Deep Dive into Denervation: Institutional Experience with Selective Denervation in Nonflaccid Facial Palsy.

Background: Selective denervation of facial nerve branches ("Modified Selective Neurectomy") improves smile dynamics in patients with nonflaccid facial palsy, but functional morbidity such as oral incompetence has been reported. A comprehensive outcomes assessment of selective denervation will help clinicians educate patients regarding risks and benefits, and improve decision making as they incorporate this procedure into treatment algorithms. Methods: Retrospective review identified selective denervation cases performed by the senior author between February 2019 and February 2020. Pre- and postoperative outcomes were assessed using chart review, the facial clinimetric evaluation (FaCE), the electronic clinician-graded facial function tool (eFACE), and an automated computer-aided facial assessment tool (Emotrics). Results: Twenty consecutive selective denervation procedures were performed in 19 patients. Review of patient-reported outcome measures demonstrated mixed results. Favorably, patients reported smile improvement (13/17, 76.5%) and improvements in facial tightness/discomfort (8/17, 47.1%). Seven patients (41.2%) had worse drooling and five patients (29.4%) had increased difficulty chewing after surgery. Clinician-graded evaluation revealed statistically significant improvements in nasolabial fold depth at rest, oral commissure (OC) position at rest, and OC movement with smile. Total, static, and dynamic eFACE scores all demonstrated significant improvements. Computer-aided facial assessment revealed a significant increase in dental display, and an increase in OC excursion that trended toward significance. Conclusions: Selective denervation improves patient-reported, clinician-graded, and automated smile metrics, but some patients experience exacerbations in oral incompetence and articulation difficulties, and must be counseled regarding these possibilities.

Safety and Dose Study of Targeted Lung Denervation in Moderate/Severe COPD Patients.

RATIONALE: Targeted lung denervation (TLD) is a novel bronchoscopic treatment for the disruption of parasympathetic innervation of the lungs. OBJECTIVES: To assess safety, feasibility, and dosing of TLD in patients with moderate to severe COPD using a novel device design. METHODS: Thirty patients with COPD (forced expiratory volume in 1 s 30-60%) were 1:1 randomized in a double-blinded fashion to receive TLD with either 29 or 32 W. Primary endpoint was the rate of TLD-associated adverse airway effects that required treatment through 3 months. Assessments of lung function, quality of life, dyspnea, and exercise capacity were performed at baseline and 1-year follow-up. An additional 16 patients were enrolled in an open-label confirmation phase study to confirm safety improvements after procedural enhancements following gastrointestinal adverse events during the randomized part of the trial. RESULTS: Procedural success, defined as device success without an in-hospital serious adverse event, was 96.7% (29/30). The rate of TLD-associated adverse airway effects requiring intervention was 3/15 in the 32 W versus 1/15 in the 29 W group, p = 0.6. Five patients early in the randomized phase experienced serious gastric events. The study was stopped and procedural changes made that reduced both gastrointestinal and airway events in the subsequent phase of the randomized trial and follow-up confirmation study. Improvements in lung function and quality of life were observed compared to baseline values for both doses but were not statistically different. CONCLUSIONS: The results demonstrate acceptable safety and feasibility of TLD in patients with COPD, with improvements in adverse event rates after procedural enhancements.

Long-term safety of bilateral targeted lung denervation in patients with COPD.

Background: Targeted lung denervation (TLD) is a novel bronchoscopic therapy for COPD which ablates parasympathetic pulmonary nerves running along the outside of the two main bronchi with the intent of inducing permanent bronchodilation. The goal of this study was to evaluate the feasibility and long-term safety of bilateral TLD during a single procedure. Patients and methods: This prospective, multicenter study evaluated 15 patients with moderate-to-severe COPD (forced expiratory volume in 1 s [FEV1] 30%-60%) who underwent bilateral TLD treatment following baseline assessment without bronchodilators. The primary safety end point was freedom from documented and sustained worsening of COPD directly attributable to TLD up to 1 year. Secondary end points included technical feasibility, change in pulmonary function tests, exercise capacity, and health-related quality of life. Follow-up continued up to 3 years for subjects who reconsented for longer-term follow-up. Results: A total of 15 patients (47% male, age 63.2±4.0 years) underwent TLD with a total procedure time of 89±16 min, and the total fluoroscopy time was 2.5±2.7 min. Primary safety end point of freedom from worsening of COPD was 100%. There were no procedural complications reported. Results of lung function analysis and exercise capacity demonstrated similar beneficial effects of TLD without bronchodilators, when compared with long-acting anticholinergic therapy at 30 days, 180 days, 365 days, 2 years, and 3 years post-TLD. Five of the 12 serious adverse events that were reported through 3 years of follow-up were respiratory related with no events being related to TLD therapy. Conclusion: TLD delivered to both lungs in a single procedure is feasible and safe with few respiratory-related adverse events through 3 years.

