Mediastinal Nerve Research Articles

Pathways and morphologic pattern of blood supply of epicardial ganglionated nerve plexus

Detailed cardiac neuroanatomy is critical for understanding cardiac function and its pathology. However, there remains a significant gap in knowledge regarding the blood supply to the intrinsic cardiac ganglionated plexus (GP). This study addresses this by mapping the routes and morphological pattern of blood supply to the epicardial GP in a large-animal pig model (Sus scrofa domesticus). Twenty-five domestic pigs were used in the study. We demonstrate that the epicardial ganglionated nerves receive blood from both coronary and extra-cardiac arteries. The coronary arterial branches supply blood to all five subplexuses constituting the epicardial GP. In contrast, the branches of extra-cardiac arteries supply blood to target heart areas: 1) the venous part of the heart hilum on the left atrium, 2) the walls of the sinuses of the right cranial (superior cava) and 3) pulmonary veins. Uniformly, epicardial nerves and ganglia are supplied with blood via a sole epineurial arteriole which, in most cases, is the fifth/sixth-order branch of the coronary arteries. The extra-cardiac arteries supplying blood to the epicardial GP accompanied the mediastinal nerves entering the epicardium within the limits of the heart hilum. Together, the dual and triple blood supply of the epicardial nerves and ganglia suggests a protective role from an ischemic event and/or ischemic heart disease. Stuctured abstractThis study details the anatomy of the blood supply of epicardial ganglionated nerve plexus, from which nerve fibres extend to the myocardium, heart conduction system, coronary vessels, and endocardium, in the most popular animal model of experimental cardiology and cardiac surgery - the domestic pig. Our observations demonstrate that the epicardial nerves and ganglia receive blood from both coronary and extra-cardiac arteries. The multi-source blood supply to the cardiac nerves and ganglia may offer protection against myocardial infarction ant other ischemic heart disorders.

Mediastinal tumors of peripheral nerve origin (so-called neurogenic tumors).

The mediastinum can be the site of origin of a variety of benign and malignant tumors of peripheral nerve sheath origin. Although schwannoma is one of the most common tumors found in the posterior mediastinum, peripheral nerve sheath tumors are reported in all compartments of the mediastinum. The majority of peripheral nerve sheath tumors in the mediastinum as in other anatomic sites occur sporadically, and a subset of them, most notably neurofibromas, and to a lesser extent, schwannomas and malignant peripheral nerve sheath tumors, occur in patients with syndromes such as neurofibromatosis 1 (NF1). In this review, the characteristics of mediastinal nerve sheath tumors along with the histologic differential diagnosis are summarized. Primary emphasis is placed upon the use of morphologic criteria for establishing a definitive diagnosis with reference to photomicrographs to illustrate the classic and sometimes unusual features of this varied group of tumors. The judicious application of ancillary testing, most frequently immunohistochemistry, for separating peripheral nerve sheath tumors from each other and from their morphologic mimics is reviewed. Included in the review are the clinicopathologic features, clinical management and prognostic implications of benign and malignant mediastinal peripheral nerve sheath tumors.

Thoracoscopic one-stage lobectomy and diaphragmatic plication for T3 lung cancer

BackgroundCombined resection of a phrenic nerve is occasionally required in T3 primary lung carcinomas invading the phrenic nerve to completely remove a malignant tumour, resulting in diaphragmatic paralysis. We describe the first case of thoracoscopic lobectomy and diaphragmatic plication as a one-stage surgery for lung cancer invading the phrenic nerve.Case presentationA 56-year-old woman with a T3N0M0 primary adenosquamous carcinoma in the left upper lobe presented with suspicious invasion to the anterior mediastinal fat tissue and left phrenic nerve and underwent left upper lobectomy, node dissection, and partial resection of the anterior mediastinal fat tissue with the left phrenic nerve. Furthermore, thoracoscopic diaphragmatic plication was performed as a concomitant procedure. The patient’s postoperative course was favourable, without any complications, and respiratory function was preserved for 1 year postoperatively.ConclusionsThoracoscopic one-stage lobectomy and diaphragmatic plication for T3 lung cancer invading the phrenic nerve is effective for preservation of postoperative pulmonary function.

Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation.

Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 μs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P < 0.001). Convergent LCNs were preferentially activated by MNS. Preemptive RCV reduced MNS-induced changes in LCN activity (by 70%) while mitigating MNS-induced AF (by 75%). Preemptive LCV reduced LCN activity by 60% while mitigating AF potential by 40%. IC neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory.

Percutaneous Image-Guided Cryoablation of Challenging Mediastinal Lesions Using Large-Volume Hydrodissection: Technical Considerations and Outcomes.

This study was designed to describe the technique of percutaneous image-guided cryoablation with large-volume hydrodissection for the treatment of challenging mediastinal lesions. Between March 2014 and June 2015, three patients (mean age 62.7years) with four neoplastic anterior mediastinal lesions underwent five cryoablation procedures using large-volume hydrodissection. Procedures were performed under general anaesthesia using CT guidance. Lesion characteristics, hydrodissection and cryoablation data, technical success, complications, and clinical outcomes were assessed using retrospective chart review. Lesions (mean size 2.7cm; range 2-4.3cm) were in contact with great vessels (n=13), trachea (n=3), and mediastinal nerves (n=6). Hydrodissection was performed intercostally (n=4), suprasternally (n=2), transsternally (n=1), or via the sternoclavicular joint (n=1) using 1-3 spinal needles over 13.4 (range 7-26) minutes; 450ml of dilute contrast was injected (range 300-600ml) and increased mean lesion-collateral structure distance from 1.9 to 7.7mm. Vulnerable mediastinal nerves were identified in four of five procedures. Technical success was 100%, with one immediate complication (recurrent laryngeal nerve injury). Mean follow-up period was 15months. One lesion demonstrated residual disease on restaging PET-CT and was retreated to achieve complete ablation. At last follow-up, two patients remained disease-free, and one patient developed distant disease after 1year without local recurrence. Cryoablation using large-volume hydrodissection is a feasible technique, enabling safe and effective treatment of challenging mediastinal lesions.

Innervation of the rabbit cardiac ventricles.

The rabbit is widely used in experimental cardiac physiology, but the neuroanatomy of the rabbit heart remains insufficiently examined. This study aimed to ascertain the architecture of the intrinsic nerve plexus in the walls and septum of rabbit cardiac ventricles. In 51 rabbit hearts, a combined approach involving: (i) histochemical acetylcholinesterase staining of intrinsic neural structures in total cardiac ventricles; (ii) immunofluorescent labelling of intrinsic nerves, nerve fibres (NFs) and neuronal somata (NS); and (iii) transmission electron microscopy of intrinsic ventricular nerves and NFs was used. Mediastinal nerves access the ventral and lateral surfaces of both ventricles at a restricted site between the root of the ascending aorta and the pulmonary trunk. The dorsal surface of both ventricles is supplied by several epicardial nerves extending from the left dorsal ganglionated nerve subplexus on the dorsal left atrium. Ventral accessing nerves are thicker and more numerous than dorsal nerves. Intrinsic ventricular NS are rare on the conus arteriosus and the root of the pulmonary trunk. The number of ventricular NS ranged from 11 to 220 per heart. Four chemical phenotypes of NS within ventricular ganglia were identified, i.e. ganglionic cells positive for choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), and biphenotypic, i.e. positive for both ChAT/nNOS and for ChAT/tyrosine hydroxylase. Clusters of small intensely fluorescent cells are distributed within or close to ganglia on the root of the pulmonary trunk, but not on the conus arteriosus. The largest and most numerous intrinsic nerves proceed within the epicardium. Scarce nerves were found near myocardial blood vessels, but the myocardium contained only a scarce meshwork of NFs. In the endocardium, large numbers of thin nerves and NFs proceed along the bundle of His and both its branches up to the apex of the ventricles. The endocardial meshwork of fine NFs was approximately eight times denser than the myocardial meshwork. Adrenergic NFs predominate considerably in all layers of the ventricular walls and septum, whereas NFs of other neurochemical phenotypes were in the minority and their amount differed between the epicardium, myocardium and endocardium. The densities of NFs positive for nNOS and ChAT were similar in the epicardium and endocardium, but NFs positive for nNOS in the myocardium were eight times more abundant than NFs positive for ChAT. Potentially sensory NFs positive for both calcitonin gene-related peptide and substance P were sparse in the myocardial layer, but numerous in epicardial nerves and particularly abundant within the endocardium. Electron microscopic observations demonstrate that intrinsic ventricular nerves have a distinctive morphology, which may be attributed to remodelling of the peripheral nerves after their access into the ventricular wall. In conclusion, the rabbit ventricles display complex structural organization of intrinsic ventricular nerves, NFs and ganglionic cells. The results provide a basic anatomical background for further functional analysis of the intrinsic nervous system in the cardiac ventricles.

