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Background: Cardioneuroablation (CNA) targets the intrinsic cardiac autonomic nervous system ganglionated plexi located in the peri-atrial epicardial fat. There is increasing interest in CNA as a treatment of vasovagal syncope (VVS), despite no randomized clinical trial (RCT) data., Objective: The purpose of this study was to poll the opinion on CNA) for VVS., Methods: A REDCap (Research Electronic Data Capture) survey was administered to international physicians treating patients with VVS on their opinion about patient selection criteria, ablation approach, RCT design, and most appropriate end points for CNA procedures., Results: The survey was completed by 118 physicians; 86% were cardiac electrophysiologists. The majority of respondents (79%) would consider referring a patient with refractory VVS for CNA, and 27% have performed CNA for VVS themselves. Most felt patient selection should require a head-up tilt test with a cardioinhibitory response (67%) and suggest a minimum age of 18 years with a median of 3 (interquartile range 2-5) episodes in the past year. There were differences in patient selection between physicians who have performed CNA themselves and those who have not. The majority felt that the ablation strategy should include both atria (70%) with an anatomical approach in combination with autonomic stimulation (85%). Performing a sham procedure in the control arm was supported by 56% of respondents, providing equipoise in RCT design. The preferred primary outcome was freedom from syncope within 1 year of follow-up., Conclusion: There is widespread support for well-designed RCTs to confirm the hypothesized clinical benefit of CNA, provide data to guide the risk-benefit equations during patient selection, and appropriately estimate the placebo effect., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Sympathetic nerve activity, heart rate (HR), and blood pressure (BP) all have very low frequency (VLF), low frequency (LF), and high frequency (HF) oscillations., Objective: The purpose of this study was to test the hypothesis that the frequency spectra of subcutaneous nerve activity (ScNA), stellate ganglion nerve activity (SGNA), HR, and BP are important to cardiac arrhythmogenesis., Methods: We used radiotransmitters to record SGNA, ScNA, HR, and BP in 6 ambulatory dogs and determined the dominant frequency and paroxysmal atrial tachyarrhythmias (PATs) episodes in 3-minute windows over a 24-hour period., Results: The frequency spectra determined in ScNA reflected that in SGNA. HF oscillations were present in both ScNA and SGNA at all time but could be overshadowed by the much larger LF and VLF burst activities. The dominant frequency could occur in any of the 3 frequency bands. There were circadian variations with more frequent occurrences of HF oscillations at night. HF oscillations in HR and BP matched HF oscillations in SGNA and ScNA. PATs occurred only when dominant frequencies of SGNA and ScNA were in the LF and VLF bands., Conclusion: HF oscillations in BP and HR correlate with HF oscillations in sympathetic nerve activity and are present at all time. HF oscillations can be overshadowed by the much larger LF and VLF burst activities. PATs occur only when LF or VLF, but not when HF, is the dominant frequency. The frequency spectra determined in ScNA reflect that in SGNA., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The intrinsic cardiac nervous system is a rich network of cardiac nerves that converge to form distinct ganglia and extend across the heart and is capable of influencing cardiac function., Objective: The goals of this study were to provide a complete picture of the neurotransmitter/neuromodulator profile of the rabbit intrinsic cardiac nervous system and to determine the influence of spatially divergent ganglia on cardiac electrophysiology., Methods: Nicotinic or electrical stimulation was applied at discrete sites of the intrinsic cardiac nerve plexus in the Langendorff-perfused rabbit heart. Functional effects on sinus rate and atrioventricular conduction were measured. Immunohistochemistry for choline acetyltransferase (ChAT), tyrosine hydroxylase, and/or neuronal nitric oxide synthase (nNOS) was performed using whole mount preparations., Results: Stimulation within all ganglia produced either bradycardia, tachycardia, or a biphasic brady-tachycardia. Electrical stimulation of the right atrial and right neuronal cluster regions produced the largest chronotropic responses. Significant prolongation of atrioventricular conduction was predominant at the pulmonary vein-caudal vein region. Neurons immunoreactive (IR) only for ChAT, tyrosine hydroxylase, or nNOS were consistently located within the limits of the hilum and at the roots of the right cranial and right pulmonary veins. ChAT-IR neurons were most abundant (1946 ± 668 neurons). Neurons IR only for nNOS were distributed within ganglia., Conclusion: Stimulation of intrinsic ganglia, shown to be of phenotypic complexity but predominantly of cholinergic nature, indicates that clusters of neurons are capable of independent selective effects on cardiac electrophysiology, therefore providing a potential therapeutic target for the prevention and treatment of cardiac disease., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Intrinsic cardiac nerve activity (ICNA) and skin nerve activity (SKNA) are both associated with cardiac arrhythmias in dogs., Objective: The purpose of this study was to test the hypothesis that ICNA and SKNA correlate with postoperative cardiac arrhythmias in humans., Methods: Eleven patients (mean age 60 ± 13 years; 4 women) were enrolled in this study. Electrical signals were simultaneously recorded from electrocardiogram (ECG) patch electrodes on the chest wall and from 2 temporary pacing wires placed during open heart surgery on the left atrial epicardial fat pad. The signals were filtered to display SKNA and ICNA. Premature atrial contractions (PACs) and premature ventricular contractions were determined manually. The SKNA and ICNA of the first 300 minutes of each patient were calculated minute by minute to determine baseline average amplitudes of nerve activities and to determine their correlation with arrhythmia burden., Results: We processed 1365 ± 973 minutes of recording per patient. Low-amplitude SKNA and ICNA were present at all time, while the burst discharges were observed much less frequently. Both SKNA and burst ICNA were significantly associated with the onset of PACs and premature ventricular contractions. Baseline average ICNA (aICNA), but not average SKNA, had a significant association with PAC burden. The correlation coefficient (r) between aICNA and PAC burden was 0.78 (P < .01). A patient with the greatest aICNA developed postoperative atrial fibrillation., Conclusion: ICNA and SKNA can be recorded from human patients in the postoperative period. The baseline magnitude of ICNA correlates with PAC burden and development of postoperative atrial