REVIEW article

Front. Neurosci., 23 January 2019

Sec. Autonomic Neuroscience

Volume 12 - 2018 | https://doi.org/10.3389/fnins.2018.01058

Sympathetic Nervous System Activation and Its Modulation: Role in Atrial Fibrillation

  • 1. Dobney Hypertension Centre, School of Medicine, Royal Perth Hospital Unit, Medical Research Foundation, The University of Western Australia, Perth, WA, Australia

  • 2. Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, WA, Australia

  • 3. Neurovascular Hypertension and Kidney Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia

Abstract

The autonomic nervous system (ANS) has a significant influence on the structural integrity and electrical conductivity of the atria. Aberrant activation of the sympathetic nervous system can induce heterogeneous changes with arrhythmogenic potential which can result in atrial tachycardia, atrial tachyarrhythmias and atrial fibrillation (AF). Methods to modulate autonomic activity primarily through reduction of sympathetic outflow reduce the incidence of spontaneous or induced atrial arrhythmias in animal models and humans, suggestive of the potential application of such strategies in the management of AF. In this review we focus on the relationship between the ANS, sympathetic overdrive and the pathophysiology of AF, and the potential of sympathetic neuromodulation in the management of AF. We conclude that sympathetic activity plays an important role in the initiation and maintenance of AF, and modulating ANS function is an important therapeutic approach to improve the management of AF in selected categories of patients. Potential therapeutic applications include pharmacological inhibition with central and peripheral sympatholytic agents and various device based approaches. While the role of the sympathetic nervous system has long been recognized, new developments in science and technology in this field promise exciting prospects for the future.

Cardiac Autonomic Nervous System (ANS) Anatomy

The heart is extensively innervated and effectively regulated by the autonomic nervous system (ANS) through its sympathetic and parasympathetic branches (Kimura et al., 2012). The cardiac neural control occurs at multiple levels with each level capable of parallel processing of afferent neurotransmission and efferent cardiac sympathetic outflow (Esler, 2004). The ganglion cells of the ANS are located either inside (intrinsic) or outside the heart (extrinsic) and play an important role in cardiac function and arrhythmogenesis. The human cardiac intrinsic nervous system is made of ganglionated plexi (GP), which contain local circuit neurons of many types and chemo- and mechanosensory neurons that are distributed across the heart (Schotten et al., 2011). The GP are typically well innervated with both adrenergic and vagal nerve terminals and are accommodated in the fat pads, which are located mainly around the pulmonary vein ostia. The extrinsic sympathetic innervation is mediated via the cervical, stellate (cervicothoracic), and thoracic ganglia. Parasympathetic extrinsic innervation is transmitted via the vagus nerve, although sympathetic fibers are located in vagal nerves and parasympathetic fibers in sympathetic nerves as well (Kawashima, 2005; Seki et al., 2014).

The extrinsic nerves run through the hilum of the heart along the great cardiac vessels and divide into seven epicardial subplexi, the intrinsic neural pathways of the ANS (Pauza et al., 2000). Small nerve fibers create a vast neural complex of small interconnecting efferent and afferent sympathetic, parasympathetic, and mixed nerve fibers, that contain the neurotransmitters, such as noradrenaline and acetylcholine, respectively, but some also include neuropeptide Y, somatostatin, vasoactive intestinal polypeptide, and substance P (Marron et al., 1994, 1995; Armour et al., 1997; Esler et al., 2006a; Tan et al., 2006; Deneke et al., 2011). The density of small fibers and ganglia is most significant in the posterior zone of the left atrium and surrounding the antrum of the left pulmonary veins (PVs) (Chevalier et al., 2005; Tan et al., 2006). The atria are mostly parasympathetically innervated, whereas the ventricles are primarily innervated by sympathetic nerve fibers (where only 16% of total cardiac ganglia reside) (Pauza et al., 2000; Kawano et al., 2003; Petraitiene et al., 2014). GP are clusters of ganglia from different subplexi and function as an intersection point of parasympathetic and sympathetic nerves and interconnect the intrinsic ANS (Armour et al., 1997; Hou et al., 2007; Malcolme-Lawes et al., 2013). The atrial GP are placed adjacent to the sinus node and PVs and are present in epicardial fat pads (Figure 1). Ventricular GP are located near the interventricular groove (Armour et al., 1997). The ligament of Marshall, the embryonic remnant of the left superior caval vein, close to the left superior PV is extensively innervated with parasympathetic and sympathetic nerves (Kim et al., 2000; Ulphani et al., 2007).

FIGURE 1

Pathophysiology of Atrial Fibrillation

Autonomic nervous system activation has been well-known as a central determining factor of atrial arrhythmogenesis, (Sharifov et al., 2004; Chen and Tan, 2007; Shen et al., 2011; Shen and Zipes, 2014). Studies involving modulation of the sympathetic limb of ANS demonstrated that suppression of sympathetic tone leads to a notable reduction in atrial vulnerability to AF induction and post-ablation AF recurrence (Linz et al., 2012; Pokushalov et al., 2012). The prevalence of AF increases with age, affecting around 0.5% of the general population under 40 years of age, >5% of the general population over 65 years of age, and >10% of the general population over 80 years of age (Sankaranarayanan et al., 2013). In young patients, there was a shift toward vagal dominance in lone AF and nocturnal paroxysmal AF predominantly (Jayachandran et al., 2000). In patients with paroxysmal AF and syncope, there is an abnormal neural response even during sinus rhythm, at which AF triggers vasovagal syncope (Brignole et al., 1993). It is also important to highlight that AF in younger patients is associated with higher mortality rate than matched controls. Patients admitted into the hospital with incidental AF had a worse prognosis when compared to patients without AF, with higher risk of all-cause mortality in the younger age group when compared to the over-75-year-old population (Andersson et al., 2013).

Atrial fibrillation promotes shortening of the atrial refractory period and AF cycle length during the first days of the arrhythmia, mostly due to downregulation of the Ca2+-inward current and upregulation of inward rectifier K+ currents (Van Wagoner et al., 1999; Dobrev et al., 2005). Conversely, the structural cardiac disease leads to an extension of the atrial refractory period, demonstrating the heterogeneity of mechanisms causing AF in different patients (Schotten et al., 2011). Hyper-phosphorylation of various Ca2+-handling proteins may contribute to increasing spontaneous Ca2+ release events and eliciting activity (Voigt et al., 2012, 2014), thus provoking atrial ectopic beats, and thereby AF. Interestingly, the instability theory of Ca2+-handling has been recently challenged (Christ et al., 2014; Greiser et al., 2014), raising the hypothesis that Ca2+-induced calcium release may mediate AF in structurally remodeled atria, demonstrating how a modified autonomic tone can cause AF (Nguyen et al., 2009).

Focal Initiation and Maintenance of AF

Haissaguerre et al. (2014) reported that a focal source in the pulmonary veins could initiate AF, and ablation of this source could eliminate recurring AF (Haissaguerre et al., 1998). The mechanisms of focal activity perhaps cover both triggered activity and local re-entry (Atienza et al., 2006; Patterson et al., 2007). Hierarchical organization of AF with rapidly activated zones promoting the arrhythmia has been demonstrated in individuals with paroxysmal AF (Mandapati et al., 2000; Sahadevan et al., 2004). However, it seems that the organization of these rapidly activated zones are less well demarcated in patients with persistent AF (Sanders et al., 2006).

The Multiple Wavelet Hypothesis and Rotors as Sources of AF

The multiple wavelets and organized sources theories, though unclear are the two principal proposed paradigms of AF perpetuation. Moe et al. (1964) proposed, through a mathematical model, that multiple wavelets randomly propagating through the atria are capable of perpetuating AF which in turn provoke wave breaks, and generates new daughter wavelets. Though AF would be sustained as long as the number of wavelets is beyond a critical level, it is still unknown whether these wavelets are driving AF or if they are simply passive, and result from the breakup of more organized waves. Whilst the multiple wavelet concept is supported by theoretical rationale (Moe and Abildskov, 1959), experimental and clinical data (Cox et al., 1991), optical mapping techniques identified that wavelets resulting from the breakup of high frequency organized waves were not capable of maintaining AF independently (Chen et al., 2000). In patients with longstanding AF, the fibrillatory waves are due to epicardial breakthrough of waves that propagate in the deep layers of the atrial wall providing a constant independent source originating over the entire epicardial surface (Allessie et al., 2010; de Groot et al., 2010). Early ablative termination of AF in the PV may not completely abolish the presence of PV antrum wavelets over time, which can in turn cause AF (Haissaguerre et al., 2005; Calkins et al., 2012) resulting in limited clinical impact (Beukema et al., 2008).

Studies showed the presence of high-frequency spiral wave-like activity emanating regularly from the left atrium, subsequently driving irregular fibrillatory conduction in the rest of the atria (Schuessler et al., 1992; Mandapati et al., 2000; Verheule et al., 2010) whilst complex signal morphologies were associated with areas of slow conduction, wave collision, fibrillatory conduction, turning into wavelet pivot points and rotor meandering, or autonomic activation (Lu et al., 2008; Vaquero et al., 2008; Zlochiver et al., 2008). Localized source premise is based on experimental models in which organized re-entrant circuits, called “rotors” (Skanes et al., 1998; Vaquero et al., 2008) or focal impulses (Sahadevan et al., 2004) disorganize into AF. Jalife and co-workers clearly demonstrated that pacing-induced AF was due to the presence of a very rapid rotor (15–20 Hz) in the left atrium (Jalife et al., 2002). The CONFIRM trial demonstrated for the first time that localized sources in the form of electrical rotors and focal impulses are capable of sustaining AF in humans (Narayan et al., 2012). Furthermore, they also proved that brief ablation (Focal Impulse and Rotor Modulation, FIRM) of patient-specific AF-sustaining sources was able to terminate or consistently reduce persistent or paroxysmal AF prior to any conventional ablation in 86% of patients, and substantially increase long-term AF elimination compared to traditional AF ablation alone (Narayan et al., 2012). However, the results of the CONFIRM trial were limited to small series of patients with mixed AF types, so the actual role of stable rotors in more persistent forms remains to be proven. Further, in the absence of convincing evidence that human AF is driven by a single rotor, it is puzzling how we should interpret the CONFIRM study. In itself, this observation does not prove that human AF is driven by a single rapid source and the reported clinical success needs to be confirmed by other centers, especially in patients with longstanding persistent AF (Allessie and de Groot, 2014). Moreover, these studies utilize a low-resolution mapping system, which is not completely satisfactory in delivering mechanistic insights to draw conclusions (Ravelli and Mase, 2014). However, the high success rate of AF termination by targeting identified local sources strongly supports the hypothesis of rapidly organizing sources as key for the maintenance of AF.

Clinical Conditions that may Act as Predisposing Factors to AF

Multiple cardiovascular diseases and associated conditions increase the risk of developing AF (Table 1), recurrent AF, and AF-related consequences. Diagnosing such conditions, as well as preventing and treating them are vital to prevent AF and its disease burden. Knowledge of these factors and their management is therefore important for optimal treatment of AF patients (Abed et al., 2013; Pathak et al., 2014). The ANS exerts significant control on both cardiac electrophysiology as well as conditions such as, hypertension which is often associated with exaggerated sympathetic tone and is the single most important clinical factor that accounts for around 80% of AF (Schotten et al., 2011). This is further complicated by the associated atrial remodeling and dilatation that increases the probability of repetitive firing or even the presence of episodic re-entrant activation circuits. Other clinical conditions commonly associated with AF include cardiomyopathy, valvular and coronary heart disease, heart failure, metabolic syndrome and diabetes, suggested to contribute to around 20–30% of AF cases (Psaty et al., 1997; Schoonderwoerd et al., 2008; Mahfoud et al., 2011; Schotten et al., 2011; Selmer et al., 2012; Schnabel et al., 2015; Vermond et al., 2015). These clinical pathologies induce electrical, structural and autonomic atrial remodeling which results in conduction abnormalities such as rapidly firing focus and multiple complex (Buch et al., 2003; Gami et al., 2007; Aizer et al., 2009; Chamberlain et al., 2011; Kim et al., 2014; Larsson et al., 2014) re-entrant circuits, thereby AF (Figure 2). In addition, increased renin-angiotensin-aldosterone system activity associated with sympathetic overdrive induced profibrotic cardiac signaling, atrial fibrosis and fibrillation (Kumagai et al., 2003; Ehrlich et al., 2006; Baber et al., 2011; Reil et al., 2012).

