Innervation and Neuronal Control of the Mammalian Sinoatrial Node a Comprehensive Atlas.

[Figure: see text].

New insights in diagnostics and therapies in syncope: a novel approach to non-cardiac syncope.

This article aims to give advice on how to identify and manage patients with syncope who are at risk of severe outcomes, that is, at risk of trauma, potentially life-threatening episodes or frequent recurrences reducing quality of life. The first step of syncope diagnostic assessment is to identify patients with cardiac syncope, and once established, these patients must receive the adequate mechanism-specific treatment. If cardiac syncope is unlikely, reflex (neurally mediated) syncope and orthostatic hypotension are the most frequent causes of transient loss of consciousness. For these presentations, efficacy of therapy is largely determined by the mechanism of syncope rather than its aetiology or clinical features. The identified mechanism of syncope should be carefully assessed and assigned either to hypotensive or bradycardic phenotype, which will determine the choice of therapy (counteracting hypotension or counteracting bradycardia). The results of recent trials indicate that 'mechanism-specific therapy' is highly effective in preventing recurrences. Established mechanism-specific treatment strategies include withdrawal of hypotensive drugs, applying fludrocortisone and midodrine for the hypotensive phenotype and cardiac pacing in the bradycardic phenotype.

Acute Cardiovascular Effects of Non-Invasive Electrical Spinal Cord Stimulation: Results from a Pilot Study in Humans.

We aimed to determine if non-invasive electrical spinal cord stimulation (NIE-SCS) is associated with acute changes in systemic and pulmonary hemodynamics and cardiac electrophysiology at rest. Nine subjects without structural heart disease referred for catheter ablation of cardiac arrhythmia were included. NIE-SCS was performed in each patient at vertebral levels T1, T7, and T11. Higher systolic BP (BPs) was detected during T1 NIE-SCS as compared with baseline (147.9 ± 22.5 vs 135.4 ± 17.4 mmHg; P = 0.02). Atrioventricular nodal effective refractory period (AVN ERP) was shorter during stimulation at T1 and T7, when compared with baseline values (baseline 303.3 ± 15.0 vs 272.0 ± 19.2 for T1 vs 278.0 ± 8.3 ms for T7; P < 0.05). NIE-SCS at the T1 level is associated with an elevation of BPs. NIE-SCS at the T1 and T7 levels shortens AVN ERP. Further studies are needed for the evaluation of chronic effects.

Initial experience with ablation of the innervation surrounding sinus and atrioventricular nodes to treat paroxysmal bradyarrhythmia.

BACKGROUND: The symptomatic bradyarrhythmia is Class I indication for pacing therapy which is not a radical cure. The present study aimed to assess the feasibility and to present the initial results of the restricted ablation of the parasympathetic innervation surrounding sinus and atrioventricular (AV) nodes for treating patients with bradyarrhythmia. METHODS: A total of 13 patients with cardiogenic syncope were included from May 2008 to June 2015. Under the guidance of fluoroscopy and /or three-dimensional geometry by 64-slice spiral computed tomography, atrial activation sequence in sinus rhythm was mapped. Chamber geometry was reconstructed manually or automatically using the Niobe II magnetic navigation system integrated with the CARTO-remote magnetic technology (RMT) system. Cardioneuroablation was targeted at the high-amplitude fractionated electrograms surrounding the regions of His bundle and the site with the earliest activation in sinus rhythm. Areas surrounding the sinus node, AV node, and the phrenic nerve were avoided. RESULTS: Thirteen patients completed the studies. Ablation was successfully performed in 12 patients and failed in one. The high-frequency potential was recorded in atrial electrograms surrounding the sinus or AV nodes in all the patients and disappeared in 15 s after radiofrequency applications. The vagal reaction was observed before the improvement of the sinus and AV node function. No complications occurred during the procedures. Patients were followed up for a mean of 13.0 ±â€Š5.9 months. During the follow up ten patients remained free of symptoms, and two patients had a permanent cardiac pacemaker implanted due to spontaneous recurrence of syncope. The heart rate of post-ablation was higher than pre-ablation (69.0 ±â€Š11.0 vs. 49.0 ±â€Š10.0 beats/min, t = 4.56, P = 0.008). The sinus node recovery time, Wenckebach block point, and atrium-His bundle interval were significantly shorter after ablation (1386.0 ±â€Š165.0 vs. 921.0 ±â€Š64.0 ms, t = 7.45, P = 0.002; 590.0 ±â€Š96.0 vs. 464.0 ±â€Š39.0 ms, t = 2.38, P = 0.023; 106.0 ±â€Š5.0 vs. 90.0 ±â€Š12.0 ms, t = 9.80, P = 0.013 before and after ablation procedure, respectively). CONCLUSIONS: Ablation of sinoatrial and AV nodal peripheral fibrillar myocardium electrical activity might provide a new treatment to ameliorate paroxysmal sinus node dysfunction, high degree AV block, and vagal-mediated syncope.