fibrillation., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: With the recent advent of high-density (HD) 3-dimensional (3D) mapping, the utility of entrainment is uncertain. However, the limitations of visual representation and interpretation of these high-resolution 3D maps are unclear., Objective: The purpose of this study was to determine the strengths and limitations of both HD 3D mapping and entrainment mapping during mapping of right atrial macroreentry., Methods: Fifteen patients were studied. The number and type of circuits accounting for ≥90% of the tachycardia cycle length using HD 3D mapping were verified using systematic entrainment mapping. Entrainment sites with an unexpectedly long postpacing interval despite proximity to the active circuit were evaluated., Results: Based on HD 3D mapping, 27 circuits were observed: 12 peritricuspid, 2 upper loop reentry, 10 lower loop reentry, and 3 lateral wall circuits. With entrainment, 17 of the 27 circuits were active: all 12 peritricuspid and 2 upper loop reentry. However, lower loop reentry was confirmed in only 3 of 10, and none of the 3 lateral wall circuits were present. Mean percentage of tachycardia cycle length covered by active circuits was 98% ± 1% vs 97% ± 2% for passive circuits (P = .09). None of the 345 entrainment runs terminated tachycardia or changed tachycardia mechanism. In 8 of 15 patients, 13 examples of unexpectedly long postpacing interval were observed at entrainment sites located distal to localized zones of slow conduction seen on HD 3D mapping., Conclusion: Using HD 3D mapping, "visual reentry" may be due to passive circuitous propagation rather than a critical reentrant circuit. HD 3D mapping provides new insights into regional conduction and helps explain unusual entrainment phenomena., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The effects of intermittent open-loop vagal nerve stimulation (VNS) on the ventricular rate (VR) during atrial fibrillation (AF) remain unclear., Objective: The purpose of this study was to test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF., Methods: We performed left cervical VNS in ambulatory dogs while recording the left SG nerve activity (SGNA) and vagal nerve activity. Tyrosine hydroxylase (TH) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess neuronal cell death in the SG., Results: We induced persistent AF by atrial pacing in 6 dogs, followed by intermittent VNS with short ON-time (14 seconds) and long OFF-time (66 seconds). The integrated SGNA and VR during AF were 4.84 mV·s (95% confidence interval [CI] 3.08-6.60 mV·s) and 142 beats/min (95% CI 116-168 beats/min), respectively. During AF, VNS reduced the integrated SGNA and VR, respectively, to 3.74 mV·s (95% CI 2.27-5.20 mV·s; P = .021) and 115 beats/min (95% CI 96-134 beats/min; P = .016) during 66-second OFF-time and to 4.07 mV·s (95% CI 2.42-5.72 mV·s; P = .037) and 114 beats/min (95% CI 83-146 beats/min; P = .039) during 3-minute OFF-time. VNS increased the frequencies of prolonged (>3 seconds) pauses during AF. TH staining showed large confluent areas of damage in the left SG, characterized by pyknotic nuclei, reduced TH staining, increased percentage of TH-negative ganglion cells, and positive TUNEL staining. Occasional TUNEL-positive ganglion cells were also observed in the right SG., Conclusion: VNS damaged the SG, leading to reduced SGNA and better rate control during persistent AF., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) is highly associated with obstructive sleep apnea (OSA) in which AF is triggered by hyperactivity of the cardiac autonomic nervous system. Previous studies showed that low-level vagosympathetic trunk stimulation (LLVS), at voltages not slowing sinus rate or AV conduction, inhibits AF by suppressing the cardiac autonomic nervous system., Objective: The purpose of this study was to investigate whether LLVS delivered at the right vagosympathetic trunk suppresses AF in a rabbit model of OSA., Methods: Eleven rabbits received a tracheostomy under general anesthesia. The endotracheal tube was clamped at end expiration for 1 minute to simulate OSA. Over a period of 4 hours, OSA was delivered every 6 minutes. Effective refractory period (ERP), blood pressure, intraesophageal pressure, and blood gases (O2, CO2, pH) were measured before and after each episode of OSA. AF duration and ERP were measured by programmed stimulation. Group 1 rabbits (n = 6) received LLVS (50% below that which slowed the sinus rate) in the first 3 hours. Group 2 rabbits (n = 5) only received OSA., Results: Group 1 ERP began to lengthen progressively from the second hour compared to group 2. AF duration increased in the first hour for both groups but began to shorten progressively after the first hour in group 1 rabbits. Blood pH, O2 or CO2 level, intraesophageal pressure, and hypertensive response during OSA were not different between the 2 groups., Conclusion: LLVS is capable of suppressing ERP shortening and AF induced by OSA. LLVS may serve as a new therapeutic approach to treat OSA-induced AF., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The features of intrinsic ganglionated plexi (GP) in both atria after extensive pulmonary vein isolation (PVI) and their clinical implications have not been clarified in patients with atrial fibrillation (AF)., Objective: The purpose of this study was to assess the features of GP response after extensive PVI and to evaluate the relationship between GP responses and subsequent AF episodes., Methods: The study population consisted of 216 consecutive AF patients (104 persistent AF) who underwent an initial ablation. We searched for the GP sites in both atria after an extensive PVI., Results: GP responses were determined in 186 of 216 patients (85.6%). In the left atrium, GP responses were observed around the right inferior GP in 116 of 216 patients (53.7%) and around the left inferior GP in 57 of 216 (26.4%). In the right atrium, GP responses were observed around the posteroseptal area: inside the CS in 64 of 216 patients (29.6%), at the CS ostium in 150 of 216 (69.4%), and in the lower right atrium in 45 of 216 (20.8%). The presence of a positive GP response was an independent risk factor for AF recurrence (hazard ratio 4.04, confidence interval 1.48-11.0) in patients with paroxysmal, but not persistent, AF. The incidence of recurrent atrial tachyarrhythmias in patients with paroxysmal AF with a positive GP response was 51% vs 8% in those without a GP response (P = .002)., Conclusion: The presence of GP responses after extensive PVI was significantly associated with increased AF recurrence after ablation in patients with paroxysmal AF., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: In patients with atrial fibrillation (AF), the autonomic nervous system is supposed to play an role in triggering AF; however, little is known of the effect on atrial conduction characteristics., Objective: The purpose of this study was to study the effect of ganglionic plexus (GP) stimulation during sinus