Table 1

Characteristic/comorbidityAssociation with AF
Genetic predisposition (based on multiple common gene variants associated with AF), ccc specified in Table 1.HR range 0.4–3.2
Older ageHR:
50–59 years1.00 (reference)
60–69 years4.98 (95% CI 3.49–7.10)
70–79 years7.35 (95% CI 5.28–10.2)
80–89 years9.33 (95% CI 6.68–13.0)
Hypertension (treated) vs. noneHR 1.32 (95% CI 1.08–1.60)
Heart failure vs. noneHR 1.43 (95% CI 0.85–2.40)
Valvular heart disease vs. noneRR 2.42 (95% CI 1.62–3.60)
Myocardial infarction vs. noneHR 1.46 (95% CI 1.07–1.98)
Thyroid dysfunction(reference: euthyroid)
HypothyroidismHR 1.23 (95% CI 0.77–1.97)
Subclinical hyperthyroidismRR 1.31 (95% CI 1.19–1.44)
Overt hyperthyroidismRR 1.42 (95% CI 1.22–1.63)
ObesityHR:
None (BMI < 25 kg/m2)1.00 (reference)
Overweight (BMI 25–30 kg/m2)1.13 (95% CI 0.87–1.46)
Obese (BMI ≥ 31 kg/m2)1.37 (95% CI 1.05–1.78)
Diabetes mellitus vs. noneHR 1.25 (95% CI 0.98–1.60)
Chronic obstructive pulmonary diseaseRR:
FEV1 ≥ 80%1.00 (reference)
FEV1 60–80%1.28 (95% CI 0.79–2.06)
FEV1 < 60%2.53 (95% CI 1.45–4.42)
Obstructive sleep apnoea vs. noneHR 2.18 (95% CI 1.34–3.54)
Chronic kidney diseaseOR:
None1.00 (reference)
Stage 1 or 22.67 (95% CI 2.04–3.48)
Stage 31.68 (95% CI 1.26–2.24)
Stage 4 or 53.52 (95% CI 1.73–7.15)
SmokingHR:
Never1.00 (reference)
Former1.32 (95% CI 1.10–1.57)
Current2.05 (95% CI 1.71–2.47)
Alcohol consumptionRR:
None1.00 (reference)
1– 6 drinks/week1.01 (95% CI 0.94–1.09)
7–14 drinks/week1.07 (95% CI 0.98–1.17)
15–21 drinks/week1.14 (95% CI 1.01–1.28)
>21 drinks/week1.39 (95% CI 1.22–1.58)
Habitual vigorous exerciseRR:
Non-exercisers1.00 (reference)
<1 day/week0.90 (95% CI 0.68-1.20)
1-2 days/week1.09 (95% CI 0.95-1.26)
3-4 days/week1.04 (95% CI 0.91-1.19)
5-7 days/week1.20 (95% CI 1.02-1.41)

Cardiovascular and other conditions independently associated with atrial fibrillation.

AF, atrial fibrillation; BMI, body mass index; CI, confidence interval; FEV1, forced expiratory volume in 1 s; HR, hazard ratio; OR, odds ratio; RR, risk ratio. Adapted from Kirchhof et al. (2016).

FIGURE 2

Autonomic remodeling may modify the reaction to ANS stimulation and the balance between the parasympathetic and sympathetic innervation (Coumel, 1996; Patterson et al., 2005; Furukawa et al., 2009; Ng et al., 2011; Shen et al., 2011). Increased sympathetic nerve density has been described in patients with permanent AF, but whether this is compensatory to increased vagal stimulation or causative of AF is unknown (Gould et al., 2006; Deneke et al., 2011). A heterogeneous increase in sympathetic innervation in the atria of dogs on rapid atrial pacing for long periods increases AF susceptibility (Jayachandran et al., 2000). Increased sympathetic and vagal nerve discharges before the onset of atrial arrhythmias in dogs with pacing-induced congestive heart failure by direct nerve recordings from the stellate ganglia and vagal nerves was also reported (Ogawa et al., 2007). Undeniably, atrial tachyarrhythmias in dogs presenting with congestive heart failure by fast cardiac pacing were prevented by prophylactic ablation of the stellate ganglion and the T2 to T4 thoracic sympathetic ganglia (Ogawa et al., 2007). In the same animal model of heart failure, Ng et al., also demonstrated increased sympathetic and parasympathetic nerve growth mostly in the pulmonary veins and the posterior wall of the left atrium (Ng et al., 2011).

In humans, PV ectopy, often originating from superior PVs, normally triggers paroxysmal AF (Haissaguerre et al., 1998). Animal and human studies have shown that stimulation of the GP close to PV triggers PV ectopies (Scherlag et al., 2005; Lim et al., 2011). In canine PVs, parasympathetic activation decreased action potential duration, while sympathetic activation increased myocardial cytoplasmatic (Ca2+) (Patterson et al., 2005). Both components were necessary for early afterdepolarizations in PVs, consequently triggering AF. Ectopic activity in other highly innervated structures (ligament of Marshall) possibly also triggers AF (Chevalier et al., 2005; Scherlag et al., 2005; Tan et al., 2006). During catheter ablation procedures stimulation of the ligament of Marshall caused ectopic beats and triggered AF (Báez-Escudero et al., 2014). On the other hand, AF triggers are not restrained to densely innervated tissue alone. A study reported that in ∼30% of patients who required a repeat PV isolation ectopic firing from the left atrial appendage was detected (Di Biase et al., 2010).

Intense atrial fibrosis formation and cardiomyocyte hypertrophy are common features of structural remodeling. Atrial tissue fibrosis damages electrophysiological cell-to-cell coupling and conduction (Allessie et al., 2001; Nattel, 2002; Iwasaki et al., 2011; Schotten et al., 2011; Wakili et al., 2011). Long-term AF induces myocyte hypertrophy and increases endomysial fibrosis. This is accompanied by dissociated conduction and electrical dissociation between the epicardial layer and the endocardial bundle connections frequently promoting permanent forms of AF (Eckstein et al., 2011; Schotten et al., 2011). Conditions other than AF can also lead to atrial structural remodeling including chronic arterial hypertension which has been shown to cause electro-structural changes characterized by conduction abnormalities, atrial inflammation and fibrosis thereby increasing the risk of AF induction (Lau et al., 2010). Congestive heart failure induces structural remodeling characterized by increased fibrosis and changes in gap junctions, provoking conduction heterogeneity which promotes formation of micro-re-entry and macro-re-entry circuit pathways (Li et al., 1999). Long-term obstructive sleep apnoea is linked to significant atrial remodeling characterized by atrial enlargement, site-specific and extensive conduction abnormalities, as well as delayed sinus node recovery time in humans (Witkowski et al., 2011; Dimitri et al., 2012). The described alterations may have a crucial role in the generation of AF substrates.

Sympathetic activation also plays a major role in atrial arrhythmias following cardiac surgeries and post-operative (post-op) AF is associated with reduced long term survival with cardiac surgeries such as the coronary bypass and valvular surgeries especially the aortic valve replacement (Girerd et al., 2011). Often finding suggestive of enhanced sympathetic activation such as elevated nor-epinephrine levels (Kalman et al., 1995), increased sinus rate, atrial ectopy and time- and frequency-domain parameters of heart rate variability are associated with the onset of AF following cardiac surgeries (Dimmer et al., 1998; Amar et al., 2003). Ventral cardiac denervation significantly reduced the incidence and severity of AF in patients undergoing low-risk coronary bypass surgery (Melo et al., 2004). Post-operative AF is also common in patients who have undergone lung transplantation rather than cardiac transplantation, an effect attenuated by cardiac autonomic denervation that occurs in heart transplant patients (Dizon et al., 2009). Moreover, in a large series of patients following orthotopic cardiac transplant, macro re-entrant tachycardias (flutter and scar re-entry) seem to be the most common supraventricular arrhythmias in stable patients which are often supressed by catheter ablation. The blockade of β-receptors in patients presenting with acute post-operative AF has been effective in preventing recurrence of this arrhythmia after successful cardioversion (Kühlkamp et al., 2000; Nergårdh et al., 2007). Though post-op AF is of multifactorial etiology, sympathetic activation appears to be the most relevant predisposing mechanism of post-op AF and in line with this, the 2010 European Society of Cardiology guidelines recommend β-blocker treatment as first-line therapy in preventing post-op AF following cardiac surgeries (Camm et al., 2010).

Sympatholytic Therapy – a Possible Strategy in the Management of AF?

Pharmacological Sympathetic Inhibition

Given the contribution of sympathetic overdrive in the development of AF, sympathetic inhibition represents a logical therapeutic approach in the management of AF and the frequently coexisting hypertension, thereby alleviating the associated cardiovascular mortality and morbidity. Autonomic dysfunction characterized by sympathetic overdrive in scenarios of organic heart disease exhibits both electrical and structural remodeling of atrial myocardium in AF. Pharmacological sympatholysis can be achieved by using drugs such as clonidine and moxonidine. Clonidine is a centrally acting α2-adrenergic agonist that supresses the sympathetic outflow in the lower brainstem (Flacke et al., 1987), the preganglionic splanchnic nerve fibers and in postganglionic cardiac nerves fibers (Langer et al., 1980). In addition, clonidine prolongs atrioventricular node refractoriness by stimulation of parasympathetic outflow with beneficial effects on the control of ventricular response in patients with new-onset rapid AF (Roth et al., 1992). Moxonidine is an imidazoline I1-receptor agonist that inhibits sympathetic outflow at the level of the rostral ventrolateral medulla. In addition to effective blood pressure (BP) lowering and metabolic benefits (Haenni and Lithell, 1999; Chazova et al., 2006), moxonidine has been demonstrated to suppress atrial arrhythmogenesis (Lepran and Papp, 1994; Edwards et al., 2012; Cagnoni et al., 2016). In a subsequent study, moxonidine significantly increased the threshold dose of ouabain-induced cardiac arrhythmia by decreasing sympathetic tone (Mest et al., 1995). Moreover, moxonidine induced sympathetic inhibition decreased the AF burden in hypertensive patients with paroxysmal AF without any side effects (Deftereos et al., 2013). Furthermore, moxonidine reduced post-ablation recurrence of AF in hypertensive patients who underwent pulmonary vein isolation for drug-refractory paroxysmal AF (Giannopoulos et al., 2014).

Moxonidine seems specifically useful in obesity related hypertension where the sympathetic overdrive sustains both obesity and BP elevation. With the well-established relationship between abdominal obesity, the metabolic syndrome, and the development of AF, obese hypertensives are at a greater risk for AF. Studies have identified that autonomic dysfunction occurs early in the pathophysiology of AF and precedes the development of metabolic abnormalities such as insulin-resistance and obesity (Huggett et al., 2006; Julius and Jamerson, 1994; Palatini et al., 1999) which in turn maintain sympathetic activation via release of adipokines and other bioactive cytokines from visceral fat depots (Grassi et al., 1995; Alvarez et al., 2002; Huggett et al., 2004; Lambert et al., 2007, 2010). Alterations in norepinephrine transport and central sympathetic outflow have also been implicated in postural tachycardia syndrome (Lambert et al., 2008), anxiety and cardiovascular disease (Esler et al., 2006b), as well as panic disorder (Lambert et al., 2002). Furthermore, studies have shown that epi-/peri-cardial adipose tissue is an independent risk factor for AF (Al Chekakie et al., 2010) and adipocytes from the epicardial fat directly infiltrate into the myocardial wall resulting in enlargement of the ventricular myocardium and atrial septum thereby increasing the risk of AF (Iacobellis et al., 2003; Sarin et al., 2008; Mahabadi et al., 2009). Another highly relevant link in the current context is the noradrenaline-mediated increase in sodium glucose co-transporter- 2 (SGLT-2) expression (Matthews et al., 2017). This is important given that SGLT-2 inhibitors such as canagliflozin effectively reduce epicardial fat (Yagi et al., 2017) and empagliflozin improved glucose control and has been demonstrated to reduce cardiovascular events in T2DM (Zinman et al., 2015).

