Effect of Catheter Ablation With Vein of Marshall Ethanol Infusion vs Catheter Ablation Alone on Persistent Atrial Fibrillation: The VENUS Randomized Clinical Trial.

Importance: Catheter ablation of persistent atrial fibrillation (AF) has limited success. Procedural strategies beyond pulmonary vein isolation have failed to consistently improve results. The vein of Marshall contains innervation and AF triggers that can be ablated by retrograde ethanol infusion. Objective: To determine whether vein of Marshall ethanol infusion could improve ablation results in persistent AF when added to catheter ablation. Design, Setting, and Participants: The Vein of Marshall Ethanol for Untreated Persistent AF (VENUS) trial was an investigator-initiated, National Institutes of Health-funded, randomized, single-blinded trial conducted in 12 centers in the United States. Patients (N = 350) with persistent AF referred for first ablation were enrolled from October 2013 through June 2018. Follow-up concluded in June 2019. Interventions: Patients were randomly assigned to catheter ablation alone (n = 158) or catheter ablation combined with vein of Marshall ethanol infusion (n = 185) in a 1:1.15 ratio to accommodate for 15% technical vein of Marshall ethanol infusion failures. Main Outcomes and Measures: The primary outcome was freedom from AF or atrial tachycardia for longer than 30 seconds after a single procedure, without antiarrhythmic drugs, at both 6 and 12 months. Outcome assessment was blinded to randomization treatment. There were 12 secondary outcomes, including AF burden, freedom from AF after multiple procedures, perimitral block, and others. Results: Of the 343 randomized patients (mean [SD] age, 66.5 [9.7] years; 261 men), 316 (92.1%) completed the trial. Vein of Marshall ethanol was successfully delivered in 155 of 185 patients. At 6 and 12 months, the proportion of patients with freedom from AF/atrial tachycardia after a single procedure was 49.2% (91/185) in the catheter ablation combined with vein of Marshall ethanol infusion group compared with 38% (60/158) in the catheter ablation alone group (difference, 11.2% [95% CI, 0.8%-21.7%]; P = .04). Of the 12 secondary outcomes, 9 were not significantly different, but AF burden (zero burden in 78.3% vs 67.9%; difference, 10.4% [95% CI, 2.9%-17.9%]; P = .01), freedom from AF after multiple procedures (65.2% vs 53.8%; difference, 11.4% [95% CI, 0.6%-22.2%]; P = .04), and success achieving perimitral block (80.6% vs 51.3%; difference, 29.3% [95% CI, 19.3%-39.3%]; P < .001) were significantly improved in vein of Marshall-treated patients. Adverse events were similar between groups. Conclusions and Relevance: Among patients with persistent AF, addition of vein of Marshall ethanol infusion to catheter ablation, compared with catheter ablation alone, increased the likelihood of remaining free of AF or atrial tachycardia at 6 and 12 months. Further research is needed to assess longer-term efficacy. Trial Registration: ClinicalTrials.gov Identifier: NCT01898221.

Atrial Ganglionated Plexus Modification: A Novel Approach to Treat Symptomatic Sinus Bradycardia.

OBJECTIVES: This study sought to determine if anatomic atrial ganglionated plexus (GP) ablation leads to long-term sinus rate (SR) increase and improves quality of life in patients with symptomatic sinus bradycardia (SB). BACKGROUND: Atrial GP ablation has been demonstrated to increase SR in our previous study. Atrial GP ablation may also be effective in treating patients with symptomatic SB. METHODS: Sixty-two patients with symptomatic SB were recruited: Group A included patients <50 years of age (n = 40); Group B included patients ≥50 years of age (n = 22). All patients underwent anatomic ablation of the main atrial GP, and 24-h Holter monitoring and quality-of-life assessment were performed during 1 year of follow-up. Quality of life was accessed by the Medical Outcomes Study Short-Form 36 Health Survey. RESULTS: Although SR markedly increased in all patients after GP ablation, the increase was significantly greater in patients <50 years of age than in patients ≥50 years of age (19.3 ± 9.9 beats/min vs. 10.8 ± 5.4 beats/min; p = 0.001). The right anterior GP and the GP at the junction of the aorta and superior vena cava made the greatest contributions to SR increase among all GP. The mean and minimal SR increased significantly after ablation and remained elevated for 12 months only in Group A patients. Although symptoms and quality of life improved in all patients, 5 of the 8 domains of the Medical Outcomes Study Short-Form 36 Health Survey did not show obvious improvements in patients of Group B at 12 months. CONCLUSIONS: Anatomic atrial GP ablation effectively increased SR and improved quality of life in patients <50 years of age with symptomatic SB.

