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Background: Moe and Abildskov proposed the multiple wavelet hypothesis of atrial fibrillation (AF) on the basis of observations in the canine vagal nerve stimulation (VNS) AF model. Data from mapping studies in an in vitro canine AF model by Allessie et al (Allessie MA, Lammers WJEP, Bonke FIM, Hollen SJ. Experimental evaluation of Moe's multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology and Arrhythmias. Orlando, FL: Grune & Stratton; 1985:265-275.) were used to evaluate the Moe/Abildskov hypothesis, which revealed that a critical number of wavelets sustained AF., Objective: The purpose of this study was to reassess VNS mapping data using the same methods used by Allessie to evaluate Moe's multiple wavelet hypothesis., Methods: Using the canine VNS AF model in 6 dogs, 510 unipolar atrial electrograms were recorded simultaneously from both atria. Activation sequence maps were produced from sustained AF during VNS in each dog. Per Allessie, consecutive 10 ms activation windows were analyzed over a period of 300 ms. Repetitive activation analysis was applied to Moe's canine VNS AF model., Results: The number of wavefronts in each AF episode was 0-8 in Allessie's studies measured by sequential atrial mapping and 0-10 in our biatrial simultaneous mapping studies. In both studies, an electrically silent period was observed in each atrium and was reactivated by wavefronts emanating from focal sources. Allessie postulated that an electrically silent atrium was reactivated by a wavefront propagating from the other atrium. However, in our biatrial simultaneous mapping studies, each electrically silent atrium was reactivated by a distinct focal source., Conclusion: Data from both studies showed a similar number of wavefronts, similar AF activation patterns, and periods of electrical atrial silence reactivated by focal sources. Also, in our studies, independent focal sources initiated wavefronts reactivating the atria, thereby explaining the mechanism maintaining AF., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Neuraxial modulation with cardiac sympathetic denervation (CSD) can potentially reduce burden of ventricular tachyarrhythmia (VT). However, despite catheter ablation and CSD, VT can recur in patients with cardiomyopathy and the role of vagal nerve stimulation (VNS) in this setting is unclear., Objective: The purpose of this study was to evaluate the electrophysiological effects of VNS after CSD in normal and infarcted hearts., Methods: In 10 normal and 6 infarcted pigs, electrophysiological and hemodynamic parameters were evaluated before and during intermittent VNS pre-CSD (bilateral stellectomy and T2-T4 thoracic ganglia removal) as well as post-CSD. The effect of VNS during isoproterenol was also assessed pre- and post-CSD. Multielectrode ventricular activation recovery interval (ARI) recordings, a surrogate of action potential duration, were obtained. VT inducibility was tested during isoproterenol infusion after CSD with and without VNS., Results: VNS increased the global ARI by 4% ± 4% pre-CSD and by 5% ± 6% post-CSD, with enhanced effects observed during isoproterenol infusion (10% ± 8% pre-CSD and 12% ± 9% post-CSD) in normal animals. In infarcted animals pre-CSD, VNS increased ARI by 6% ± 7% before and by 13% ± 8% during isoproterenol infusion. Post-CSD, VNS increased ARI by 6% ± 5% before and by 11% ± 7% during isoproterenol infusion. VT was inducible in all infarcted animals post-CSD during isoproterenol infusion; this inducibility was reduced by 67% with VNS (P = .01). In all animals, the hemodynamic effects of VNS remained after CSD., Conclusion: After CSD, the beneficial electrophysiological effects of VNS remain. Furthermore, VNS can reduce VT inducibility beyond CSD in the setting of circulating catecholamines, suggesting a role for additional parasympathetic modulation in the treatment of ventricular arrhythmias., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: We recently reported that skin sympathetic nerve activity (SKNA) can be used to estimate sympathetic tone in humans. In animal models, vagal nerve stimulation (VNS) can damage the stellate ganglion, reduce stellate ganglion nerve activity, and suppress cardiac arrhythmia. Whether VNS can suppress sympathetic tone in humans remains unclear., Objective: The purpose of this study was to test the hypothesis that VNS suppresses SKNA in patients with drug-resistant epilepsy., Methods: ECG patch electrodes were used to continuously record SKNA in 26 patients with drug-resistant epilepsy who were admitted for video electroencephalographic monitoring. Among them, 6 (2 men, age 40 ± 11 years) were previously treated with VNS and 20 (7 men, age 37 ± 8 years) were not. The