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• W2100030317 abstract "HomeCirculation: Arrhythmia and ElectrophysiologyVol. 5, No. 4Recent Insights Into the Role of the Autonomic Nervous System in the Creation of Substrate for Atrial Fibrillation Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBRecent Insights Into the Role of the Autonomic Nervous System in the Creation of Substrate for Atrial FibrillationImplications for Therapies Targeting the Atrial Autonomic Nervous System Rishi Arora, MD Rishi AroraRishi Arora From the Northwestern Memorial Hospital, Chicago, IL. Search for more papers by this author Originally published1 Aug 2012https://doi.org/10.1161/CIRCEP.112.972273Circulation: Arrhythmia and Electrophysiology. 2012;5:850–859IntroductionIn this review, we discuss recent developments in our understanding of the role of the autonomic nervous system in creating atrial fibrillation (AF) substrate and on how these findings relate to rapidly evolving therapeutic strategies (eg, ablation, surgery) to disrupt autonomic signaling in AF. AF is the most common sustained arrhythmia disturbance and is associated with significant morbidity and mortality. The morbidity and mortality associated with AF are especially increased in the setting of congestive heart failure (HF), with up to half of all patients with HF having concomitant AF.1Several mechanisms contribute to the electrophysiological and structural substrate of AF, including fibrosis, stretch, oxidative stress, and altered Ca2+-handling characteristics.2 In addition, neurohumoral factors have been invoked for their possible contribution to the creation of AF substrate. An important neurohumoral factor that has been studied fairly extensively for its involvement in AF is the autonomic nervous system.3 Both the sympathetic and the parasympathetic nervous systems have been shown to play a role in the genesis of AF.4,5During the past few years, the pulmonary veins (PVs) and the posterior left atrium (PLA) have been shown to play a significant role in the genesis of AF. These regions have been shown to possess unique structural, molecular, and electrophysiologi­cal characteristics, all of which appear to contribute to AF substrate. The autonomic characteristics of this region of the atrium have also been explored.6–8 Since the development of new ablative and surgical techniques during the past few years to treat AF, several investigators have also attempted to target the neural innervation of the atria and PVs at the time of ablation or surgery. These attempts include generalized denervation of the atria, as well as more targeted atrial denervation by using atrial electrograms—specifically, complex fractionated atrial electrograms (CFAEs) that are frequently noted in the fibrillating atrium—to identify regions of high autonomic activity. An increased understanding of the role of the autonomic nervous system in AF has also been accompanied by attempts to better image the neural innervation of the atria to better guide ablative strategies for AF.In this review, we examine the contribution of both clinical and animal studies to our understanding of the role of the autonomic nervous system in AF. We, specifically, review the studies in the recent literature (ie, during the past decade) that have (1) assessed the relative role of the vagal and sympathetic nervous system in the genesis and maintenance of AF; (2) assessed the autonomic profile of focal AF (ie, AF arising from the PVs and PLA); (3) explored the role of autonomic triggers in the creation of AF substrate in the setting of structural heart disease, specifically HF; (4) assessed the contribution of the autonomic nervous system to the characteristics of AF electrograms (eg, CFAEs); (5) assessed the feasibility of achieving autonomic denervation of the atria by means of ablation or surgery; (6) examined new ways to image the autonomic innervation of the atria, especially in light of recently developed ablative strategies targeted at the neural innervation of the atria; and (7) explored new and novel gene-based therapies directed at the autonomic nervous system in AF.Potential Role of the Autonomic Nervous System in the Creation of Substrate for AFEarlier studies suggested that exercise-induced AF may be sympathetically driven; in contrast, the parasympathetic nervous system may be contributing to AF in young patients with no structural heart disease.9,10 Sympathetic activation of the heart is thought to be proarrhythmic by increasing Ca2+ entry and the spontaneous release of Ca2+ from the sarcoplasmic reticulum.11,12 Animal studies show that vagal stimulation contributes to the genesis of AF by nonuniform shortening of the atrial effective refractory periods, thereby setting up substrate for reentry. Vagal stimulation can also lead to the emergence of focal triggers in the atrium.13 More recently, both the parasympathetic and the sympathetic nervous systems have been shown to play a role in AF. Amar et al showed that the onset of AF was preceded by a