There have been dramatic expansions of research in the field of atrial fibrillation (AF), both clinically and in basic science, which is propelled by advent of catheter ablation as the treatment option for patients with AF. Currently, the primary end point of the ablation procedure targets the isolation myocardial sleeves in the pulmonary vein (PV), i.e., PV isolation. However, the clinical outcome of the “purely” myocardial approach remains suboptimal despite of significant technological improvement in ablation procedures with better mapping and energy delivery systems. There has been increasing evidence that dysfunction of the autonomic nervous system that encompasses the sympathetic, parasympathetic and intrinsic neural network is involved in the pathogenesis of AF. Studies are under the way to evaluate the effects of targeting these neural components on improving the outcome of therapy for AF. We aimed to review the evidence in the literature on the role of autonomic dysfunction in the pathophysiology of AF.
Epidemiology and impact on public health
AF is the most common sustained cardiac arrhythmia that affect over 2.2 million in the United States and 4.5 million in the European Union (1). Furthermore, the incidence of AF is expected to increase dramatically because of the aging populations (2-5) and the increased prevalence of precipitating diseases such as heart failure (6-11) and diabetes (12). The economic burden on the health care system is horrendous, approximately $3,600 annually per patient or 15.7 billion dollars a year in direct medical costs and loss productivity (13,14).
AF is also among the oldest cardiac rhythm disorders known to man, first described over more than 130 years ago as “delirium cordis”, a term that reflects the irregular heart beats characteristic of AF (15). The first ECG showing AF was recorded with the introduction of surface electrocardiography in 1906 (16). Although the linkage between the mechanical and electrical manifestations of AF was not made until later (17,18).
There has been extensive investigation into the autonomic mechanisms underlying AF. Scherf and associates first proposed focal hypothesis based upon their observations that either aconitine or acetylcholine (ACh) applied locally could lead to rapid focal firing and/or AF and that such atrial tachyarrhythmia could be terminated once focal source of firing was removed by cooling (19,20). Studies by Moe et al. demonstrated that AF could be initiated by premature beats during vagal stimulation and sustained by multiple reentrant circuits (multiple wavelet theory) (21). The reentrant nature of AF are further supported the evidence provided by Allessie and his coworkers with sophisticated mapping techniques (22) and Skanes and his associates with frequency-domain analysis of induced AF (23).
Last two decades have witnessed tremendous advance in the management of AF, especially in non-pharmacological approach to restore and maintain sinus rhythm. Following the initial results of surgical compartmentalization of the atria during open-heart surgery (Maze procedure), early attempts were made to achieve the similar results with catheter-based percutaneous approach (24). It was the seminal work by Jaïs et al. and Haïssaguerre et al. (25,26) that identified the PVs as the most important source of premature activation triggering paroxysmal AF. Sophisticated 3D mapping techniques and effective modes of ablation energy delivery have further facilitated the extension of PV isolation to patients with chronic AF (27). On the other hand, advance in pharmacological approach in restoring sinus rhythm has been relatively limited. Alternatively, more conservative approach with rate control may be more appropriate therapy, particularly for those asymptomatic patients (28).
Autonomic influences in AF
The importance of autonomic disturbance in the pathogenesis of AF has long been recognized even in patients with ventricular systolic dysfunction (29,30). However, current strategies of restoring or maintaining sinus rhythm in patients with AF focus primarily on the atrial myocardium. This approach has been proven effective and superior to antiarrhythmic agents in relief of symptoms (27). However, the outcomes of recent clinical investigations highlight the limitation of this myocardial approach (31,32). The myocardial approach was further challenged by clinical reports that complete PV isolation may not been seen in all patients with successful AF ablation (33,34).