Catheter Ablation of Bradyarrhythmia: From the Beginning to the Future.

Enhanced parasympathetic tone may cause sinus bradycardia or pauses, transient or permanent atrioventricular block, with resultant vasovagal syncope. A substantial portion of these patients may be highly symptomatic and refractory to the conventional therapies and may require cardiac pacemaker implantation. Cardioneuroablation is a little known technique for management of patients with excessive vagal activation based on radiofrequency catheter ablation of main parasympathetic autonomic ganglia around the heart. Due to complicated inclusion criteria, ganglia detection methods, and ablation endpoints, routine usage of the procedure cannot be recommended at this time. In this comprehensive review, we aimed to discuss all aspects of cardioneuroablation procedure in bradyarrhythmias.

Parasympathectomy increases resting salivary secretion in normal and irradiated submandibular glands of rats.

Fluid and ion secretion from the submandibular gland (SMG) is mainly regulated by parasympathetic nerves. This study evaluated the effect of parasympathectomy on salivary secretion from normal and irradiated rat SMGs from 1 to 24 wk after denervation. Although stimulated salivary secretion was significantly lower in denervated SMGs compared with contralateral self-controls, the resting salivary flow rates were markedly higher in the denervated SMGs at 1, 12, and 24 wk after denervation. The levels of muscarinic acetylcholine M1 and M3 receptors, as well as of aquaporin 5, were up-regulated. Notably, although irradiated SMGs showed significantly lower resting and stimulated salivary secretion rates than non-irradiated SMGs, the resting salivary secretion rates of the irradiated and denervated SMGs were markedly higher than seen in the irradiated self-control SMGs at 1, 12, and 24 wk after parasympathectomy, and were even higher than seen in the non-irradiated sham-operated rats. The expression of M1 and M3 receptors was similarly elevated. Taken together, our results suggest that parasympathetic denervation increases resting salivary secretion of both normal and irradiated SMGs. This approach might provide a potential modality for relieving radiation-induced xerostomia, which is a common complication following treatment of head and neck cancer.

Atrioventricular Node Slow-Pathway Ablation Reduces Atrial Fibrillation Inducibility: A Neuronal Mechanism.

BACKGROUND: Radiofrequency ablation (RFA) for atrioventricular nodal reentrant tachycardia appears to reduce atrial tachycardia, which might relate to parasympathetic denervation at cardiac ganglionated plexuses. METHODS AND RESULTS: Compared to 7 control canines without RFA, in 14 canines, RFA at the bottom of Koch's triangle attenuated vagal stimulation-induced effective refractory periods prolongation in atrioventricular nodal and discontinuous atrioventricular conduction curves but had no effect on the sinoatrial node. RFA attenuated vagal stimulation-induced atrial effective refractory periods shortening and vulnerability window of atrial fibrillation widening in the inferior right atrium and proximal coronary sinus but not in the high right atrium and distal coronary sinus. Moreover, RFA anatomically impaired the epicardial ganglionated plexuses at the inferior vena cava‒inferior left atrial junction. This method was also investigated in 42 patients who had undergone ablation of atrioventricular nodal reentrant tachycardia, or 12 with an accessory pathway (AP) at the posterior septum (AP-PS), and 34 patients who had an AP at the free wall as control. In patients with atrioventricular nodal reentrant tachycardia and AP-PS, RFA at the bottom of Koch's triangle prolonged atrial effective refractory periods and reduced vulnerability windows of atrial fibrillation widening at the inferior right atrium, distal coronary sinus and proximal coronary sinus but not the high right atrium. In patients with AP-free wall, RFA had no significant atrial effects. CONCLUSIONS: RFA at the bottom of Koch's triangle attenuated local autonomic innervation in the atrioventricular node and atria, decreased vagal stimulation-induced discontinuous atrioventricular nodal conduction, and reduced atrial fibrillation inducibility due to impaired ganglionated plexuses. In patients with atrioventricular nodal reentrant tachycardia or AP-PS, RFA prolonged atrial effective refractory periods, and narrowed vulnerability windows of atrial fibrillation.

The morphological substrate for Renal Denervation: Nerve distribution patterns and parasympathetic nerves. A post-mortem histological study.