primary increase in the sympathetic drive, followed by marked modulation toward vagal predominance.4,14 Other studies also indicate that the onset of AF is associated with an imbalance between these 2 arms of the autonomic nervous system.15–19 Studies in animal models using direct nerve recordings from the stellate ganglia, vagal nerve, as well as the intrinsic cardiac autonomic ganglia also demonstrate an interaction between the sympathetic and the parasympathetic nervous systems in creating paroxysmal atrial tachyarrhythmias, including AF.20–23 These studies using direct nerve recordings reveal characteristic patterns of sympathovagal discharge before the initiation of atrial tachyarrhythmias, both in dogs that underwent chronic rapid atrial pacing and in dogs subjected to HF by rapid ventricular pacing. Data from the same laboratory suggest that sympathovagal interactions may also be contributing to the development of sustained AF.24 Sharifov et al25 showed that acetylcholine-induced AF was facilitated by isoproterenol, which decreased the concentration of acetylcholine required for AF induction and maintenance. The physiological studies by Patterson et al5 further indicate that sympathetic stimulation plays an important modulatory role in the emergence of focal drivers in the presence of an increased vagal tone. In their proposed model, Patterson et al5 suggest that Ca2+ transient triggering can generate rapid discharges under conditions in which atrial repolarization is abbreviated by IKAch activation (eg, by vagal stimulation), and the Ca2+ transient is augmented by β-adrenergic stimulation.The above suggests that the autonomic nervous system is involved in the genesis of both AF triggers (ie, ectopic foci that result from interaction between vagal and sympathetic stimulation) and the creation of a more established AF substrate that is needed for the maintenance of AF (and is enhanced in the setting of structural heart disease, see section on Role of Autonomic Signaling in Creating AF Substrate in the Setting of Structural Heart Disease).Autonomic Profile of the PVs and PLA and Its Relationship to the Genesis of AFThe discovery of PVs as being an important contributor to AF has led to a renewed interest in understanding the detailed anatomy and physiology of the cardiovascular nervous system. PV ectopic foci appear to be at least partially modulated by autonomic signaling, with sympathetic stimulation with isoproterenol being frequently used to bring out these triggers in patients undergoing AF ablation. Clinical studies have demonstrated a change in heart rate variability after PV ablation.26 Several investigators have also noted Bezold-Jarisch–like or vagal reflexes during radiofrequency ablation of the PVs. Indeed, Pappone et al27 have suggested that elimination of vagal reflexes during ablation may improve the efficacy of AF ablation procedures. Vagal responsiveness also appears to decrease after ablation in the left atrium.28 In fact, in some series,29 adding ganglionated plexi (GP) ablation to PV isolation appears to increase the success of AF ablation.Anatomic studies of the autonomic innervation of the atria also indicate that the PVs and PLA have a unique autonomic profile. Several years ago, Armour and Randall demonstrated the presence of an intricate pattern of autonomic innervation in the heart, with the atria being innervated by at least 5 major atrial fad pads.30 More recently, Hou et al31,32 have suggested the presence of an intricate, interconnecting neural network in the left atrium, which may contribute to substrate for focal AF. In a recent human study, Chevalier et al described the heterogeneity of nerve distribution in the region of the PVs and surrounding left atrium, demonstrating the presence of several gradients of innervation at discrete sites.33In light of these prior studies, Arora et al7 compared the distribution and physiology of sympathetic and parasympathetic nerves among the PVs, the PLA, and left atrial appendage in canine hearts. The PLA was the most richly innervated, with nerve bundles containing both the parasympathetic and the sympathetic fibers. Parasympathetic fibers predominated over sympathetic fibers within bundles. M2 receptor (M2R) distribution was also most pronounced in the PLA. In a related study, Ulphani et al34 discovered a particularly high concentration of parasympathetic fibers in the ligament of Marshall. The ligament of Marshall could be traced back to a major branch of the left cervical vagus nerve. Ablation of the ligament of Marshall led to an attenuation of vagal-induced effective refractory period shortening in the left-sided PVs and the PLA. The course of the ligament of Marshall along the posterior wall of the left atrium further highlights the potential importance of this region in the creation of autonomic substrate for AF. These canine studies are in agreement with human studies, where Tan et al35 demonstrated colocalization of sympathetic and parasympathetic nerve fibers in the human left atrium.35 