Sympathetic versus parasympathetic effects in AF
Previous studies suggested that sympathetic nerve driven most of excised-induced AF, but, the parasympathetic system is contribute to most of AF in young patients (35). Sympathetic system may promote arrhythmia by increasing Ca2+ transient. Activated β-adrenergic signal pathways increase Ca2+ entry and the spontaneous release of Ca2+ from sarcoplasmic reticulum (36). However, vagal stimulation or perfusion of ACh in experiments contributes to development of AF by heterogeneous shortening of action potential duration and refractory period. With vagal hyperactivity, the atrial repolarization is abbreviated by ACh-activated potassium current (IKACh) (37), and/or non-cholinergic and non-adrenergic neurotransmitters, such vasoactive intestinal polypeptide VIP (38). Furthermore, studies have demonstrated that the interaction between sympathetic and parasympathetic nervous systems in developing AF by recording nerve activities directly from stellate ganglia, and vagal nerve (39).
Parasympathetic stimulation has long been associated with increased propensity to AF (40,41). The onset of paroxysmal AF often may be preceded by evidence of increased vagal tone, especially in patients with lone AF who otherwise have structurally normal heart (29). It also been shown that there is significant vagal innervation of the atrial muscle sleeves extending into the PVsand other thoracic veins (42). The vagal effects in AF have been largely attributed to Ach that causes shortening of atrial action potential duration with increased spatial heterogeneity. Vagal stimulation has also been shown to cause conduction delays (43,44). ACh activates the muscarinic receptors (mainly M2 in the heart) which in turn modulate cardiac ionic channels through (I) direct activation of an IKACh that accelerates repolarization and leads to hyperpolarization; and (II) indirect regulation through modulation of cAMP mediated responses (45).
In addition, recent studies have revealed evidence of noncholinergic vagal effects that could also contribute to the pathogenesis of vagally induced AF (46-49). Such noncholinergic vagal effects may be mediated by vagally released polypeptide and vasoactive intestinal polypeptide, which enhances the delayed rectifier K+ current (IKs) and decreases sodium current and thereby contributes to the vagal effects on atrial action potential duration and conduction velocity as well as the increased propensity to AF.
Recent studies have also revealed an important role of the sympathetic nervous system and its complex interaction with the vagal system in triggering AF (50). The muscle sleeves in the PV are capable of generating focal discharges that may be related to intracellular calcium transient (51). Patterson et al. showed that simultaneous infusing of norepinephrine and ACh could facilitate the development of early after depolarization and triggered activity during pacing (52). In an elegant study by Tan et al., simultaneous sympathovagal discharges were recorded immediately preceded atrial tachyarrhythmia in a canine model (53).
Evidence from both the clinical and basic science investigations has been emerging to indicate that the cardiac ganglionated plexi (GP) may play an important role in the pathogenesis of AF. Anatomically, GPs are the neuronal relay stations that are located within the epicardial fat pads near the PV-atrial junctions. Clinically, the sites of ablation during PV isolation are often adjacent to the locations of GPs and PV isolation could lead to vagal denervation of the left atrium (LA) (47). Furthermore, recent report by Nademanee et al. indicates targeting complex fractionated atrial electrograms (CFAE) during AF could significantly improve the long-term success rate of AF suppression (54). Again, further analysis of the sites of CFAE often demonstrates overlapping with the anatomic locations of GPs. Platt et al. provided the first to describe ablation of GPs may aid termination of AF during ablation (55). Pokushalov et al. further demonstrated the feasibility of selectively targeting GPs to suppress AF. However, localization or identification of the GPs was limited to the anatomic approach or high frequency stimulation as first proposed by Platt et al. (55).
Remodeling of the autonomic system during AF
Progression of AF from rare episodes to more frequent paroxysmal and eventual persistent and permanent AF characterizes the natural clinical course of AF in patients. The seminal work by Wijffels et al. first described a process of atrial remodeling that led to the hypothesis of “AF begets AF” (56). Increasing evidence now supports that, in addition to electrical remodeling characterized by progressive changes in action potential duration/refractory periods and rate maladaptation, there are structural remodeling (apoptosis and scaring) and autonomic remodeling, all of which further promote the propensity to AF (57).
The average density and heterogeneity of both tyrosine hydroxylase- and choline acetyltransferase-positive nerves at the PV-LA junctions were significantly higher after chronic rapid pacing. There is evidence that indicates an increased GP activity with AF (58). “Metastatic spread” of CFAE was noted with progression of AF from the PV-left atrial junction to the rest of the atria, especially the LA appendage (59), prompting the hypothesis of autonomic remodeling during AF. However, the exact extent and the mechanism(s) of such neural remodeling remain poorly defined.
