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Background: Improvement in outcome of infants born with congenital heart defects has been accompanied by an increasing frequency of late arrhythmias. Ablation is difficult because of multiple tachycardias in the presence of complex anatomy with limited accessibility. We report on remote-controlled ablation using magnetic navigation in conjunction with 3D image integration in patients with previous intra-atrial baffle procedures., Methods and Results: Thirteen patients (8 male; age, 30.5±8 years) with supraventricular tachycardia (SVT) underwent catheter ablation. Group A had a medical history of a Mustard or Senning operation, whereas group B had undergone total cavopulmonary connection. A total of 26 tachycardias were treated in 17 procedures (median cycle length of 280 ms). Group A patients had more inducible SVTs than group B, and all index SVTs were located in the remainder of the morphological right atrium in all but 1 patient. Retrograde access through the aorta was performed and led to successful ablation, using magnetic navigation with a very low total radiation exposure (median of 3.8 minutes in group A versus 5.9 minutes in group B). Only 1 of 13 patients continued to have short-lasting SVTs despite 3 ablation procedures during a median follow-up time of >200 days., Conclusions: Remote-controlled catheter ablation by magnetic navigation in combination with accurate 3D image integration allowed safe and successful elimination of SVTs, using an exclusively retrograde approach, resulting in low radiation exposure for patients after intra-atrial baffle procedures (Mustard, Senning, or total cavopulmonary connection).

Background: Catheter ablation of ganglionated plexi (GP) in the left atrium has been proposed in different subgroup of patients with atrial fibrillation (AF). Anatomic studies found a high prevalence of GP in the posterior surface of the right atrium (RA). Experimental data suggested the potential role of right atrial GP in the AF initiation and maintenance. The aim of our study was to assess the efficacy of GP ablation in RA in patients with vagal AF., Methods and Results: Thirty-four patients without structural heart diseases were randomly assigned for a selective ablation procedure targeted on the elimination of vagal reflex evoked by high frequency stimulation or an extensive approach at anatomic sites of GP. All patients underwent Holter ECG and heart rate variability evaluation at baseline and at 3, 6, 12, and 18 months of follow-up. At a mean follow-up of 19.7±5.2 months, AF recurred in 5 of 17 patients with anatomic ablation and in 13 of 17 patients with a selective approach (P=0.01). No patient had major complications. After ablation, heart rate variability parameters showed a significant parasympathetic (and sympathetic) denervation in the first 6 months, which was more prominent in patients with anatomic GP ablation and in those without AF recurrence., Conclusions: This study demonstrates that in a selected population of vagal paroxysmal AF, the anatomic ablation of GPs in the RA is effective in about 70% of patients. These results confirm that atrial vagal denervation can abolish AF, as suggested by experimental and clinical data.

Percutaneous transseptal left atrial (LA) access is increasingly becoming a routine procedure in the electrophysiology and cardiac catheterisation laboratories. Our aim was to review an unselected large series of this procedure performed over a period of five years. We clinically characterised difficult cases and presented a method of safe and expeditious LA access. Overall, 543 transseptal punctures were performed. Of those, 10 were classified as difficult, with failure to access the LA in three or more attempts. In all 10 cases, surgical electrocautery was successfully used to facilitate needle puncture of the septum. All patients subsequently underwent an uncomplicated procedure. In conclusion, we describe a method to trouble-shoot the difficult transseptal access procedure, outlining the clinical characteristics, echocardiographic features and special precautions that need to be considered when utilising this method., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Atrial fibrillation (AF) is the most common arrhythmia in humans. The majority of patients with AF can function reasonably well on a daily basis with anti-arrhythmic drugs. A small proportion of patients with AF remain symptomatic despite anti-arrhythmic drugs. They might have an indication for invasive treatment for AF, such as endovascular catheter ablation (effective particularly in paroxysmal AF) or the Cox-Maze procedure (open heart surgery), in which the conductivity between the pulmonary veins and the left atrium is blocked. Hybrid thoracoscopic pulmonary vein isolation (VATS-PVI) is a new minimally invasive treatment for AF where the cardiothoracic surgeon and cardiologist work closely together. During this procedure the cardiologist performs electrophysiological measurements to verify whether the blockade of conductivity is successful. This approach has a success rate of 86% at a follow-up of 12 months.

Background: Recent studies demonstrated that atrial fibrillation (AF) induced heterogeneous sympathetic hyperinnervation and baroreflex impartation, but the changes of vagal and afferent nerve are not clear., Methods: Six dogs underwent atrial pacing at 600 beats/min (AF group). All paced dogs developed sustained AF by 5 weeks of pacing. Tissues from six healthy dogs were used as controls. Immunohistochemistry staining of cardiac nerves was performed using anti-growth-associated protein 43 (anti-GAP43), anti-tyrosine hydroxylase, antiacetylcholine (anti-ACh), and anti-substance P (anti-SP) antibodies., Results: In AF group, the density of GAP43-positive in the right atrium (RA), atrial septum (AS), and left atrium (LA) was 5590.24±1417.51, 8083.22±1271.39, and 10854.56±1877.56 μm(2)/mm(2), respectively, which was significantly (P<.01) higher than the control group. Most of the newly sprouting nerves are sympathetic nerve. Sympathetic nerve density in AF group was significantly higher than that of control group (P<.001). Whereas denervation of parasympathetic and SP-immunoreactive nerve occurred in AF group. In the dogs with AF, the density of ACh-positive nerve in the RA, AS, and LA was 506.04±104.44, 317.72±84.10, and 114.9±29. 62 μm(2)/mm(2), respectively, which was lower than the control group (P<.01). At the same time, the density of SP-positive nerve in the atria of AF dogs was also significantly lower than the control tissues (P<.01)., Conclusion: AF led to significant nerve sprouting and sympathetic hyperinnervation in the canine models, but the newly sprouting nerve did not include parasympathetic and SP-immunoreactive nerve. Heterogeneous parasympathetic and SP-immunoreactive nerve denervation occurred in the AF dogs., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Complex fractionated atrial electrograms (CFAEs) are supposed to be related to structural and electrical remodeling. Animal studies suggest a role of the autonomic nervous system (ANS). However, this has never been studied in humans., Objective: The goal of this study was to investigate the influence of ANS on CFAEs in patients with idiopathic atrial fibrillation (AF)., Methods: Thirty-six patients (28 men, 55 ± 9 years) were included before undergoing catheter ablation. In the 24 hours preceding the procedure, 20 patients were in AF (group 1) and 16 were in sinus rhythm (SR, group 2). With 2 decapolar catheters, 1 in the right atrium (RA) and 1 in the left atrium (LA), 20 unipolar electrograms were simultaneously recorded during a 100-second AF-period (in group 2 after induction of AF). After atropine and metoprolol administration, a second 100-second AF-period was recorded 30 minutes later. Five patients of group 2 served as controls and did not receive atropine and metoprolol prior to the second recording. CFAEs were assessed and the prevalence of CFAEs was expressed as percentage of the recording time., Results: The prevalence of CFAEs was greater in group 1 than in group 2 in both RA and LA (P = 0.026, P < 0.001, respectively). Atropine and metoprolol significantly reduced CFAEs in group 1 (P < 0.001) and prevented the time-dependent increase of CFAEs in group 2., Conclusion: The prevalence of CFAEs is greater in long-lasting AF episodes. Atropine and metoprolol administration reduces CFAEs in both atria. Thus, CFAEs are at least partly influenced by the ANS., (© 2011 Wiley Periodicals, Inc.)