Sympathetic blockade at the periphery can also be achieved by beta-adrenergic blockers. Though beta-blockers are not generally regarded as membrane stabilizing agents, they delay atrial repolarization and protect against AF. It was speculated that beta-blockers suppress the pulmonary vein ectopy that triggers AF (Chen et al., 1999) as well as protect against adrenergically mediated shortening of the action potential duration (APD) which precipitates and maintains AF (Kühlkamp et al., 2000). Beta-blockers are a good first choice for the control of the ventricular response in AF and are widely used in the prevention of AF in patients following cardiothoracic surgery, in which AF occurs in approximately 30% of patients (Prystowsky et al., 1996).

Device-Based Therapeutic Approaches for Sympathetic Inhibition

Other interventions include device-based therapeutic approaches to modulate ANS to lower central sympathetic nerve activity such as renal denervation (RDN) and carotid body ablation. These approaches are primarily aimed at reducing sympathetic activity and BP in resistant hypertensive patients but are now investigated as potential treatment strategies in the context of AF.

Renal Denervation and Ganglionated Plexi Ablation

Recently, the AFFORD study, a single-arm pilot study including 20 patients with symptomatic paroxysmal or persistent AF, suggested that RDN alone was safe and able to decrease AF burden in min/day as measured using an implantable cardiac monitor (ICM) at 12-month follow-up accompanied by an improvement in quality of life (Feyz et al., 2018). A clinical study that assessed the antiarrhythmic effect of RDN in addition to pulmonary vein isolation (PVI) in HTN patients with symptomatic AF demonstrated that a mean BP reduction of 5–10 mmHg led to a 7% decrease in AF burden as measured with an ICM (Romanov et al., 2017). Pokushalov et al. (2012) showed that RDN on top of PVI in patients with symptomatic AF and resistant HTN reduced the incidence of AF recurrence significantly. At 1 year 69% of the patients in the PVI + RDN group were free of AF episodes, while in the PVI only group, only 29% of the patients remained free of AF episodes (Pokushalov et al., 2012).

Mechanistic studies demonstrated that modulation of the SNS via RDN improved AF control (Hou et al., 2013). Linz et al. (2013a,b) demonstrated the effect of RDN on heart rate (RR-interval, 708 ± 12 ms (∼85 bpm) vs. 577 ± 19 ms (∼104 bpm), post- and pre-procedure respectively; P = 0.0021) and ventricular rate response in pigs with permanent AF. The authors described a reduction of 24% in ventricular rate response in the treated pigs vs. sham, as well shorter AF episodes post-RDN compared with sham (12 ± 3 vs. 34 ± 4 s; P = 0.0091) (Linz et al., 2013a,b). Effects of RDN on cardiac electrophysiology have already been extensively studied and found to be effective in animal models and humans (Okin et al., 2006; Symplicity HTN-2 Investigators et al., 2010; Brandt et al., 2012b). RDN predominantly impacts sympathetic tone and results in a reduction in heart rate and atrioventricular-conduction velocity in resistant hypertension population (Krum et al., 2009; Schlaich et al., 2010; Ukena et al., 2013). Recently, the SPYRAL HTN-OFF MED trial reported that the higher baseline heart rate was associated with higher BP decrease, which may indicate that RDN works better in patients with high sympathetic drive (assessed in the absence of interfering drugs) (Bohm et al., 2018).

In a prospective, longitudinal study of patients with controlled hypertension, paroxysmal AF and either normal renal function or chronic kidney disease (CKD), Kiuchi et al., applying an extensive ablation technique reported the incidence of AF recurrence. It was higher in CKD patients treated with PVI alone (61.5%) than in CKD patients treated with PVI + RDN (38.5%, P = 0.0251) or non- CKD patients who underwent PVI (35.6%, P < 0.0001) over 22.4 ± 12.1 months following intervention. In addition, they found an improvement in echocardiographic parameters such as indexed left atrial volume, left ventricular end-diastolic diameter, and left ventricular mass index in patients who underwent RDN compared to baseline and to other groups. Another important finding was that patients with CKD stage 4 who underwent only PVI (64.41%) demonstrated a higher rate of AF recurrence than those subjected to PVI + RDN (33.33%, P = 0.0409) (Kiuchi et al., 2017).

Chronic kidney disease and AF share risk factors and putative mechanisms suggesting that common pathophysiologic processes may drive both pathologies. One possible common link between AF and CKD is activation of the renin–angiotensin–aldosterone system (RAAS) (Goette et al., 2000; Tsai et al., 2004; Wachtell et al., 2005; Baber et al., 2011; Tsai et al., 2017). Angiotensin II can increase atrial pressure, promote atrial fibrosis, and modulate ion channels, all of which are involved in structural and electrical remodeling of the atria resulting in AF (Goette et al., 2000). In addition, gene polymorphisms in encoding components of this pathway have been linked to the development of AF (Tsai et al., 2004; Lubitz et al., 2014). Supporting these results are data demonstrating that BP reduction after RDN is associated with improvements in regional and global atrial conduction with reduction in ventricular mass and fibrosis (McLellan et al., 2015). Though the antiarrhythmic effects of RDN could be due to a synergistic effect of better BP control, withdrawing this important risk factor for AF recurrence, improves AF control by electrophysiological modification such as the prolongation of the atrial effective refractory period (Manolis et al., 2012; Wang et al., 2015).

Tsai et al. (2017) demonstrated that bilateral RDN, possibly via interrupting afferent renal innervation, led to substantial brain stem and bilateral stellate ganglion remodeling at 8 weeks’ post-procedure in ambulatory canines (Tsai et al., 2017). These changes were associated with reduced 18FDG (fluorodeoxyglucose) – uptake in the brainstem, left stellate ganglion nerve activity and atrial tachyarrhythmic events. It was proposed that neural remodeling in the brain stem and stellate ganglion may partially explain the described antiarrhythmic effects of RDN (Tsai et al., 2017). Trans-synaptic degeneration is a phenomenon in the central and peripheral nervous system that may remain active both at the level of the insult and in remote brain structures for as long as 1 year following trauma (Bramlett and Dietrich, 2007) resulting in long-term functional consequences following RDN as shown in Figure 3. Meckler and Weaver (1984) showed that approximately 10% of bilateral renal sympathetic neurons in cats originated from the thoracic chain ganglia (stellate through T13). Because of the connections between these two structures, RDN may directly result in retrograde cell death of the stellate ganglion. Furthermore, the application of fluorescent dyes in the renal nerves results in fluorescent labeling of the sympathetic cell bodies in paravertebral and prevertebral ganglia (Ferguson et al., 1986; Gattone et al., 1986; Sripairojthikoon and Wyss, 1987).

FIGURE 3

Since the sympathetic preganglionic neurons that project to the stellate ganglion are dispersed in spinal cord segments sections T1–T10 (Pilowsky et al., 1992), they have ample chances to interrelate with the preganglionic cells that link indirectly with sympathetic nerve fibers surrounding the renal arteries. However, some other pathways might contribute to the trans-synaptic degeneration (Tsai et al., 2017), as the ganglion cells of renal afferent nerves in thoracic and lumbar spine dorsal root ganglia link to the posterior and lateral hypothalamic nuclei as well as the locus ceruleus in the brain stem (Campese and Kogosov, 1995; Jansen et al., 1995). RDN may affect the described connections and result in remodeling of the critical brainstem areas and the stellate ganglia. Because transneuronal degeneration may remain active for prolonged periods of time, the effects of RDN on arrhythmia control may persist for months after the procedure (Tsai et al., 2017).

PV Isolation

Pulmonary vein isolation with ganglionated plexi ablation has been used in autonomic modulation of interactions between the systemic and intrinsic cardiac ANS. PVI combined with autonomic ganglia modification significantly improved success rates after PVI compared to PVI alone (Katritsis et al., 2011). In animal models of vagal induced AF, the effectiveness of pulmonary vein isolation was due to the ablation of the autonomic ganglia at the base of the pulmonary veins which eliminated rapid pulmonary vein firing in response to high-frequency stimulation of the ganglionated plexi (Lu et al., 2009). GP ablation inhibited AF inducibility in sleep apnea animal models (Ghias et al., 2009) and has been used in patients with both paroxysmal and persistent AF alone or combined with pulmonary vein isolation with better success rate in patients with paroxysmal AF (Pokushalov et al., 2009; Katritsis et al., 2011; Mikhaylov et al., 2011). However, though ganglionated plexi ablation appears to be a safe and efficacious adjunctive technique to improve outcomes of pulmonary vein isolation in patients with paroxysmal AF, GP ablation in animal models after acute myocardial ischemia exhibited ventricular arrhythmogenic effects compared with GP ablation of the normal heart (He et al., 2013). Hence further studies are warranted to investigate the application of these procedures in various cardiac conditions.

Botulinum Toxin Injection

Recent studies have reported that an abundance of epicardial fat is associated with direct adipocyte infiltration into the underlying atrial myocardium (Hatem and Sanders, 2014; Mahajan et al., 2015). Moreover, increased overall adiposity has been shown to be associated with shortened effective refractory periods in the pulmonary veins, leading to the speculation that adiposity can predispose to AF initiation (Munger et al., 2012). Indeed, there is some evidence that areas of epicardial fat accumulation correlate with sites of high dominant frequency, suggesting that epicardial fat may influence AF triggers (Nagashima et al., 2012; Nakahara et al., 2014). Also, it may be possible that encasing epicardial fat influences ganglionated plexi and thus contributes to arrhythmogenesis. Recently, in a prospective, double-blind randomized controlled clinical trial (Pokushalov et al., 2015) reported that injections of botulinum toxin into epicardial fat pads in patients undergoing coronary artery bypass grafting (CABG) resulted in a substantial reduction in the incidence of atrial tachyarrhythmia (most pronounced in the first 14 months postoperatively) and AF burden throughout the 3-year follow-up period, accompanied by reduction in need for hospitalization (Pokushalov et al., 2015; Romanov et al., 2018).

Stellate Ganglion Blockade

Studies demonstrate that stimulation of the stellate ganglion increased sinus rate and predisposes to atrial arrhythmias (Mohan et al., 2001; Tan et al., 2008a,b). Increased extrinsic cardiac nerve activity in the left stellate ganglion often preceded paroxysmal atrial tachycardia or AF in animal models (Choi et al., 2010). Unilateral electrical stimulation of the stellate ganglion aggravated atrial electrical remodeling facilitating induction of AF in animal models, an effect attenuated by unilateral ganglionectomy (Zhou et al., 2013). In animal models of pacing-induced congestive heart failure, cryoablation of bilateral stellate and T2–T4 thoracic ganglia reduced sympathetic activation-induced paroxysmal AF (Ogawa et al., 2009). Bilateral ANS remodeling resulting from the increased synaptic density of stellate ganglia following myocardial infarction was associated with increased ganglion activity (Han et al., 2012). Surgical excision of stellate ganglion (left cardiac sympathetic denervation) together with T2 and T3 thoracic ganglia reduced arrhythmia in high-risk patients and animal models following myocardial infarction (Schwartz et al., 1976, 1992) and in patients with catecholaminergic polymorphic ventricular tachycardia and long-QT syndrome (Collura et al., 2009).