BACKGROUND: Renal Denervation as a possible treatment for hypertension has been studied extensively, but knowledge on the distribution of nerves surrounding the renal artery is still incomplete. While sympathetic and sensory nerves have been demonstrated, there is no mention of the presence of parasympathetic nerve fibers. OBJECTIVES: To provide a description of the distribution patterns of the renal nerves in man, and, in addition, provide a detailed representation of the relative contribution of the sympathetic, parasympathetic and afferent divisions of the autonomic nervous system. METHODS: Renal arteries of human cadavers were each divided into four longitudinal segments and immunohistochemically stained with specific markers for afferent, parasympathetic and sympathetic nerves. Nerve fibers were semi-automatically quantified by computerized image analysis, and expressed as cross-sectional area relative to the distance to the lumen. RESULTS: A total of 3372 nerve segments were identified in 8 arteries of 7 cadavers. Sympathetic, parasympathetic and afferent nerves contributed for 73.5% (95% CI: 65.4-81.5%), 17.9% (10.7-25.1%) and 8.7% (5.0-12.3%) of the total cross-sectional nerve area, respectively. Nerves are closer to the lumen in more distal segments and larger bundles that presumably innervate the kidney lie at 1-3.5mm distance from the lumen. The tissue-penetration depth of the ablation required to destroy 50% of the nerve fibers is 2.37 mm in the proximal segment and 1.78 mm in the most distal segments. CONCLUSION: Sympathetic, parasympathetic and afferent nerves exist in the vicinity of the renal artery. The results warrant further investigation of the role of the parasympathetic nervous system on renal physiology, and may contribute to refinement of the procedure by focusing the ablation on the most distal segment.

Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve.

BACKGROUND: The central nervous origins of functional parasympathetic innervation of cardiac ventricles remain controversial. OBJECTIVE: This study aimed to identify a population of vagal preganglionic neurons that contribute to the control of ventricular excitability. An animal model of synuclein pathology relevant to Parkinson's disease was used to determine whether age-related loss of the activity of the identified group of neurons is associated with changes in ventricular electrophysiology. METHODS: In vivo cardiac electrophysiology was performed in anesthetized rats in conditions of selective inhibition of the dorsal vagal motor nucleus (DVMN) neurons by pharmacogenetic approach and in mice with global genetic deletion of all family members of the synuclein protein. RESULTS: In rats anesthetized with urethane (in conditions of systemic beta-adrenoceptor blockade), muscarinic and neuronal nitric oxide synthase blockade confirmed the existence of a tonic parasympathetic control of cardiac excitability mediated by the actions of acetylcholine and nitric oxide. Acute DVMN silencing led to shortening of the ventricular effective refractory period (vERP), a lowering of the threshold for triggered ventricular tachycardia, and prolongation of the corrected QT (QTc) interval. Lower resting activity of the DVMN neurons in aging synuclein-deficient mice was found to be associated with vERP shortening and QTc interval prolongation. CONCLUSION: Activity of the DVMN vagal preganglionic neurons is responsible for tonic parasympathetic control of ventricular excitability, likely to be mediated by nitric oxide. These findings provide the first insight into the central nervous substrate that underlies functional parasympathetic innervation of the ventricles and highlight its vulnerability in neurodegenerative diseases.

Transoral submandibular ganglion neurectomy: an anatomical feasibility study.

BACKGROUND: The management of sialorrhea can be difficult for both the patient and the clinician. Current management includes behavioral modification, anticholinergics, botulinum injections, and a variety of surgical options, which all have demonstrated some efficacy. As minimally invasive procedures flourish, we explore the feasibility of highly selective transoral submandibular neurectomy (TOSN) for the management of sialorrhea. METHODS: Ten human cadaver dissections of the floor of mouth were performed bilaterally, for a total of 20 separate cases. An intraoral technique for highly selective, submandibular ganglion neurectomy is demonstrated. RESULTS: A transoral submandibular ganglion neurectomy was performed in 10 cadavers (20 neurectomies) easily and reliably, without injury to the submandibular duct or the main trunk of the lingual nerve. CONCLUSION: Transoral submandibular neurectomy is an attractive addition to the armamentarium of surgical options for the treatment of medically intractable sialorrhea. Further study in selected patients would need to be performed to demonstrate clinical feasibility.

Reinnervated nerves contribute to the secretion function and regeneration of denervated submandibular glands in rabbits.