signals from ECG leads I and II were filtered to detect SKNA., Results: VNS had an on-time of 30 seconds and off-time of 158 ± 72 seconds, with output of 1.92 ± 0.42 mA at 24.17 ± 2.01 Hz. Average SKNA during VNS off-time was 1.06 μV (95% confidence interval [CI] 0.93-1.18) in lead I and 1.13 μV (95% CI 0.99-1.27) in lead II, which was significantly lower than 1.38 μV (95% CI 1.01-1.75; P = .036) and 1.38 μV (95% CI 0.98-1.78; P = .035) in the control group, respectively. Heart rate was 65 bpm (95% CI 59-71) in the VNS group, which was significantly lower than 77 bpm (95% CI 71-83) in the control group., Conclusion: Patients with VNS had significantly lower SKNA than those without VNS., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Detection of atrial repolarization waves free of far-field signal contamination by ventricular activation would allow investigation of atrial electrophysiology and factors that influence susceptibility to atrial tachycardia and atrial fibrillation (AF)., Objective: The purpose of this study was to identify means for high-resolution intracardiac recording of atrial repolarization (Ta) waves using standard clinical electrocatheters and to assess fundamental electrophysiologic properties relevant to AF risk., Methods: In alpha-chloralose anesthetized Yorkshire pigs, we studied effects of vagus nerve stimulation (VNS) on PTa and QT intervals and effects of acute atrial ischemia or administration of intrapericardial acetylcholine followed by intravenous epinephrine on susceptibility to AF., Results: Electrocatheters with closely spaced (1-mm) electrode pairs yielded high-resolution tracings of atrial repolarization waves. These recordings permitted detection of differential effects of right or left VNS, which shortened atrial PTa interval by 30% vs. 21% (P <.01) and lengthened QT interval by 1.5% vs. 9%, respectively (P < .05). During atrial ischemia, STa segments were elevated 3.4-fold (P < .01), and the threshold for inducing AF was reduced 3.1-fold (P = .004). Ischemia amplified atrial T-wave alternans (TWAa) and spatiotemporal heterogeneity (TWHa) by 23- and 13-fold, respectively, in inverse correlation to AF threshold (r = 0.74, P <.01; r = 0.61, P = .03). TWAa and TWHa increased by 4.5- and 2-fold shortly before autonomically triggered atrial premature beats and AF., Conclusion: This study used standard electrocatheters to demonstrate that TWAa and TWHa analysis provides means to assess vulnerability to AF without provocative electrical stimuli. These parameters could be evaluated in the clinical electrophysiology laboratory to determine risk for this prevalent arrhythmia and efficacy of contemporary and new agents., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Autonomic regulation therapy (ART) with chronic vagus nerve stimulation improves ventricular function in patients with chronic heart failure, but its effects on quantitative T-wave alternans (TWA), ventricular tachycardia (VT), baroreflex sensitivity, and autonomic tone remained unknown., Objective: Effects on TWA, a marker of risk of life-threatening arrhythmias; heart rate turbulence (HRT), an indicator of baroreflex sensitivity; heart rate variability; and VT incidence were studied in 25 patients with chronic symptomatic heart failure and reduced ejection fraction enrolled in the ANTHEM-HF study (NCT01823887)., Methods: Twenty-four-hour ambulatory electrocardiographic recordings made before ART system (Cyberonics, Inc., Houston, TX) implantation involving the left or right vagus nerve and after 6 and 12 months of chronic therapy (10-Hz frequency, 250-μs pulse width, maximum tolerable current amplitude after 10 weeks of titration) at low-intensity (<2 mA; n = 10, 40%) or high-intensity (≥2 mA; n = 15, 60%) stimulation levels were analyzed., Results: At 12 months, peak TWA levels were reduced by 29% from 71.0 ± 4.6 to 50.5 ± 1.8 μV (P < .0001). The number of patients with severely abnormal TWA (≥60 μV) was reduced by 76% from 17 to 4 (P < .0005), and the number of patients with nonsustained VT decreased by 73% from 11 to 3 (P < .025). HRT slope (P < .025), high frequency heart rate variability (HRV) (P = .05), and square root of the mean squared differences of successive normal-to-normal interval HRV (P = .013) increased. The mean heart rate derived from 24-hour Holter electrocardiograms decreased by 10% from 77 ± 2 to 69 ± 2 beats/min (P = .0002). HRT onset was unchanged., Conclusion: Chronic ART in patients with symptomatic heart failure improves cardiac electrical stability, as reflected by reduced TWA levels and heart rate, suppresses VT, and increases baroreceptor sensitivity. These observations deserve study in a larger population., (Copyright © 2016 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.)