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., (© 2011 Wiley Periodicals, Inc.)

Background: Pharmacologic and ablative therapies for atrial fibrillation (AF) have suboptimal efficacy. Newer gene-based approaches that target specific mechanisms underlying AF are likely to be more efficacious in treating AF. Parasympathetic signaling appears to be an important contributor to AF substrate., Objective: The purpose of this study was to develop a nonviral gene-based strategy to selectively inhibit vagal signaling in the left atrium and thereby suppress vagal-induced AF., Methods: In eight dogs, plasmid DNA vectors (minigenes) expressing Gα(i) C-terminal peptide (Gα(i)ctp) was injected in the posterior left atrium either alone or in combination with minigene expressing Gα(o)ctp, followed by electroporation. In five control dogs, minigene expressing scrambled peptide (Gα(R)ctp) was injected. Vagal- and carbachol-induced left atrial effective refractory periods (ERPs), AF inducibility, and Gα(i/o)ctp expression were assessed 3 days following minigene delivery., Results: Vagal stimulation- and carbachol-induced effective refractory period shortening and AF inducibility were significantly attenuated in atria receiving a Gα(i2)ctp-expressing minigene and were nearly eliminated in atria receiving both Gα(i2)ctp- and Gα(o1)ctp-expressing minigenes., Conclusion: Inhibition of both G(i) and G(o) proteins is necessary to abrogate vagal-induced AF in the left atrium and can be achieved via constitutive expression of Gα(i/o)ctps expressed by nonviral plasmid vectors delivered to the posterior left atrium., (Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: We sought to extend the use of low-level vagal stimulation by applying it only to the right vagus nerve (LL-RVS) to suppress atrial fibrillation (AF)., Methods: In 10 pentobarbital anesthetized dogs, LL-RVS (20 Hz, 0.1 ms pulse width) was delivered to the right vagal trunk via wire electrodes at voltages 50% below that which slowed the sinus rate (SR) or atrio-ventricular conduction. Electrode catheters were sutured at multiple atrial and pulmonary vein (PV) sites to record electrograms. LL-RVS continued for 3 hours. At the end of each hour, 40 ms of high-frequency stimulation (HFS; 100 Hz, 0.01 ms pulse width) was delivered 2 ms after atrial pacing (during the refractory period) to determine the AF threshold (AF-TH) at each site. Other electrodes were attached to the superior left ganglionated plexi (SLGP) and right stellate ganglion (RSG) so that HFS (20 Hz, 0.1 ms pulse width) to these sites induced SR slowing and acceleration, respectively. Microelectrodes inserted into the anterior right ganglionated plexi (ARGP) recorded neural activity., Results: (1) Three hours of LL-RVS induced a progressive increase in AF-TH at all sites (all P < 0.05). (2) The SR slowing and acceleration response induced by SLGP and RSG stimulation, respectively, was blunted by LL-RVS. (3) The frequency and amplitude of the neural activity recorded from the ARGP were markedly inhibited by LL-RVS., Conclusions: LL-RVS suppressed AF inducibility and the chronotropic responses to parasympathetic and sympathetic stimulation. Inhibition of neural activity in the GP may be a mechanism underlying these results., (© 2011 Wiley Periodicals, Inc.)

Background: Left atrial (LA) remodeling is a factor in atrial fibrillation (AF) recurrence after pulmonary vein catheter ablation (CA), but right atrium (RA) remodeling has not been investigated for possible associations to AF recurrence., Methods and Results: Using 64-slice multidetector computed tomography, RA and LA volumes were measured 3-dimensionally before CA in 65 patients with initially proven idiopathic paroxysmal AF (mean age, 60±10 years, 81.5% men). The CA procedure was guided by CARTO Merge atrial electroanatomic mapping. Sixteen patients (24.6%) had AF recurrence within the 6-month period after the CA. The recurrence was associated with a large RA volume [odds ratio, 1.04; 95% confidence interval (CI), 1.02 to 1.07, P<0.0001], a large LA volume with 1.04 [95% CI, 1.01 to 1.06, P=0.002], and low LA mean voltage with 1.03 [95% CI, 1.01 to 1.05, P=0.002]. After adjustment for potential confounding variables, RA and LA volumes remained predictive of AF recurrence. Large atrial volumes (mL) (RA ≥87 or LA ≥99) predicted AF recurrence (sensitivity of RA volume: 81.3% in 13 of 16 patients with AF recurrence; specificity: 75.5% in 37 of 49 patients without AF recurrence; sensitivity of LA volume: 81.3% in 13 of 16 patients with AF recurrence; specificity: 69.4% in 34 of 49 patients without AF recurrence), and the combined estimate of both atrial volumes was incremental and additive prognostic power (sensitivity: 75% in 12 of 16 patients with AF recurrence; specificity: 93.9% in 46 of 49 patients without AF recurrence)., Conclusions: Both LA and RA remodeling are equally associated with post-CA AF recurrence.

Endurance athletes have an increased risk of developing atrial fibrillation (AF) at 40 to 50 years of age. Signal-averaged P-wave analysis has been used for identifying patients at risk for AF. We evaluated the impact of lifetime training hours on signal-averaged P-wave duration and modifying factors. Nonelite men athletes scheduled to participate in the 2010 Grand Prix of Bern, a 10-mile race, were invited. Four hundred ninety-two marathon and nonmarathon runners applied for participation, 70 were randomly selected, and 60 entered the final analysis. Subjects were stratified according to their lifetime training hours (average endurance and strength training hours per week × 52 × training years) in low (<1,500 hours), medium (1,500 to 4,500 hours), and high (>4,500 hours) training groups. Mean age was 42 ± 7 years. From low to high training groups signal-averaged P-wave duration increased from 131 ± 6 to 142 ± 13 ms (p = 0.026), and left atrial volume increased from 24.8 ± 4.6 to 33.1 ± 6.2 ml/m(2) (p = 0.001). Parasympathetic tone expressed as root of the mean squared differences of successive normal-to-normal intervals increased from 34 ± 13 to 47 ± 16 ms (p = 0.002), and premature atrial contractions increased from 6.1 ± 7.4 to 10.8 ± 7.7 per 24 hours (p = 0.026). Left ventricular mass increased from 100.7 ± 9.0 to 117.1 ± 18.2 g/m(2) (p = 0.002). Left ventricular systolic and diastolic function and blood pressure at rest were normal in all athletes and showed no differences among training groups. Four athletes (6.7%) had a history of paroxysmal AF, as did 1 athlete in the medium training group and 3 athletes in the high training group (p = 0.252). In conclusion, in nonelite men athletes lifetime training hours are associated with prolongation of signal-averaged P-wave duration and an increase in left atrial volume. The altered left atrial substrate may facilitate occurrence of AF. Increased vagal tone and atrial ectopy may serve as modifying and triggering factors., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aims: To verify whether spectral components of atrial electrograms (AE) during sinus rhythm (SR) correlate with cardiac ganglionated plexus (GP) sites., Methods and Results: Thirteen patients undergoing atrial fibrillation (AF) ablation were prospectively enrolled. Prior to radio frequency application, endocardial AE were recorded with a sequential point-by-point approach. Electrical stimuli were delivered at 20 Hz, amplitude 100 V, and pulse width of 4 ms. A vagal response was defined as a high-frequency stimulation (HFS) evoked atrioventricular block or a prolongation of RR interval. Spectral analysis was performed on single AE during SR, sampling rate of 1000 Hz, Hanning window. Overall, 1488 SR electrograms were analysed from 186 different left atrium sites, 129 of them corresponding to negative vagal response sites, and 57 to positive response sites. The electrogram duration and the number of deflections were similar in positive and negative response sites. Spectral power density of sites with vagal response was lower between 26 and 83 Hz and higher between 107 and 200 Hz compared with negative response sites. The area between 120 and 170 Hz normalized to the total spectrum area was tested as a diagnostic parameter. Receiver operating characteristic curve analysis demonstrated that an area 120-170/area(total) value >0.14 identified vagal sites with 70.9% sensitivity and 72.1% specificity., Conclusion: Spectral analysis of AE during SR in sites that correspond to the anatomical location of the GP is feasible and may be a simpler method of mapping the cardiac autonomic nervous system, compared with the HFS technique.