This study aimed to investigate the contribution of redistributed nerves in the secretory function and regeneration of a denervated submandibular gland (SMG). The postganglionic parasympathetic and sympathetic denervated SMGs of rabbits were wrapped in polyester or acellular dermal matrices to block nerve regeneration either partially or completely. Submandibular glands were removed 4, 8, 16, and 24 wk after the operation and examined histologically. Furthermore, the aquaporin-5 (AQP5), muscarinic-3 (M3), and ß1-adrenergic receptors were evaluated by immunofluorescence and western blot analysis. After denervation, salivary flow was decreased and acinar cells were atrophic, and the expression levels of the M3, ß1-adrenergic, and AQP5 receptors were decreased. However, both impaired secretion function and atrophic parenchyma were gradually ameliorated with the growing redistribution of parasympathetic and sympathetic nerves. Apoptosis was markedly inhibited and expression of the M3, ß1-adrenergic, and AQP5 receptors was increased after reinnervation. In contrast, SMGs without reinnervated nerves maintained hyposecretion and atrophic parenchyma. In conclusion, reinnervated nerves in a rabbit's denervated SMG played an important role in the secretion function and regeneration of SMGs via up-regulation of the expression of neurotransmitter receptors and AQP5.

Ethanol infusion in the vein of Marshall leads to parasympathetic denervation of the human left atrium: implications for atrial fibrillation.

OBJECTIVES: This study sought to determine whether ethanol infusion in the vein of Marshall (VOM) can ablate intrinsic cardiac nerves (ICN). BACKGROUND: ICN cluster around the left atrial epicardium and are implicated in the genesis of atrial fibrillation (AF). METHODS: Patients undergoing catheter AF ablation underwent adjunctive ethanol injection in the VOM. A multipolar catheter was introduced in the VOM and used for high-frequency stimulation (HFS), either as HFS with P-wave synchronized (SynchHFS), 30 pulses, 100 Hz (n = 8) or as HFS with 3 to 10 s bursts (BurstHFS), 33 Hz (n = 72) at 25 mA for 1-ms duration. Atrioventricular (AV) nodal conduction slowing (asystole >2 s or R-R interval prolongation >50%) and AF inducibility were assessed before and after VOM ethanol infusion. Up to 4 1-ml infusions of 98% ethanol were delivered via an angioplasty balloon in the VOM. RESULTS: SynchHFS induced AF in 8 of 8 patients. In 4 of 8 AF initiated spontaneously without VOM capture. No parasympathetic responses were elicited by SynchHFS. BurstHFS was performed in 32 patients undergoing de novo AF ablation (Group 1) and 40 patients undergoing repeat ablation (Group 2). Parasympathetic responses were found in all 32 Group 1 patients and in 75% of Group 2 patients. After VOM ethanol infusion, parasympathetic responses were abolished in all patients (both groups). There were no acute complications related to VOM ethanol infusion. CONCLUSIONS: The VOM contains ICN that connect with the AV node and can trigger AF. Retrograde ethanol infusion in the VOM reliably eliminates local ICN responses. The VOM is a vascular route for ICN-targeting therapies.

Endoscopic microdebrider-assisted inferior turbinoplasty with and without posterior nasal neurectomy.

OBJECTIVE: Endoscopic microdebrider-assisted inferior turbinoplasty (EMAIT) has been recognized as an efficient surgical technique in the management of hypertrophied inferior turbinate. In an attempt to further increase surgical successful outcomes, posterior nasal neurectomy (PNN) was developed. The aim of this retrospective case-control study was to assess the position of PNN in the surgery of hypertrophied turbinate. METHODS: Seventy patients were assigned to the two treatment groups: Group A (EMAIT) and Group B (EMAIT and PNN). Subjective outcomes were represented by symptom score and quality of life scores (Rhinoconjunctivitis Quality of Life Questionnaire - RQLQ). Objective outcomes were nasal resistance, saccharin transit time and acoustic rhinometry parameters. RESULTS: The survey demonstrated that symptoms and objective parameters improved postoperatively in both groups, with no statistical significant differences in objective and subjective outcomes between the surgical groups. CONCLUSION: The addition of PNN appears to offer no additional benefit in the subjective and objective outcome related with surgery of hypertrophied inferior turbinate. However, longer follow-up studies and larger number of patients are required in order to validate our results.

[Effect of parasympathectomy on the salivary secretion of submandibular gland in rats].