Complexity of GP ablation to suppress AF
Increased autonomic nerve activities are detected during AF at GPs, and stimulation of GPs also promotes AF induction. Therefore, it is reasonable to hypothesis that GP ablation could reduce AF episodes. Several clinical studies have been conducted to suppress AF by GP ablation alone or in combination with PV isolation (58,60-63). In an acute experiment setting, Katritsis et al. concluded that combination of PV isolation and GP ablation has the higher success in suppressing AF, comparing to PV isolation alone (64). However, recent study reported that animals showed increased atrial vulnerability to arrhythmias, and progressively developed atrial tachycardia/AF after GP ablation (65). It indicated that there should be better way to maintain the balance of autonomic nerve system than simply destroying the GPs. Certainly further studies are warranted to delineate the exact role of GPs and the best way(s) to restore such balance.
It is clear now that autonomic dysfunctions and the complex interactions among the different components of the cardiac autonomic innervations play an important role in the pathogenesis of AF. However, further investigation is required to determine whether intervention aiming at the specific components of the cardiac autonomic innervation could lead to improve clinical outcome of AF management, especially that of the ablation procedure. Low-level vagosympathetic stimulation was shown to inhibit intrinsic neural activities of the GPs and to reduce AF inducibility (66-68). It can be expected that investigation into the role of autonomic dysfunction in AF, both mechanistic and clinical, will significantly advance our understanding of AF pathophysiology and may provide the foundation for innovative therapy with neural modulation.
Funding: This work was supported by a Grant-in-Aid award from the American Heart Association (11GRNT8000093 to Jie Cheng) and a Cardiovascular Initiative Grant from THI (Jie Cheng).
Disclosure: The authors declare no conflict of interest.
- Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2011;123:e269-367. [PubMed]
- Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study. Arch Intern Med 1987;147:1561-4. [PubMed]
- Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation 1997;96:2455-61. [PubMed]
- Furberg CD, Psaty BM, Manolio TA, et al. Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol 1994;74:236-41. [PubMed]
- Farrell B, Godwin J, Richards S, et al. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991;54:1044-54. [PubMed]
- Massie BM, Fisher SG, Radford M, et al. Effect of amiodarone on clinical status and left ventricular function in patients with congestive heart failure. CHF-STAT Investigators. Circulation 1996;93:2128-34. [PubMed]
- Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-7. [PubMed]
- The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-91. [PubMed]
- The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302. [PubMed]
- Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advanced heart failure. A study of 390 patients. Circulation 1991;84:40-8. [PubMed]
- Stevenson WG, Stevenson LW, Middlekauff HR, et al. Improving survival for patients with atrial fibrillation and advanced heart failure. J Am Coll Cardiol 1996;28:1458-63. [PubMed]
- Nichols GA, Reinier K, Chugh SS. Independent contribution of diabetes to increased prevalence and incidence of atrial fibrillation. Diabetes Care 2009;32:1851-6. [PubMed]
- Le Heuzey JY, Paziaud O, Piot O, et al. Cost of care distribution in atrial fibrillation patients: the COCAF study. Am Heart J 2004;147:121-6. [PubMed]
- Stewart S, Murphy NF, Walker A, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004;90:286-92. [PubMed]
- Nothnagel H. Ueber arythmische Herzthatigkeit. Deutsches Archiv fur. Klinische Medizin 1876;17:190-220.
- Einthoven W. Le telecardiogramme. Archives Internationales de Physiologie 1906;4:132-64.
- Rothberger CJ, Winterberg H. Vorhofflimmern Und Arrhythmia Perpetua. Wien Klin Wochenschr 1909;22:839-44.