rhythm on atrial and pulmonary vein conduction in patients during thoracoscopic surgery for AF METHODS: In 25 patients, the anterior right ganglionic plexus (ARGP) was stimulated (16 Hz, at 1, 2, and 5 mA). Epicardial electrograms were recorded using a 48-electrode map from the right pulmonary vein (RPV) or right atrial (RA). Intra-atrial activation time (IAT), local activation time (LAT), and inhomogeneity of conduction (IIC) were determined. ECG parameters (P-P, P-R interval) were measured., Results: P-P interval was 956 ± 157 ms (range 768-1368 ms), and P-R interval was 203 ± 37 ms (range 136-280 ms). After ARGP stimulation, a short-lasting increase of P-P interval was observed, more prominent at higher output (1 mA = 82 ms, 2 mA = 180 ms, 5 mA = 268 ms, all P <.01 vs baseline). P-R interval remained unchanged. IAT was 34.4 ms (range 5.6-50.3 ms) at the RA and 105.8 ms (range 79.7-163.3 ms) at the RPV. After 1-mA stimulation IAT increased, in patients taking beta-blockers (P = .001), or it decreased, and this change persisted after subsequent stimulation at higher current (1 mA, P = .001; 2 mA, P = .401; 5 mA, P = .593). Similar changes were observed for LAT and IIC., Conclusion: ARGP stimulation results in a short-lasting, output-dependent decrease in sinus node frequency due to a parasympathetic response. Stimulation of the ARGP induced a prolonged increase or decrease in conduction characteristics in patients with AF, consistent with a persistent differential parasympathetic and/or sympathetic response., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The ganglionated plexi (GP) located at the junction of the superior vena cava, aorta, and right pulmonary artery (SVC-Ao GP) was proposed to be the "head station" between the extrinsic and the intrinsic cardiac autonomic nervous system (ECANS and ICANS, respectively)., Objective: To investigate the chronic effects after interrupting the ECANS-ICANS connections by ablating the SVC-Ao GP., Methods: A right thoracotomy in 10 dogs allowed stimulation at the right superior and inferior pulmonary veins (RSPV and RIPV, respectively), right atrial appendage (RAA), and SVC to determine effective refractory period (ERP) and atrial fibrillation (AF) inducibility in the first operation. Group 1 (n = 5) received SVC-Ao GP ablation; group 2 (n = 5) received no ablation. A second operation and the same measurements were made 10 weeks later. A pacemaker with lead implanted at the RSPV recorded atrial fibrillation or tachycardia (AF/AT)., Results: During the first operation in group 1, ERPs increased significantly in the SVC but not at the RSPV, RIPV, or RAA site immediately after ablation, whereas ERPs decreased significantly in the RSPV, RIPV, and RAA but not the SVC in the second operation performed 10 weeks later (compared to the ERP in the first operation). ERPs decreased and AF/AT burden increased significantly from weeks 4 and 5, respectively, after the first operation in group 1 dogs. The ERP and AF/AT burden in group 2 remained unchanged between operations., Conclusions: Ablation of the head station GP between the ECANS and the ICANS prolonged the ERP acutely, but shortened regional ERPs and increased AF/AT burden chronically, suggesting that the ECANS may tonically inhibit the ICANS activity., (Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The strategy for catheter ablation of persistent atrial fibrillation (AF) and the procedural end point remain controversial., Objective: To evaluate the feasibility of a sequential defragmentation approach., Methods: One hundred thirty-five patients (aged 62.4 ± 9 years; 76 long-standing persistent AF) underwent first ablation procedure for persistent AF. With an end point of AF termination, the ablation procedure was performed sequentially in the following order: pulmonary vein antrum isolation, linear defragmentation of complex fractionated electrograms at left atrial (LA) roof, bottom, septum, inferior LA, base of LA appendage, anterior LA, right atrial septum, crista terminalis, and base of right atrial appendage. Ensuing atrial tachycardias (ATs) were mapped and ablated., Results: AF termination was achieved in 69 (51%) patients (59 in the left atrium and 10 in the right atrium). The total procedure and fluoroscopic times were 145.4 ± 36.1 and 35.1 ± 14.3 minutes, respectively. At median 19.0 months, 105 (78%) patients demonstrated recurrent atrial tachyarrhythmia necessitating repeat ablation procedure(s). With mean 1.7 ± 0.7 procedures per patient, 100 (74%) patients were free from atrial tachyarrhythmia at median 15.0-month follow-up. Among 73 mappable ATs, 49 were macroreentrant ATs. On multivariate Cox regression analysis, greater LA diameter (hazard ratio 1.10; 95% confidence interval 1.04-1.17; P = .0004) and non-AF termination (hazard ratio 1.50; 95% confidence interval 1.01-2.36; P = .036) were independent predictors of AF recurrence after single and multiple ablation procedures, respectively., Conclusions: Pulmonary vein antrum isolation followed by biatrial substrate modification in a predetermined order of linear ablation of specific anatomical regions with predilection for complex fractionated atrial electrograms is a feasible alternative persistent AF ablation strategy., (Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Spinal cord stimulation (SCS) has been shown to modulate atrial electrophysiology and confer protection against ischemia and ventricular arrhythmias in animal models., Objective: To determine whether SCS reduces the susceptibility to atrial fibrillation (AF) induced by tachypacing (TP)., Methods: In 21 canines, upper thoracic SCS systems and custom cardiac pacing systems were implanted. Right atrial and left atrial effective refractory periods were measured at baseline and after 15 minutes of SCS. Following recovery in a subset of canines, pacemakers were turned on to induce AF by alternately delivering TP and searching for AF. Canines were randomized to no SCS therapy (CTL) or intermittent SCS therapy on the initiation of TP (EARLY) or after 8 weeks of TP (LATE). AF burden (percent AF relative to total sense time) and AF inducibility (percentage of TP periods resulting in AF) were monitored weekly. After 15 weeks, echocardiography and histology were performed., Results: Effective refractory periods increased by 21 ± 14 ms (P = .001) in the left atrium and 29 ± 12 ms (P = .002) in the right atrium after acute SCS. AF burden was reduced for 11 weeks in EARLY compared with CTL (P <.05) animals. AF inducibility remained lower by week 15 in EARLY compared with CTL animals (32% ± 10% vs 91% ± 6%; P <.05). AF burden and inducibility were not significantly different between LATE and CTL animals. There were no structural differences among any groups., Conclusions: SCS prolonged atrial effective refractory periods and reduced AF burden and inducibility in a canine AF model induced by TP. These data suggest that SCS may represent a treatment option for AF., (Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