The aim of the present study was to determine and quantify the cardiac autonomic innervation of the canine atria and pulmonary vein. Tissue specimens were taken from the canine pulmonary veins (PVs), posterior left atrium (PLA), left atrial roof (LAR), anterior left atrium (ALA), interatrial septum (IAS), and left atrial appendage (LAA) respectively for immunohistochemical analysis and nerve density determination. Both sympathetic and parasympathetic nerve densities decreased in the order: PLA>PV>IAS>LAR>ALA>LAA. For sympathetic nerve, multiple comparisons between any two regions showed a significant difference (P<0.05-P<0.01) except for PV vs. PLA, IAS vs. LAR, and LAR vs. ALA; for parasympathetic nerve, all the differences between any pair of regions were statistically significant (P<0.05-P<0.01) with the exception of PV vs. PLA, IAS vs. LAR, LAR vs. ALA, and ALA vs. LAA. For both nerve types, there was a decreasing gradient of nerve densities from the external to internal layer (P<0.001, for each comparisons). Nerve density at the ostia for either nerve type was significantly higher than at the distal segments of PVs (P<0.001). In summary, the LA and PVs are innervated by sympathetic and parasympathetic nerves in a regionally heterogeneous way, which may be important for the pathophysiological investigation and ablation therapy of atrial fibrillation (AF)., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Unlabelled: Slowed atrial conduction may contribute to reentry circuits and vulnerability for atrial fibrillation (AF). The autonomic nervous system (ANS) has modulating effects on electrophysiological properties. However, complex interactions of the ANS with the arrhythmogenic substrate make it difficult to understand the mechanisms underlying induction and maintenance of AF., Aim: To determine the effect of acute ANS modulation in atrial activation times in patients (P) with paroxysmal AF (PAF)., Methods and Results: 16P (9 men; 59±14years) with PAF, who underwent electrophysiological study before AF ablation, and 15P (7 men; 58±11years) with atrioventricular nodal reentry tachycardia, without documentation or induction of AF (control group). Each group included 7P with arterial hypertension but without underlying structural heart disease. The study was performed while off drugs. Multipolar catheters were placed at the high right atrium (HRA), right atrial appendage (RAA), coronary sinus (CS) and His bundle area (His). At baseline and with HRA pacing (600ms, shortest propagated S2) we measured: i) intra-atrial conduction time (IACT, between RAA and atrial deflection in the distal His), ii) inter-atrial conduction time (interACT, between RAA and distal CS), iii) left atrial activation time (LAAT, between atrial deflection in the distal His and distal CS), iv) bipolar electrogram duration at four atrial sites (RAA, His, proximal and distal CS). In the PAF group, measurements were also determined during handgrip and carotid sinus massage (CSM), and after pharmacological blockade of the ANS (ANSB). AF was induced by HRA programmed stimulation in 56% (self-limited - 6; sustained - 3), 68.8% (self-limited - 6; sustained - 5), and 50% (self-limited - 5; sustained - 3) of the P, in basal, during ANS maneuvers, and after ANSB, respectively (p=NS). IACT, interACT and LAAT significantly lengthened during HRA pacing in both groups (600ms, S2). P with PAF have longer IACT (p<0.05), a higher increase in both IACT, interACT (p<0.01) and electrograms duration (p<0.05) with S2, and more fragmented activity, compared with the control group. Atrial conduction times and electrograms duration were not significantly changed during ANS stimulation. Nevertheless, ANS maneuvers increased heterogeneity of the local electrograms duration. Also, P with sustained AF showed longer interACT and LAAT during CSM., Conclusion: Atrial conduction times, electrograms duration and fractionated activity are increased in PAF, suggesting a role for conduction delays in the arrhythmogenic substrate. Acute vagal stimulation is associated with prolonged interACT and LAAT in P with inducible sustained AF and ANS modulation may influence the heterogeneity of atrial electrograms duration., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Catheter ablation is an established therapeutic option for certain patients with atrial fibrillation (AF), but the reported success rates of anatomically oriented ablation techniques are low compared with those for other ablation indications, particularly for persistent AF. Electrophysiologically oriented ablation techniques have emerged over the last decade that aim at modifying the arrhythmogenic substrate to the extent that it cannot maintain fibrillatory activity. Electrogram-guided ablation procedures are the most common substrate-targeted ablation approaches and can be broadly divided into procedures that target atrial sites with particular electrogram characteristics in either the time domain (complex fractionated electrograms) or frequency components in the frequency domain (dominant frequencies). The concept of electrogram-based catheter ablation of AF by identifying complex fractionated electrograms and dominant frequency sites is valid only if these sites are temporally stable.

High thoracic epidural anesthesia (HTEA) blocks the afferent and efferent cardiac sympathetic nerve fibers and may affect atrial electrophysiological characteristics and nerve sprouting in patients with atrial fibrillation (AF). In this study, 18 dogs were randomly divided into a control group (n = 6), in which dogs were atrially paced at 400 beats/min for 6 weeks; an HTEA group (n = 6), in which dogs underwent atrial pacing and HTEA for 6 weeks; and a sham-operated group (n = 6), in which dogs underwent the operation but did not receive atrial pacing or HTEA. Electrophysiological examinations were performed in all groups. Cardiac nerves were immunocytochemically stained with anti-growth-associated protein 43 (GAP43) and anti-tyrosine hydroxylase (TH) antibodies. The protein expressions of nerve growth factor (NGF), GAP43 and TH in atrial myocardium were also studied by western blot. In addition, the plasma levels of C-reactive protein (CRP) and norepinephrine, as well as atrial production of superoxide anion (O(2)(·-)) and malondialdehyde, were measured. In the HTEA group, atrial effective refractory period increased (P < 0.05) and AF maintenance decreased (P < 0.01) significantly compared with the control group. The densities of GAP43-positive nerves and TH-positive nerves were significantly lower in the HTEA group compared with the control group. The protein levels of NGF, GAP43 and TH were also lower in the HTEA group compared with the control group. A significant positive correlation between the expressions of NGF and GAP43 (P < 0.01) was observed. A similar correlation was demonstrated for NGF and TH (P < 0.01) in our study. Furthermore, the plasma levels of CRP and norepinephrine, as well as the amount of O(2)(·-) and malondialdehyde produced from myocardium, decreased in the HTEA group compared with the control group. In conclusion, HTEA inhibited electrical and nerve remodeling and reduced the maintenance of AF in a canine AF model, in which process HTEA exhibited anti-inflammatory and antioxidant effects, indicating that, in addition to the efferent cardiac sympathetic nerve, afferent fibers also play an important role in the initiation and/or maintenance of AF.