High Thoracic Epidural Anesthesia

In patients undergoing cardiac surgery and cardiopulmonary bypass, high thoracic epidural anesthesia was found to markedly reduce sympathetic tone (Scott et al., 2001; Liu et al., 2004) and the risk of post-operative supraventricular arrhythmias (Svircevic et al., 2011). Initiation of high thoracic epidural anesthesia decreased the arrhythmia burden in patients with refractory electrical storm (Bourke et al., 2010) and in animal models of rapid atrial pacing was found to be associated with inhibition of atrial autonomic nerve sprouting (Yang et al., 2011). However variable results have been obtained pertaining to the decreased incidence of post-operative sustained AF despite a marked reduction in sympathetic activity (Groban et al., 2000; Jidéus et al., 2001) and warrants further detailed studies to explore the definitive effect of high thoracic epidural anesthesia on atrial electrophysiology and arrhythmogenesis.

Carotid Body Ablation

Hypersensitive chemoreceptors result in sympathetic excitation. Enhanced chemoreflex sensitivity potentially increasing central sympathetic drive was observed in animal models of pacing-induced congestive heart failure (Schultz and Li, 2007). Surgical denervation of peripheral chemoreceptors prevented sympathetic activation- mediated hypertensive response to hypoxic stimuli in rats with intermittent hypoxia (Lesske et al., 1997). Bilateral denervation of the carotid body and the carotid sinus baroreceptors prevented the development of hypertension in young pre-hypertensive animals and significantly decreased arterial pressure in the adult population of spontaneously hypertensive rats (Tan et al., 2010) and hypertensive humans (Nakayama, 1961). Though carotid ablation appears as a logical approach to attenuate sympathetic overdrive, hypertension and arrhythmogenic atrial autonomic signaling in AF, there are currently no studies characterizing its effects on atrial electrophysiology and atrial arrhythmogenesis.

Conclusion and Perspectives

Enhanced sympathetic activation increases circulating catecholamines and causes hypertension and associated complication such as AF and congestive heart failure. Hypertension often coexists with comorbidities like obesity, metabolic syndrome, and obstructive sleep apnea that further exaggerate and sustain the sympathetic overdrive. Substantial evidence indicates that targeting sympathetic overactivity either by pharmacotherapy or device-based interventions seems to be a logical and useful approach for the management of AF. Sympathetic ablation by RDN appears to be a promising strategy to achieve atrial antiarrhythmic effects in animal models and humans. While carotid body ablation is a proven strategy to attenuate sympathetic overdrive, the potential anti-arrhythmic effects are yet to be investigated in future studies. Other techniques employed to reduce sympathetic activity are applied in specific conditions such as stellate blockade in high-risk patients and following myocardial infarction, ganglionic plexus ablation to lower AF recurrence in patients following circumferential pulmonary vein isolation, and high thoracic epidural anesthesia in post-surgical AF management. However further clinical studies are needed to substantiate the role of various sympatholytic approaches in the management of AF.

Statements

Author contributions

RC and MS have drafted the manuscript. MK, JH, and VM have researched data, contributed to inidvidual sections, and critically reviewed the manuscript.

Conflict of interest

MS is supported by an NHMRC Research Fellowship and has received consulting fees, and/or travel and research support from Medtronic, Abbott, Novartis, Servier, Pfizer, and Boehringer-Ingelheim. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  • 1

    AbedH. S.WittertG. A.LeongD. P.ShiraziM. G.BahramiB.MiddeldorpM. E.et al (2013). Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial.JAMA3102050–2060. 10.1001/jama.2013.280521

  • 2

    AizerA.GazianoJ. M.CookN. R.MansonJ. E.BuringJ. E.AlbertC. M. (2009). Relation of vigorous exercise to risk of atrial fibrillation.Am. J. Cardiol.1031572–1577. 10.1016/j.amjcard.2009.01.374

  • 3

    Al ChekakieM. O.WellesC. C.MetoyerR.IbrahimA.ShapiraA. R.CytronJ.et al (2010). Pericardial fat is independently associated with human atrial fibrillation.J. Am. Coll. Cardiol.56784–788. 10.1016/j.jacc.2010.03.071

  • 4

    AllessieM.de GrootN. (2014). Crosstalk opposing view: rotors have not been demonstrated to be the drivers of atrial fibrillation.J. Physiol.5923167–3170. 10.1113/jphysiol.2014.271809

  • 5

    AllessieM. A.BoydenP. A.CammA. J.KleberA. G.LabM. J.LegatoM. J.et al (2001). Pathophysiology and prevention of atrial fibrillation.Circulation103769–777. 10.1161/01.CIR.103.5.769

  • 6

    AllessieM. A.de GrootN. M.HoubenR. P.SchottenU.BoersmaE.SmeetsJ. L.et al (2010). Electropathological substrate of long-standing persistent atrial fibrillation in patients with structural heart disease: longitudinal dissociation.Circ. Arrhythm. Electrophysiol.3606–615. 10.1161/CIRCEP.109.910125

  • 7

    AlvarezG. E.BeskeS. D.BallardT. P.DavyK. P. (2002). Sympathetic neural activation in visceral obesity.Circulation1062533–2536. 10.1161/01.CIR.0000041244.79165.25

  • 8

    AmarD.ZhangH.MiodownikS.KadishA. H. (2003). Competing autonomic mechanisms precede the onset of postoperative atrial fibrillation.J. Am. Coll. Cardiol.421262–1268. 10.1016/S0735-1097(03)00955-0

  • 9

    AnderssonT.MagnusonA.BryngelssonI. L.FrobertO.HenrikssonK. M.EdvardssonN.et al (2013). All-cause mortality in 272,186 patients hospitalized with incident atrial fibrillation 1995-2008: a Swedish nationwide long-term case-control study.Eur. Heart J.341061–1067. 10.1093/eurheartj/ehs469

  • 10

    ArmourJ. A.MurphyD. A.YuanB. X.MacdonaldS.HopkinsD. A. (1997). Gross and microscopic anatomy of the human intrinsic cardiac nervous system.Anat. Rec.247289–298. 10.1002/(SICI)1097-0185(199702)247:2<289::AID-AR15>3.0.CO;2-L

  • 11

    AtienzaF.AlmendralJ.MorenoJ.VaidyanathanR.TalkachouA.KalifaJ.et al (2006). Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: evidence for a reentrant mechanism.Circulation1142434–2442. 10.1161/CIRCULATIONAHA.106.633735

  • 12

    BaberU.HowardV. J.HalperinJ. L.SolimanE. Z.ZhangX.McClellanW.et al (2011). Association of chronic kidney disease with atrial fibrillation among adults in the United States: REasons for Geographic and Racial Differences in Stroke (REGARDS) Study.Circ. Arrhythm. Electrophysiol.426–32. 10.1161/CIRCEP.110.957100

  • 13

    Báez-EscuderoJ. L.KeidaT.DaveA. S.OkishigeK.ValderrabanoM. (2014). Ethanol infusion in the vein of Marshall leads to parasympathetic denervation of the human left atrium: implications for atrial fibrillation.J. Am. Coll. Cardiol.631892–1901. 10.1016/j.jacc.2014.01.032

  • 14

    BeukemaW. P.SieH. T.MisierA. R.DelnoyP. P.WellensH. J.ElvanA. (2008). Predictive factors of sustained sinus rhythm and recurrent atrial fibrillation after a radiofrequency modified Maze procedure.Eur. J. Cardiothorac. Surg.34771–775. 10.1016/j.ejcts.2008.07.026

  • 15

    BohmM.KandzariD.TownsendR.MahfoudF.WeberM.FahyM.et al (2018). Spyral Htn-off med trial: changes in office and ambulatory heart rate.J. Hypertens.36e23–e24. 10.1097/01.hjh.0000539024.31308.8d

  • 16

    BourkeT.VaseghiM.MichowitzY.SankhlaV.ShahM.SwapnaN.et al (2010). Neuraxial modulation for refractory ventricular arrhythmias: value of thoracic epidural anesthesia and surgical left cardiac sympathetic denervation.Circulation1212255–2262. 10.1161/CIRCULATIONAHA.109.929703

  • 17

    BramlettH. M.DietrichW. D. (2007). Progressive damage after brain and spinal cord injury: pathomechanisms and treatment strategies.Prog. Brain Res.161125–141. 10.1016/S0079-6123(06)61009-1

  • 18

    BrandtM. C.MahfoudF.RedaS.SchirmerS. H.ErdmannE.BohmM.et al (2012a). Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension.J. Am. Coll. Cardiol.59901–909. 10.1016/j.jacc.2011.11.034

  • 19

    BrandtM. C.RedaS.MahfoudF.LenskiM.BohmM.HoppeU. C. (2012b). Effects of renal sympathetic denervation on arterial stiffness and central hemodynamics in patients with resistant hypertension.J. Am. Coll. Cardiol.601956–1965. 10.1016/j.jacc.2012.08.959

  • 20

    BrignoleM.GianfranchiL.MenozziC.RavieleA.OddoneD.LolliG.et al (1993). Role of autonomic reflexes in syncope associated with paroxysmal atrial fibrillation.J. Am. Coll. Cardiol.221123–1129. 10.1016/0735-1097(93)90426-2

  • 21

    BuchP.FribergJ.ScharlingH.LangeP.PrescottE. (2003). Reduced lung function and risk of atrial fibrillation in the Copenhagen city heart study.Eur. Respir. J.211012–1016. 10.1183/09031936.03.00051502

  • 22

    CagnoniF.DestroM.BontempelliE.LocatelliG.HeringD.SchlaichM. P. (2016). Central sympathetic inhibition: a neglected approach for treatment of cardiac arrhythmias?Curr. Hypertens. Rep.18:13. 10.1007/s11906-015-0619-0

  • 23

    CalkinsH.KuckK. H.CappatoR.BrugadaJ.CammA. J.ChenS. A.et al (2012). 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design.J. Interv. Card. Electrophysiol.33171–257. 10.1007/s10840-012-9672-7

  • 24

    CammA. J.KirchhofP.LipG. Y.SchottenU.SavelievaI.ErnstS.et al (2010). Guidelines for the management of atrial fibrillation: the task force for the management of Atrial Fibrillation of the European Society of Cardiology (ESC).Europace121360–1420. 10.1093/europace/euq350

  • 25

    CampeseV. M.KogosovE. (1995). Renal afferent denervation prevents hypertension in rats with chronic renal failure.Hypertension25(4 Pt 2)878–882. 10.1161/01.HYP.25.4.878

  • 26

    ChamberlainA. M.AgarwalS. K.FolsomA. R.DuvalS.SolimanE. Z.AmbroseM.et al (2011). Smoking and incidence of atrial fibrillation: results from the Atherosclerosis Risk in Communities (ARIC) study.Heart Rhythm81160–1166. 10.1016/j.hrthm.2011.03.038

  • 27

    ChazovaI.AlmazovV. A.ShlyakhtoE. (2006). Moxonidine improves glycaemic control in mildly hypertensive, overweight patients: a comparison with metformin.Diabetes Obes. Metab.8456–465. 10.1111/j.1463-1326.2006.00606.x

  • 28

    ChenP. S.TanA. Y. (2007). Autonomic nerve activity and atrial fibrillation.Heart Rhythm4(3 Suppl.)S61–S64. 10.1016/j.hrthm.2006.12.006

  • 29

    ChenS. A.HsiehM. H.TaiC. T.TsaiC. F.PrakashV. S.YuW. C.et al (1999). Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation.Circulation1001879–1886. 10.1161/01.CIR.100.18.1879

  • 30

    ChenJ.MandapatiR.BerenfeldO.SkanesA. C.GrayR. A.JalifeJ. (2000). Dynamics of wavelets and their role in atrial fibrillation in the isolated sheep heart.Cardiovasc. Res.48220–232.