Surgical management of myeloma in the cervical spine

BACKGROUND CONTEXT: Mediastinal neoplasms, including mesenchymal, nerve sheath or sympathetic chain tumours in the region of the cervicothoracic junction present a technical challenge due to their inaccessibility. We report on our technique of anterior transsternal approach for directly accessing such lesions, comprising a bisection of the manubrium and sparing of the sternoclavicular joint and clavicle. PURPOSE: To evaluate the efficacy and safety of anterior approaches to neoplasms involving the thoracic outlet. STUDY DESIGN/SETTING: Prospective Observational Study. PATIENT SAMPLE: 26 patients with thoracic outlet neoplasms involving vertebral/paravertebral structures operated through a transsternal or a thoracotomy approach in two tertiary referral London centres. OUTCOME MEASURES: i)Extent of resection ii)Major post-operative complications. METHODS: Review of prospectively populated patient databases, operative logbooks, electronic notes and imaging between 19982014. RESULTS: The cervical transsternal approach was successfully performed in 11 (30%) patients. 65% were female and mean age at operation was 46 years. Extent of resection was complete in 20 (80%) cases. No major postoperative complications occurred in the transsternal group whilst a plexus injury and vascular injury without cardiovascular or permanent neurological sequelae occurred in 2 out 13 patient patients (7%) in the thoracotomy group. Histological findings included schwannomas(n57) and sarcomas(Ewing’s (n52);leiomyosarcomas (n54);liposarcomas (2);chondrosarcomas (n54). CONCLUSIONS: The anterior cervical transsternal approach offers excellent exposure of the thoracic outlet structures and permits safe and controlled resection and is a suitable choice in subclavian vasculature encasing tumours. It can be combined with standard thoracotomy techniques for locally invasive pathologies. It exhibits a low complication profile whilst avoiding the functional and cosmetic problems associated with the nonclavicle sparing alternatives. CONFLICTS OF INTEREST: None. FUNDING SOURCES: None.

Abstract 13957: Vagal Nerve Stimulation Mitigates Atrial Fibrillation by Attenuating the Intrinsic Cardiac Local Circuit Neuronal Activity

Background: Burst electrical stimuli delivered to intra-pericardial mediastinal nerves (MNS) during the atrial refractory period reproducibly evoke atrial fibrillation (AF), an effect dependent upon heterogeneous activation of intrinsic cardiac (IC) neurons. The objective of this study was to determine whether pre-emptive vagus nerve stimulation (VNS) alters MNS-induced neuronal imbalance within the IC neurons thereby impacting susceptibility to AF. Methods: Activities of right atrial ganglionated plexus neurons were identified in anesthetized canines (n=11) using a linear microelectrode array. IC neuron activity was characterized in response to: 1) touch and great vessel occlusion versus (2) stellate ganglion or vagal stimulation. Right MNS was evaluated in relation to evoked IC activity and the potential to induce atrial tachyarrhythmias. Responses were assessed prior to and after pre-emptive left (LCV) or right (RCV) cervical VNS (15 Hz, 500 μs; 1.2x chronotropic threshold; 3 min). Results: In control, 100% MNS sites induced AF. Pre-emptive RCV VNS prevented MNS-induced AF induction from 37% of sites; it shortened AF duration in 56% of sites. Pre-emptive LCV VNS potentiated AF in 46% of right-sided MNS sites, prevented AF in 27% of sites, shortened AF in 7% of sites; it was without effect in 20% of sites. Pre-emptive VNS induced a memory effect of ~40 minutes before the MNS-induced AF returned. VNS effects on IC neuronal responses were related primarily to neurons that responded to both touch/vessel occlusion and efferent activation, as such being defined as local circuit neurons (LCNs). A RCV VNS related decrease in IC LCNs activity (0.61±1.83 to 0.16±0.57 Hz) was correlated with reduction in AF inducibility (p&lt;0.05). Chi-square analysis indicated that an increase in LCN neuronal synchrony during MNS-induced AF was mitigated post VNS (p&lt;0.01). Conclusions: VNS decreases the activity of the IC LCNs while maintaining their stochastic behavior, thereby mitigating AF excitability secondary to local neural imbalances. These anti-arrhythmic effects of VNS exhibit memory. Ipsilateral VNS projections more effectively stabilize discrete IC neuronal networks, likely owing to preferential nerve distributions.