- Lewis T. Report cxix. Auricular fibrillation: a common clinical condition. Br Med J 1909;2:1528. [PubMed]
- Scherf D, Morgenbesser LJ, Nightingale EJ, et al. Further studies on mechanism of auricular fibrillation. Proc Soc Exp Biol Med 1950;73:650-4. [PubMed]
- Scherf D. Studies on auricular tachycardia caused by aconitine administration. Proc Soc Exp Biol Med 1947;64:233-9. [PubMed]
- Moe GK, Mendez C. Basis of pharmacotherapy of cardiac arrhythmias. Mod Concepts Cardiovasc Dis 1962;31:739-44. [PubMed]
- Allessie MA, Lammers WJ, Bonke FI, et al. Experimental evaluation of Moe's multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP, Jalife J. eds. Cardiac electrophysiology and arrhythmias. NY: Grune and Stratton, 1985:265-75.
- Skanes AC, Mandapati R, Berenfeld O, et al. Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart. Circulation 1998;98:1236-48. [PubMed]
- Swartz JF, Pellersels G, Silvers J. A catheter-based curative approach to atrial fibrillation in humans. Circulation 1993;88:I-335.
- Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659-66. [PubMed]
- Jaïs P, Haïssaguerre M, Shah DC, et al. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 1997;95:572-6. [PubMed]
- Cappato R, Calkins H, Chen SA, et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:32-8. [PubMed]
- AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003;42:20-9. [PubMed]
- Coumel P. Autonomic influences in atrial tachyarrhythmias. J Cardiovasc Electrophysiol 1996;7:999-1007. [PubMed]
- Jons C, Raatikainen P, Gang UJ, et al. Autonomic dysfunction and new-onset atrial fibrillation in patients with left ventricular systolic dysfunction after acute myocardial infarction: a CARISMA substudy. J Cardiovasc Electrophysiol 2010;21:983-90. [PubMed]
- Weerasooriya R, Khairy P, Litalien J, et al. Catheter ablation for atrial fibrillation: are results maintained at 5 years of follow-up? J Am Coll Cardiol 2011;57:160-6. [PubMed]
- Bertaglia E, Tondo C, De Simone A, et al. Does catheter ablation cure atrial fibrillation? Single-procedure outcome of drug-refractory atrial fibrillation ablation: a 6-year multicentre experience. Europace 2010;12:181-7. [PubMed]
- Stabile G, Turco P, La Rocca V, et al. Is pulmonary vein isolation necessary for curing atrial fibrillation? Circulation 2003;108:657-60. [PubMed]
- Lemola K, Oral H, Chugh A, et al. Pulmonary vein isolation as an end point for left atrial circumferential ablation of atrial fibrillation. J Am Coll Cardiol 2005;46:1060-6. [PubMed]
- Coumel P. Paroxysmal atrial fibrillation: a disorder of autonomic tone? Eur Heart J 1994;15:9-16. [PubMed]
- Francis GS. Modulation of peripheral sympathetic nerve transmission. J Am Coll Cardiol 1988;12:250-4. [PubMed]
- Oberhauser V, Schwertfeger E, Rutz T, et al. Acetylcholine release in human heart atrium: influence of muscarinic autoreceptors, diabetes, and age. Circulation 2001;103:1638-43. [PubMed]
- Xi Y, Wu G, Ai T, et al. Ionic mechanisms underlying the effects of vasoactive intestinal polypeptide on canine atrial myocardium. Circ Arrhythm Electrophysiol 2013;6:976-83. [PubMed]
- Chen PS, Chen LS, Fishbein MC, et al. Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. Circ Res 2014;114:1500-15. [PubMed]
- Lewis T, Drury AN, Bulger HA. Observations upon atrial flutter and fibrillation. VI. Refractory period and rate of propagation in the auricle: their relation to block in the auricular walls and to flutter etc. Heart 1921;8:84-134.
- Hoff HE, Geddes LA. Cholinergic factor in auricular fibrillation. J Appl Physiol 1955;8:177-92. [PubMed]
- Zipes DP, Knope RF. Electrical properties of the thoracic veins. Am J Cardiol 1972;29:372-6. [PubMed]
- Rosenshtraukh LV, Zaitsev AV, Fast VG, et al. Vagally induced block and delayed conduction as a mechanism for circus movement tachycardia in frog atria. Circ Res 1989;64:213-26. [PubMed]
- Hirose M, Carlson MD, Laurita KR. Cellular mechanisms of vagally mediated atrial tachyarrhythmia in isolated arterially perfused canine right atria. J Cardiovasc Electrophysiol 2002;13:918-26. [PubMed]
- Harvey RD, Belevych AE. Muscarinic regulation of cardiac ion channels. Br J Pharmacol 2003;139:1074-84. [PubMed]
- Xi Y, Wu G, Mathuria N, et al. Vasoactive intestinal polypeptide shorten action potential duration via increased slow delayed rectifier K+ in human atrial myocytes. Heart Rhythm 2009;6 Suppl 5:PO02-76.