Macro-reentrant atrial tachycardia conducting through a left superior vena cava after catheter ablation in a patient with paroxysmal atrial fibrillation.

A left superior vena cava can be a cause of cardiac rhythm or conduction abnormalities, and can also be the arrhythmogenic source of atrial fibrillation (AF) with connections to the coronary sinus and left atrium. In the present study, we report a case with a macro re-entrant atrial tachycardia that coursed through the left superior vena cava after a previous AF ablation, which successfully ablated paroxysmal AF.

Paradoxical long-term proarrhythmic effects after ablating the "head station" ganglionated plexi of the vagal innervation to the heart.

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.

Lead design and initial applications of a new lead for long-term endovascular vagal stimulation.

BACKGROUND: Vagal nerve stimulation (VNS) has negative chronotropic and dromotropic effects. We developed and tested an endovascular spiral vagal stimulation lead (ESVL) designed to follow the projection of the cardiac branches of the vagus nerve around the superior vena cava (SVC) to optimize VNS. METHODS: ESVL contained six 5-mm coil electrodes, spaced 5-mm apart with a spiral guidewire to provide shape. The tightness and diameter of the guidewire were changed before each placement to simulate different lead designs. Various 2-, 3-, and 4-electrode combinations were used and several lead positions were tested each time. Each VNS protocol included 2-12 V, 15-second pulse trains at 20 Hz, with 2 ms pulse duration. A basket catheter (BC) was used as control and to approximate the initial VNS location. The VNS protocol was performed at the optimal location, using first the BC and then several ESVL configurations. RESULTS: VNS caused a voltage-dependent decrease in heart rate (HR). Using the optimal ESVL configuration at 7 V, HR decreased by 30.4% (37.2 bpm) in dog no. 1 and 12.4% (16.6 bpm) in dog no. 2, versus 15.5% (16.6 bpm) and 16.7% (19.5 bpm) with the BC. CONCLUSIONS: A new endovascular spiral lead that takes advantage of the anatomy of the cardiac branches of the vagus nerve in the SVC was developed. VNS using ESVL produced significant HR slowing at voltages slightly below the highest pulse generator output of 7.5 V, which may be suitable for long-term implantation.

Endovascular stimulation of autonomic neural elements in the superior vena cava using a flexible loop catheter.

It has been previously shown that parasympathetic nerve stimulation (PNS) can be achieved via basket electrode catheters (BEC) positioned in the superior vena cava (SVC). Since questions have been raised regarding formation of thrombi between and/or on the splines of the BECs, we investigated the use of a flexible loop "Lasso" catheter (LC) to achieve autonomic nerve stimulation in the SVC without clot formation. In 5 dogs, anesthetized with Na-pentobarbital, standard ECG leads II and aVR, blood pressure and right atrial electrograms were continuously monitored. The LC is a 7-French catheter at the end of which is a circular ring, 25 mm in diameter, equipped with ten 1-mm electrodes. The circular loop is made of a flexible, shape retaining, covered metal, which can be straightened in order to be inserted transvenously. The catheter was inserted through a sheath in the external jugular vein and positioned in the SVC. Stimulation was performed sequentially across each of the five bipolar pairs of electrodes, and consisted of square wave stimuli, each 0.1 msec duration, frequency 20 Hz at voltages from 1-40 V. The average voltage required to produce a 50% decrease in heart rate was 15 +/- 7 V, compared to 22 +/- 12 V with the standard BEC and 10 +/- 5 V with a modified BEC. We did not observe any thrombus formation at the end of a four-hour period during which the catheter was stabilized in the SVC. PNS can be achieved safely and effectively by the LC in the SVC in dogs.

Vagal control of the cranial venae cavae of the rat heart.