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.)

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.)

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.)

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.)

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: 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.)

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.)

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: 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: Recent evidence indicates that spontaneous sarcoplasmic reticulum (SR) calcium (Ca) release underlies the mechanism of sinoatrial node (SAN) acceleration during beta-stimulation, indicating the importance of the Ca clock in SAN automaticity. Whether or not the same mechanism applies to atrial ectopic pacemakers (AEPs) remains unclear., Objective: The purpose of this study was to assess the mechanism of AEP., Methods: We simultaneously mapped intracellular calcium (Ca(i)) and membrane potential in 12 isolated canine right atria. The late diastolic Ca(i) elevation (LDCAE) was used to detect the Ca clock activity. Pharmacological interventions with isoproterenol (ISO), ryanodine, and ZD7288, a blocker of the I(f) membrane current, were performed., Results: Ryanodine, which inhibits SR Ca release, reduced LDCAE in SAN, resulting in an inferior shift of the pacemaking site. Cycle length increased significantly in a dose-dependent way. In the presence of 3 to 10 mumol/l of ryanodine, ISO infusion consistently induces AEPs from the lower crista terminalis. All ectopic beats continuing over 30 seconds were located at the lower crista terminalis. These AEPs were resistant to ryanodine treatment even at high doses. Subsequent blockade of I(f) inhibited the AEP and resulted in profound bradycardia., Conclusion: Spontaneous SR Ca release underlies ISO-induced increase of superior SAN activity. As compared with SAN, the AEP is less dependent on the Ca clock and more dependent on the membrane clock for its automaticity. AEPs outside the SAN can effectively serve as backup pacemakers when the Ca clock functionality is reduced.

The intrinsic cardiac autonomic nervous system (ganglionated plexuses [GP]) plays a significant role in the initiation and maintenance of atrial fibrillation (AF) in both experimental models and AF patients. Left atrial GP, located in epicardial fat pads and the ligament of Marshall, contain afferent neurons from the atrial myocardium and the central autonomic nervous system, efferent neurons (cholinergic and adrenergic neurons), and interconnecting neurons, which allow communication between GP. Stimulation of the GP produces both parasympathetic stimulation (markedly shortens action potential duration) and sympathetic stimulation (increases calcium transient) in the pulmonary vein (PV) myocardium and atrial myocardium. In a canine model, GP stimulation resulted in early afterdepolarizations, and calcium transient triggered firing in the adjacent PV and initiated AF. Fractionated atrial potentials (FAP) were consistently located in the left atrium close to the stimulated GP. Ablation of the stimulated GP eliminated the FAP surrounding the GP. In patients with paroxysmal AF, epicardial and endocardial high-frequency stimulation produced a positive vagal response (transient AV block during AF and hypotension), allowing the identification and localization of five major left atrial GP (superior left GP, inferior left GP, Marshall tract GP, anterior right GP, inferior right GP). High-density electroanatomic maps of the left atrium and PVs obtained during AF showed the FAP are located in four main left atrial areas (left atrial appendage ridge FAP area, superior-left FAP area, inferoposterior FAP area, anterior-right FAP area). All five GP are located within one of the four FAP areas. In 63 patients with paroxysmal AF, GP ablation alone (before PV antrum isolation) significantly decreased the occurrence of PV firing (47/63 patients before ablation vs 9/63 patients after ablation, P <.01). GP ablation also decreased the inducibility of sustained AF (43/63 patients vs 23/63 patients, P <.01) and markedly reduced or eliminated the left atrial FAP areas.