  • 31

    ChevalierP.TabibA.MeyronnetD.ChalabreysseL.RestierL.LudmanV.et al (2005). Quantitative study of nerves of the human left atrium.Heart Rhythm2518–522. 10.1016/j.hrthm.2005.01.022

  • 32

    ChoiE. K.ShenM. J.HanS.KimD.HwangS.SayfoS.et al (2010). Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs.Circulation1212615–2623. 10.1161/CIRCULATIONAHA.109.919829

  • 33

    ChristT.RozmaritsaN.EngelA.BerkE.KnautM.MetznerK.et al (2014). Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation.Proc. Natl. Acad. Sci. U.S.A.11111193–11198. 10.1073/pnas.1324132111

  • 34

    ColluraC. A.JohnsonJ. N.MoirC.AckermanM. J. (2009). Left cardiac sympathetic denervation for the treatment of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia using video-assisted thoracic surgery.Heart Rhythm6752–759. 10.1016/j.hrthm.2009.03.024

  • 35

    CoumelP. (1996). Autonomic influences in atrial tachyarrhythmias.J. Cardiovasc. Electrophysiol.7999–1007. 10.1111/j.1540-8167.1996.tb00474.x

  • 36

    CoxJ. L.CanavanT. E.SchuesslerR. B.CainM. E.LindsayB. D.StoneC.et al (1991). The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation.J. Thorac. Cardiovasc. Surg.101406–426.

  • 37

    de GrootN. M.HoubenR. P.SmeetsJ. L.BoersmaE.SchottenU.SchalijM. J.et al (2010). Electropathological substrate of longstanding persistent atrial fibrillation in patients with structural heart disease: epicardial breakthrough.Circulation1221674–1682. 10.1161/CIRCULATIONAHA.109.910901

  • 38

    DeftereosS.GiannopoulosG.KossyvakisC.EfremidisM.PanagopoulouV.RaisakisK.et al (2013). Effectiveness of moxonidine to reduce atrial fibrillation burden in hypertensive patients.Am. J. Cardiol.112684–687. 10.1016/j.amjcard.2013.04.049

  • 39

    DenekeT.ChaarH.de GrootJ. R.WildeA. A.LawoT.MundigJ.et al (2011). Shift in the pattern of autonomic atrial innervation in subjects with persistent atrial fibrillation.Heart Rhythm81357–1363. 10.1016/j.hrthm.2011.04.013

  • 40

    Di BiaseL.BurkhardtJ. D.MohantyP.SanchezJ.MohantyS.HortonR.et al (2010). Left atrial appendage: an underrecognized trigger site of atrial fibrillation.Circulation122109–118. 10.1161/CIRCULATIONAHA.109.928903

  • 41

    DimitriH.NgM.BrooksA. G.KuklikP.StilesM. K.LauD. H.et al (2012). Atrial remodeling in obstructive sleep apnea: implications for atrial fibrillation.Heart Rhythm9321–327. 10.1016/j.hrthm.2011.10.017

  • 42

    DimmerC.TavernierR.GjorgovN.Van NootenG.ClementD. L.JordaensL. (1998). Variations of autonomic tone preceding onset of atrial fibrillation after coronary artery bypass grafting.Am. J. Cardiol.8222–25. 10.1016/S0002-9149(98)00231-8

  • 43

    DizonJ. M.ChenK.BacchettaM.ArgenzianoM.ManciniD.BivianoA.et al (2009). A comparison of atrial arrhythmias after heart or double-lung transplantation at a single center: insights into the mechanism of post-operative atrial fibrillation.J. Am. Coll. Cardiol.542043–2048. 10.1016/j.jacc.2009.08.029

  • 44

    DobrevD.FriedrichA.VoigtN.JostN.WettwerE.ChristT.et al (2005). The G protein-gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation.Circulation1123697–3706. 10.1161/CIRCULATIONAHA.105.575332

  • 45

    EcksteinJ.MaesenB.LinzD.ZeemeringS.van HunnikA.VerheuleS.et al (2011). Time course and mechanisms of endo-epicardial electrical dissociation during atrial fibrillation in the goat.Cardiovasc. Res.89816–824. 10.1093/cvr/cvq336

  • 46

    EdwardsL. P.Brown-BryanT. A.McLeanL.ErnsbergerP. (2012). Pharmacological properties of the central antihypertensive agent, moxonidine.Cardiovasc. Ther.30199–208. 10.1111/j.1755-5922.2011.00268.x

  • 47

    EhrlichJ. R.HohnloserS. H.NattelS. (2006). Role of angiotensin system and effects of its inhibition in atrial fibrillation: clinical and experimental evidence.Eur. Heart J.27512–518. 10.1093/eurheartj/ehi668

  • 48

    EslerM. (2004). Looking at the sympathetic nervous system as a primary source.Handb. Hypertens.2281–102.

  • 49

    EslerM.AlvarengaM.PierC.RichardsJ.El-OstaA.BartonD.et al (2006a). The neuronal noradrenaline transporter, anxiety and cardiovascular disease.J. Psychopharmacol.20(4 Suppl.)60–66. 10.1177/1359786806066055

  • 50

    EslerM.StraznickyN.EikelisN.MasuoK.LambertG.LambertE. (2006b). Mechanisms of sympathetic activation in obesity-related hypertension.Hypertension48787–796. 10.1161/01.HYP.0000242642.42177.49

  • 51

    FergusonM.RyanG. B.BellC. (1986). Localization of sympathetic and sensory neurons innervating the rat kidney.J. Auton Nerv. Syst.16279–288. 10.1016/0165-1838(86)90034-2

  • 52

    FeyzL.TheunsD. A.BhagwandienR.StrachinaruM.KardysI.Van MieghemN. M.et al (2018). Atrial fibrillation reduction by renal sympathetic denervation: 12 months’ results of the AFFORD study.Clin. Res. Cardiol.10.1007/s00392-018-1391-3[Epub ahead of print].

  • 53

    FlackeJ. W.BloorB. C.FlackeW. E.WongD.DazzaS.SteadS. W.et al (1987). Reduced narcotic requirement by clonidine with improved hemodynamic and adrenergic stability in patients undergoing coronary bypass surgery.Anesthesiology6711–19. 10.1097/00000542-198707000-00003

  • 54

    FurukawaT.HiraoK.Horikawa-TanamiT.HachiyaH.IsobeM. (2009). Influence of autonomic stimulation on the genesis of atrial fibrillation in remodeled canine atria not the same as in normal atria.Circ. J.73468–475. 10.1253/circj.CJ-08-0869

  • 55

    GamiA. S.HodgeD. O.HergesR. M.OlsonE. J.NykodymJ.KaraT.et al (2007). Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation.J. Am. Coll. Cardiol.49565–571. 10.1016/j.jacc.2006.08.060

  • 56

    GattoneV. H.IIMarfurtC. F.DallieS. (1986). Extrinsic innervation of the rat kidney: a retrograde tracing study.Am. J. Physiol.250(2 Pt 2)F189–F196. 10.1152/ajprenal.1986.250.2.F189

  • 57

    GhiasM.ScherlagB. J.LuZ.NiuG.MoersA.JackmanW. M.et al (2009). The role of ganglionated plexi in apnea-related atrial fibrillation.J. Am. Coll. Cardiol.542075–2083. 10.1016/j.jacc.2009.09.014

  • 58

    GiannopoulosG.KossyvakisC.EfremidisM.KatsivasA.PanagopoulouV.DoudoumisK.et al (2014). Central sympathetic inhibition to reduce postablation atrial fibrillation recurrences in hypertensive patients: a randomized, controlled study.Circulation1301346–1352. 10.1161/CIRCULATIONAHA.114.010999

  • 59

    GirerdN.MagneJ.PibarotP.VoisineP.DagenaisF.MathieuP. (2011). Postoperative atrial fibrillation predicts long-term survival after aortic-valve surgery but not after mitral-valve surgery: a retrospective study.BMJ Open1:e000385. 10.1136/bmjopen-2011-000385

  • 60

    GoetteA.StaackT.RockenC.ArndtM.GellerJ. C.HuthC.et al (2000). Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation.J. Am. Coll. Cardiol.351669–1677. 10.1016/S0735-1097(00)00611-2

  • 61

    GouldP. A.YiiM.McLeanC.FinchS.MarshallT.LambertG. W.et al (2006). Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation.Pacing Clin. Electrophysiol.29821–829. 10.1111/j.1540-8159.2006.00447.x

  • 62

    GrassiG.SeravalleG.CattaneoB. M.BollaG. B.LanfranchiA.ColomboM.et al (1995). Sympathetic activation in obese normotensive subjects.Hypertension25(4 Pt 1)560–563. 10.1161/01.HYP.25.4.560

  • 63

    GreiserM.KerfantB. G.WilliamsG. S.VoigtN.HarksE.DibbK. M.et al (2014). Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytes.J. Clin. Invest.1244759–4772. 10.1172/JCI70102

  • 64

    GrobanL.DolinskiS. Y.ZvaraD. A.OaksT. (2000). Thoracic epidural analgesia: its role in postthoracotomy atrial arrhythmias.J. Cardiothorac. Vasc. Anesth.14662–665. 10.1053/jcan.2000.18318

  • 65

    HaenniA.LithellH. (1999). Moxonidine improves insulin sensitivity in insulin-resistant hypertensives.J. Hypertens.17S29–S35.

  • 66

    HaissaguerreM.HociniM.DenisA.ShahA. J.KomatsuY.YamashitaS.et al (2014). Driver domains in persistent atrial fibrillation.Circulation130530–538. 10.1161/CIRCULATIONAHA.113.005421

  • 67

    HaissaguerreM.JaisP.ShahD. C.TakahashiA.HociniM.QuiniouG.et al (1998). Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins.N. Engl. J. Med.339659–666. 10.1056/NEJM199809033391003

  • 68

    HaissaguerreM.SandersP.HociniM.TakahashiY.RotterM.SacherF.et al (2005). Catheter ablation of long-lasting persistent atrial fibrillation: critical structures for termination.J. Cardiovasc. Electrophysiol.161125–1137. 10.1111/j.1540-8167.2005.00307.x

  • 69

    HanS.KobayashiK.JoungB.PiccirilloG.MaruyamaM.VintersH. V.et al (2012). Electroanatomic remodeling of the left stellate ganglion after myocardial infarction.J. Am. Coll. Cardiol.59954–961. 10.1016/j.jacc.2011.11.030

  • 70

    HatemS. N.SandersP. (2014). Epicardial adipose tissue and atrial fibrillation.Cardiovasc. Res.102205–213. 10.1093/cvr/cvu045

  • 71

    HeB.LuZ.HeW.WuL.CuiB.HuX.et al (2013). Effects of ganglionated plexi ablation on ventricular electrophysiological properties in normal hearts and after acute myocardial ischemia.Int. J. Cardiol.16886–93. 10.1016/j.ijcard.2012.09.067

  • 72

    HouY.HuJ.PoS. S.WangH.ZhangL.ZhangF.et al (2013). Catheter-based renal sympathetic denervation significantly inhibits atrial fibrillation induced by electrical stimulation of the left stellate ganglion and rapid atrial pacing.PLoS One8:e78218. 10.1371/journal.pone.0078218

  • 73

    HouY.ScherlagB. J.LinJ.ZhouJ.SongJ.ZhangY.et al (2007). Interactive atrial neural network: determining the connections between Ganglionated plexi.Heart Rhythm456–63. 10.1016/j.hrthm.2006.09.020

  • 74

    HuggettR. J.BurnsJ.MackintoshA. F.MaryD. A. (2004). Sympathetic neural activation in nondiabetic metabolic syndrome and its further augmentation by hypertension.Hypertension44847–852. 10.1161/01.HYP.0000147893.08533.d8

  • 75

    HuggettR. J.HogarthA. J.MackintoshA. F.MaryD. A. (2006). Sympathetic nerve hyperactivity in non-diabetic offspring of patients with type 2 diabetes mellitus.Diabetologia492741–2744. 10.1007/s00125-006-0399-9

  • 76

    IacobellisG.RibaudoM. C.AssaelF.VecciE.TibertiC.ZappaterrenoA.et al (2003). Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk.J. Clin. Endocrinol. Metab.885163–5168. 10.1210/jc.2003-030698

  • 77

    IwasakiY. K.NishidaK.KatoT.NattelS. (2011). Atrial fibrillation pathophysiology: implications for management.Circulation1242264–2274. 10.1161/CIRCULATIONAHA.111.019893

  • 78

    JalifeJ.BerenfeldO.MansourM. (2002). Mother rotors and fibrillatory conduction: a mechanism of atrial fibrillation.Cardiovasc. Res.54204–216. 10.1016/S0008-6363(02)00223-7