The cranial venae cavae of the rat heart are composed of cardiac muscle. We tested whether the vagus nerve has an inotropic action on these blood vessels. Stimulation of right or left vagal fibres (n = 7 animals) produced a negative chronotropic and inotropic effect. Before stimulation the basal cardiac interval was 319 +/- 25 ms and the vena caval diastolic force was 1.82 +/- 0.29 mN and the systolic force was 3.28 +/- 0.39 mN. Ten second stimulation increased the cardiac interval to a maximum of 484 +/- 77 ms and reduced the systolic force significantly to 2.83 +/- 0.39 mN (two-tailed paired t test). The diastolic or baseline force was unaffected by vagal stimulation (1.85 +/- 0.29 mN). The vagal negative inotropic action took significantly longer to reach peak effect (9.5 +/- 1.0 s versus 3.2 +/- 0.9 s) and lasted longer than the chronotropic effect (20.4 +/- 2.1 s versus 10.25 +/- 1.2 s). The negative inotropic action was still observed in paced preparations and preparations with transient constant-rate tachyarrhythmias. Both the chronotropic and inotropic effects were abolished by atropine (10(-6) M) and mimicked by acetylcholine chloride (10 nM). In order to minimize an atrial contribution to the force production a more reduced preparation was used and ganglion clusters at the cavo-atrial junction were stimulated electrically (n = 4 animals). Similar negative inotropic and chronotropic effects sensitive to hexamethonium were seen. After hexamethonium administration, positive inotopic and chronotropic effects were uncovered and these were abolished by atenolol (0.1 mg %). Methylene Blue staining of the preparation at the end of the experiment showed the presence of ganglion cells at the sites of stimulation. Ganglion clusters were never seen on the venae cavae per se. The results of this investigation show that the vagus has a powerful action on the venae cavae resembling that on the atria and mediated by acetylcholine.

Role of GABA and NO in the paraventricular nucleus-mediated reflex inhibition of renal sympathetic nerve activity following stimulation of right atrial receptors in the rat.

The aim of this study was to determine the site within the brain at which inhibition of renal sympathetic nerve activity (RSNA) occurs following right atrial receptor stimulation. The atrial receptors were stimulated by inflating a balloon at the right vena cava-atrium junction and the reflex effect was observed before and during application of neurotransmitter agonists and antagonists into the paraventricular nucleus (PVN), or intrathecally to the spinal cord. Balloon inflation reduced RSNA by 29.1 +/- 3 % without changing blood pressure in anaesthetised Wistar rats. Microinjection of the GABA(A) receptor antagonist bicuculline (0.025 mM, 100 nl) into the PVN increased RSNA by 42.3 +/- 5 % and this was changed little by balloon inflation when PVN increased RSNA by 50.6 +/- 6.3 %. Microinjection of the nitric oxide synthase (NOS) inhibitors L-NAME (0.1 mM, 100 nl) or L-NMMA (0.2 mM, 100 nl) into PVN elicited increases in RSNA of 36 +/- 8 % or 54 +/- 10 %, respectively. Balloon inflation during PVN stimulation plus NOS inhibition resulted in RSNA activity of 8 +/- 4 % or -1 +/- 1 %, respectively, compared to baseline control. Baseline RSNA was similar throughout this series of tests ranging from 9.1 +/- 1.3 to 11.5 +/- 1.1 spike counts s(-1). To rule out the possibility that the atrial reflex inhibition was in part dependent on a dopamine-mediated PVN-spinal projection pathway inhibiting RSNA at a spinal locus, a dopamine D1 receptor antagonist SCH 23390 was intrathecally applied to the spinal cord. The effect of subsequent balloon inflation on RSNA was not significantly reduced. It was concluded that atrial receptor activation causes an inhibition of RSNA at the PVN and that this effect is mediated by GABA.

Catheter stimulation of cardiac parasympathetic nerves in humans: a novel approach to the cardiac autonomic nervous system.

BACKGROUND: Cardiac parasympathetic nerves run alongside the superior vena cava (SVC) and accumulate particularly epicardially adjacent to the orifice of the coronary sinus (CS). In animals, these nerves can be electrically stimulated inside the SVC or CS, which results in negative chronotropic/dromotropic effects and negative inotropic effects in the atria but not the ventricles. Parasympathetic nerve stimulation (PS) with 20 Hz in the CS, however, also excites the atria, thereby inducing atrial fibrillation. The present study overcomes this limitation by applying high-frequency nerve stimuli within the atrial refractory period. Using this technique, we investigated for the first time whether neurophysiological effects similar to those in animals can be obtained in humans. METHODS AND RESULTS: In 25 patients, parasympathetic nerves were stimulated via a multipolar electrode catheter placed in the SVC (stimulation with 20 Hz; n=14) or CS (pulsed 200-Hz stimuli; n=11). A significant sinus rate decrease and prolongation of the antegrade Wenckebach period was achieved during PS in the SVC. During PS in the CS, a graded-response prolongation of the antegrade Wenckebach interval was observed with increasing PS voltage until third-degree AV block occurred in 8 of 11 patients. The negative chronotropic/dromotropic effects started and terminated immediately after the onset and termination of PS, respectively. Atropine abolished these effects (n=11). CONCLUSIONS: Human parasympathetic efferent nerve stimulation induces reversible negative chronotropic and dromotropic effects. PS may serve as an adjunctive tool for the diagnosis/treatment of supraventricular tachycardias and may be beneficial for ventricular rate slowing during tachycardic atrial fibrillation in patients with congestive heart failure.