- Yang D, Xi Y, Ai T, et al. Vagal stimulation promotes atrial electrical remodeling induced by rapid atrial pacing in dogs: evidence of a noncholinergic effect. Pacing Clin Electrophysiol 2011;34:1092-9. [PubMed]
- 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. [PubMed]
- Henning RJ, Sawmiller DR. Vasoactive intestinal peptide: cardiovascular effects. Cardiovasc Res 2001;49:27-37. [PubMed]
- Chou CC, Chen PS. New concepts in atrial fibrillation: mechanism and remodeling. Med Clin North Am 2008;92:53-63. [PubMed]
- Chou CC, Nihei M, Zhou S, et al. Intracellular calcium dynamics and anisotropic reentry in isolated canine pulmonary veins and left atrium. Circulation 2005;111:2889-97. [PubMed]
- Patterson E, Lazzara R, Szabo B, et al. Sodium-calcium exchange initiated by the Ca2+ transient: an arrhythmia trigger within pulmonary veins. J Am Coll Cardiol 2006;47:1196-206. [PubMed]
- Tan AY, Zhou S, Ogawa M, et al. Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines. Circulation 2008;118:916-25. [PubMed]
- Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044-53. [PubMed]
- Platt M, Mandapati R, Scherlag BJ, et al. Limiting the number and extent of radiofrequency applications to terminate atrial fibrillation and subsequently prevent its inducibility. Heart Rhythm 2004;S11.
- Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 1995;92:1954-68. [PubMed]
- Zheng S, Zhang Y, Wang Z, et al. Autonomic neural remodeling of the pulmonary vein-left atrium junction in a prolonged right atrial pacing canine model. Pacing Clin Electrophysiol 2014;37:745-50. [PubMed]
- Hou Y, Scherlag BJ, Lin J, et al. Ganglionated 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. [PubMed]
- Lu Z, Scherlag BJ, Lin J, et al. Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing. Circ Arrhythm Electrophysiol 2008;1:184-92. [PubMed]
- Pokushalov E, Romanov A, Shugayev P, et al. Selective ganglionated plexi ablation for paroxysmal atrial fibrillation. Heart Rhythm 2009;6:1257-64. [PubMed]
- Scherlag BJ, Yamanashi W, Patel U, et al. Autonomically induced conversion of pulmonary vein focal firing into atrial fibrillation. J Am Coll Cardiol 2005;45:1878-86. [PubMed]
- Lin J, Scherlag BJ, Lu Z, et al. Inducibility of atrial and ventricular arrhythmias along the ligament of marshall: role of autonomic factors. J Cardiovasc Electrophysiol 2008;19:955-62. [PubMed]
- Cummings JE, Gill I, Akhrass R, et al. Preservation of the anterior fat pad paradoxically decreases the incidence of postoperative atrial fibrillation in humans. J Am Coll Cardiol 2004;43:994-1000. [PubMed]
- Katritsis D, Sougiannis D, Batsikas K, et al. Autonomic modulation of complex fractionated atrial electrograms in patients with paroxysmal atrial fibrillation. J Interv Card Electrophysiol 2011;31:217-23. [PubMed]
- Mao J, Yin X, Zhang Y, et al. Ablation of epicardial ganglionated plexi increases atrial vulnerability to arrhythmias in dogs. Circ Arrhythm Electrophysiol 2014;7:711-7. [PubMed]
- Spragg DD. Images in cardiovascular medicine. Resolution of expressive aphasia. Circulation 2009;120:645. [PubMed]
- 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]
- 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;57:563-71. [PubMed]