Prevalence and predictors of ventriculo-atrial conduction in structurally normal hearts.

BACKGROUND: The prevalence of ventriculo-atrial (VA) conduction varies from 20% to 90%, depending on the population studied (Militianu et al., 1997; Inoue et al., 1985; Kazmierczak et al., 1993; Ciemniewski et al., 1990; Hayes and Furman, 1983; Westveer et al., 1984). This wide range is mostly based on studies done in patients with implanted devices or impaired atrioventricular conduction. However, the prevalence of VA conduction in structurally normal heart has not been well documented till date. OBJECTIVE: To study the prevalence and identify predictors of retrograde conduction via the His-Purkinje system and AV node in structurally normal hearts. METHODS: We included 54 consecutive adults without structural heart disease who underwent electrophysiological (EP) study for various tachycardias. The basic parameters including PR, AH and HV intervals, atrioventricular Wenckebach point (AVWP) and anterograde effective refractory period (ERP) of atrioventricular node (AVNERP), were measured after ablation. The VA conduction was assessed basally and if absent, after isoprenaline. The VA Wenckebach point (VAWP) and retrograde ERP(VAERP) were recorded in patients showing VA conduction. RESULTS: The mean age was 37.1±12.6years. Twenty five (46%) of the patients were men. VA conduction was present in 30 (55%) patients at baseline. Of the remaining 24 patients, 18 (34%) showed VA conduction after isoprenaline. Only 6 (11%) patients failed to reveal VA conduction even after adequate response to isoprenaline. Amongst all clinical and EP variables analysed, only the HV interval was shorter (p<0.01) in patients with VA conduction. CONCLUSION: In structurally normal hearts, VA conduction was present at baseline in 55% of patients. Isoprenaline unmasked VA conduction in an additional 34% of the subjects. The HV interval was longer in patients without VA conduction.

Integrity of the Ganglionated Plexi Is Essential to Parasympathetic Innervation of the Atrioventricular Node by the Right Vagus Nerve.

INTRODUCTION: Radiofrequency isolation of pulmonary vein can be accompanied by transient sinus bradycardia or atrioventricular nodal (AVN) block, suggesting an influence on vagal cardiac innervation. However, the importance of the atrial fat pads in relation with the vagal innervation of AVN in humans remains largely unknown. The aim of this study was to evaluate the role of ganglionated plexi (GP) in the innervation of the AVN by the right vagus nerve. METHODS AND RESULTS: Direct epicardial high-frequency stimulation (HFS) of the GP (20 patients) and the right vagus nerve (10 patients) was performed before and after fat pad exclusion or destruction in 20 patients undergoing thoracoscopic epicardial ablation for the treatment of persistent AF. Asystole longer than 3 seconds or acute R-R prolongation over 25% was considered as a positive response to HFS. Prior to the ablation, positive responses to HFS were detected in 3 GPs in 7 patients (35%), 2 GPs in 5 patients (25%), and one GP in 8 patients (40%). After exclusion of the fat pads, all patients had a negative response to HFS. All the patients who exhibited a positive response to right vagus nerve stimulation (n = 10) demonstrated negative responses after the ablation. CONCLUSION: The integrity of the GP is essential for the right vagus nerve to exert physiological effects of on AVN in humans.

The Current State and Future Potential of Pediatric and Congenital Electrophysiology.

