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Background Vagal hyperactivity promotes atrial fibrillation (AF), which has been almost exclusively attributed to acetylcholine. Vasoactive intestinal polypeptide (VIP) and acetylcholine are neurotransmitters co-released during vagal stimulation. Exogenous VIP has been shown to promote AF by shortening action potential duration (APD), increasing APD spatial heterogeneity, and causing intra-atrial conduction block. Objective The purpose of this study was to investigate the effects of neuronally released VIP on atrial electrophysiologic properties during vagal stimulation. Methods We used a specific VIP antagonist (H9935) to uncover the effects of endogenous VIP released during vagal stimulation in canine hearts. Results H9935 significantly attenuated (1) the vagally induced shortening of atrial effective refractory period and widening of atrial vulnerability window during stimulation of cervical vagosympathetic trunks (VCNS) and (2) vagal effects on APD during stimulation through fat-pad ganglion plexus (VGPS). Atropine completely abolished these vagal effects during VCNS and VGPS. In contrast, VGPS-induced slowing of local conduction velocity was completely abolished by either VIP antagonist or atropine. In pacing-induced AF during VGPS, maximal dominant frequencies and their spatial gradients were reduced significantly by H9935 and, more pronouncedly, by atropine. Furthermore, VIP release in the atria during vagal stimulation was inhibited by atropine, which may account for the concealment of VIP effects with muscarinic blockade. Conclusion Neuronally released VIP contributes to vagal effects on atrial electrophysiologic properties and affects the pathophysiology of vagally induced AF. Neuronal release of VIP in the atria is inhibited by muscarinic blockade, a novel mechanism by which VIP effects are concealed by atropine during vagal stimulation. [ABSTRACT FROM AUTHOR]

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 &y& Elsevier]

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 ≤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 &y& Elsevier]

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

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 ≤40% SCL prolongation) did not increase AF inducibility, while strong VNS (i.e., producing ≥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 ≥60% SCL prolongation) facilitates AF, while moderate VNS (producing ≤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. [Copyright &y& Elsevier]

Objectives: The aim of this study was to achieve regular slow ventricular rhythm during atrial fibrillation (AF) without destroying the AV node (AVN).Background: Recent experimental and clinical studies have demonstrated that selective AVN vagal stimulation (AVN-VS) can be used to slow ventricular rate during AF; however, an irregular rhythm remains. Alternatively, ventricular on-demand (VVI) pacing achieves rate regularization but at rates faster than the already fast intrinsic rate during AF. We hypothesized that AVN-VS combined with VVI pacing would achieve slow, regular rhythm during AF without requiring AVN ablation.Methods: AF was induced in eight dogs. AVN-VS was applied to the epicardial fat pad that projects vagal nerve fibers to the AVN. A computer-controlled algorithm adjusted AVN-VS intensity to achieve three levels of mean ventricular RR interval: 75%, 100%, or 125% of the spontaneous sinus cycle length. At each of the three levels, concomitant VVI pacing was delivered at a constant cycle length equal to the corresponding target. Hemodynamic measurements were performed during the study to elucidate the advantages of the proposed method.Results: AF resulted in rapid, irregular ventricular rates (RR = 287 +/- 36 ms, or 56% of sinus cycle length). AVN-VS achieved average ventricular rate slowing to the three target levels in all dogs (RR increased to 381 +/- 41, 508 +/- 54, and 632 +/- 68 ms, respectively). At each of the three target rate levels, AVN-VS combined with VVI pacing fully eliminated rate irregularities. The regular slow ventricular rhythms during AF were associated with significant hemodynamic improvement.Conclusions: A novel approach combining AVN-VS with VVI pacing results in a regular, slow ventricular rhythm during AF that does not necessitate AVN ablation. Rate regularization achieved by this approach was associated with pronounced hemodynamic benefits during AF. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study is to ascertain the effects of spatially variable ACh distributions on arrhythmogenesis in a morphologically realistic computer model of canine atria.Background: Vagal stimulation releases acetylcholine (ACh), which causes a dose-dependent reduction in action potential duration (APD) in the atria. Due to the nonuniform distribution of nerve endings, APD dispersion may result, which has been shown to play a role in the breakup of activity.Methods: Reentry was initiated in a computationally efficient, morphologically realistic computer model of the atria. Discrete regions corresponding to ACh release sites, referred to as islands, were assigned shortened APDs in an ACh-dependent fashion. Island APD was varied as well as the basal APD. The window of vulnerability for ectopic beat-induction of sustained reentry was determined for both left atrial(LA) and right atrial (RA) stimulation. The resulting reentries were categorized based on type and location.Results: 1) Atrial geometry severely restricts the formation of reentrant circuits. 2) Wave fractionation only occurred for large differences between island and basal APD. 3) Small ACh concentration differences produced stable figure-of-8 reentrant patterns. 4) Large islands displayed more wave breakup but could sometimes anchor reentries.Conclusions: Large APD gradients produced by ACh heterogeneity can lead to a breakdown of organized activity. [ABSTRACT FROM AUTHOR]