In canines, excessive activation of select mediastinal nerve inputs to the intrinsic cardiac nervous system induces atrial fibrillation (AF). Since ablation of neural elements is proposed as an adjunct to circumferential pulmonary vein ablation for AF, we investigated the short and long-term effects of mediastinal nerve ablation on AF inducibility. Under general anesthesia, in 11 dogs several mediastinal nerve sites were identified on the superior vena cava that, when stimulated electrically during the atrial refractory period, reproducibly initiated AF. Cryoablation of one nerve site was then performed and inducibility retested early (1-2 months post Cryo; n=7) or late (4 months post Cryo; n=4). Four additional dogs that underwent a sham procedure were retested 1 to 2 months post-surgery. Stimulation induced AF at 91% of nerve sites tested in control versus 21% nerve sites early and 54% late post-ablation (both P<0.05). Fewer stimuli were required to induce AF in controls versus the Early Cryo group; this capacity returned to normal values in the Late Cryo group. AF episodes were longer in control versus the Early or Late Cryo groups. Heart rate responses to vagal or stellate ganglion stimulation, as well as to local nicotine infusion into the right coronary artery, were similar in all groups. In conclusion, focal damage to intrinsic cardiac neuronal inputs causes short-term stunning of neuronal inducibility of AF without major loss of overall adrenergic or cholinergic efferent neuronal control. That recovery of AF inducibility occurs rapidly post-surgery indicates the plasticity of intrathoracic neuronal elements to focal injury., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Ganglionated plexus (GP) ablation has been shown effective for eliminating atrial fibrillation (AF), the most common clinical tachyarrhythmia. However, the safety of destroying the main cardiac autonomic structures remains unclear. This study investigated the acute effects of GP ablation on the sinoatrial nodal (SAN) and atrioventricular nodal (AVN) functions in a canine model. In 10 open-chest dogs, multiple electrode catheters were sutured at both atria for recording and pacing. SAN and AVN function were evaluated. GP ablation caused no significant change of sinus rate immediately after GP ablation compared with the baseline state. After GP ablation, the sinus node recovery time (SNRT) and corrected SNRT did not show significant changes at long pacing cycle lengths (CLs), and only showed significant decrease at shorter pacing CLs. The AH interval at different pacing CLs, the Wenckebach atrioventricular block (AVB) CL, 2:1 AVB CL or the ventricular rate during AF were not significantly altered by GP ablations. Vagal suppression of SAN and AVN functions was eliminated by GP ablation. GP staining showed abundant choline acetyl transferase or tyrosine hydroxylase positive neurons. These findings suggest the functions of the SAN and AVN are mainly retained after GP ablation. These results may be partially related to destroying both parasympathetic and sympathetic elements in the GP by ablation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Autonomic nervous system activation can result in significant changes of atrial electrophysiology and facilitate induction of atrial fibrillation. By recording influence of different concentrations of acetylcholine (ACh) on atrial fibers (AF), we investigated the role of the increased vagal tone in electrical remodeling in atrial fibrillation. Parameters of action potentials and force contraction (Fc) in atrial fibers were recorded by using standard intracellular microelectrode technique and force transducer. It was found that: (1) ACh at 0.1 μmol/L had no significant influence on spontaneous action potentials (SAPs) and Fc (n=6, P>0.05); ACh at both 1.0 and 10.0 μmol/L shortened action potential duration (APD) and Fc of human AF from right atrium (n=6, P<0.05); there was no significant difference in shortening APD between 10.0 and 1.0 μmol/L of ACh; (2) ACh at 0.1 μmol/L had no significant desensitization (n=6, P>0.05), but ACh at 1.0 and 10.0 μmol/L had desensitization (n=6, P<0.05) to SAPs and Fc. The desensitization of ACh on APD in AF was concentration- and time-dependent. It was shown that APD was longer than the control along with extending time of continuous Tyrode's solution perfusion after desensitization. It is concluded that ACh changes the electrophysiological characteristics of human AF, indicating that increased vagal tone plays a role in the development of a vulnerable substrate for atrial electrical remodeling in atrial fibrillation.

Background: Whether autonomic nerve activity is important in the development of pacing-induced sustained atrial fibrillation (AF) is unclear., Objective: The purpose of this study was to test the hypothesis that patterns of baseline autonomic nerve activity are important in the development of pacing-induced sustained AF., Methods: Radiotransmitters were implanted in 12 ambulatory dogs to record left stellate ganglion nerve activity (SGNA) and vagal nerve activity (VNA). Sustained (>48 hours) AF was induced with intermittent rapid atrial pacing., Results: At baseline (before pacing), 1-minute integrated nerve activity between SGNA and VNA demonstrated either a single linear relationship with excellent correlation (group 1, N = 3, r = 0.816 ± 0.105) or nonlinear relationships with poor correlation (group 2, N = 9, r = 0.316 ± 0.162, P <.05 vs group 1). Group 1 dogs had higher VNA (97.0 ± 11.5 mV-s) compared to group 2 (33.4 ± 21.7 mV-s, P <.001). Group 1 dogs had more frequent sympathovagal co-activation episodes than did group 2 (50 ± 19 per day vs 15 ± 6 per day, P <.05) and more paroxysmal atrial tachycardia (PAT; 5 ± 1 per day vs 2 ± 1 per day, P <.05) at baseline. Sustained AF occurred after 16 ± 4 days (range 13-20 days) of pacing in group 1 and after 46 ± 18 days (range 23-72 days) of pacing in group 2 (P <.05). In the week before development of sustained AF, VNA of group 2 dogs was significantly increased compared to baseline (P <.05)., Conclusion: Ambulatory dogs with good linear sympathovagal correlation and higher vagal tone at baseline have more PAT episodes at baseline and faster induction of sustained AF by rapid pacing. Rapid atrial pacing increased the VNA of the remaining dogs before induction of sustained AF., (Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Our aim was to evaluate early results of ganglionic plexus (GP) ablation with modified Cox maze lesion sets for concomitant atrial fibrillation (AF) during corrective valve surgery., Methods: Between December 2006 and April 2008, 20 patients (7 men; median age, 65 years; range, 52 to 82 years) with valvular heart disease and AF (intermittent in 12 [60%]) underwent corrective valve surgery with maze and GP ablation. Patients were then compared with a case-matched control cohort who underwent radiofrequency ablation maze alone., Results: Procedures included mitral valve repair in 7 patients (35%), multivalve procedures in 5 (25%), mitral valve replacement in 4 (20%), aortic valve replacement in 3 (15%), and valve-sparing aortic root replacement in 1 (5%). All patients underwent concomitant AF ablation procedures (biatrial maze in 11 [55%], left-sided maze in 9 [45%]). Ganglionic plexus stimulation was performed in all patients. Sites at which the R-R interval doubled were considered active and were ablated. There were no early deaths. Freedom from AF at 1 year was significantly higher (90% versus 50%; p=0.01) and mean New York Heart Association functional class was better (1 versus 1.7; p<0.001) in the group that underwent maze and GP ablation compared with maze alone., Conclusions: Active left atrial GP are frequently present in patients with AF and valvular heart disease, and GP ablation can be safely performed as an adjunct to AF ablation during valve surgery. Early results are promising and may yield higher freedom from AF compared with radiofrequency ablation maze alone., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: prior studies indicated that ablation of the 4 major atrial ganglionated plexi (GP) suppressed atrial fibrillation., Methods and Results: superparamagnetic nanoparticles (MNPs) made of Fe(3)O(4) (core), thermoresponsive polymeric hydrogel (shell), and neurotoxic agent (N-isopropylacrylamide monomer [NIPA-M]) were synthesized. In 23 dogs, a right thoracotomy exposed the anterior right GP (ARGP) and inferior right GP (IRGP). The sinus rate and ventricular rate slowing responses to high-frequency stimulation (20 Hz, 0.1 ms) were used as the surrogate for the ARGP and IRGP functions, respectively. In 6 dogs, MNPs carrying 0.4 mg NIPA-M were injected into the ARGP. In 4 other dogs, a cylindrical magnet (2600 G) was placed epicardially on the IRGP. MNPs carrying 0.8 mg NIPA-M were then infused into the circumflex artery supplying the IRGP. The hydrogel shell reliably contracted in vitro at temperatures ≥ 37°C, releasing NIPA-M. MNPs injected into the ARGP suppressed high-frequency stimulation-induced sinus rate slowing response (40 ± 8% at baseline; 21 ± 9% at 2 hours; P=0.006). The lowest voltage of ARGP high-frequency stimulation inducing atrial fibrillation was increased from 5.9 ± 0.8 V (baseline) to 10.2 ± 0.9 V (2 hours; P=0.009). Intracoronary infusion of MNPs suppressed the IRGP but not ARGP function (ventricular rate slowing: 57 ± 8% at baseline, 20 ± 8% at 2 hours; P=0.002; sinus rate slowing: 31 ± 7% at baseline, 33 ± 8 % at 2 hours; P=0.604). Prussian Blue staining revealed MNP aggregates only in the IRGP, not the ARGP., Conclusions: intravascularly administered MNPs carrying NIPA-M can be magnetically targeted to the IRGP and reduce GP activity presumably by the subsequent release of NIPA-M. This novel targeted drug delivery system can be used intravascularly for targeted autonomic denervation.