Pediatric electrophysiologists specialize in the diagnosis and treatment of rhythm abnormalities in pediatric, congenital heart disease, and inherited arrhythmia syndrome patients. The field originated out of the unique knowledge base that rhythm management in young patients required. In the 1970s, pediatric electrophysiology was recognized as a distinct cardiac subspecialty and it has evolved rapidly since that time. Despite the considerable growth in personnel, technology, and complexity that the field has undergone, further opportunities to progress pediatric electrophysiology exist. In this review, we highlight some of the clinical focus of pediatric and adult congenital electrophysiologists to date and identify areas within this specialty where the pediatric and congenital electrophysiology community could come together in order to drive improvements in rhythm management for patients.

Zebrafish heart as a model to study the integrative autonomic control of pacemaker function.

The cardiac pacemaker sets the heart's primary rate, with pacemaker discharge controlled by the autonomic nervous system through intracardiac ganglia. A fundamental issue in understanding the relationship between neural activity and cardiac chronotropy is the identification of neuronal populations that control pacemaker cells. To date, most studies of neurocardiac control have been done in mammalian species, where neurons are embedded in and distributed throughout the heart, so they are largely inaccessible for whole-organ, integrative studies. Here, we establish the isolated, innervated zebrafish heart as a novel alternative model for studies of autonomic control of heart rate. Stimulation of individual cardiac vagosympathetic nerve trunks evoked bradycardia (parasympathetic activation) and tachycardia (sympathetic activation). Simultaneous stimulation of both vagosympathetic nerve trunks evoked a summative effect. Effects of nerve stimulation were mimicked by direct application of cholinergic and adrenergic agents. Optical mapping of electrical activity confirmed the sinoatrial region as the site of origin of normal pacemaker activity and identified a secondary pacemaker in the atrioventricular region. Strong vagosympathetic nerve stimulation resulted in a shift in the origin of initial excitation from the sinoatrial pacemaker to the atrioventricular pacemaker. Putative pacemaker cells in the sinoatrial and atrioventricular regions expressed adrenergic ß2 and cholinergic muscarinic type 2 receptors. Collectively, we have demonstrated that the zebrafish heart contains the accepted hallmarks of vertebrate cardiac control, establishing this preparation as a viable model for studies of integrative physiological control of cardiac function by intracardiac neurons.

Increase of ventricular interval during atrial fibrillation by atrioventricular node vagal stimulation: chronic clinical atrioventricular-nodal stimulation download study.

BACKGROUND: Patients with a high ventricular rate during atrial fibrillation (AF) are at increased risk of receiving inappropriate implantable cardioverter defibrillator shocks. The objective was to demonstrate the feasibility of high frequency atrioventricular-nodal stimulation (AVNS) to reduce the ventricular rate during AF to prevent inappropriate implantable cardioverter defibrillator shocks. METHODS AND RESULTS: Patients with a new atrial lead placement as part of a cardiac resynchronization therapy and defibrillator implant and a history of paroxysmal or persistent AF were eligible. If proper atrial lead position was confirmed, AVNS software was uploaded to the cardiac resynchronization therapy device, tested, and optimized. AVNS was delivered via a right atrial pacing lead positioned in the posterior right atrium. Software allowed initiation of high frequency bursts triggered on rapidly conducted AF. Importantly, the efficacy was evaluated during spontaneous AF episodes between 1 and 6 months after implant. Forty-four patients were enrolled in 4 centers. Successful atrial lead placement occurred in 74%. Median implant time of the AVNS lead was 37 minutes. In 26 (81%) patients, manual AVNS tests increased the ventricular interval by >25%. Between 1 and 6 months, automatic AVNS activations occurred in 4 patients with rapidly conducted AF, and in 3 patients, AVNS slowed the ventricular rate out of the implantable cardioverter defibrillator shock zone. No adverse events were associated with the AVNS software. CONCLUSIONS: The present study demonstrated the feasibility of implementation of AVNS in a cardiac resynchronization therapy and defibrillator system. AVNS increased ventricular interval >25% in 81% of patients. AVNS did not influence the safety profile of the cardiac resynchronization therapy and defibrillator system. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; Unique Identifier: NCT01095952.

[Treatment of a patient with refractory cardiac arrhythmias using stellate ganglion block. Access by the classical and ultrasound-guided approach]. / Tratamiento de las arritmias cardíacas refractarias mediante bloqueo del ganglio estrellado en un paciente. Acceso por técnica clásica y ecodirigida.