The autonomic nervous system is known to play a significant role in the genesis and maintenance of arrhythmias. Neuromodulation, mostly designed to increase the parasympathetic tone and suppress the sympathetic tone, has become an emerging therapeutic strategy for the treatment of arrhythmias. Emerging therapeutic approaches include cervical vagal stimulation, transcutaneous auricular vagal stimulation, baroreceptor activation therapy spinal cord stimulation, ganglionated plexi ablation, renal sympathetic denervation, and left cardiac sympathetic denervation., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is an implantable device for antiarrhythmic therapy with no intravascular leads., Objective: The purpose of this study was to describe the technical feasibility of combining the S-ICD with other cardiac implantable electronic devices (CIEDs), including pacemakers with transvenous or epicardial electrodes. We also provide the first experience of combining an S-ICD with catheter-based therapies, including cardiac contractility modulation (CCM) and vagus nerve stimulation., Methods: Between July 2011 and November 2014, 6 patients received a CCM device and S-ICD, 3 patients with a single-chamber pacemaker using either transvenous or epicardial pacing electrodes received and S-ICD, and 1 patient with an implanted S-ICD received vagus nerve stimulation. In all patients, intraoperative S-ICD testing, crosstalk tests, and postoperative ergometric testing were performed., Results: In all 10 patients, device implantations were successfully performed without complications. S-ICD therapy was shown to be technically feasible with concomitant CIED. Mean follow-up was nearly 17 months. S-ICD testing and crosstalk testing before and during exercise enabled device programming across a broad range of test conditions and was associated with no subsequent evidence of adverse device interaction. None of the devices required permanent inactivation or removal, and no patient received an inappropriate shock., Conclusion: In suitable patients, combining an S-ICD with CCM or pacemaker may provide an acceptable means to reduce the number of transvascular leads. S-ICD appeared safe with CCM over an intermediate follow-up period. Additional prospective randomized controlled trials examining S-ICD in conjunction with CIEDs are warranted., (Copyright © 2015 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: Extremely low-level electromagnetic fields have been proposed to cause significant changes in neural networks., Objective: We sought to investigate whether low-level electromagnetic fields can suppress atrial fibrillation (AF)., Methods: In 17 pentobarbital anesthetized dogs, bilateral thoracotomies allowed the placement of multielectrode catheters in both atria and at all pulmonary veins. AF was induced by rapid atrial pacing (RAP) or programmed atrial extrastimulation. At baseline and end of each hour of RAP, during sinus rhythm, atrial programmed stimulation gave both the effective refractory period (ERP) and the width of the window of vulnerability. The latter was a measure of AF inducibility. Microelectrodes inserted into the anterior right ganglionated plexi recorded neural firing. Helmholtz coils were powered by a function generator inducing an electromagnetic field (EMF; 0.034 μG, 0.952 Hz). The study sample was divided into 2 groups: group 1 (n = 7)-application of EMF to both cervical vagal trunks; group 2 (n = 10)-application of EMF across the chest so that the heart was located in the center of the coil., Results: In group 1, EMF induced a progressive increase in AF threshold at all pulmonary vein and atrial sites (all P < .05). In group 2, the atrial ERP progressively shortened and ERP dispersion and window of vulnerability progressively increased (P < .05 compared to baseline values) during 3 hours of RAP and then returned to baseline values during 3 hours of combined application of RAP and EMF (P < .05 compared to the end of the third hour of RAP). The frequency and amplitude of the neural activity recorded from the anterior right