Background: The proximity to vascular structures is a limiting factor during radiofrequency ablation. However, little or no attention has been given to the atrial arterial circulation during the development of atrial fibrillation (AF) catheter ablation techniques., Methods and Results: We examined the atrial arterial circulation in areas involved in AF ablation in 24 heart specimens by colored resin injection and careful dissection. The sinus node artery (SNA) arose from the circumflex artery in 42% of case; proximal to the LA appendage in 29%, crossing the left atrium (LA) anterior wall; and after the LA appendage in the remaining 13%, crossing the mitral isthmus and passing close to the left pulmonary veins (PVs), the LA roof, and the right superior PV. In 58%, the SNA arose from the right coronary artery. Major arteries (≥ 1 mm in external diameter) were found in the mitral isthmus in 54%, at the LA roof in 54%, and at the LA anterior wall in 29%. Around the left PV ostia, there were areas with major arteries in up to 37% (at the roof and inferior segments) and around the right PV ostia in up to 29% (at the roof segment)., Conclusions: Major atrial coronary arteries, including the SNA, were commonly found in the areas involved in AF ablation and could cause difficulties in obtaining transmural lesions and electric isolation or even lead to ischemic sinus node or atrial dysfunction.

Background: Over a time course of months, the stability of atrial fibrillation (AF) gradually increases and the efficacy of pharmacological cardioversion declines both in humans and in animal models. Changes in fibrillatory conduction over this period largely are unexplored., Methods and Result: Goats were instrumented with an atrial endocardial pacemaker lead and a burst pacemaker. AF was maintained for 3 weeks (short-term AF [ST], n = 10) or 6 months (long-term AF [LT], n = 7). AF could be cardioverted pharmacologically at the early time point (persistent AF), but not at the later time point (permanent AF). At follow-up, a high-resolution mapping electrode was used to record epicardial conduction patterns in the free walls of the right atrium (RA) and left atrium (LA). A new method for mapping of fibrillation waves was used to describe AF conduction patterns. Wavefronts propagated uniformly during slow pacing in both groups, although conduction velocity was significantly lower in the LT group (LA, 93 ± 14 versus 72 ± 10 cm/s; RA, 94 ± 8 versus 78 ± 8 cm/s). Median AF cycle length (AFCL) was not significantly different between the groups. However, the LT group showed highly complex activation patterns during AF, with an increased number of simultaneously propagating waves (LT group RA, 8.4 ± 3.0 waves/AFCL; LA, 12.8 ± 2.4 waves/AFCL; versus ST group RA, 4.3 ± 2.2 waves/AFCL; LA, 4.5 ± 2.5 waves/AFCL). Fibrillation waves in the LT group showed pronounced dissociation with large activation time differences. The incidence of waves newly appearing within the recording area also was increased in both atria. These alterations in conduction were accompanied by myocyte hypertrophy and increased endomysial fibrosis., Conclusions: Long-term AF in goats leads to dissociated conduction in the atrial free walls that may contribute to increased AF stability.

It has long been recognized that increased sympathetic nerve activity during physiologic stress (exercise, swimming, emotion, arousal, loud noise, etc.) has profound influences on the electrical and contractile functions of the heart. In the severely predisposed heart, these stressors may lead to ventricular tachyarrhythmias and sudden death. Still little is known about the temporal relationship between instantaneous autonomic nerve activity and arrhythmias. There is a large variety of autonomically-driven arrhythmias, from serious ventricular tachycardia in pathological conditions to single supraventricular and ventricular extrasystolic beats in the healthy heart. The latter are considered harmless if occurring at low frequency. In the atria, mounting data indicate the presence of a sophisticated network of ganglionated plexi with major influences on cardiac function. The ablation of multiple such ganglia can suppress pulmonary vein potentials and atrial fibrillation. At the cellular level, recent studies have focused on the spatiotemporal details of cyclic nucleotide signaling influencing ion channel function during neurohumoral stimulation. We have come to understand that sarcolemmal ion channels and other electrogenic transporters are macromolecular complexes that interact with structural elements (other than the phospholipid bilayer) to promote regionalization and targeting by regulatory proteins. Compartmentation of these regulatory proteins in subdomains of the myocyte is increasingly recognized and thought to segregate the functional (including electrogenic) responses induced by different neuromediators and hormones. In this article, contemporary issues are discussed regarding arrhythmias that are triggered by influences from the neurocardiac interface, covering the field from the molecular genetic to the intact integrated level. Actual questions are listed per topic, and viewpoints are expressed., (Copyright © 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: the aim of this study was to establish the electrophysiological consequences of pulmonary vein encircling ablation (PVEA) and linear left atrial roof ablation (LARA) for the atrial fibrillation (AF) substrate in an experimental model., Background: sequential application of ablation lesions is often used in the management of AF, almost always incorporating PVEA and LARA., Methods: Atrial tachypacing (400 beats/min, 5 weeks) was used to create an AF substrate in 13 dogs. PVEA and LARA were applied in randomized order. Regional atrial refractoriness, AF vulnerability, AF duration, and activation during AF were assessed before and after applying ablation lesion sets., Results: PVEA failed to terminate AF or affect AF duration (742 ± 242 s before vs. 627 ± 227 s after PVEA) but decreased AF vulnerability to single extrastimuli from 91 ± 4% to 59 ± 5% (p < 0.001) by increasing effective refractory periods at sites with suppressed AF induction (from 78 ± 4 ms to 102 ± 8 ms, p < 0.01). LARA terminated AF in 67% of dogs (p < 0.05 vs. PVEA) and reduced AF duration (from 934 ± 232 s to 322 ± 183 s, p < 0.01) without affecting AF vulnerability. Baseline AF mapping showed left atrial (LA)-dominant complex reactivations (LA 9.4 ± 0.9 vs. right atrial 1.1 ± 0.3 reactivations/500-ms window, p < 0.001), with the LA roof frequently involved in re-entry circuits (44 ± 9% of LA reactivations). LARA terminated AF by interrupting LA roof reactivation circuits. In 5 of 13 cases, macro-re-entrant tachycardias (usually perimitral) occurred after LARA eliminated persistent AF., Conclusions: both PVEA and LARA had beneficial but limited actions in this canine model. LARA suppressed AF perpetuation by interrupting LA roof reactivation, without affecting AF vulnerability. PVEA suppressed AF initiation by prolonging regional effective refractory period but failed to affect the AF-perpetuating substrate. These findings indicate the need to systematically study individual stepwise components to refine AF ablation procedures., (2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Modification of left atrial ganglionated plexi (GP) is a promising technique for the treatment of paroxysmal atrial fibrillation (AF) but its therapeutic efficacy is not established. This study aimed at evaluating the effectiveness of anatomic GP modification by means of an implantable arrhythmia monitoring device., Methods: In 56 patients with paroxysmal AF, radiofrequency ablation at anatomic sites, where the main clusters of GP have been identified in the left atrium, was performed. In all patients, an electrocardiogram monitor (Reveal XT, Medtronic Inc., Minneapolis, MN, USA) was implanted before (n = 7) or immediately after (n = 49) AF ablation., Results: Average duration of the procedure was 142 ± 18 min and average fluoroscopy time 20 ± 7 min. In total, 53-81 applications of RF energy were delivered (mean of 18.2 ± 3.8 at each of the four areas of GP ablation). Heart rate variability was assessed in 31 patients. Standard deviation of RR intervals over the entire analyzed period, the root mean square of differences between successive RR intervals, and high frequencies decreased, while HRmin, HRmean, and LF to HF ratio increased immediately postablation; these values returned to baseline 6 months after the procedure. At end of 12-month follow-up, 40 (71%) patients were free of arrhythmia recurrence. Ten patients had AF recurrence, two patients had left atrial flutter, and four patients had episodes of flutter as well as AF recurrence. Duration of episodes of AF after ablation gradually decreased over the follow-up period., Conclusions: Regional ablation at the anatomic sites of the left atrial GP can be safely performed and enables maintenance of sinus rhythm in 71% of patients with paroxysmal AF for a 12-month period., (©2010, The Authors. Journal compilation ©2010 Wiley Periodicals, Inc.)