  • 79

    JansenA. S.WessendorfM. W.LoewyA. D. (1995). Transneuronal labeling of CNS neuropeptide and monoamine neurons after pseudorabies virus injections into the stellate ganglion.Brain Res.6831–24. 10.1016/0006-8993(95)00276-V

  • 80

    JayachandranJ. V.SihH. J.WinkleW.ZipesD. P.HutchinsG. D.OlginJ. E. (2000). Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation.Circulation1011185–1191. 10.1161/01.CIR.101.10.1185

  • 81

    JideusL.JoachimssonP. O.StridsbergM.EricsonM.TydenH.NilssonL.et al (2001). Thoracic epidural anesthesia does not influence the occurrence of postoperative sustained atrial fibrillation.Ann. Thorac. Surg.7265–71. 10.1016/S0003-4975(01)02631-5

  • 82

    JuliusS.JamersonK. (1994). Sympathetics, insulin resistance and coronary risk in hypertension: the ’chicken-and-egg’ question.J. Hypertens.12495–502. 10.1097/00004872-199405000-00001

  • 83

    KalmanJ. M.MunawarM.HowesL. G.LouisW. J.BuxtonB. F.GutteridgeG.et al (1995). Atrial fibrillation after coronary artery bypass grafting is associated with sympathetic activation.Ann. Thorac. Surg.601709–1715. 10.1016/0003-4975(95)00718-0

  • 84

    KatritsisD. G.GiazitzoglouE.ZografosT.PokushalovE.PoS. S.CammA. J. (2011). Rapid pulmonary vein isolation combined with autonomic ganglia modification: a randomized study.Heart Rhythm8672–678. 10.1016/j.hrthm.2010.12.047

  • 85

    KawanoH.OkadaR.YanoK. (2003). Histological study on the distribution of autonomic nerves in the human heart.Heart Vessel1832–39. 10.1007/s003800300005

  • 86

    KawashimaT. (2005). The autonomic nervous system of the human heart with special reference to its origin, course, and peripheral distribution.Anat. Embryol.209425–438. 10.1007/s00429-005-0462-1

  • 87

    KimD. T.LaiA. C.HwangC.FanL. T.KaragueuzianH. S.ChenP. S.et al (2000). The ligament of Marshall: a structural analysis in human hearts with implications for atrial arrhythmias.J. Am. Coll. Cardiol.361324–1327. 10.1016/S0735-1097(00)00819-6

  • 88

    KimE. J.LyassA.WangN.MassaroJ. M.FoxC. S.BenjaminE. J.et al (2014). Relation of hypothyroidism and incident atrial fibrillation (from the Framingham Heart Study).Am. Heart. J.167123–126. 10.1016/j.ahj.2013.10.012

  • 89

    KimuraK.IedaM.FukudaK. (2012). Development, maturation, and transdifferentiation of cardiac sympathetic nerves.Circ. Res.110325–336. 10.1161/CIRCRESAHA.111.257253

  • 90

    KirchhofP.BenussiS.KotechaD.AhlssonA.AtarD.CasadeiB.et al (2016). 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.Eur. Heart J.372893–2962. 10.1093/eurheartj/ehw210

  • 91

    KiuchiM. G.ChenS.E SilverG. R.Rodrigues PazL. M.KiuchiT.de Paula FilhoA. G.et al (2017). The addition of renal sympathetic denervation to pulmonary vein isolation reduces recurrence of paroxysmal atrial fibrillation in chronic kidney disease patients.J. Interv. Card. Electrophysiol.48215–222. 10.1007/s10840-016-0186-6

  • 92

    KrumH.SchlaichM.WhitbournR.SobotkaP. A.SadowskiJ.BartusK.et al (2009). Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.Lancet3731275–1281. 10.1016/S0140-6736(09)60566-3

  • 93

    KühlkampV.SchirdewanA.StanglK.HombergM.PlochM.BeckO. A. (2000). Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled study.J. Am. Coll. Cardiol.36139–146. 10.1016/S0735-1097(00)00693-8

  • 94

    KumagaiK.NakashimaH.UrataH.GondoN.ArakawaK.SakuK. (2003). Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation.J. Am. Coll. Cardiol.412197–2204. 10.1016/S0735-1097(03)00464-9

  • 95

    LambertE.EikelisN.EslerM.DawoodT.SchlaichM.BaylesR.et al (2008). Altered sympathetic nervous reactivity and norepinephrine transporter expression in patients with postural tachycardia syndrome.Circ. Arrhythm Electrophysiol.1103–109. 10.1161/CIRCEP.107.750471

  • 96

    LambertE.SariC. I.DawoodT.NguyenJ.McGraneM.EikelisN.et al (2010). Sympathetic nervous system activity is associated with obesity-induced subclinical organ damage in young adults.Hypertension56351–358. 10.1161/HYPERTENSIONAHA.110.155663

  • 97

    LambertE.StraznickyN.EikelisN.EslerM.DawoodT.MasuoK.et al (2007). Gender differences in sympathetic nervous activity: influence of body mass and blood pressure.J. Hypertens.251411–1419. 10.1097/HJH.0b013e3281053af4

  • 98

    LambertE. A.ThompsonJ.SchlaichM.LaudeD.ElghoziJ. L.EslerM. D.et al (2002). Sympathetic and cardiac baroreflex function in panic disorder.J. Hypertens.202445–2451. 10.1097/01.hjh.0000042882.24999.27

  • 99

    LangerS. Z.CaveroI.MassinghamR. (1980). Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents.Hypertension2372–382. 10.1161/01.HYP.2.4.372

  • 100

    LarssonS. C.DrcaN.WolkA. (2014). Alcohol consumption and risk of atrial fibrillation: a prospective study and dose-response meta-analysis.J. Am. Coll. Cardiol.64281–289. 10.1016/j.jacc.2014.03.048

  • 101

    LauD. H.MackenzieL.KellyD. J.PsaltisP. J.BrooksA. G.WorthingtonM.et al (2010). Hypertension and atrial fibrillation: evidence of progressive atrial remodeling with electrostructural correlate in a conscious chronically instrumented ovine model.Heart Rhythm71282–1290. 10.1016/j.hrthm.2010.05.010

  • 102

    LepranI.PappJ. G. (1994). Effect of moxonidine on arrhythmias induced by coronary artery occlusion and reperfusion.J. Cardiovasc. Pharmacol.24(Suppl. 1)S9–S15. 10.1097/00005344-199424001-00003

  • 103

    LesskeJ.FletcherE. C.BaoG.UngerT. (1997). Hypertension caused by chronic intermittent hypoxia–influence of chemoreceptors and sympathetic nervous system.J. Hypertens.15(12 Pt 2)1593–1603.

  • 104

    LiD.FarehS.LeungT. K.NattelS. (1999). Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort.Circulation10087–95. 10.1161/01.CIR.100.1.87

  • 105

    LimP. B.Malcolme-LawesL. C.StuberT.WrightI.FrancisD. P.DaviesD. W.et al (2011). Intrinsic cardiac autonomic stimulation induces pulmonary vein ectopy and triggers atrial fibrillation in humans.J. Cardiovasc. Electrophysiol.22638–646. 10.1111/j.1540-8167.2010.01992.x

  • 106

    LinzD.HohlM.NickelA.MahfoudF.WagnerM.EwenS.et al (2013a). Effect of renal denervation on neurohumoral activation triggering atrial fibrillation in obstructive sleep apnea.Hypertension62767–774. 10.1161/HYPERTENSIONAHA.113.01728

  • 107

    LinzD.MahfoudF.SchottenU.UkenaC.HohlM.NeubergerH. R.et al (2013b). Renal sympathetic denervation provides ventricular rate control but does not prevent atrial electrical remodeling during atrial fibrillation.Hypertension61225–231. 10.1161/HYPERTENSIONAHA.111.00182

  • 108

    LinzD.MahfoudF.SchottenU.UkenaC.NeubergerH. R.WirthK.et al (2012). Renal sympathetic denervation suppresses postapneic blood pressure rises and atrial fibrillation in a model for sleep apnea.Hypertension60172–178. 10.1161/HYPERTENSIONAHA.112.191965

  • 109

    LiuS. S.BlockB. M.WuC. L. (2004). Effects of perioperative central neuraxial analgesia on outcome after coronary artery bypass surgery: a meta-analysis.Anesthesiology101153–161. 10.1097/00000542-200407000-00024

  • 110

    LuZ.ScherlagB. J.LinJ.NiuG.GhiasM.JackmanW. M.et al (2008). Autonomic mechanism for complex fractionated atrial electrograms: evidence by fast fourier transform analysis.J. Cardiovasc. Electrophysiol.19835–842. 10.1111/j.1540-8167.2008.01131.x

  • 111

    LuZ.ScherlagB. J.LinJ.YuL.GuoJ. H.NiuG.et al (2009). Autonomic mechanism for initiation of rapid firing from atria and pulmonary veins: evidence by ablation of ganglionated plexi.Cardiovasc. Res.84245–252. 10.1093/cvr/cvp194

  • 112

    LubitzS. A.LunettaK. L.LinH.ArkingD. E.TrompetS.LiG.et al (2014). Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.J. Am. Coll. Cardiol.631200–1210. 10.1016/j.jacc.2013.12.015

  • 113

    MahabadiA. A.MassaroJ. M.RositoG. A.LevyD.MurabitoJ. M.WolfP. A.et al (2009). Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study.Eur. Heart J.30850–856. 10.1093/eurheartj/ehn573

  • 114

    MahajanR.LauD. H.BrooksA. G.ShippN. J.ManavisJ.WoodJ. P.et al (2015). Electrophysiological, electroanatomical, and structural remodeling of the Atria as consequences of sustained obesity.J. Am. Coll. Cardiol.661–11. 10.1016/j.jacc.2015.04.058

  • 115

    MahfoudF.SchlaichM.KindermannI.UkenaC.CremersB.BrandtM. C.et al (2011). Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study.Circulation1231940–1946. 10.1161/CIRCULATIONAHA.110.991869

  • 116

    Malcolme-LawesL. C.LimP. B.WrightI.KojodjojoP.Koa-WingM.Jamil-CopleyS.et al (2013). Characterization of the left atrial neural network and its impact on autonomic modification procedures.Circ. Arrhythm Electrophysiol.6632–640. 10.1161/CIRCEP.113.000193

  • 117

    MandapatiR.SkanesA.ChenJ.BerenfeldO.JalifeJ. (2000). Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart.Circulation101194–199. 10.1161/01.CIR.101.2.194

  • 118

    ManolisA. J.RoseiE. A.CocaA.CifkovaR.ErdineS. E.KjeldsenS.et al (2012). Hypertension and atrial fibrillation: diagnostic approach, prevention and treatment. Position paper of the Working Group ’Hypertension Arrhythmias and Thrombosis’ of the European Society of Hypertension.J. Hypertens.30239–252. 10.1097/HJH.0b013e32834f03bf

  • 119

    MarronK.WhartonJ.SheppardM. N.FaganD.RoystonD.KuhnD. M.et al (1995). Distribution, morphology, and neurochemistry of endocardial and epicardial nerve terminal arborizations in the human heart.Circulation922343–2351. 10.1161/01.CIR.92.8.2343

  • 120

    MarronK.WhartonJ.SheppardM. N.GulbenkianS.RoystonD.YacoubM. H.et al (1994). Human endocardial innervation and its relationship to the endothelium: an immunohistochemical, histochemical, and quantitative study.Cardiovasc. Res.281490–1499. 10.1093/cvr/28.10.1490

  • 121

    MatthewsV. B.ElliotR. H.RudnickaC.HricovaJ.HeratL.SchlaichM. P. (2017). Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2.J. Hypertens.352059–2068. 10.1097/HJH.0000000000001434

  • 122

    McLellanA. J.SchlaichM. P.TaylorA. J.PrabhuS.HeringD.HammondL.et al (2015). Reverse cardiac remodeling after renal denervation: atrial electrophysiologic and structural changes associated with blood pressure lowering.Heart Rhythm12982–990. 10.1016/j.hrthm.2015.01.039