Another human study by Deneke et al36 not only demonstrates colocalization of sympathetic and parasympathetic nerves, but also shows that patients with persistent AF had a shift toward a lower density of cholinergic nerves and a higher density of nerves containing adrenergic components.A related functional study in a canine model suggests a differential electrophysiological response of the PVs and adjoining PLA from that in the rest of the left atrium in response to autonomic maneuvers.6 In that physiological study, there was a greater decrease in refractory periods in the PVs and PLA compared with the rest of the left atrium in response to vagal stimulation. In this study, the heterogeneity of vagal responses in the left atrium was found to correlate with the pattern of distribution of IKAch.Taken together, the above studies indicate that the PVs and the adjoining PLA have a unique autonomic profile that differs from the rest of the atria and likely contributes to the genesis of both focal triggers and sustained microreentry in this region. Indeed, although it has been demonstrated that the normal PVs have marked heterogeneity of conduction and repolarization at baseline, with resulting substrate for reentry,37 it has also been shown that microreentry within the PVs could be sustained only in the presence of isoproterenol or acetylcholine, indicating that sympathomimetic or cholinergic stimulation appears to be necessary to promote the development of sustained focal activity in the PVs.37Role of Autonomic Signaling in Creating AF Substrate in the Setting of Structural Heart DiseaseStudies performed in the past few years suggest that the autonomic nervous system may also be playing a role in the genesis of AF in diseased hearts, which are known to have increased predisposition to persistent AF. Jayachandran et al38 demonstrated a heterogeneous increase in sympathetic innervation in the atria of dogs subjected to rapid atrial pacing for prolonged periods of time. There is also evidence of sympathetic hyperinnervation in patients with persistent AF.39 More recently, Ogawa et al,8 using direct nerve recordings from the stellate ganglia and vagal nerves, have shown increased sympathetic and vagal nerve discharges before the onset of atrial arrhythmias in dogs with pacing-induced HF. Indeed, the atrial tachyarrhythmias in this model were prevented by prophylactic ablation of the stellate ganglion and the T2 to T4 thoracic sympathetic ganglia.22 In the same model of pacing-induced HF, Ng et al1 recently demonstrated increased sympathetic and parasympathetic nerve growth in the left atrium1; nerve growth was most pronounced in the PVs and PLA (Figure 1). In this model, the increase in sympathetic innervation was accompanied by an increase in β1-adrenergic innervation in the PVs and by an increase in sympathetic responsiveness in the PVs and PLA; this increase in sympathetic innervation is consistent with that previously noted in human AF.39 The increase in parasympathetic innervation noted in the HF model of AF was paradoxically accompanied by (1) no change in M2 binding, and (2) a significant decrease in vagal-induced effective refractory period shortening in the left atrium. This decrease in vagal responsiveness was accounted for by an increase in acetylcholinesterase activity, with inhibition of acetylcholinesterase by physostigmine completely restoring vagal responsiveness in the left atrium. More importantly, despite this decrease in vagal responsiveness, parasympathetic tone was still an important contributor to the maintenance of AF; administration of atropine resulted in a significant decrease in the duration of induced AF, indicating the importance of parasympathetic remodeling in the creation of AF substrate. Although double autonomic blockade did not result in a further decrease in AF duration, it did decrease AF dominant frequency, thus indicating the additional influences of sympathetic activity on AF characteristics. The sensitivity of activation patterns in the PVs and PLA to parasympathetic manipulation noted in this study suggests that vagal effects on conduction may play a role in creating substrate for AF in HF. Figure 2 shows a proposed model of how sympathetic and parasympathetic remodeling contribute to the creation of AF substrate in the setting of HF.Download figureDownload PowerPointFigure 1. Comparison of nerve density and distribution in heart failure (HF) vs normal atria. A, Examples of sympathetic and parasympathetic nerve staining in HF atria. Sympathetic fibers were stained by dopamine β-hydroxylase, whereas parasympathetic fibers were stained by acetylcholine esterase. A(i), Example of a nerve bundle located in the fibrofatty tissue overlying the epicardium (EPI) (×10). A(ii), Example of nerve bundles located in fibrofatty tissue on the epicardial aspect of pulmonary vein (PV) (×4). Sympathetic fibers are shown (arrows). A(iii), Examples of cardiac ganglia, with parasympathetic fibers arising from cardiac ganglion on the left side (×20). A(iv), Example of cardiac ganglia on the left and nerve bundle on the right; nerve fibers showing colocalized sympathetic and parasympathetic fibers (×20). B, Quantitative analysis of nerve staining in HF vs normal atria. B(i), Nerve bundle density; B(ii), nerve bundle size; B(iii), number of parasympathetic nerve fibers/bundle; B(iv), number of sympathetic nerve fibers/bundle; B(v), density of cardiac ganglia; B(vi), number of cell bodies/cardiac ganglion; B(vii), density of sympathetic fibers; B(viii), density of parasympathetic fibers. ENDO indicates endocardium; PLA, posterior left atrium; LAA, left atrial appendage (modified from Ng et al1).Download figureDownload PowerPointFigure 2. Proposed model of creation of autonomic substrate for atrial fibrillation (AF) in congestive heart failure. The model suggests the likely presence of synergistic interactions between structural changes (fibrosis) and autonomic remodeling in the creation of AF substrate in heart failure. ACh indicates acetylcholine; AChE, acetylcholinesterase; β1AR, β11 adrenergic receptor; ERP, effective refractory period (modified from Ng et al1).Figure 2 also illustrates how autonomic remodeling may be interacting with other AF mechanisms (eg, fixed structural changes in the atrium) to create the necessary substrate for the maintenance of AF in the setting of HF. In addition to alterations in the ion channel and gap junction expression that occur in AF,40 an important structural abnormality that has been studied extensively for its role in creating electrophysiological abnormalities in the atrium is fibrosis. Fibrosis promotes heterogeneity of conduction and pathways, facilitating microreentry and macroreentry.41 The findings by Ng et al1 suggest that autonomic remodeling may also play a significant role in the creation of chronic AF substrate. It appears that although fibrosis may lead to conduction heterogeneity in the atrium and create a fixed substrate for reentry and consequent AF, parasympathetic and sympathetic remodeling in the PLA and PVs contribute to a more dynamic AF substrate that is dependent on the autonomic state of the left atrium.Taken together, the above studies indicate an important role for the autonomic nervous system in the genesis of AF not only in normal hearts but also in the setting of structural heart disease. These data underscore the potential importance of the autonomic nervous system as a suitable therapeutic target in AF in both normal and diseased hearts. The studies mentioned above also highlight the differences in autonomic remodeling in the atrium and ventricle in the setting of HF. Unlike in the ventricle, where the vagus appears to be protective against arrhythmias, the parasympathetic nervous system is clearly playing an important role in the creation of AF substrate.Contribution of the Autonomic Nervous System to the Formation of CFAEsOver the past few years, electrophysiologically guided ablation techniques have been developed to modify the arrhythmogenic substrate underlying AF. Electrogram-guided ablation procedures are the most common of these electrophysiologically guided techniques and can be broadly divided into procedures that target atrial sites, with either particular electrogram characteristics in the time domain (CFAEs) or frequency components in the frequency domain (dominant frequencies). Dominant frequency (DF) is a known electrophysiological variable by which atrial sites of periodic activity during AF can be identified. It has been suggested by several investigators that spatially organized high DF sites may play an important role in the maintenance of AF.42,43 Indeed, some studies have attempted to target high DF areas during AF ablation, with varying degrees of success.44,45 Related studies also demonstrate the heightened autonomic responsiveness of some high DF sites in patients with AF,46 thereby suggesting a mechanistic role for autonomic hyperactivity in the creation of these sites.Clinical studies performed in the past decade suggests that areas in the atrium demonstrating CFAEs may also represent a suitable target site for ablation; ablation at these sites appears to increase the efficacy of PV isolation procedures.47,48 One possible explanation for this improvement in ablation success is that several CFAE sites may be located in the anatomic vicinity of autonomic GP.49,50 Indeed, Katritsis et al50 showed that not only did CFAEs occur over presumed GP sites in over two thirds of patients with paroxysmal AF, but also in patients who did not have CFAEs at the GP sites, CFAEs were rarely recorded elsewhere in the left atrial wall. A recent study by Pokushalov et al51 suggests that additional identification of CFAEs around the atrial regions with a positive reaction to high-frequency stimulation might improve the accuracy of GP’s boundary location and even enhance the success rate of AF ablation. Nonetheless, the precise relationship of CFAEs to vagal inputs is not entirely clear, especially as vagal responses are not evoked at all presumed