Background: We sought to characterize patients with persistent atrial fibrillation (AF) who were successfully treated by ablation targeting the left atrium (LA)., Methods and Results: Ninety-three patients (58±10 years, 79 male) undergoing ablation of persistent AF were studied. During the first procedure, ablation was performed in the LA and coronary sinus, consisting of pulmonary vein isolation, linear ablation, and electrogram-based ablation. During follow-up after the first procedure, 35 patients (38%) remained free from tachyarrhythmias, 27 patients (29%) had atrial tachycardia, and 31 patients (33%) had AF. Duration of persistent AF according to medical history and whether AF was terminated by ablation were associated with the outcome (P=0.005, P=0.004, respectively). In multivariate analysis, the duration of persistent AF was the only predictor of freedom from AF (sinus rhythm or atrial tachycardia) (odds ratio, 0.80 for a 1-year increase; 95% confidence interval, 0.67 to 0.95; P=0.01). Of 31 patients in whom AF recurred during follow-up, electrogram-based ablation was performed in the right atrium in 26 patients. Sixteen of those patients (62%) remained free from AF during follow-up. Overall, 82% of patients were free from any tachyarrhythmias at 2-year follow-up after a median of 2 procedures., Conclusions: Patients with shorter duration of persistent AF were more likely to be free from AF by LA ablation. Right atrial ablation may provide incremental efficacy in patients who are refractory to LA ablation.

Background: The role of ligament of Marshall (LOM) in the mechanism of "vagal" atrial fibrillation (AF) is still unknown., Objective: To investigate the impact of LOM ablation on atrial vulnerability to AF induced by inferior left atrial fat pad (ILAFP) stimulation in dogs., Methods: AF inducibility and atrial effective refractory period (ERP) were elevated before and after LOM ablation in 8 of 14 dogs (the ablation group). Same protocol but without LOM ablation was conducted in the remaining 6 dogs (the control group). The activation patterns of LOM and left pulmonary veins (LPVs) during sustained AF were analyzed. The distribution of epicardial cholinergic nerve fibers between LOM and ILAFP was investigated in the control group., Results: Ablation of LOM significantly attenuated AF inducibility (87.5% vs 33.3%, P < 0.001) and prolonged ERPs of the structures in contiguity with LOM (P < 0.05) in the ablation group. In contrast, there was no significant change in ERPs and AF inducibility in the control group. During sustained AF, fractionated atrial electrograms were more common in the LOM area than the LPVs (84% vs 18% of the analyzed episodes, P < 0.001). In 46.7% of the episodes with identifiable LOM spikes, atrial potentials, and LOM spikes were related in 2:1 or 3:2 pattern during the intermittent organized activity. Acetylcholinesterase staining revealed a close cholinergic nerved relationship between LOM and ILAFP., Conclusions: LOM plays a critical role in maintaining AF induced by stimulation of ILAFP. Ablation of LOM can markedly attenuate AF inducibility in this model., (© 2010 Wiley Periodicals, Inc.)

Recent data have suggested a relation among long-term endurance sport practice, left atrial remodeling, and atrial fibrillation. We investigated the influence of an increased vagal tone, represented by the early repolarization (ER) pattern, on diastolic function and left atrial size in professional soccer players. Fifty-four consecutive athletes underwent electrocardiography, echocardiography, and exercise testing as part of their preparticipation screening. Athletes were divided into 2 groups according to presence or absence of an ER pattern, defined as a ST-segment elevation at the J-point (STE) > or =0.1 mm in 2 leads. For linear comparisons average STE was calculated. Mean age was 24 +/- 4 years. Twenty-five athletes (46%) showed an ER pattern. Athletes with an ER pattern had a significant lower heart rate (54 +/- 9 vs 62 +/- 11 beats/min, p = 0.024), an increased E/e' ratio (6.1 +/- 1.2 vs 5.1 +/- 1.0, p = 0.002), and larger volumes of the left atrium (25.6 +/- 7.3 vs 21.8 +/- 5.0 ml/m(2), p = 0.031) compared to athletes without an ER pattern. There were no significant differences concerning maximum workload, left ventricular dimensions, and systolic function. Univariate regression analysis revealed significant correlations among age, STE, and left atrial volume. In a stepwise multivariate regression analysis age, STE and e' contributed independently to left atrial size (r = 0.659, p <0.001). In conclusion, athletes with an ER pattern had an increased E/e' ratio, reflecting a higher left atrial filling pressure, contributing to left atrial remodeling over time.

Objective: To evaluate the nerve remodeling induced by 48 hours right atrial pacing in a canine model., Methods: Rapid right atrial pacing (600 beats/min) was performed in 6 mongrel dogs of either sex for 48 hours to induce sustained atrial fibrillation (AF). Six dogs without pacing served as controls. Cardiac nerves were immunocytochemically stained using anti-growth-associated protein 43 (GAP43) and anti-choline acetyltransferase (CHAT) antibodies to compare nerve sprouting and pneumogastric nerve remodeling between the 2 groups., Results: In dogs with AF, the GAP43-positive and CHAT-positive nerve densities in the left atrium, left auricular appendage, right atrium and right auricular appendage were significantly higher than in control animals (all P < 0.05). Moreover, nerve density was significantly higher in the right atrium than in the left atrium in dogs with AF. Microscopic examinations revealed an inhomogeneous distribution of cardiac nerves., Conclusion: Significant nerve sprouting and pneumogastric nerve remodeling were evidenced in the right and left atrium in a canine model of sustained AF induced by 48 hours right atrial pacing.