Stellate ganglion block is a technique that is often used by anesthesiologists for the treatment of complex regional pain syndromes of the upper extremity. This technique interrupts cardiac sympathetic innervation and has been proposed as treatment for refractory arrhythmias. We present the case of a patient with arrhythmias that were refractory to pharmacological treatment, and were finally treated by continuous stellate ganglion block. Left stellate ganglion is a lynchpin of cardiac arrhythmias due to being a structure where the majority of postganglion sympathetic fibers responsible for preferentially innervating the atriventricular node, bundle of His and ventricular mass are originated, fundamentals in the origin and maintenance of ventricular arrhythmias.

Vagally mediated atrioventricular block: pathophysiology and diagnosis.

Vagally mediated atrioventricular (AV) block is defined as a paroxysmal AV block, localised within the AV node, associated with slowing of the sinus rate. All types of second-degree AV block, including pseudo-Mobitz II block, and complete AV block, may be present. Most of the patients have normal AV conduction. Differential diagnosis with intrinsic AV block is based on the behaviour of the sinus rate. Vagally mediated AV block is benign; it can be recorded as an asymptomatic or symptomatic event (syncope/presyncope). Syncope due to this form of AV block should be diagnosed and managed as neurally mediated syncope. When this block is fortuitously recorded in asymptomatic patients, pacemaker implantation is not indicated.

Does reducing unnecessary right ventricular pacing improve sympathetic activity and innervation of heart in sinus node disease patients? MVP and SafeR study.

Ventricular desynchronization imposed by ventricular pacing causes regional disturbances of adrenergic innervation in the left ventricular myocardium and increases the risk of heart failure and atrial fibrillation (AF) in patients with sinus node disease (SND). As a result, decreased iodine-123 metaiodobenzylguanidine (I-(123 )MIBG) uptake occurs in patients with an implanted permanent pacemaker. Fourteen SND patients with an implanted pacemaker equipped with an algorithm for reducing unnecessary right ventricular pacing (RURVP) were enrolled. Pacemakers were programmed to RURVP mode for the first 12 weeks, and then reprogrammed to DDD for the last 12 weeks. At the end of each mode, data on cumulative percent ventricular pacing (%Vp), atrial high rate episodes (%AHR), I-(123 )MIBG myocardial scintigraphy, brain natriuretic peptide (BNP), human atrial natriuretic peptide (hANP), and myocardial damage indices typified by troponin T and C-reactive protein (CRP) were collected. %Vp was lower in RURVP than in DDD (0.2% versus 95.7%, P = 0.00098). BNP, hANP, troponin T, and CRP did not differ significantly between the pacing modes. However, I-(123 )MIBG findings of patients with full ventricular pacing in DDD improved in RURVP. In contrast, among patients without full ventricular pacing in DDD, their I-(123 )MIBG findings did not differ significantly between the pacing modes. In SND patients with normal cardiac function and intact atrioventricular conduction, the reduction of %Vp in RURVP was due to the reduction of ineffective pacing and fusion pacing in DDD. Therefore, these 2 types of pacing do not affect cardiac pump function.

Stimulation of the intra-cardiac vagal nerves innervating the AV-node to control ventricular rate during AF: specificity, parameter optimization and chronic use up to 3 months.

BACKGROUND: Stimulation of the intra-cardiac vagal nerves innervating the AV-node (AVNS) is a promising approach to slow down ventricular rate (VR) during atrial fibrillation (AF). Our purpose was to demonstrate that effects on R-R-interval during stable AF can be maintained for several months once optimized and that AVNS affects specifically the nerves innervating the AV-node. METHODS: Our study included both an acute and chronic phase. Fifteen goats were implanted with a pacemaker connected to an atrial and ventricular lead and a neurostimulator connected to an atrial lead placed at a certain septal site, to induce an AV prolongation. In the chronic experiments (n = 9), after assessment of optimal AVNS parameters, the effect of continuous AVNS on VR was studied during stable AF for up to 3 months. The mechanism of AVNS was studied using atropine and esmolol. Next, the effects of AVNS during the atrial refractory period on electrophysiological and hemodynamic parameters were investigated acutely (n = 7). RESULTS: The maximal effect was found at a stimulation frequency of 40 Hz, and increased with increasing pulse width (at lower voltages) and increasing voltage. After 0, 1, and 3 months of AVNS during stable AF, AVNS decreased average VR, respectively, 55% (n = 9), 48% (n = 8), and 28% (n = 6). The AVNS effect appeared to be dominantly parasympathetic. AVNS did not influence (1) the sinus node, (2) the refractory period of the atrial, ventricular tissue, and His and (3) hemodynamic parameters. CONCLUSION: AVNS is efficient in reducing ventricular rate for at least 3 months using optimized parameters and specifically affects the parasympathetic nerves innervating the AV-node.