Background: Selective ganglionated plexi (GP) ablation guided by high-frequency stimulation has been proposed for the treatment of paroxysmal atrial fibrillation (AF), but the efficacy of the method is not established., Objective: This study sought to compare selective ablation of GP identified by high-frequency stimulation with extensive regional ablation targeting the anatomic areas of GP in patients with paroxysmal AF., Methods: Eighty patients with paroxysmal AF (age 53 +/- 9 years) were randomized to undergo selective GP ablation or regional left atrial ablation at the anatomic sites of GP. For selective GP ablation (n = 40), ablation targets were the sites where vagal reflexes were evoked by high-frequency stimulation. Vagal reflexes were defined as prolongation of the R-R interval by >50% and a concomitant decrease in blood pressure (>20 mm Hg) during AF. The end point of the procedure was failure to reproduce vagal reflexes with repeated high-frequency stimulation. For anatomic ablation, lesions were delivered at the sites of GP clustering., Results: At 13.1 +/- 1.9 months, 42.5% of patients with selective GP and 77.5% of patients with anatomic ablation were free of symptomatic paroxysmal AF (PAF) (P = .02). Parasympathetic denervation was more prominent in patients with anatomic than selective GP ablation, and in patients free of AF compared to these with AF recurrence immediately after ablation, but this trend was abolished at 6 months., Conclusion: Selective GP ablation directed by high-frequency stimulation does not eliminate paroxysmal AF in the majority of patients. An anatomic approach for regional ablation at the sites of GP confers better results.

Background: The angiotensin-converting enzyme (ACE) gene contains a common polymorphism based on the insertion (I) or deletion (D) of a 287-bp intronic DNA fragment. The D allele is associated with higher ACE activity and thus higher angiotensin II levels. Angiotensin II stimulates cardiac fibrosis and conduction heterogeneity., Objective: The purpose of this study was to determine whether the ACE I/D polymorphism modulates cardiac electrophysiology., Methods: Three different cohorts of patients were studied: 69 patients with paroxysmal lone atrial fibrillation (AF), 151 patients with structural heart disease and no history of AF, and 161 healthy subjects without cardiovascular disease or AF. Patients taking drugs that affect cardiac conduction were excluded from the study. ECG parameters during sinus rhythm were compared among the ACE I/D genotypes., Results: The ACE I/D polymorphism was associated with the PR interval and heart block in the lone AF cohort. In multivariable linear regression models, the D allele was associated with longer PR interval in the lone AF and heart disease cohorts (12.0-ms and 7.1-ms increase per D allele, respectively). P-wave duration showed a similar trend, with increase in PR interval across ACE I/D genotypes in the lone AF and heart disease cohorts., Conclusion: The ACE D allele is associated with electrical remodeling in patients with lone AF and in those with heart disease, but not in control subjects. ACE activity may play a role in cardiac remodeling after the development of AF and heart disease.

Background: The regional distribution of the low-voltage zones (LVZs) may relate to the maintenance of atrial arrhythmias in the right atrium (RA)., Objectives: The purpose of this study was to investigate the RA substrate characteristics in different types of atrial arrhythmias originating from RA and left atrium (LA)., Methods: Forty-five patients (35 men, age = 62 +/- 15 years) with RA atypical atrial flutter (n = 15, group 1), RA atrial fibrillation (AF; n = 15, no PV initiating foci, group 2), and LA AF (n = 1 5, no RA arrhythmias, group 3) referred for three-dimensional EnSite mapping were included. Voltage and activation maps were visualized., Results: The mean voltage of the RA was lower in group 2, and compared with group 3, a voltage reduction during atrial pacing was evident in groups 1 and 2. The fixed LVZs (independent of the rhythm) were mostly located along the lower crista terminalis (CT). A functional extension of the LVZ was located on the CT in 84% of patients, sinus venosa in 18%, and free-wall region in 27%, forming the borders of the slow conduction isthmus for the reentrant circuits. The number of slow conduction isthmuses was 1.3 +/- 0.9, 2.2 +/- 1.0, and 0.87 +/- 0.74, for the groups 1-3 patients, respectively (P <.05). Radiofrequency ablation connecting the LVZs successfully eliminated those isthmuses. The long-term follow-up revealed that 66% of the patients remained in sinus rhythm., Conclusions: Single and multiple slow conduction isthmuses bordered by the fixed and functional LVZs were critical for the reentrant circuits in the RA. The conduction isthmuses could be identified by their substrate characteristics and ablated successfully.

Background: Fractionated atrial electrograms (CFAEs) have been implicated in the mechanism of atrial fibrillation (AF). The prevalence and distribution of CFAEs in normal populations have not been clearly defined., Objective: This study sought to determine the influence of age on CFAEs and investigate the relationship between CFAEs and the underlying atrial substrate., Methods: Twenty-one patients without structural heart disease underwent electroanatomic mapping of their right atrium (RA). Patients were categorized into 3 groups according to age: group A, patients <30 years (25.1 +/- 3.1 years, n = 7); group B, patients between 31 and 59 years (51.7 +/- 10.3 years, n = 6); group C, patients >60 years (66.9 +/- 7.7 years, n = 8). The proportion of points with CFAEs was analyzed for the high and low septal RA, high and low lateral RA, and high and low posterior RA. The mean atrial voltage and conduction velocity were assessed in each of these regions., Results: The percentage of CFAEs was greater in group C (14.6% +/- 7.7%) than in group A (2.7% +/- 2.1%; P = 0.001). The percentage of CFAEs in group B (8.5% +/- 3.5%) was not significantly different from that in group A (P = 0.21) and group C (P = 0.14). The CFAEs were predominantly located in the posterior RA and high septal RA. There were significant correlations between the proportion of CFAEs and age (R = 0.72; P < 0.01), atrial voltage (R = -0.57; P < 0.01), and conduction velocity (R = -0.73; P < 0.001)., Conclusion: CFAEs increase with age and occur in regions of low atrial voltage and slowed conduction. The distribution of CFAE is predominantly along the posterior and high septal RA, regions where there are marked changes in myocardial fiber orientation. This suggests that the underlying myocardial architecture is the main influence on electrogram morphology.