[Treatment of tachycardic atrial fibrillation by catheter-assisted electrical stimulation of the cardiac parasympathetic nervous system]. / Die Behandlung des tachykarden Vorhofflimmerns durch kathetergestützte elektrische Stimulation des kardialen parasympathischen Nervensystems.

UNLABELLED: Treatment of tachycardic atrial fibrillation (AF) is difficult in patients with congestive heart failure because many drugs which exert negative dromotropic effects (beta-blockers, calcium channel antagonists) may depress ventricular contractility and/or decrease arterial blood pressure. We have identified 2 intravascular sites in the superior (SVC) and inferior vena cava (IVC) where parasympathetic nerves, which innervate the atrioventricular node, can be stimulated electrically. In 8 dogs, a 7-F catheter with an expandable electrode basket at its tip was non-fluoroscopically positioned in the SVC and in the proximal IVC (time for positioning: 3-5 minutes). High-frequency electrical parasympathetic stimulation (PS) with 20 Hz at an impulse duration of 0.1 ms was performed during pacing induced AF. RESULTS: With increasing stimulus strength, a graded ventricular rate slowing was observed during PS in the SVC and IVC (P < 0.01, ANOVA). The negative dromotropic effect started instantaneously after onset of PS and ceased immediately after termination of PS. During ventricular pacing at a constant rate, no decrease of the arterial blood pressure was observed during PS. PS in the IVC yielded significantly lower stimulation thresholds than in the SVC. CONCLUSIONS: Transvenous parasympathetic stimulation for ventricular rate control during AF can easily be achieved in the SVC and IVC in dogs. This procedure may provide a foundation for investigating the usefulness of PS in humans. If the results translate to patients, PS may be very beneficial in the treatment of AF in patients with congestive heart failure.

Inotropic, chronotropic, and dromotropic effects mediated via parasympathetic ganglia in the dog heart.

Some parasympathetic ganglionic cells are located in the epicardial fat pad between the medial superior vena cava and the aortic root (SVC-Ao fat pad) of the dog. We investigated whether the ganglionic cells in the SVC-Ao fat pad control the right atrial contractile force, sinus cycle length (SCL), and atrioventricular (AV) conduction in the autonomically decentralized heart of the anesthetized dog. Stimulation of both sides of the cervical vagal complexes (CVS) decreased right atrial contractile force, increased SCL, and prolonged AV interval. Stimulation of the rate-related parasympathetic nerves to the sinoatrial (SA) node (SAPS) increased SCL and decreased atrial contractile force. Stimulation of the AV conduction-related parasympathetic nerves to the AV node prolonged AV interval. Trimethaphan, a ganglionic nicotinic receptor blocker, injected into the SVC-Ao fat pad attenuated the negative inotropic, chronotropic, and dromotropic responses to CVS by 33 approximately 37%. On the other hand, lidocaine, a sodium channel blocker, injected into the SVC-Ao fat pad almost totally inhibited the inotropic and chronotropic responses to CVS and partly inhibited the dromotropic one. Lidocaine or trimethaphan injected into the SAPS locus abolished the inotropic responses to SAPS, but it partly attenuated those to CVS, although these treatments abolished the chronotropic responses to SAPS or CVS. These results suggest that parasympathetic ganglionic cells in the SVC-Ao fat pad, differing from those in SA and AV fat pads, nonselectively control the atrial contractile force, SCL, and AV conduction partially in the dog heart.

Effects of right atrial distension on the activity of magnocellular neurons in the supraoptic nucleus.