OBJECTIVE: To investigate the effect of parasympathectomy on secretion of submandibular glands and the feasibility of treatment for xerostomia in rats. METHODS: Twenty Sprague-Dawley male rats weighing 200 - 300 g were randomly divided into the experimental group (n = 12), in which the right chorda-lingual nerve was cut, and the control group (n = 8). The secretion of submandibular gland was measured for 5 min by Schirmer test for both groups. RESULTS: The stimulated saliva flow rate decreased on 1st, 12th and 24th week after denervation in the right operated submandibular glands (P < 0.05). No difference in secretion was found between the left non-operated glands and the control group. Comparing with the left non-operated gland and the control gland, the saliva flow rate at rest in the right operated submandibular gland increased on the 1st, 12th and 24th week (P < 0.05). CONCLUSIONS: After parasympathectomy of rat submandibular glands, the saliva flow rate at rest increased in the denervated gland, which suggests that parasympathectomy of submandibular gland might be used as a therapy for xerostomia.

Intragastric infusion of pea-protein hydrolysate reduces test-meal size in rats more than pea protein.

Because protein hydrolysates are digested faster than the corresponding proteins, they may increase or hasten the acute eating-inhibitory effect of protein. Potential mediating mechanisms include accelerated or greater release of satiating gut peptides and activation of metabolic signals that inhibit eating. We tested these hypotheses in adult male rats that were surgically equipped with intragastric (IG) cannulas and adapted to 30-min test meals at dark onset after 14-h food deprivation. Equiosmotic 12 ml loads of saline-urea control (C), 13.6% pea protein (PP), or 13.6% PP hydrolysate (PPH, DSM/DFS, Delft, The Netherlands) solutions were IG infused in 1 min just before test meals. PPH reduced test-meal size compared to C more than PP (-3.8±0.3 g vs. -2.6±0.4 g; P<0.0001). Plasma glutamate increased more after PPH than PP (P<0.0001). Plasma lactate, alanine, insulin, glucagon, GLP-1 and paracetemol (an index of gastric emptying) all increased similarly, and glucose decreased similarly, after PPH or PP. Finally, PPH still reduced test-meal size more than PP (-4.6±0.3 g vs. -3.1±0.4 g; P<0.001) in rats after subdiaphragmatic vagal deafferentation, indicating that abdominal vagal afferents are not necessary for the eating-inhibitory effects of PP and PPH and, by extension, that gut peptides whose satiating effects depend on intact vagal afferents (e.g., CCK and glucagon) do not play crucial roles. Thus, PPH reduced short-term food intake more than PP under our conditions, but the mechanism(s) involved remain unclear.

[Surgical correction of overactive bladder resistant to standard therapy].

Surgical treatment was given to 45 patients with overactive bladder: transurethral detrusorotomy was made in 21 patients (group 1), bladder hydrodilation (BH) was made in 24 patients (group 2). Detrusorotomy was performed by transurethral median cut of the bladder posterior wall by needle electrode leading to destroyment of intramural sympathic and parasympathic nervous fibres. Hydrodilation of the bladder was made under intravesical pressure equal to systolic arterial pressure with 2 min exposure. On day thirty after the operation regress of the lower urinary tract symptoms was registered in 20 (95.2%) patients of group 1 and 11 (45.8%) patients of group 2. Urge to voiding (UV) disappeared in 90.5% patients of group 1 and in 45.8% of group 2 (p < 0.05), the number of patients with miction pain reduced 6-fold and 1.9-fold, with UV--8.5 and 1.2-fold, respectively (p < 0.05). The number of diurnal mictions in group 1 decreased 3.2-fold vs 1.9-fold in group 2. The bladder size in urgency in group 1 patients increased 2.5-fold, the pressure fell also 2.5-fold. In group 2 these parameters changed only 1.2 times (p < 0.05). Cystometry recorded recurrent detrusor overactivity in 13 (54.2%) patients after hydrodilation and only in 3 (14.3%)--after cut of the bladder wall (p < 0.05). Thus, transurethral detrusorotomy in overactive bladder resistant to conventional treatment is much more effective than hydrodilation. The operation is low invasive and is well tolerated. Simple performance and good short-time results are advantages of this technique.

Autonomic effects on the spectral analysis of heart rate variability after exercise.