Background: There is a lack of understanding of the substrate for microreentrant circuits and triggered activity of the pulmonary vein (PV) muscle sleeves and atria in patients with atrial fibrillation (AF)., Objective: This study sought to examine the histological substrate of patients with chronic AF., Methods: We stained 23 biopsies taken from the PV-left atrium (LA) junction and right atrial appendage from 5 chronic AF patients and 3 sinus rhythm (SR) patients undergoing mitral valve surgery using periodic acid-Schiff (PAS) test, and antibodies to hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4), CD117/c-kit, myoglobin, tyrosine hydroxylase (TH), growth-associated protein 43, cholineacetyltransferase, and synaptophysin, as well as trichrome., Results: As opposed to being clustered together in the subendocardial layer in SR patients, PAS-positive cells were separated from each other by inflammatory infiltrate and collagen fibers in AF patients. These cells stained positively for HCN4 and myoglobin, indicating they were cardiomyocytes that might have a potential pacemaking function, but different from CD117/c-kit-positive interstitial Cajal-like cells (ICLC). In AF patients, the intercellular space was occupied by a lymphomononuclear infiltrate (100% vs 33% in SR patients, P = .002), and a greater amount of interstitial fibrosis (37% +/- 5.6% vs 7.4% +/- 2.8%, P = .009). Nerve densities did not differ between AF and SR patients. However, the density of sympathetic nerve twigs in AF patients was significantly greater as compared to the others nerves (P = .03)., Conclusion: HCN4-/PAS-positive cardiomyocytes and CD117/c-kit-positive ICLC scattered among abundant inflammatory infiltrate, fibrous tissue, and sympathetic nerve structures in the atria and at the PV-LA junctions might be a substrate for the maintenance of chronic AF.

Background: This prospective multicenter randomized study aimed to compare the efficacy of 3 common ablation methods used for longstanding permanent atrial fibrillation (AF)., Methods: A total of 144 patients with longstanding permanent AF (median duration 28 months) were randomly assigned to circumferential pulmonary vein ablation (CPVA, group 1, n = 47), to pulmonary vein antrum isolation (PVAI, group 2, n = 48) or to a hybrid strategy combining ablation of complex fractionated or rapid atrial electrograms (CFAE) in both atria followed by a pulmonary vein antrum isolation (CFAE + PVAI, group 3, n = 49)., Results: Scarring in the left atrium and structural heart disease/hypertension were present in most patients (65%). After a mean follow-up of 16 months, 11% of patients in group 1, 40% of patients in group 2 and 61% of patients in group 3 were in sinus rhythm after one procedure and with no antiarrhythmic drugs (P < .001). Sinus rhythm maintenance would increase respectively to 28% (group 1), 83% (group 2), and 94% (group 3) after 2 procedures and with antiarrhythmic drugs (AADs, P < .001). The AF terminated during ablation, either by conversion to sinus rhythm or organization into an atrial tachyarrhythmia, in 13% of patients (group 1), 44% (group 2), and 74% (group 3) respectively. CFAE alone, performed as the first step of the ablation in group 3, organized AF in only 1 patient., Conclusion: In this study, the hybrid AF ablation strategy including antrum isolation and CFAE ablation had the highest likelihood of maintaining sinus rhythm in patients with longstanding permanent AF. Electrical isolation of the PVs, although inadequate if performed alone, is relevant to achieve long-term sinus rhythm maintenance after ablation. Bi-atrial CFAE ablation had a minimal impact on AF termination during ablation.

Background: Current strategies of engineering bioartificial pacemakers from otherwise silent yet excitable adult atrial and ventricular cardiomyocytes primarily rely on either maximizing the hyperpolarization-activated I(f) or on minimizing its presumptive opponent, the inwardly rectifying potassium current I(K1)., Objective: The purpose of this study was to determine quantitatively the relative current densities of I(f) and I(K1) necessary to induce automaticity in adult atrial cardiomyocytes., Methods: Automaticity of adult guinea pig atrial cardiomyocytes was induced by adenovirus (Ad)-mediated overexpression of the gating-engineered HCN1 construct HCN1-DeltaDeltaDelta with the S3-S4 linker residues EVY235-7 deleted to favor channel opening., Results: Whereas control atrial cardiomyocytes remained electrically quiescent and had no I(f), 18% of Ad-CMV-GFP-IRES-HCN1-DeltaDeltaDelta (Ad-CGI-HCN1-DeltaDeltaDelta)-transduced cells demonstrated automaticity (240 +/- 14 bpm) with gradual phase 4 depolarization (143 +/- 28 mV/s), a depolarized maximal diastolic potential (-45.3 +/- 2.2 mV), and substantial I(f) at -140 mV (I(f,-140 mV) = -9.32 +/- 1.84 pA/pF). In the remaining quiescent Ad-CGI-HCN1-DeltaDeltaDelta-transduced atrial cardiomyocytes, two distinct immediate phenotypes were observed: (1) 13% had a hyperpolarized resting membrane potential (-56.7 +/- 1.3 mV) with I(f,-140 mV) of -4.85 +/- 0.97 pA/pF; and (2) the remaining 69% displayed a depolarized resting membrane potential (-27.6 +/- 1.3 mV) with I(f,-140 mV) of -23.0 +/- 3.71 pA/pF. Upon electrical stimulation, both quiescent groups elicited a single action potential with incomplete phase 4 depolarization that was never seen in controls. Further electrophysiologic analysis indicates that an intricate balance of I(K1) and I(f) is necessary for induction of atrial automaticity., Conclusion: Optimized pacing induction and modulation can be better achieved by engineering the I(f)/I(K1) ratio rather than the individual currents.