Chronic spinal cord stimulation modifies intrinsic cardiac synaptic efficacy in the suppression of atrial fibrillation.

We sought to determine whether spinal cord stimulation (SCS) therapy, when applied chronically to canines, imparts long-lasting cardio-protective effects on neurogenic atrial tachyarrhythmia induction and, if so, whether its effects can be attributable to i) changes in intrinsic cardiac (IC) neuronal transmembrane properties vs ii) modification of their interneuronal stochastic interactivity that initiates such pathology. Data derived from canines subjected to long-term SCS [(group 1: studied after 3-4 weeks SCS; n = 5) (group 2: studied after 5 weeks SCS; n = 11)] were compared to data derived from 10 control animals (including 4 sham SCS electrode implantations). During terminal studies conducted under anesthesia, chronotropic and inotropic responses to vagal nerve or stellate ganglion stimulation were similar in all 3 groups. Chronic SCS suppressed atrial tachyarrhythmia induction evoked by mediastinal nerve stimulation. When induced, arrhythmia durations were shortened (controls: median of 27 s; SCS 3-4 weeks: median of 16s; SCS 5 weeks: median of 7s). Phasic and accommodating right atrial neuronal somata displayed similar passive and active membrane properties in vitro, whether derived from sham or either chronic SCS group. Synaptic efficacy was differentially enhanced in accommodating (not phasic) IC neurons by chronic SCS. Taken together these data indicate that chronic SCS therapy modifies IC neuronal stochastic inter-connectivity in atrial fibrillation suppression by altering synaptic function without directly targeting the transmembrane properties of individual IC neuronal somata.

Network interactions within the canine intrinsic cardiac nervous system: implications for reflex control of regional cardiac function

The aims of the study were to determine how aggregates of intrinsic cardiac (IC) neurons transduce the cardiovascular milieu versus responding to changes in central neuronal drive and to determine IC network interactions subsequent to induced neural imbalances in the genesis of atrial fibrillation (AF). Activity from multiple IC neurons in the right atrial ganglionated plexus was recorded in eight anaesthetized canines using a 16-channel linear microelectrode array. Induced changes in IC neuronal activity were evaluated in response to: (1) focal cardiac mechanical distortion; (2) electrical activation of cervical vagi or stellate ganglia; (3) occlusion of the inferior vena cava or thoracic aorta; (4) transient ventricular ischaemia, and (5) neurally induced AF. Low level activity (ranging from 0 to 2.7 Hz) generated by 92 neurons was identified in basal states, activities that displayed functional interconnectivity. The majority (56%) of IC neurons so identified received indirect central inputs (vagus alone: 25%; stellate ganglion alone: 27%; both: 48%). Fifty per cent transduced the cardiac milieu responding to multimodal stressors applied to the great vessels or heart. Fifty per cent of IC neurons exhibited cardiac cycle periodicity, with activity occurring primarily in late diastole into isovolumetric contraction. Cardiac-related activity in IC neurons was primarily related to direct cardiac mechano-sensory inputs and indirect autonomic efferent inputs. In response to mediastinal nerve stimulation, most IC neurons became excessively activated; such network behaviour preceded and persisted throughout AF. It was concluded that stochastic interactions occur among IC local circuit neuronal populations in the control of regional cardiac function. Modulation of IC local circuit neuronal recruitment may represent a novel approach for the treatment of cardiac disease, including atrial arrhythmias.