ganglionated plexi were markedly suppressed by EMF in both groups., Conclusion: Pulsed EMF applied to the vagal trunks or noninvasively across the chest can significantly reverse AF inducibility., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: We previously reported that vagus nerve stimulation (VNS) applied immediately at the onset of cardiac ischemia provides cardioprotection against cardiac ischemic-reperfusion (I/R) injury., Objective: This study aimed to determine whether VNS applied during ischemia or at the onset of reperfusion exerts differential cardioprotection against cardiac I/R injury., Methods: Twenty-eight swine (25-30 kg) were randomized into 4 groups: Control (sham-operated, no VNS), VNS-ischemia (VNS applied during ischemia), VNS-reperfusion (VNS applied during reperfusion), and VNS-ischemia+atropine (VNS applied during ischemia with 1 mg/kg atropine administration). Ischemia was induced by left anterior descending (LAD) coronary artery occlusion for 60 minutes, followed by 120 minutes of reperfusion. VNS was applied either 30 minutes after LAD coronary artery occlusion or at the onset of reperfusion and continued until the end of reperfusion. Cardiac function, infarct size, myocardial levels of connexin 43, cytochrome c, tumor necrosis factor α, and interleukin 4, and cardiac mitochondrial function were determined., Results: VNS applied 30 minutes after LAD coronary artery occlusion, but not at reperfusion, markedly reduced ventricular fibrillation incidence and infarct size (~59%), improved cardiac function; attenuated cardiac mitochondrial reactive oxygen species production, depolarization, swelling, and cytochrome c release; and increased the amount of phosphorylated connexin 43 and interleukin 4 as compared with the Control group. These beneficial effects of VNS were abolished by atropine., Conclusion: VNS could provide significant cardioprotective effects even when initiated later during ischemia, but was not effective after reperfusion. These findings indicate the importance of timing of VNS initiation and warrant the potential clinical application of VNS in protecting myocardium at risk of I/R injury., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Right cervical vagus nerve stimulation (VNS) provides cardioprotective effects against acute ischemia-reperfusion injury in small animals. However, inconsistent findings have been reported., Objective: To determine whether low-amplitude, left cervical VNS applied either intermittently or continuously imparts cardioprotection against acute ischemia-reperfusion injury., Methods: Thirty-two isoflurane-anesthetized swine (25-30 kg) were randomized into 4 groups: control (sham operated, no VNS), continuous-VNS (C-VNS; 3.5 mA, 20 Hz), intermittent-VNS (I-VNS; continuously recurring cycles of 21-second ON, 30-second OFF), and I-VNS + atropine (1 mg/kg). Left cervical VNS was applied immediately after left anterior descending artery occlusion (60 minutes) and continued until the end of reperfusion (120 minutes). The ischemic and nonischemic myocardium was harvested for cardiac mitochondrial function assessment., Results: VNS significantly reduced infarct size, improved ventricular function, decreased ventricular fibrillation episodes, and attenuated cardiac mitochondrial reactive oxygen species production, depolarization, and swelling, compared with the control group. However, I-VNS produced the most profound cardioprotective effects, particularly infarct size reduction and decreased ventricular fibrillation episodes, compared to both I-VNS + atropine and C-VNS. These beneficial effects of VNS were abolished by atropine., Conclusions: During ischemia-reperfusion injury, both C-VNS and I-VNS provide significant cardioprotective effects compared with I-VNS + atropine. These beneficial effects were abolished by muscarinic blockade, suggesting the importance of muscarinic receptor modulation during VNS. The protective effects of VNS could be due to its protection of mitochondrial function during ischemia-reperfusion., (© 2013 Heart Rhythm Society. All rights reserved.)