Background: Block of ultrarapid delayed rectified potassium current (I(Kur)), present in atria but not in ventricles, is thought to be a promising approach for atrial-specific therapy of atrial fibrillation (AF). However, it has been shown that I(Kur) block may abbreviate atrial repolarization and that loss-of-function mutations in KCNA5, which encodes K(v) 1.5 channels responsible for I(Kur), is associated with familial AF., Objective: Our objective in this study was to use low concentrations of 4-aminopyridine (4-AP, 10 to 50 microM), known to selectively block I(Kur), to assess the proarrhythmic and antiarrhythmic effects of I(Kur) block in healthy and remodeled atria., Methods: Isolated canine coronary-perfused right atrial preparations were used. Acetylcholine or ischemia/reperfusion was used to acutely remodel the atria. Transmembrane action potentials and a pseudo-electrocardiogram were simultaneously recorded., Results: Normal (healthy) atria typically displayed action potentials (AP) with a prominent plateau, whereas remodeled atria displayed triangular-shaped APs (remodeled). In healthy atria, in which AF could not be induced with programmed stimulation, 4-AP abbreviated action potential measured at 90% repolarization (APD(90)) and effective refractory period (ERP), permitting the induction of AF in 4 of 12 preparations (33%). In remodeled atria, 4-AP produced little (50 microM) to no (10 to 25 microM) prolongation of APD(90) or ERP and was either ineffective or poorly effective in terminating AF or preventing its induction., Conclusion: Our findings suggest that block of I(Kur) can provide the substrate for development of AF in healthy canine atria, presumably via abbreviation of APD and ERP.

Background: Radiofrequency ablation therapy of atrial fibrillation (AF) recently incorporated the analysis of dominant frequency (DF) and/or electrogram fractionation for guidance. However, the relationships between DF, fractionation, and spatiotemporal characteristics of the AF source remain unclear., Objective: We hypothesize that a meandering reentrant AF source contributes to the wave fractionation and is reflected in the power spectrum of local electrograms elsewhere in the rotor's surroundings., Methods: Meandering rotors as AF sources were simulated in 2-dimensional models of human atrial tissue and recorded in isolated sheep hearts. Nondominant elements of the signals were differentiated from the dominant elements using singular value decomposition, whereby the purely periodic constituent (PC) relating to the rotor's DF was eliminated rendering a residual constituent (RC) that consisted of all other activity., Results: Spectral analysis of the decomposed constituents revealed peaks corresponding to the meandering frequency of the rotor tip, the magnitudes of which were proportional to the size of and the distance to the rotor core. Similar analyses on epicardial optical signals and electrograms from isolated sheep hearts, as well as human complex fractionated atrial electrograms, showed applicability of the approach., Conclusion: Increased meandering of the rotor driving AF reduces activation periodicity and increases fractionation. The spectral manifestation of the rotor activity beyond the meandering region makes it possible to characterize AF source stability, as well as DF in humans using electrode mapping.

Background: Left atrial (LA) volume is a predictor of cardiovascular events in patients with heart failure. Improvement of LA function and reverse remodeling was observed after cardiac resynchronization therapy (CRT)., Objective: The purpose of this study was to explore the clinical significance of improvement in LA function after CRT., Methods: Echocardiographic studies were performed before and 3 months after CRT in 97 patients (72 men and 25 women; age 63.8 +/- 13.3 years) with standard CRT indication but no history of atrial fibrillation (AF). LA active emptying fraction based on the change in volumes (LAV-EF) were calculated, and significant improvement in LA function (LA responder) was defined as a relative increase >/=50% from baseline LAV-EF. The primary end-points were newly developed AF detected by ECG or device and all-cause mortality., Results: After 1,200 +/- 705 days of follow-up, LA responders (n = 47 [48.5%]) had a significantly lower incidence of AF (12.8% vs 40%, P = .002) and mortality (17% vs 44%, P = .004) than did LA nonresponders. In Cox proportional hazard analysis, LA responders was the only independent predictor of lower risk of new-onset AF (hazard ratio 0.22, 95% confidence interval 0.08-0.61, P = .003), whereas both LA responders (hazard ratio 0.22, 95% confidence interval 0.09-0.53, P <.001) and left ventricular reverse remodeling (>10% reduction in left ventricular end-systolic volume at 3 months; hazard ratio 0.96, 95% confidence interval 0.93-0.99, P = .03) were independent predictors of lower risk of death after CRT., Conclusion: Improvement of LA function after CRT was associated with a lower incidence of AF and mortality in AF naïve patients with severe heart failure.