Stimulation of the intrinsic cardiac autonomic nervous system results in a gradient of fibrillatory cycle length shortening across the atria during atrial fibrillation in humans.

INTRODUCTION: The intrinsic cardiac autonomic nervous system (ANS) is implicated in atrial fibrillation (AF) but little is known about its role in maintenance of the electrophysiological substrate during AF in humans. We hypothesized that ANS activation by high-frequency stimulation (HFS) of ganglionated plexi (GP) increases dispersion of atrial AF cycle lengths (AFCLs) via a parasympathetic effect. METHODS AND RESULTS: During AF in 25 patients, HFS was delivered to presumed GP sites to provoke a bradycardic vagal response and AFCL was continuously monitored from catheters placed in the pulmonary vein (PV), coronary sinus (CS), and high right atrium (HRA). A total of 163 vagal responses were identified from 271 HFS episodes. With a vagal response, the greatest reduction in AFCL was seen in the PV adjacent to the site of HFS (16% reduction, 166 ± 28 to 139 ± 26 ms, P < 0.0001) followed by the PV-atrial junction (9% reduction, 173 ± 21 to 158 ± 20 ms, P < 0.0001), followed by the rest of the atrium (3-7% reduction recorded in HRA and CS). Without a vagal response, AFCL changes were not observed. In 10 patients, atropine was administered in between HFS episodes. Before atropine administration, HFS led to a vagal response and a reduction in PV AFCL (164 ± 28 to 147 ± 26 ms, P < 0.0001). Following atropine, HFS at the same GP sites no longer provoked a vagal response, and the PV AFCL remained unchanged (164 ± 30 to 166 ± 33 ms, P = 0.34). CONCLUSIONS: Activation of the parasympathetic component of the cardiac ANS may cause heterogenous changes in atrial AFCL that might promote PV drivers.

Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice.

The mouse is widely used as a genetic platform to investigate the molecular mechanisms of sinoatrial node (SAN) pacemaking. Recently, it has been shown that isolated SAN cells from the ankyrin-B (AnkB)-deficient mice display severe pacemaking dysfunction similar to individuals harboring ankyrin 2 allele variants. However, these results have been limited to isolated SAN cells only and thus did not evaluate the functional anatomy of the widely distributed atrial pacemaker complex (e.g., the dynamic interaction of primary and subsidiary pacemakers). We studied pacemaker function in an intact mouse atrial preparation, which included the SAN, atrioventricular junction (AVJ), and both atria, excluding most of the septum. Optical mapping with a voltage-sensitive dye and CMOS camera ULTIMA-L was used to map spontaneous pacemaker activity with or without autonomic modulation in wild-type (WT) mice (n = 7) and in the AnkB heterozygous (AnkB(+/-); n = 9) mouse model of human SAN disease. In WT mice, isoproterenol accelerated the SAN rate (for 10 microM: from 325 + or - 19 to 510 + or - 33 beat/min, P < 0.01) and shifted the leading pacemaker site superiorly by 0.77 + or - 0.11 mm within the SAN. ACh decreased the SAN rate (from 333 + or - 26 to 96 + or - 22 beats/min, P < 0.01) and shifted the leading pacemaker either inferiorly within the SAN or abruptly toward the AVJ. After isoproterenol, AnkB(+/-) mice exhibited a larger beat-to-beat variability (SD of a cycle length: 13.4 + or - 3.6 vs. 2.5 + or - 0.8 ms, P < 0.01 vs. WT mice), disorganized shift of the leading pacemaker (2.04 + or - 0.37 mm, P < 0.05 vs. WT mice), and competing multiple pacemakers, resulting in beat-to-beat changes of the leading pacemaker location site between the SAN and AVJ regions. Notably, AnkB(+/-) mice also displayed a reduced sensitivity to ACh (rate slowing by 32 + or - 12% vs. 67 + or - 4%, P < 0.05, AnkB(+/-) vs. WT mice, respectively). In conclusion, AnkB dysfunction results in SAN abnormalities in an isolated mouse atria preparation. While AnkB dysfunction dramatically alters single SAN cell function, the mechanisms underlying cardiac automaticity are clearly complex, and phenotypes may be partially compensated by the dynamic interaction of cells within the pacemaker complex. These new findings highlight the importance of the functional anatomy of the entire atrial distributed pacemaker complex, including the SAN and AVJ, and clearly demonstrate the role of AnkB in cardiac automaticity.