Although frequency-domain analysis of heart rate variability (HRV) has been performed in the setting of exercise and recovery from exercise, the relationship of specific frequency components to sympathetic and parasympathetic inputs has not been validated in this setting. The aim of this study is to evaluate the relationship of frequency components of HRV to sympathetic and parasympathetic modulation in the setting of recovery after exercise using selective autonomic blockade. Normal subjects (n = 27, 17 men, 53 +/- 7 yr old) underwent bicycle stress testing on four separate days. On day 1, a baseline study without autonomic blockade was performed. On days 2 through 4, either beta-adrenergic, parasympathetic, or double blockade was administered during exercise and completed 3 min before recovery. Continuous ECG was recorded for 5 min starting from the end of exercise. Time- and frequency-domain measures of HRV were computed for each of the five 1-min segments of RR intervals. Parasympathetic blockade significantly decreased all the HRV measures compared with baseline (P < 0.02 for all). Root mean square of successive differences of RR intervals (rMSSD) was increased by beta-adrenergic blockade (P < 0.0002). All the HRV measures except rMSSD showed increases with time after the first minute of recovery. The low frequency-to-high frequency ratio did not respond to autonomic blockade or to recovery time, consistent with the expected changes in sympathovagal influence. Root mean square (detrended SD) and rMSSD were highly correlated with the square root of the total power (r = 0.96) and high-frequency power (r = 0.95), respectively. Although there are marked reductions in the frequency-domain measures in recovery versus rest, the fluctuations in the low- and high-frequency bands respond to autonomic blockade in the expected fashion. Time-domain measures of HRV were highly correlated with frequency-domain measures and therefore provide a computationally more efficient assessment of autonomic influences during recovery from exercise that is less susceptible to anomalies of frequency-domain analysis.

Modulation of heart rate variability during severe hemorrhage at different rates in conscious rats.

This study was undertaken to evaluate heart rate (HR) regulation during severe hemorrhage (HEM) at different rates of blood loss. Chronically instrumented male rats underwent HEM at one of three rates: slow (0.5 ml/min/kg; S-HEM), intermediate (1.0 ml/min/kg I-HEM), or 2.0 ml/min/kg (fast; F-HEM) until 30% of the estimated total blood volume (ETBV) was withdrawn. Heart rate variability analysis was performed and the absolute power within the low frequency (LF; 0.16-0.6 Hz) and high frequency (HF; 0.6-3 Hz) ranges was evaluated. During the first 15% of ETBV loss, arterial pressure (AP) was maintained while HR increased. The increase in HR was greatest in the S-HEM and I-HEM groups and was associated with a significant reduction in HF power in the S-HEM group only. As blood loss progressed, AP and HR declined in all treatment groups. The decrease in HR was associated with a significant increase in HF power in the F-HEM and I-HEM groups only. Parasympathetic blockade with atropine methyl bromide eliminated all decreases in HR, independent of the rate of hemorrhage. Blockade of parasympathetic activity also significantly increased the AP at ETBV losses > or =20% independent of the rate of hemorrhage. The effect of atropine on AP was most noticeable in the S-HEM and F-HEM groups. These results demonstrate that rate of blood loss has an important impact on autonomic regulation during severe HEM and support previous findings that neural strategies underlying autonomic control may vary depending on the rate of blood loss.

Targeted G-protein inhibition as a novel approach to decrease vagal atrial fibrillation by selective parasympathetic attenuation.

AIMS: The parasympathetic nervous system is thought to play a key role in atrial fibrillation (AF). Since parasympathetic signalling is primarily mediated by the heterotrimeric G-protein, Galpha(i)betagamma, we hypothesized that targeted inhibition of Galpha(i) interactions in the posterior left atrium (PLA) would modify the substrate for vagal AF. METHODS AND RESULTS: Cell-penetrating(cp)-Galpha(i)1/2 and cp-Galpha(i)3 C-terminal peptides were assessed for their ability to attenuate cholinergic-parasympathetic signalling in isolated feline atrial myocytes and in canine left atrium (LA). Confocal fluorescence microscopy indicated that cp-Galpha(i)1/2 and/or cp-Galpha(i)3 peptides moderated carbachol attenuation of cellular Ca(2+) transients in isolated atrial myocytes. High-density epicardial mapping of dog PLA, left atrial pulmonary veins (PVs), and left atrial appendage (LAA) indicated that the delivery of cp-Galpha(i)1/2 peptide or cp-Galpha(i)3 peptide into the PLA prolonged effective refractory periods at baseline and during vagal stimulation in the PLA and to varying extents also in the LAA and PV regions. After delivery of cp-Galpha(i) peptides into the PLA, AF inducibility during vagal stimulation was significantly diminished. CONCLUSION: These results demonstrate the feasibility of using specific G(i)-protein inhibition to achieve selective parasympathetic denervation in the PLA, with a resulting change in vagal responsiveness across the entire LA.