana A, Omodeo E, Gnecchi M, Zerbi P, Vago G, Busca G, Schwartz PJ. Vagal stimulation, through its nicotinic action, limits infarct size and the inflammatory response to myocardial ischemia and reperfusion. J Cardiovasc Pharmacol. 2011; 58:500–507.CrossrefMedlineGoogle Scholar16. Li S, Scherlag BJ, Yu L, Sheng X, Zhang Y, Ali R, Dong Y, Ghias M, Po SS. Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of atrial fibrillation. Circ Arrhythm Electrophysiol. 2009; 2:645–651.LinkGoogle Scholar17. Yu L, Sheng X, Zhang Y, Ali R, Dong Y, Ghias M, Po SS. Low-level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia. J Cardiovasc Electrophysiol. 2011; 22:455–463.CrossrefMedlineGoogle Scholar18. Sheng X, Scherlag BJ, Yu L, Li S, Ali R, Zhang Y, Fu G, Nakagawa H, Jackman WM, Lazzara R, Po SS. Prevention and reversal of atrial fibrillation inducibility and autonomic remodeling by low-level vagosympathetic nerve stimulation. J Am Coll Cardiol. 2011; 57:563–571.CrossrefMedlineGoogle Scholar19. Shen MJ, Shinohara T, Park HW, Frick K, Ice DS, Choi EK, Han S, Maruyama M, Sharma R, Shen C, Fishbein MC, Chen LS, Lopshire JC, Zipes DP, Lin SF, Chen PS. Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines. Circulation. 2011; 123:2204–2212.LinkGoogle Scholar20. Yu L, Scherlag BJ, Li S, Fan Y, Dyer J, Ghias M, Lazzara R, Po SS. Low level transcutaneous electrical stimulation suppresses atrial fibrillation (abstract). Heart Rhythm. 2011; 8:S262.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Podziemski P and Żebrowski J (2013) A simple model of the right atrium of the human heart with the sinoatrial and atrioventricular nodes included, Journal of Clinical Monitoring and Computing, 10.1007/s10877-013-9429-6, 27:4, (481-498), Online publication date: 1-Aug-2013. Kapa S, Man J and Supple G (2013) Future Trends in the Evolution of Remote Monitoring and Physiologic Sensing Technologies, Cardiac Electrophysiology Clinics, 10.1016/j.ccep.2013.05.010, 5:3, (371-379), Online publication date: 1-Sep-2013. BILLETTE J and TADROS R (2012) Concealed Autonomic Mechanisms Underlying Atrial Fibrillation, Journal of Cardiovascular Electrophysiology, 10.1111/jce.12050, 24:2, (196-198), Online publication date: 1-Feb-2013. Carlos Pachon Mateos J, I Pachón Mateos E, Higuti C, Guilhermo Santillana Peña T, Julio Lobo T, Thiene Cunha Pachón C, Carlos Pachón Mateos J, Carlos Zerpa Acosta J, Ortencio F and Amarante R (2020) Cardioneuroablação: A Denervação Vagal por Cateter Como Nova Terapia para Síncope Cardioinibitória, Journal of Cardiac Arrhythmias, 10.24207/jca.v32n3.067_PT, 32:3, (182-196) Carlos Pachon Mateos J, I Pachón Mateos E, Higuti C, Guilhermo Santillana Peña T, Julio Lobo T, Thiene Cunha Pachón C, Carlos Pachón Mateos J, Carlos Zerpa Acosta J, Ortencio F and Amarante R (2020) Cardioneuroablation: Catheter Vagal Denervation as a New Therapy for Cardioinhibitory Syncope, Journal of Cardiac Arrhythmias, 10.24207/jca.v32n3.067_IN, 32:3, (182-196) April 2012Vol 5, Issue 2 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/CIRCEP.112.972307PMID: 22511657 Originally publishedApril 1, 2012 Keywordsablationvaso-vagal syncopeganglionated plexiautonomic nervous systemEditorialsPDF download Advertisement SubjectsArrhythmias