Background: Defibrillation shock is known to induce atrial stunning, which is electrical and mechanical dysfunction., Objective: We hypothesized that atrial stunning is caused by higher atrial susceptibility to electroporation vs ventricles. We also hypothesize that electroporation may be responsible for early recurrence of atrial fibrillation., Methods: We investigated electroporation induced by 10-ms epicardial high-intensity shocks applied locally in atria and ventricles of Langendorff-perfused rabbit hearts (n = 12) using optical mapping., Results: Electroporation was centered at the electrode and was evident from transient diastolic depolarization and reduction of action potential amplitude and maximum upstroke derivative. Electroporation was voltage-dependent and polarity-dependent and was significantly more pronounced in the atria vs ventricles (P <.01), with a summary 50% of Effective Dose (ED50) for main measured parameters of 9.2 +/- 3.6 V/cm and 13.6 +/- 3.2 V/cm in the atria vs 37.4 +/- 1.5 V/cm and 48.4 +/- 2.8 V/cm in the ventricles, for anodal and cathodal stimuli, respectively. In atria (n = 5), shocks of both polarities (27.2 +/- 1.1 V/cm) transiently induced conduction block and reentry around the inexcitable area. Electroporation-induced ectopic activity was a possible trigger for reentry. However, in the thicker ventricles, electroporation and resulting conduction slowing and block were restricted to the surface only, preventing complete block and arrhythmia. The upstroke morphology revealed that the wave front dived below the electroporated region and resurfaced into unaffected epicardial tissue., Conclusion: We showed that the atria are more vulnerable to electroporation and resulting block and arrhythmia than the ventricles.

Rapid repetitive activities arising from pulmonary veins may initiate atrial fibrillation. The basis of these rapid repetitive activities remains unclear, but recent evidence suggests that the autonomic nervous system plays an important role in their formation. Pulmonary veins and the adjoining left atrium are highly innervated structures. This review summarizes recent developments in the understanding of the anatomy of autonomic nerves in and around pulmonary veins and their implications for atrial fibrillation.

Background: Part of the esophagus is contiguous to the posterior wall (PW) of the left atrium (LA). Esophageal injury has occurred during LA ablation for atrial fibrillation (AF). The ability to identify the esophagus and monitor LAPW lesions with intracardiac echocardiography (ICE) has not been documented., Methods: We report an index case of atrioesphageal fistula as a complication of transcatheter ablation of AF. After the index case, we retrospectively reviewed morphologic changes with radiofrequency (RF) delivered at LAPW during pulmonary vein (PV) electrical isolation using an 8-mm tip electrode (up to 70 W at a maximum of 50-52 degrees C for 60 seconds) or Chilli catheter (up to 50 W at a maximum of 40 degrees C for 60 seconds). ICE did not influence lesion application. After the index case, RF power was reduced at areas adjacent to the esophagus (8 mm/30-50 W at 50 degrees C or Chilli/40 W at a maximum of 38 degrees C). Duration of RF, 10-30 seconds, was titrated based on accelerated bubble formation or early echogenic lesion formation., Results: The longitudinal extent of the contiguous LAPW-esophageal wall (length 18-59 mm) was identified in all 152 patients (ages 56 +/- 10 years, 117 men). Preablation LAPW (2.8 +/- 0.7 mm) and contiguous anterior esophageal wall (3.0 +/- 0.8 mm) thickness were noted. A total of 6 +/- 4.9 lesions/patient were delivered to the LAPW contiguous to the esophagus. Echogenic LAPW thickness increased to 7.5 +/- 2.1 mm (vs. 2.8 +/- 0.5 mm preablation) before the index case (n = 70 patients) and 4.7 +/- 1.6 mm (vs. 2.9 +/- 0.6 mm) after the index case (n = 67), with power reduction and titration of duration of energy delivery RF (P <.01) and PV isolation in all., Conclusions: The LAPW-esophageal region can be identified and monitored with ICE imaging during ablation procedures. RF lesions to the LAPW in PV isolation can produce dramatic morphologic changes immediately adjacent to the anterior esophageal wall. A reduction in power amount and duration as described coupled with online lesion monitoring to further titrate duration (<30 seconds) of power delivery decreases the depth of lesion formation and limits the risk of esophageal involvement.

Background: Congestive heart failure (CHF) results in decreased cardiac sympathetic innervation., Objectives: The purpose of this study was to test the hypothesis that therapy with the vasopeptidase inhibitor omapatrilat (OMA) attenuates cardiac neuronal remodeling in CHF., Methods: We induced CHF in dogs with rapid ventricular pacing for 5 weeks with (CHF+OMA group, n = 8) or without (CHF group, n = 10) concomitant OMA treatment (10 mg/kg twice daily). Cardiac catheterization and echocardiography were performed to determine cardiac structure and hemodynamic parameters. Myocardial nerve density was determined by immunocytochemical staining with anti-growth associated protein 43 (GAP43) and anti-tyrosine hydroxylase (TH) antibodies. Seven normal dogs were used as histologic controls., Results: In the CHF group, ascites developed in 3 dogs and 4 dogs died, compared with no ascites or death in the CHF+OMA group (P = .07). In the 6 CHF dogs that survived, all had atrial fibrosis, severely depressed left ventricular systolic function, and increased atrial and ventricular chamber size. OMA treatment decreased the atrial and ventricular chamber sizes and the degree of atrial fibrosis. Most CHF dogs showed severe myocardial denervation, although some showed normal or abnormally high nerve counts. OMA treatment prevented heterogeneous reduction of nerve density. The left ventricular TH-positive nerve densities were 128 +/- 170 microm(2)/mm(2), 261 +/- 185 microm(2)/mm(2), and 503 +/- 328 microm(2)/mm(2) (P < .05), and the atrial GAP43-positive nerve densities were 1,683 +/- 1,365 microm(2)/mm(2), 305 +/- 368 microm(2)/mm(2), and 1,278 +/- 1,479 microm(2)/mm(2) (P < .05) for the control, CHF, and CHF+OMA groups, respectively., Conclusion: CHF results in heterogeneous cardiac denervation. Long-term OMA treatment prevented the reduction of nerve density and promoted beneficial cardiac structural remodeling.