Background: The relation between left ventricular filing velocities determined by Doppler echocardiography and autonomic nervous system function assessed by heart rate variability (HRV) is unclear. The aim of this study was to evaluate the influence of the autonomic nervous system assessed by the time and frequency domain indices of HRV in the Doppler indices of left ventricular diastolic filling velocities in patients without heart disease., Methods: We studied 451 healthy individuals (255 female [56.4%]) with normal blood pressure, electrocardiogram, chest x-ray, and treadmill electrocardiographic exercise stress test results, with a mean age of 43+/-12 (range 15-82) years, who underwent transthoracic Doppler echocardiography and 24-hour electrocardiographic ambulatory monitoring. We studied indices of HRV on time (standard deviation [SD] of all normal sinus RR intervals during 24 hours, SD of averaged normal sinus RR intervals for all 5-minute segments, mean of the SD of all normal sinus RR intervals for all 5-minute segments, root-mean-square of the successive normal sinus RR interval difference, and percentage of successive normal sinus RR intervals>50 ms) and frequency (low frequency, high frequency, very low frequency, low frequency/high frequency ratio) domains relative to peak flow velocity during rapid passive filling phase (E), atrial contraction (A), E/A ratio, E-wave deceleration time, and isovolumic relaxation time. Statistical analysis was performed with Pearson correlation and logistic regression., Results: Peak flow velocity during rapid passive filling phase (E) and atrial contraction (A), E/A ratio, and deceleration time of early mitral inflow did not demonstrate a significant correlation with indices of HRV in time and frequency domain. We found that the E/A ratio was<1 in 45 individuals (10%). Individuals with an E/A ratio<1 had lower indices of HRV in frequency domain (except low frequency/high frequency) and lower indices of the mean of the SD of all normal sinus RR intervals for all 5-minute segments, root-mean-square of the successive normal sinus RR interval difference, and percentage of successive normal sinus RR intervals>50 ms in time domain. Logistic regression demonstrated that an E/A ratio<1 was associated with lower HF., Conclusion: Individuals with no evidence of heart disease and an E/A ratio<1 demonstrated a significant decrease in indexes of HRV associated with parasympathetic modulation., (Copyright (c) 2010 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Background: Sheep are routinely used in experimental cardiac electrophysiology and surgery., Objective: The purpose of this study was to (1) ascertain the topography and architecture of the ovine epicardial neural plexus (ENP), (2) determine the relationships of ENP with vagal and sympathetic cardiac nerves and ganglia, and (3) evaluate gross anatomic differences and similarities of ENP in humans, sheep, and other species., Methods: Ovine ENP and extrinsic sympathetic and vagal nerves were stained histochemically for acetylcholinesterase in whole heart and/or thorax-dissected preparations from 23 newborn lambs, with subsequent examination by stereomicroscope., Results: Intrinsic cardiac nerves extend from the venous part of the ovine heart hilum along the roots of the cranial (superior) caval and left azygos veins to both atria and ventricles via five epicardial routes: dorsal right atrial, middle dorsal, left dorsal, right ventral, and ventral left atrial nerve subplexuses. Intrinsic nerves proceeding from the arterial part of the heart hilum along the roots of the aorta and pulmonary trunk extend exclusively into the ventricles as the right and left coronary subplexuses. The dorsal right atrial, right ventral, and middle dorsal subplexuses receive the main extrinsic neural input from the right cervicothoracic and right thoracic sympathetic T(2) and T(3) ganglia as well as from the right vagal nerve. The left dorsal is supplied by sizeable extrinsic nerves from the left thoracic T(4)-T(6) sympathetic ganglia and the left vagal nerve. Sheep hearts contained an average of 769 +/- 52 epicardial ganglia. Cumulative areas of epicardial ganglia on the root of the cranial vena cava and on the wall of the coronary sinus were the largest of all regions (P <.05)., Conclusion: Despite substantial interindividual variability in the morphology of ovine ENP, right-sided epicardial neural subplexuses supplying the sinoatrial and atrioventricular nodes are mostly concentrated at a fat pad between the right pulmonary veins and the cranial vena cava. This finding is in sharp contrast with a solely left lateral neural input to the human atrioventricular node, which extends mainly from the left dorsal and middle dorsal subplexuses. The abundance of epicardial ganglia distributed widely along the ovine ventricular nerves over respectable distances below the coronary groove implies a distinctive neural control of the ventricles in human and sheep hearts., (Copyright 2010 Heart Rhythm Society. All rights reserved.)

Introduction: The influence of the autonomic nervous system on the pathogenesis of complex fractionated atrial electrograms (CFAE) during atrial fibrillation (AF) is incompletely understood. This study evaluated the impact of pharmacological autonomic blockade on CFAE characteristics., Methods and Results: Autonomic blockade was achieved with propanolol and atropine in 29 patients during AF. Three-dimensional maps of the fractionation degree were made before and after autonomic blockade using the Ensite Navx system. In 2 patients, AF terminated following autonomic blockade. In the remaining 27 patients, 20,113 electrogram samples of 5 seconds duration were collected randomly throughout the left atrium (10,054 at baseline and 10,059 after autonomic blockade). The impact of autonomic blockade on fractionation was assessed by blinded investigators and related to the type of AF and AF cycle length. Globally, CFAE as a proportion of all atrial electrogram samples were reduced after autonomic blockade: 61.6 +/- 20.3% versus 57.9 +/- 23.7%, P = 0.027. This was true/significant for paroxysmal AF (47 +/- 23% vs 40 +/- 22%, P = 0.003), but not for persistent AF (65 +/- 22% vs 62 +/- 25%, respectively, P = 0.166). Left atrial AF cycle length prolonged with autonomic blockade from 170 +/- 33 ms to 180 +/- 40 ms (P = 0.001). Fractionation decreases only in the 14 of 27 patients with a significant (>6 ms) prolongation of the AF cycle length (64 +/- 20% vs 59 +/- 24%, P = 0.027), whereas fractionation did not reduce when autonomic blockade did not affect the AF cycle length (58 +/- 21% vs 56 +/- 25%, P = 0.419)., Conclusions: Pharmacological autonomic blockade reduces CFAE in paroxysmal AF, but not persistent AF. This effect appears to be mediated by prolongation of the AF cycle length.