GP sites52 or sites where CFAEs are recorded. Other data indicate that heightened vagal activity may contribute to the formation of CFAE-like electrograms.49,53 More recently, Habel et al54 showed that CFAEs organize and DF decreases in the atrium in response to autonomic blockade. Knecht et al55 also showed that CFAEs organize in response to autonomic blockade, with organization being noted in patients with paroxysmal but not persistent AF. Importantly, in the study by Knecht et al,55 CFAE organization in response to double autonomic blockade was accompanied by an increase in AF cycle length, suggesting that the latter was a possible mechanism mediating autonomic responsiveness of CFAEs. Chaldoupi et al56 showed that CFAEs in the right atrial free wall and the superior/posterior wall of the left atrium are autonomically sensitive, with CFAEs in both atria organizing in the presence of double autonomic blockade. Data from our laboratory in a canine model of HF-induced AF indicate the following: (1) autonomic blockade significantly decreases DF and increases the fractionation interval (with a resulting decrease in CFAEs) in the PLA, and (2) the autonomic responsiveness of AF electrograms (ie, entropy of AF signals) is directly correlated with the amount and distribution of nerve-rich fatty tissue present in the myocardium.57 Taken together, the findings of these studies support a role for the autonomic nervous system in contributing to AF electrograms, both in the absence and in the presence of structural heart disease. The contribution of autonomic nerves to time- and frequency-domain measures of electrogram characteristics suggests that a detailed assessment of AF electrogram content in the presence of autonomic blockade may help better target autonomic ganglia during ablation.Recent Developments in Imaging of the Autonomic Innervation of the Atria: Implications for AF AblationAs alluded to earlier, much of the data supporting the involvement of the autonomic nervous system in patients with AF come from noninvasive measures of autonomic tone, such as heart rate variability.26 It must be remembered, however, that heart rate variability is a measure of autonomic modulation on the sinus node and does not reliably quantify sympathetic and parasympathetic activities.58 As discussed earlier, more recent studies in animal models, which include data from direct nerve recordings,21 as well as histological characterization of autonomic nerves,7,35 have helped shed light on the precise role of the autonomic nerves in the genesis of AF. Noninvasive methods of directly assessing neural activity in patients (eg, with imaging-based methods) would hopefully further improve our understanding of the role of the autonomic nervous system in AF.Radionuclide-based imaging modalities that have been used to assess the autonomic function of the heart include 123-I-metaiodobenzylguanidine (MIBG) imaging59–62 and 11C-meta-hydroxyephedrine-positron emission tomography.63–65 Of these, 123-I-MIBG imaging, which allows an assessment of global sympathetic function in the heart, has been the most widely studied. The role of 123-I-MIBG imaging has been evaluated in assessing the risk of worsening congestive HF, death from cardiac causes, and the risk of developing malignant ventricular arrhythmias in patients with coronary artery disease and in the setting of idiopathic dilated cardiomyopathy12 and has been shown to have good prognostic value in assessing the risk of ventricular tachyarrhythmias. Recently, 123-I-MIBG has undergone study for its potential use in the setting of AF. Akutsu et al66 showed in a study of 98 patients with paroxysmal AF that a reduced heart-to-mediastinum ratio—a measure of 123-I-MIBG uptake derived by drawing regions of interest over the heart and over the upper mediastinum in an anterior planar image and taking the ratio of mean counts per pixel in the heart to the mean counts per pixel in the mediastinum59—was a powerful independent predictor of the development of permanent AF alone and HF plus permanent AF. In a related study, Akutsu et al66 showed that 123-I-MIBG may be predictive of vascular events in patients with idiopathic paroxysmal AF. Lately, Arimoto et al67 have demonstrated that a high washout rate on 123-I-MIBG imaging was an independent predictor of AF recurrence in patients with paroxysmal and persistent AF who had undergone AF ablation. The authors also demonstrated a decreased heart-to-mediastinum ratio, both in patients with paroxysmal and persistent AF. The study by Arimoto et al67 underscores a need for more studies examining autonomic imaging in patients undergoing AF ablation.68 Although 123-I-MIBG imaging is specific to the sympathetic nervous system, thus indicating the potential role of sympathetic activity in the recurrence of AF after ablation, it is possible that 123-I-MIBG imaging may also, in part, reflect parasympathetic activity in the atrium, especially as sympathetic and parasympathetic nerve fibers are colocalized in the majority of