Vagal tone augmentation to the atrioventricular node in humans: efficacy and safety of burst endocardial stimulation.

BACKGROUND: Control of atrioventricular (AV) nodal conduction by endocardial stimulation of efferent AV nodal vagal fibers [atrioventricular nodal vagal stimulation (AVNS)] is a promising approach for long-term device-based modulation of ventricular rate during atrial fibrillation (AF). However, few data on the efficacy of AVNS delivered as high-frequency stimulus packages (burst AVNS) in humans are available. OBJECTIVE: The purpose of this study was to determine whether burst AVNS can to modulate AV nodal conduction during AF and whether burst AVNS delivered during sinus rhythm (SR) in the effective atrial refractory period allows safe implantation of a permanent lead in a position suitable for AVNS. METHODS: Twenty patients (10 in SR and 10 in AF) who were candidates for dual-chamber pacemaker implantation for sick sinus syndrome were enrolled in the study. The posteroseptal right atrium was mapped to identify a location at which burst AVNS would achieve AV nodal conduction modulation (lengthening of PR interval in SR and reduction of ventricular rate in AF). Subsequently, a lead was screwed in at that site and burst stimulation (pulse rate 50 Hz, burst duration 180 ms) was delivered at different burst rates, pulse durations, and amplitudes. RESULTS: In all SR patients, PR-interval prolongation was evoked at 90 and 120 bursts/minute with pulse durations < or =1 ms. Specifically, the mean voltages required to obtain PR-interval prolongation and advanced AV block were 4.3 +/- 2.2 V and 5.4 +/- 1.8 V (at 90 bursts/minute and 1 ms), respectively. Similarly, ventricular rate reduction was obtained in all AF patients, starting from 90 bursts/minute and 0.5-ms pulse duration (at 5.4 +/- 1.8 V). Ventricular arrhythmias were never induced during AVNS. CONCLUSION: Endocardial right atrial burst AVNS reduces ventricular rate during AF. Burst AVNS delivered during SR in the effective atrial refractory period allows optimization of lead positioning for AVNS.

Atrioventricular (AV) node vagal stimulation by transvenous permanent lead implantation to modulate AV node function: safety and feasibility in humans.

BACKGROUND: Atrioventricular (AV) node vagal stimulation (AVNVS) has recently emerged as a novel approach to controlling AV dromotropic function. Animal studies have demonstrated that selective epicardial AVNVS is effective in controlling ventricular rate (VR) acutely and in the long term. Endocardial AVNVS has been shown to significantly reduce VR acutely during atrial fibrillation (AF) in humans. However, no data are available on its long-term reproducibility. OBJECTIVES: The purpose of this study was to demonstrate that the posteroseptal right atrium is a suitable site for permanent pacing and allows AVNVS in humans both acutely and during follow-up. METHODS: In 12 candidates for implantable cardioverter-defibrillator with a history of AF, the atrial lead was implanted in the posteroseptal right atrium, where advanced AV block was achieved during temporary high-frequency stimulation (HFS). On implantation and 3-month follow-up examination, HFS was delivered through the permanent lead to demonstrate the possibility to gradually slow the VR until complete AV block. RESULTS: On implantation, VR during AF was gradually slowed until complete AV block, which was elicited at 4.3 V (0.2 ms, 50 Hz). After 3 months, this effect remained reproducible. No significant change in pacing thresholds was observed after 3 months. We observed one dislodgment and one microdislodgement of atrial leads. CONCLUSIONS: Our study demonstrates, for the first time in humans, that selective placement of the atrial lead yields electrical characteristics suitable for permanent pacing and enables VR to be significantly reduced under HFS. These results, which were reproducible during follow-up, provide data for the development of device-based control of VR during AF.