Aims: The effects of ganglionated plexi (GP) ablation on atrial fibrillation (AF) inducibility and atrial autonomic innervation remodelling have not been elucidated., Methods and Results: Thirteen dogs were randomly divided into sham-operated group and GP ablation group. All animals underwent a right thoracotomy at the fourth intercostal space. Atrial fibrillation inducibility was assessed by burst rapid pacing at right atrium (RA). After anterior right GP and inferior right GP ablation, AF inducibility was assessed in the GP ablation group. The animals were allowed to recover for 8 weeks, after which, AF was measured again. The levels of atrial natriuretic peptide (ANP) in blood and atrial tissues were examined by radioimmunoassay. Immunocytochemical staining of cardiac nerves was performed in tissues from the dogs. Atrial fibrillation was induced easily in the GP ablation group after 8 weeks although AF was not observed in the sham-operated group, and after instant GP ablation. Compared with that in the sham-operated group, the levels of ANP in the blood and RA increased significantly 8 weeks after GP ablation (111.4 +/- 18.2 vs. 175.1 +/- 25.9; 184.9 +/- 36.3 vs. 299.1 +/- 32.5; P < 0.05). In the GP ablation group, the density of growth-associated protein 43-positive, tyrosine hydroxylase-positive, and choline acetyltransferase-positive nerves in the RA was 821 +/- 752, 481 +/- 627, and 629 +/- 644 per mm(2), respectively, which was significantly (P < 0.01) lower than the nerve density in sham-operated tissues (2590 +/- 841, 1752 +/- 605, and 3147 +/- 886 per mm(2), respectively)., Conclusion: Atrial autonomic innervations remodelling may be the mechanism of induced AF after GP ablation.

Two cases of "locked-in" sensitivity in the managed ventricular pacing mode are reported. Patient A was a 22-year-old man with a history of hypertrophic obstructive cardiomyopathy and a prophylactic dual-chamber automatic implantable cardioverter-defibrillator who manifested paradoxic T-wave oversensing on the ventricular lead at a sensitivity setting of 1.2 mV but not earlier when the sensitivity had been set to 0.9 mV. Patient B was a 74-year-old patient with ischemic cardiomyopathy and a dual-chamber defibrillator who presented with persistent paradoxic undersensing of the P wave on the atrial lead even at the maximal sensitivity of 0.15 mV, although P-wave sensing was normal earlier when sensitivity was set to 0.3 mV. The phenomenon and the mechanism for its behavior are described., (Copyright (c) 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Mapping and ablation of atrial tachycardias (ATs) secondary to catheter ablation of atrial fibrillation (AF) is often challenging due to the complex atrial substrate, different AT mechanisms, and potential origin not only in the left atrium (LA) but also from the right atrium (RA) and the adjacent thoracic veins., Objective: This study sought to develop an algorithm to facilitate localization of successful ablation regions based on limited activation data from simultaneous RA and coronary sinus (CS) recordings acquired from a single 20-pole catheter., Methods: Simultaneous lateral RA and CS atrial activation patterns (AAPs) from a 20-electrode catheter were analyzed for 155 successfully ablated ATs in 133 patients (age 58 +/- 9.6 years; 104 male [78.2%]) with prior ablation for AF. The first 125 ATs in 109 patients were analyzed retrospectively to define specific AAPs related to the location of critical AT sites as defined by effective ablation in 1 of 3 atrial regions. A classification algorithm was developed and tested retrospectively in a second blinded evaluation of the 125 previously analyzed ATs. The accuracy of the algorithm was then prospectively tested in 30 ATs in 24 patients., Results: Seven different lateral RA-CS activation patterns were identified as indicating AT origin from the left lateral atrium, septum, roof, or RA, with the pattern for some regions dependent on whether conduction block was present in common atrial flutter isthmuses. The algorithm derived identified the region of effective ablation with a sensitivity of 93%, a specificity of 97%, and a positive predictive value of 80% in the blinded analysis. In the prospective series, overall accuracy was 96%., Conclusion: Simultaneous assessment of RA and CS activation patterns from a single RA catheter suggests the likely region of origin of ATs that emerge after AF ablation, and may therefore facilitate ablation of these complex arrhythmias., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: It has been proposed that sequential mapping of dominant frequency (DF) and complex fractionated atrial electrograms (CFAE) can identify target sites for ablation of atrial fibrillation (AF). These mapping strategies are valid only if DF and CFAE are temporally stable on the timescale of the mapping procedure. We postulate that DF and CFAE are temporally variable; consequently, sequential mapping can be misleading., Objective: To make prolonged spatially stable multielectrode recordings to assess the temporal stability of DF and CFAE., Methods: We recorded electrical activity for 5 minutes with the use of a 64-electrode basket catheter placed in the left atrium of 18 patients presenting for AF ablation. DF and CFAE were determined off-line, and their temporal variability was quantified. Maps created from simultaneous versus sequentially acquired data were compared., Results: DF was temporally variable: the average temporal coefficient of variation was 22.7% +/- 5.4%. DF sites were transient, meeting criteria for only 22.1 seconds out of 5 minutes. Similarly, CFAEs were transient (average duration of CFAE 8.8 +/- 11.3 seconds). DF and CFAE sequential maps failed to identify 93.0% +/- 12.4% and 35.9% +/- 14.9% of DF and CFAE sites, respectively., Conclusion: Because of temporal variability, sequential DF and CFAE maps do not accurately reflect the spatial distribution of excitation frequency during any given sampling interval. The spatial distribution of DF and CFAE sites on maps created with sequential point acquisition depends upon the time at which each site is sampled., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Increasingly, interventional procedures require accessing the left atrium from the inside of the heart as well as from the pericardial space. The right phrenic nerve running along the fibrous pericardium is close to the atrial insertion of the right superior pulmonary vein while the left phrenic nerve passes over the left atrial appendage. Posteriorly, the esophagus descends adjacent to the fibrous pericardium covering the posterior and postero-inferior walls of the left atrium. The component parts of the left atrium are reviewed with emphasis on the structure of the atrial septum, the left atrial ridge, the mitral isthmus, and the left atrial walls. Although the atrial walls are mainly smooth, pits and crevices are common in the region of the mitral isthmus and the vicinity of the os of the atrial appendage. The muscular rim around the valve of the oval fossa delimits the extent of the true atrial septum. Interatrial muscular connections exist at the septum, along Bachmann's bundle and also at the muscular sleeves of the coronary sinus and pulmonary veins. Anatomical features relevant to interventional electrophysiologists are highlighted.

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., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: There is evidence that verapamil promotes the persistence of paroxysmal atrial fibrillation (AF). Little is known about the underlying mechanisms., Objective: The purpose of this study was to determine the effect of verapamil on dominant frequencies (DFs) in the pulmonary veins (PVs) and atria during paroxysmal AF with reference to its potential arrhythmogenicity., Methods: Forty-three patients with paroxysmal AF were studied. Bipolar electrograms were recorded simultaneously during AF from the right atrial free wall (RAFW), coronary sinus (CS) and three PVs, or two PVs and the left atrial appendage (LAA). The DFs were obtained by fast Fourier transform analysis before and after infusion of verapamil (0.1 mg/kg, intravenously)., Results: At baseline, the maximum DF among the PVs (6.9 +/- 0.9 Hz) was significantly higher than the DF in the RAFW (6.2 +/- 0.7 Hz), CS (5.7 +/- 0.5 Hz), or LAA (5.9 +/- 0.7 Hz) (P<.01); there was a substantial PV-to-atrial DF gradient (RAFW 0.7 +/- 0.9, CS 1.1 +/- 0.7, LAA 0.7 +/- 0.9 Hz). Verapamil increased the atrial DF to 6.9 +/- 0.8, 6.6 +/- 0.7, and 7.2 +/- 1.0 Hz in the RAFW, CS, and LAA, respectively (P<.0001) but did not affect the maximum PV DF (7.1 +/- 0.7 Hz). The PV-to-atrial DF gradient was eliminated after verapamil (RAFW 0.2 +/- 0.8, CS 0.5 +/- 0.6, LAA -0.4 +/- 0.8 Hz; P<.01 vs. baseline)., Conclusion: Verapamil increases the activation frequency in the atria but not in the PVs, eliminating the PV-to-atrial DF gradient during paroxysmal AF., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)