Background: We studied the effects of transcutaneous electrical stimulation at the tragus, the anterior protuberance of the outer ear, for inhibiting atrial fibrillation (AF)., Objective: To develop a noninvasive transcutaneous approach to deliver low-level vagal nerve stimulation to the tragus in order to treat cardiac arrhythmias such as AF., Methods: In 16 pentobarbital anesthetized dogs, multielectrode catheters were attached to pulmonary veins and atria. Three tungsten-coated microelectrodes were inserted into the anterior right ganglionated plexi to record neural activity. Tragus stimulation (20 Hz) in the right ear was accomplished by attaching 2 alligator clips onto the tragus. The voltage slowing the sinus rate or atrioventricular conduction was used as the threshold for setting the low-level tragus stimulation (LL-TS) at 80% below the threshold. At baseline, programmed stimulation determined the effective refractory period (ERP) and the window of vulnerability (WOV), a measure of AF inducibility. For hours 1-3, rapid atrial pacing (RAP) was applied alone, followed by concomitant RAP+LL-TS for hours 4-6 (N = 6). The same parameters were measured during sinus rhythm when RAP stopped after each hour. In 4 other animals, bivagal transection was performed before LL-TS., Results: During hours 1-3 of RAP, there was a progressive and significant decrease in ERP, increase in WOV, and increase in neural activity vs baseline (all P < .05). With RAP+LL-TS during hours 4-6, there was a linear return of ERP, WOV, and neural activity toward baseline levels (all P < .05, compared to the third-hour values). In 4 dogs, bivagal transection prevented the reversal of ERP and WOV despite 3 hours of RAP+LL-TS., Conclusions: LL-TS can reverse RAP-induced atrial remodeling and inhibit AF inducibility, suggesting a potential noninvasive treatment of AF., (Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Surgical cardiac revascularization produces a high degree of systemic inflammation and the secretion of several cytokines. Intensive postoperative inflammation may increase the incidence of postoperative atrial fibrillation and favor organ dysfunctions. No data documenting the anti-inflammatory properties of epicardial vagal ganglionated plexus stimulation are available., Objective: To verify the feasibility and safety of postoperative inferior vena cava-inferior atrial ganglionated plexus (IVC-IAGP) burst stimulation and the effectiveness of this approach in reducing serum levels of inflammatory cytokines., Methods: In 27 patients who were candidates for off-pump surgical revascularization, the IVC-IAGP was located during surgery, a temporary wire was inserted, and a negative atrioventricular node dromotropic effect was obtained in 20 patients on applying high-frequency burst stimulation. In 5 patients atrial fibrillation or phrenic nerve stimulation was induced, and the remaining 15 patients served as the experimental group. Twenty additional patients underwent off-pump surgical revascularization without IVC-IAGP stimulation and served as the control group. On arrival in the intensive care unit, the experimental group underwent IVC-IAGP stimulation for 6 hours. Blood samples were collected at different times., Results: The serum levels of cytokines were not statistically different at baseline and on arrival in the intensive care unit between the groups, while they proved statistically different after 6 hours of stimulation: interleukin-6 (EG: 121 ± 71 pg/mL vs CG: 280 ± 194 pg/mL; P = .004), tumor necrosis factor-α (EG: 2.68 ± 1.81 pg/mL vs CG: 5.87 ± 3.48 pg/mL; P = .003), vascular endothelial growth factor (EG: 93 ± 43 pg/mL vs CG: 177 ± 86 pg/mL; P = .002), and epidermal growth factor (EG: 79 ± 48 pg/mL vs CG: 138 ± 76 pg/mL; P = .012)., Conclusions: Prolonged burst IVC-IAGP stimulation after surgical revascularization appears to be feasible and safe and significantly reduces inflammatory cytokines in the postoperative period., (Copyright © 2012 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: Strong vagus nerve stimulation (VNS) is routinely used to induce and maintain atrial fibrillation (AF) in acute animal studies. Taken as a surrogate of increased vagal tone, such observations suggest an arrhythmogenic role of VNS in AF. In contrast, VNS has been demonstrated to have profound therapeutic effects in heart failure and other ailments., Objective: The purpose of this study was to examine the relationship between right cervical VNS and AF, especially the potential arrhythmogenic effects of therapeutic VNS., Methods: The relationship between VNS intensities and AF inducibility was studied in eight acute dogs at baseline and four different levels of VNS, which were set to prolong spontaneous sinus cycle length (SCL) by 20%, 40%, 60%, or 100%. The effect of mild VNS treatment on AF induction was further investigated in six chronically instrumented conscious dogs. These dogs were implanted with right cervical VNS stimulators and specialized atrial pacemakers. VNS intensity was titrated to slow the sinus rate by 10%., Results: In acute studies, it was found that mild to moderate VNS (i.e., producing < or =40% SCL prolongation) did not increase AF inducibility, while strong VNS (i.e., producing > or =60% SCL prolongation) did. In chronic studies, compared with controls, AF induction did not change during the 4-week VNS treatment., Conclusions: AF inducibility by right cervical VNS is intensity dependent: strong VNS (producing > or =60% SCL prolongation) facilitates AF, while moderate VNS (producing < or =40% SCL prolongation) appears not to affect AF. The nonarrhythmogenic effect of therapeutic chronic VNS was further verified in conscious animals. We conclude that VNS with moderate intensities can be used to deliver therapeutic benefits without arrhythmogenic risk.