  • 123

    MecklerR. L.WeaverL. C. (1984). Comparison of the distributions of renal and splenic neurons in sympathetic ganglia.J. Auton Nerv. Syst.11189–200. 10.1016/0165-1838(84)90076-6

  • 124

    MeloJ.VoigtP.SonmezB.FerreiraM.AbecasisM.RebochoM.et al (2004). Ventral cardiac denervation reduces the incidence of atrial fibrillation after coronary artery bypass grafting.J. Thorac. Cardiovasc. Surg.127511–516. 10.1016/S0022

  • 125

    MestH. J.ThomsenP.RaapA. (1995). Antiarrhythmic effect of the selective I1-imidazoline receptor modulator moxonidine on ouabain-induced cardiac arrhythmia in guinea pigs.Ann. N. Y. Acad. Sci.763620–633. 10.1111/j.1749-6632.1995.tb32457.x

  • 126

    MikhaylovE.KanidievaA.SviridovaN.AbramovM.GureevS.Szili-TorokT.et al (2011). Outcome of anatomic ganglionated plexi ablation to treat paroxysmal atrial fibrillation: a 3-year follow-up study.Europace13362–370. 10.1093/europace/euq416

  • 127

    MoeG. K.AbildskovJ. A. (1959). Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge.Am. Heart. J.5859–70. 10.1016/0002-8703(59)90274-1

  • 128

    MoeG. K.RheinboldtW. C.AbildskovJ. A. (1964). A computer model of atrial fibrillation.Am. Heart J.67200–220. 10.1016/0002-8703(64)90371-0

  • 129

    MohanR. M.GoldingS.PatersonD. J. (2001). Intermittent hypoxia modulates nNOS expression and heart rate response to sympathetic nerve stimulation.Am. J. Physiol. Heart Circ. Physiol.281H132–H138. 10.1152/ajpheart.2001.281.1.H132

  • 130

    MungerT. M.DongY. X.MasakiM.OhJ. K.MankadS. V.BorlaugB. A.et al (2012). Electrophysiological and hemodynamic characteristics associated with obesity in patients with atrial fibrillation.J. Am. Coll. Cardiol.60851–860. 10.1016/j.jacc.2012.03.042

  • 131

    NagashimaK.OkumuraY.WatanabeI.NakaiT.OhkuboK.KofuneM.et al (2012). Does location of epicardial adipose tissue correspond to endocardial high dominant frequency or complex fractionated atrial electrogram sites during atrial fibrillation?Circ. Arrhythm Electrophysiol.5676–683. 10.1161/CIRCEP.112.971200

  • 132

    NakaharaS.HoriY.KobayashiS.SakaiY.TaguchiI.TakayanagiK.et al (2014). Epicardial adipose tissue-based defragmentation approach to persistent atrial fibrillation: its impact on complex fractionated electrograms and ablation outcome.Heart Rhythm111343–1351. 10.1016/j.hrthm.2014.04.040

  • 133

    NakayamaK. (1961). Surgical removal of the carotid body for bronchial asthma.Dis. Chest40595–604. 10.1378/chest.40.6.595

  • 134

    NarayanS. M.KrummenD. E.ShivkumarK.CloptonP.RappelW. J.MillerJ. M. (2012). Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial.J. Am. Coll. Cardiol.60628–636. 10.1016/j.jacc.2012.05.022

  • 135

    NattelS. (2002). New ideas about atrial fibrillation 50 years on.Nature415219–226. 10.1038/415219a

  • 136

    NergårdhA. K.RosenqvistM.NordlanderR.FrickM. (2007). Maintenance of sinus rhythm with metoprolol CR initiated before cardioversion and repeated cardioversion of atrial fibrillation: a randomized double-blind placebo-controlled study.Eur. Heart J.281351–1357. 10.1093/eurheartj/ehl544

  • 137

    NgJ.VilluendasR.CokicI.SchliamserJ. E.GordonD.KoduriH.et al (2011). Autonomic remodeling in the left atrium and pulmonary veins in heart failure: creation of a dynamic substrate for atrial fibrillation.Circ. Arrhythm Electrophysiol.4388–396. 10.1161/CIRCEP.110.959650

  • 138

    NguyenB. L.FishbeinM. C.ChenL. S.ChenP. S.MasroorS. (2009). Histopathological substrate for chronic atrial fibrillation in humans.Heart Rhythm6454–460. 10.1016/j.hrthm.2009.01.010

  • 139

    OgawaM.TanA. Y.SongJ.KobayashiK.FishbeinM. C.LinS. F.et al (2009). Cryoablation of stellate ganglia and atrial arrhythmia in ambulatory dogs with pacing-induced heart failure.Heart Rhythm61772–1779. 10.1016/j.hrthm.2009.08.011

  • 140

    OgawaM.ZhouS.TanA. Y.SongJ.GholmiehG.FishbeinM. C.et al (2007). Left stellate ganglion and vagal nerve activity and cardiac arrhythmias in ambulatory dogs with pacing-induced congestive heart failure.J. Am. Coll. Cardiol.50335–343. 10.1016/j.jacc.2007.03.045

  • 141

    OkinP. M.WachtellK.DevereuxR. B.HarrisK. E.JernS.KjeldsenS. E.et al (2006). Regression of electrocardiographic left ventricular hypertrophy and decreased incidence of new-onset atrial fibrillation in patients with hypertension.JAMA2961242–1248. 10.1001/jama.296.10.1242

  • 142

    PalatiniP.VrizO.NesbittS.AmerenaJ.MajahalmeS.ValentiniM.et al (1999). Parental hyperdynamic circulation predicts insulin resistance in offspring: the Tecumseh Offspring Study.Hypertension33769–774. 10.1161/01.HYP.33.3.769

  • 143

    PathakR. K.MiddeldorpM. E.LauD. H.MehtaA. B.MahajanR.TwomeyD.et al (2014). Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study.J. Am. Coll. Cardiol.642222–2231. 10.1016/j.jacc.2014.09.028

  • 144

    PattersonE.JackmanW. M.BeckmanK. J.LazzaraR.LockwoodD.ScherlagB. J.et al (2007). Spontaneous pulmonary vein firing in man: relationship to tachycardia-pause early afterdepolarizations and triggered arrhythmia in canine pulmonary veins in vitro.J. Cardiovasc. Electrophysiol.181067–1075. 10.1111/j.1540-8167.2007.00909.x

  • 145

    PattersonE.PoS. S.ScherlagB. J.LazzaraR. (2005). Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation.Heart Rhythm2624–631. 10.1016/j.hrthm.2005.02.012

  • 146

    PauzaD. H.SkripkaV.PauzieneN.StropusR. (2000). Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart.Anat. Rec.259353–382. 10.1002/1097-0185(20000801)259:4<353::AID-AR10>3.0.CO;2-R

  • 147

    PetraitieneV.PauzaD. H.BenetisR. (2014). Distribution of adrenergic and cholinergic nerve fibres within intrinsic nerves at the level of the human heart hilum.Eur. J. Cardiothorac. Surg.451097–1105. 10.1093/ejcts/ezt575

  • 148

    PilowskyP.Llewellyn-SmithI. J.MinsonJ.ChalmersJ. (1992). Sympathetic preganglionic neurons in rabbit spinal cord that project to the stellate or the superior cervical ganglion.Brain Res.577181–188. 10.1016/0006-8993(92)90272-B

  • 149

    PokushalovE.KozlovB.RomanovA.StrelnikovA.BayramovaS.SergeevichevD.et al (2015). Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: One-year follow-up of a randomized pilot study.Circ. Arrhythm. Electrophysiol.81334–1341. 10.1161/CIRCEP.115.003199

  • 150

    PokushalovE.RomanovA.CorbucciG.ArtyomenkoS.BaranovaV.TurovA.et al (2012). A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension.J. Am. Coll. Cardiol.601163–1170. 10.1016/j.jacc.2012.05.036

  • 151

    PokushalovE.RomanovA.ShugayevP.ArtyomenkoS.ShirokovaN.TurovA.et al (2009). Selective ganglionated plexi ablation for paroxysmal atrial fibrillation.Heart Rhythm61257–1264. 10.1016/j.hrthm.2009.05.018

  • 152

    PrystowskyE. N.BensonD. W.Jr.FusterV.HartR. G.KayG. N.MyerburgR. J. (1996). Management of patients with atrial fibrillation. A statement for healthcare professionals. From the subcommittee on electrocardiography and electrophysiology, American Heart Association.Circulation931262–1277. 10.1161/01.CIR.93.6.1262

  • 153

    PsatyB. M.ManolioT. A.KullerL. H.KronmalR. A.CushmanM.FriedL. P.et al (1997). Incidence of and risk factors for atrial fibrillation in older adults.Circulation962455–2461. 10.1161/01.CIR.96.7.2455

  • 154

    RavelliF.MaseM. (2014). Computational mapping in atrial fibrillation: how the integration of signal-derived maps may guide the localization of critical sources.Europace16714–723. 10.1093/europace/eut376

  • 155

    ReilJ. C.HohlM.SelejanS.LippP.DrautzF.KazakowA.et al (2012). Aldosterone promotes atrial fibrillation.Eur. Heart J.332098–2108. 10.1093/eurheartj/ehr266

  • 156

    RomanovA.PokushalovE.PonomarevD.BayramovaS.ShabanovV.LosikD.et al (2018). Long-term suppression of atrial fibrillation by botulinum toxin injection into epicardial fat pads in patients undergoing cardiac surgery: three-year follow-up of a randomized study.Heart Rhythm10.1016/j.hrthm.2018.08.019[Epub ahead of print].

  • 157

    RomanovA.PokushalovE.PonomarevD.StrelnikovA.ShabanovV.LosikD.et al (2017). Pulmonary vein isolation with concomitant renal artery denervation is associated with reduction in both arterial blood pressure and atrial fibrillation burden: data from implantable cardiac monitor.Cardiovasc. Ther.35:e12264. 10.1111/1755-5922.12264

  • 158

    RothA.KaluskiE.FelnerS.HellerK.LaniadoS. (1992). Clonidine for patients with rapid atrial fibrillation.Ann. Intern. Med.116388–390. 10.7326/0003-4819-116-5-388

  • 159

    SahadevanJ.RyuK.PeltzL.KhrestianC. M.StewartR. W.MarkowitzA. H.et al (2004). Epicardial mapping of chronic atrial fibrillation in patients: preliminary observations.Circulation1103293–3299. 10.1161/01.CIR.0000147781.02738.13

  • 160

    SandersP.NalliahC. J.DuboisR.TakahashiY.HociniM.RotterM.et al (2006). Frequency mapping of the pulmonary veins in paroxysmal versus permanent atrial fibrillation.J. Cardiovasc. Electrophysiol.17965–972. 10.1111/j.1540-8167.2006.00546.x

  • 161

    SankaranarayananR.KirkwoodG.DibbK.GarrattC. J. (2013). Comparison of Atrial Fibrillation in the young versus that in the elderly: a review.Cardiol. Res. Pract.2013:976976. 10.1155/2013/976976

  • 162

    SarinS.WengerC.MarwahaA.QureshiA.GoB. D.WoomertC. A.et al (2008). Clinical significance of epicardial fat measured using cardiac multislice computed tomography.Am. J. Cardiol.102767–771. 10.1016/j.amjcard.2008.04.058

  • 163

    ScherlagB. J.YamanashiW.PatelU.LazzaraR.JackmanW. M. (2005). Autonomically induced conversion of pulmonary vein focal firing into atrial fibrillation.J. Am. Coll. Cardiol.451878–1886. 10.1016/j.jacc.2005.01.057

  • 164

    SchlaichM. P.KrumH.SobotkaP. A. (2010). Renal sympathetic nerve ablation: the new frontier in the treatment of hypertension.Curr. Hypertens. Rep.1239–46. 10.1007/s11906-009-0078-6

  • 165

    SchnabelR. B.YinX.GonaP.LarsonM. G.BeiserA. S.McManusD. D.et al (2015). 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study.Lancet386154–162. 10.1016/S0140-6736(14)61774-8