A small balloon placed at the junction of the superior vena cava and right atrium was used to stimulate cardiac volume receptors in pentobarbital sodium-anesthetized male rats. Extracellular recordings were obtained from antidromically identified vasopressinergic and oxytocinergic neurosecretory cells of the supraoptic nucleus. Cells were considered sensitive to the stimulus if balloon inflation resulted in a 30% change in firing frequency. Balloon inflation that did not stretch the caval-atrial junction had no significant effect on vasopressin neurons (n = 51, P > 0.05). Stretch of the caval-atrial junction decreased the firing activity in 64 of 83 putative vasopressin neurons (P < 0.01 compared with control). Stretch of the caval-atrial junction influenced the firing activity of only 3 of 26 antidromically activated oxytocinergic neurons, an effect not statistically different from control (P > 0. 05). When bilateral vagotomy was performed while recording from vasopressin neurons (n = 5), sensitivity to stretch of the caval-atrial junction was eliminated. Cardiac receptors located at the junction of the superior vena cava and right atrium may be important in regulating the activity of vasopressinergic but not oxytocinergic neurons of the supraoptic nucleus.

Anatomical study of the neural ganglionated plexus in the canine right atrium: implications for selective denervation and electrophysiology of the sinoatrial node in dog.

The aim of the present study was to elucidate the topography and architecture of the intrinsic neural plexus (INP) in the canine right atrium because of its importance for selective denervation of the sinoatrial node (SAN). The morphology of the intrinsic INP was revealed by a histochemical method for acetylcholinesterase in whole hearts of 36 mongrel dogs and examined by stereoscopic, contact, and electron microscopes. At the hilum of the heart, nerves forming a right atrial INP were detected in five sites adjacent to the right superior pulmonary veins and superior vena cava (SVC). Nerves entered the epicardium and formed a INP, the ganglia of which, as a wide ganglionated field, were continuously distributed on the sides of the root of the SVC (RSVC). The epicardiac ganglia located on the RSVC were differentially involved in the innervation of the sinoatrial node, as revealed by epicardiac nerves emanating from its lower ganglia that proceed also into the atrial walls and right auricle. The INP on the RSVC (INP-RSVC) varied from animal to animal and in relation to the age of the animal. The INP-RSVC of juvenile dogs contained more small ganglia than that of adult animals. Generally, the canine INP-RSVC included 434+/-29 small, 17+/-4 medium-sized, and 3+/-1 large epicardiac ganglia that contained an estimated 44,700, 6,400, and 2,800 neurons, respectively. Therefore, the canine right atrium, including the SAN, may be innervated by more than 54,000 intracardiac neurons residing mostly in the INP-RSVC. In conclusion, the present study indicates that epicardiac ganglia that project to the SA-node are distributed more widely and are more abundant than was previously thought. Therefore, both selective and total denervation of the canine SAN should involve the whole region of the RSVC containing the INP-RSVC.

Differential sympathetic regulation of automatic, conductile, and contractile tissue in dog heart.

Sympathetic pathways mediating chronotropic, dromotropic, and inotropic responses during ansae subclavia stimulation were determined by sequential dissection around major cardiac vessels. Right sympathetic (RS) projections influencing ventricular contractile force converge at the common pulmonary artery and within the pulmonary artery nerves (PAN). RS projections influencing left atrial contractile force course within the PANs. RS pathways to pacemaker and right atrial contractile tissue were localized between the superior vena cava and ascending aorta. RS projections influencing conductile tissue converge between the common pulmonary artery and proximal right pulmonary artery. Left sympathetic (LS) projections to ventricular contractile tissue were localized at the common pulmonary artery, within the PANs, and in the ventral lateral cardiac nerve (VLCN). LS pathways influencing heart rate and conductile tissue were localized at the left pulmonary artery and coursing between the right pulmonary artery and left superior pulmonary vein. LS projections to atrial contractile tissue were localized within the PANs and coursing between the right pulmonary artery and left superior pulmonary vein. We conclude that there are parallel, yet distinct, projections of sympathetic efferents to automatic, conductile, and contractile tissue of the canine heart.

[Neural connections of the heart and superior vena cava in the rabbit and man]. / Nervnye sviazi serdtsa i verkhnei poloi veny u krolika i cheloveka.

Innervational connections of the heart and the superior vena cava wall have been studied in the rabbit and the man. Besides, series of their embryos, impregnated with silver salts after Cajal-Favorsky have been investigated. Methods of Bielschowsky-Gros, Gomori and Karnovsky-Roots have also been applied. Adrenergic nervous elements have been revealed by means of incubation the slices in 2% solution of glyoxylic acid. Abundant cholinergic and adrenergic nervous plexuses are revealed on the wall of the superior vena cava, they are tightly connected with corresponding plexuses of the heart. Developmental of these nervous connections is followed, when embryogenesis of the cardiac nervous plexuses and large major vessels is studied in serial sections of embryos and fetuses of the rabbit and the man.