nerve trunks in the atrium.7,35In a related surgical study, there was evidence of reinnervation of sympathetic nerves in patients who have undergone the MAZE procedure for AF.69 These findings are consistent with animal studies that have demonstrated autonomic reinnervation, with restoration of vagal responsiveness a few weeks after epicardial GP denervation had been performed.70 The reinnervation noted in the atrium is not unlike that noted in the ventricle after surgical denervation, eg, at the time of cardiac transplant.72 It has also been shown that ablation itself can lead to nerve growth in the atrium,72 usually several weeks after ablation. Future studies are, therefore, needed to look at the long-term effects of ablation on 123-I-MIBG imaging.Selective Autonomic Denervation of the Atria: A New Therapeutic Target During AF Ablation or Surgery?In light of the above-mentioned data supporting the role of the autonomic nervous system in the creation of AF substrate, recent years have, therefore, seen the development of a variety of strategies targeted at ≥1 GPs either surgically73,74 or through an endocardial approach. A strategy targeting the GPs is supported by large animal studies, where ablation of the autonomic ganglia at the base of the PVs was shown to contribute to the effectiveness of PV-directed ablation procedures in vagally induced AF75 and was also found to eliminate rapid PV firing in response to high-frequency stimulation.76GP ablation, alone or together with PV isolation, has been used in patients with both paroxysmal and persistent AF with variable success, although success rates appear to better in patients with paroxysmal compared with persistent AF.77–79 Scanavacca et al80 demonstrated the feasibility of selective atrial vagal denervation, guided by evoked vagal reflexes, to treat patients with paroxysmal AF. Pokushalov et al51 have reported that regional ablation at the anatomic sites of the left atrial GP can be safely performed and enables maintenance of sinus rhythm in 71% of patients with paroxysmal AF. Calò et al81 have recently shown that in a selected population of vagal paroxysmal AF, anatomic ablation of GPs in the right atrium is effective in ≈70% of patients. Mikhaylov et al82 compared 35 subjects with paroxysmal AF who underwent anatomic GP ablation with another 35 patients who underwent circumferential PV isolation; they discovered that anatomic GP ablation yields a significantly lower success rate over the long-term follow-up period compared with circumferential PV isolation. However, Katritsis et al29 and others83 have demonstrated that when GP ablation is combined with PV isolation, it yields better results than PV isolation alone, with success rates approaching up to 80%.29 Pokushalov et al78 reported success rates of <40% at 1 year after performing isolated GP ablation for symptomatic, drug refractory persistent AF; circumferential isolation of the PVs was needed in these patients to increase the success rate of GP ablation. Recent surgical studies have also attempted to add GP ablation/excision to PV isolation, albeit with varying efficacy.73,74,84,85 However, it is clear while minimally invasive surgery consisting of bipolar radiofrequency PV isolation and limited GP ablation is effective in reducing AF in patients with paroxysmal AF, it is less effective in those with persistent AF or long-standing persistent AF.86 In the latter setting, the addition of linear lesion sets appears to increase surgical success.86Despite the success rates of some of the above-mentioned studies in decreasing AF, it must be remembered that even if AF inducibility decreases in the short term after GP ablation, long-term suppression of AF is not guaranteed, in part, because of the possibility of reinnervation of ablated autonomic nerves.70 An added disadvantage of an anatomic ablative approach is that it inevitably causes transmural atrial tissue damage. Last, even though a majority of nerve trunks are located within the fat/fibrofatty tissue itself, up to a third of nerve trunks in the PLA can be located away from the fat in adjoining/underlying myocardium.7 This finding suggests that anatomic ablation strategies directed at atrial fat pads may not result in complete or sustained denervation of the PLA.As mentioned earlier, it appears that some CFAEs appear to be autonomically mediated, both in paroxysmal and in persistent AF. It is, therefore, possible that ablation strategies targeted at autonomically sensitive CFAEs may help increase the efficacy of AF ablation. Future studie" @default.
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• W2100030317 date "2012-08-01" @default.
• W2100030317 modified "2023-09-30" @default.
• W2100030317 title "Recent Insights Into the Role of the Autonomic Nervous System in the Creation of Substrate for Atrial Fibrillation" @default.
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• W2100030317 doi "https://doi.org/10.1161/circep.112.972273" @default.
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