  • 166

    SchoonderwoerdB. A.SmitM. D.PenL.Van GelderI. C. (2008). New risk factors for atrial fibrillation: causes of ’not-so-lone atrial fibrillation’.Europace10668–673. 10.1093/europace/eun124

  • 167

    SchottenU.VerheuleS.KirchhofP.GoetteA. (2011). Pathophysiological mechanisms of atrial fibrillation: a translational appraisal.Physiol. Rev.91265–325. 10.1152/physrev.00031.2009

  • 168

    SchuesslerR. B.GraysonT. M.BrombergB. I.CoxJ. L.BoineauJ. P. (1992). Cholinergically mediated tachyarrhythmias induced by a single extrastimulus in the isolated canine right atrium.Circ. Res.711254–1267. 10.1161/01.RES.71.5.1254

  • 169

    SchultzH. D.LiY. L. (2007). Carotid body function in heart failure.Respir. Physiol. Neurobiol.157171–185. 10.1016/j.resp.2007.02.011

  • 170

    SchwartzP. J.MotoleseM.PollaviniG.LottoA.RubertiU. G. O.TrazziR.et al (1992). Prevention of sudden cardiac death after a first myocardial infarction by pharmacologic or surgical antiadrenergic interventions.J. Cardiovasc. Electrophysiol.32–16. 10.1111/j.1540-8167.1992.tb01090.x

  • 171

    SchwartzP. J.SneboldN. G.BrownA. M. (1976). Effects of unilateral cardiac sympathetic denervation on the ventricular fibrillation threshold.Am. J. Cardiol.371034–1040. 10.1016/0002-9149(76)90420-3

  • 172

    ScottN. B.TurfreyD. J.RayD. A.NzewiO.SutcliffeN. P.LalA. B.et al (2001). A prospective randomized study of the potential benefits of thoracic epidural anesthesia and analgesia in patients undergoing coronary artery bypass grafting.Anesth. Analg.93528–535. 10.1097/00000539-200109000-00003

  • 173

    SekiA.GreenH. R.LeeT. D.HongL.TanJ.VintersH. V.et al (2014). Sympathetic nerve fibers in human cervical and thoracic vagus nerves.Heart Rhythm111411–1417. 10.1016/j.hrthm.2014.04.032

  • 174

    SelmerC.OlesenJ. B.HansenM. L.LindhardsenJ.OlsenA. M.MadsenJ. C.et al (2012). The spectrum of thyroid disease and risk of new onset atrial fibrillation: a large population cohort study.BMJ345:e7895. 10.1136/bmj.e7895

  • 175

    SharifovO. F.FedorovV. V.BeloshapkoG. G.GlukhovA. V.YushmanovaA. V.RosenshtraukhL. V. (2004). Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs.J. Am. Coll. Cardiol.43483–490. 10.1016/j.jacc.2003.09.030

  • 176

    ShenM. J.ChoiE. K.TanA. Y.LinS. F.FishbeinM. C.ChenL. S.et al (2011). Neural mechanisms of atrial arrhythmias.Nat. Rev. Cardiol.930–39. 10.1038/nrcardio.2011.139

  • 177

    ShenM. J.ZipesD. P. (2014). Role of the autonomic nervous system in modulating cardiac arrhythmias.Circ. Res.1141004–1021. 10.1161/CIRCRESAHA.113.302549

  • 178

    SkanesA. C.MandapatiR.BerenfeldO.DavidenkoJ. M.JalifeJ. (1998). Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart.Circulation981236–1248. 10.1161/01.CIR.98.12.1236

  • 179

    SripairojthikoonW.WyssJ. M. (1987). Cells of origin of the sympathetic renal innervation in rat.Am. J. Physiol.252(6 Pt 2)F957–F963. 10.1152/ajprenal.1987.252.6.F957

  • 180

    SvircevicV.van DijkD.NierichA. P.PassierM. P.KalkmanC. J.van der HeijdenG. J.et al (2011). Meta-analysis of thoracic epidural anesthesia versus general anesthesia for cardiac surgery.Anesthesiology114271–282. 10.1097/ALN.0b013e318201d300

  • 181

    Symplicity HTN-2 Investigators, EslerM. D.KrumH.SobotkaP. A.SchlaichM. P.SchmiederR. E.et al (2010). Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.Lancet3761903–1909. 10.1016/S0140-6736(10)62039-9

  • 182

    TanA. Y.LiH.Wachsmann-HogiuS.ChenL. S.ChenP. S.FishbeinM. C. (2006). Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implications for catheter ablation of atrial-pulmonary vein junction.J. Am. Coll. Cardiol.48132–143. 10.1016/j.jacc.2006.02.054

  • 183

    TanA. Y.ZhouS.JungB. C.OgawaM.ChenL. S.FishbeinM. C.et al (2008a). Ectopic atrial arrhythmias arising from canine thoracic veins during in vivo stellate ganglia stimulation.Am. J. Physiol. Heart Circ. Physiol.295H691–H698. 10.1152/ajpheart.01321.2007

  • 184

    TanA. Y.ZhouS.OgawaM.SongJ.ChuM.LiH.et al (2008b). Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines.Circulation118916–925. 10.1161/CIRCULATIONAHA.108.776203

  • 185

    TanZ. Y.LuY.WhiteisC. A.SimmsA. E.PatonJ. F.ChapleauM. W.et al (2010). Chemoreceptor hypersensitivity, sympathetic excitation, and overexpression of ASIC and TASK channels before the onset of hypertension in SHR.Circ. Res.106536–545. 10.1161/CIRCRESAHA.109.206946

  • 186

    TsaiC. T.LaiL. P.LinJ. L.ChiangF. T.HwangJ. J.RitchieM. D.et al (2004). Renin-angiotensin system gene polymorphisms and atrial fibrillation.Circulation1091640–1646. 10.1161/01.CIR.0000124487.36586.26

  • 187

    TsaiW. C.ChanY. H.ChindaK.ChenZ.PatelJ.ShenC.et al (2017). Effects of renal sympathetic denervation on the stellate ganglion and brain stem in dogs.Heart Rhythm14255–262. 10.1016/j.hrthm.2016.10.003

  • 188

    UkenaC.MahfoudF.SpiesA.KindermannI.LinzD.CremersB.et al (2013). Effects of renal sympathetic denervation on heart rate and atrioventricular conduction in patients with resistant hypertension.Int. J. Cardiol.1672846–2851. 10.1016/j.ijcard.2012.07.027

  • 189

    UlphaniJ. S.AroraR.CainJ. H.VilluendasR.ShenS.GordonD.et al (2007). The ligament of marshall as a parasympathetic conduit.Am. J. Physiol. Heart Circ. Physiol.293H1629–H1635. 10.1152/ajpheart.00139.2007

  • 190

    Van WagonerD. R.PondA. L.LamorgeseM.RossieS. S.McCarthyP. M.NerbonneJ. M. (1999). Atrial L-type Ca2+ currents and human atrial fibrillation.Circ. Res.85428–436. 10.1161/01.RES.85.5.428

  • 191

    VaqueroM.CalvoD.JalifeJ. (2008). Cardiac fibrillation: from ion channels to rotors in the human heart.Heart Rhythm5872–879. 10.1016/j.hrthm.2008.02.034

  • 192

    VerheuleS.TuylsE.van HunnikA.KuiperM.SchottenU.AllessieM. (2010). Fibrillatory conduction in the atrial free walls of goats in persistent and permanent atrial fibrillation.Circ. Arrhythm Electrophysiol.3590–599. 10.1161/CIRCEP.109.931634

  • 193

    VermondR. A.GeelhoedB.VerweijN.TielemanR. G.Van der HarstP.HillegeH. L.et al (2015). Incidence of Atrial Fibrillation and relationship with cardiovascular events, heart failure, and mortality: a community-based study from the Netherlands.J. Am. Coll. Cardiol.661000–1007. 10.1016/j.jacc.2015.06.1314

  • 194

    VoigtN.HeijmanJ.WangQ.ChiangD. Y.LiN.KarckM.et al (2014). Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation.Circulation129145–156. 10.1161/CIRCULATIONAHA.113.006641

  • 195

    VoigtN.LiN.WangQ.WangW.TraffordA. W.Abu-TahaI.et al (2012). Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation.Circulation1252059–2070. 10.1161/CIRCULATIONAHA.111.067306

  • 196

    VollmannD.SossallaS.SchroeterM. R.ZabelM. (2013). Renal artery ablation instead of pulmonary vein ablation in a hypertensive patient with symptomatic, drug-resistant, persistent atrial fibrillation.Clin. Res. Cardiol.102315–318. 10.1007/s00392-012-0529-y

  • 197

    WachtellK.LehtoM.GerdtsE.OlsenM. H.HornestamB.DahlofB.et al (2005). Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study.J. Am. Coll. Cardiol.45712–719. 10.1016/j.jacc.2004.10.068

  • 198

    WakiliR.VoigtN.KaabS.DobrevD.NattelS. (2011). Recent advances in the molecular pathophysiology of atrial fibrillation.J. Clin. Invest.1212955–2968. 10.1172/JCI46315

  • 199

    WangX.HuangC.ZhaoQ.HuangH.TangY.DaiZ.et al (2015). Effect of renal sympathetic denervation on the progression of paroxysmal atrial fibrillation in canines with long-term intermittent atrial pacing.Europace17647–654. 10.1093/europace/euu212

  • 200

    WitkowskiA.PrejbiszA.FlorczakE.KadzielaJ.SliwinskiP.BielenP.et al (2011). Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea.Hypertension58559–565. 10.1161/HYPERTENSIONAHA.111.173799

  • 201

    YagiS.HirataY.IseT.KusunoseK.YamadaH.FukudaD.et al (2017). Canagliflozin reduces epicardial fat in patients with type 2 diabetes mellitus.Diabetol. Metab. Syndr.9:78. 10.1186/s13098-017-0275-4

  • 202

    YangS. S.HanW.CaoY.DongG.ZhouG.LiW. M.et al (2011). Effects of high thoracic epidural anesthesia on atrial electrophysiological characteristics and sympathetic nerve sprouting in a canine model of atrial fibrillation.Basic Res. Cardiol.106495–506. 10.1007/s00395-011-0154-3

  • 203

    ZhouQ.HuJ.GuoY.ZhangF.YangX.ZhangL.et al (2013). Effect of the stellate ganglion on atrial fibrillation and atrial electrophysiological properties and its left-right asymmetry in a canine model.Exp. Clin. Cardiol.1838–42.

  • 204

    ZinmanB.WannerC.LachinJ. M.FitchettD.BluhmkiE.HantelS.et al (2015). Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N. Engl. J. Med.3732117–2128. 10.1056/NEJMoa1504720

  • 205

    ZlochiverS.YamazakiM.KalifaJ.BerenfeldO. (2008). Rotor meandering contributes to irregularity in electrograms during atrial fibrillation.Heart Rhythm5846–854. 10.1016/j.hrthm.2008.03.010

Summary

Keywords

autonomic nervous system, hypertension, neuromodulation, atrial fibrillation, sympathetic overdrive

Citation

Carnagarin R, Kiuchi MG, Ho JK, Matthews VB and Schlaich MP (2019) Sympathetic Nervous System Activation and Its Modulation: Role in Atrial Fibrillation. Front. Neurosci. 12:1058. doi: 10.3389/fnins.2018.01058

Received

03 September 2018

Accepted

31 December 2018

Published

23 January 2019

Volume

12 - 2018

Edited by

Alberto Porta, University of Milan, Italy

Reviewed by

Michela Masè, University of Trento, Italy; Raffaello Furlan, Humanitas Research Hospital, Italy

Updates

Copyright

© 2019 Carnagarin, Kiuchi, Ho, Matthews and Schlaich.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Markus P. Schlaich,

This article was submitted to Autonomic Neuroscience, a section of the journal Frontiers in Neuroscience

Disclaimer

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Outline

Figures

Cite article

Copy to clipboard


Export citation file


Share article

Share on WeChat

Scan with WeChat to share this article

Article metrics