Network interactions within the intrinsic cardiac nervous system: Implications for reflex control of regional cardiac function

ObjectiveTo determine how aggregates of intrinsic cardiac (IC) neurons transduce the cardiovascular milieu vs respond to changes in central drive. Also to determine how IC network interactions, subsequent to induced neural imbalances, subserve the genesis of atrial fibrillation (AF).MethodsActivity from multiple IC neurons within the right atrial ganglionated plexus was recorded from anesthetized canines. Induced changes in IC neuronal activity were evaluated in response to: (1) cardiac touch; (2) electrical activation of the cervical vagus or stellate ganglia; (3) occlusion of the inferior vena cava or thoracic aorta; (4) focal left ventricular ischemia and (5) neurally induced atrial arrhythmias (AF).ResultsThe majority of IC neurons were local circuit in nature and in basal states displayed low level functional interconnectivity. The majority of IC neurons received indirect central inputs (vagus and stellate) and a lesser proportion transduced the cardiac milieu including responding to multimodal stressors applied to the great vessels and heart. In response to mediastinal nerve stimulation most IC neurons became excessive excited and their functional interconnectivity enhanced; such network behavior preceding and continuing throughout AF.ConclusionStochastic interactions among IC neuronal populations underlie control of regional cardiac function. (Supported by HL71830)

Para-recurrent lymph node metastasis was a significant predictor for cervical lymph nodes metastasis in thoracic esophageal carcinoma

Objective To evaluate correlation factors of cervical lymph nodes metastasis in thoracic esophageal carcinoma.Methods Local-regional metastasis of lymph node for 126 cases with esophageal squamous cell cancer after surgery from 2004 to 2009 were reviewed.Risk factors of cervical lymph nodes metastasis were examined by multiple Logistic regression analysis.Results In 126 cases,supraclavicular lymph node metastasis rate was 43.7％ (55/126).By logistic regression,none of the primary site,T stage,N stage,histological grade,lymph node metastasis rate,lymph node metastasis degree and number of lymph nodes metastatic field was not the high risk of cervical lymph nodes metastasis.In addition,multivariate analysis found that lymph node metastasis in mediastinum region 1 was high risk factor for lymph node metastasis of region 1 ( x2 =12.14,9.27,P =0.000,0.002),lymph node metastasis in region Ⅲ and region 2 were high risk factors for lymph node metastasis of region Ⅱa ( x2 =14.56,8.27,8.02,3.93,P =0.000,0.004,0.005,0.047 ).Conclusion Mediastinal para-recurrent nerve lymph node metastasis is a significant predictor for cervical lymph nodes metastasis. Key words: Esophageal neoplasms/surgery; Neoplasms meatstasis,neck lymph nodes; Neoplasms metastasis,para-recurrent nerve lymph node

Neuromodulation targets intrinsic cardiac neurons to attenuate neuronally mediated atrial arrhythmias

Our objective was to determine whether atrial fibrillation (AF) results from excessive activation of intrinsic cardiac neurons (ICNs) and, if so, whether select subpopulations of neurons therein represent therapeutic targets for suppression of this arrhythmogenic potential. Trains of five electrical stimuli (0.3-1.2 mA, 1 ms) were delivered during the atrial refractory period to mediastinal nerves (MSN) on the superior vena cava to evoke AF. Neuroanatomical studies were performed by injecting the neuronal tracer DiI into MSN sites that induced AF. Functional studies involved recording of neuronal activity in situ from the right atrial ganglionated plexus (RAGP) in response to MSN stimulation (MSNS) prior to and following neuromodulation involving either preemptive spinal cord stimulation (SCS; T(1)-T(3), 50 Hz, 200-ms duration) or ganglionic blockade (hexamethonium, 5 mg/kg). The tetramethylindocarbocyanine perchlorate (DiI) neuronal tracer labeled a subset (13.2%) of RAGP neurons, which also colocalized with cholinergic or adrenergic markers. A subset of DiI-labeled RAGP neurons were noncholinergic/nonadrenergic. MSNS evoked an ∼4-fold increase in RAGP neuronal activity from baseline, which SCS reduced by 43%. Hexamethonium blocked MSNS-evoked increases in neuronal activity. MSNS evoked AF in 78% of right-sided MSN sites, which SCS reduced to 33% and hexamethonium reduced to 7%. MSNS-induced bradycardia was maintained with SCS but was mitigated by hexamethonium. We conclude that MSNS activates subpopulations of intrinsic cardiac neurons, thereby resulting in the formation of atrial arrhythmias leading to atrial fibrillation. Stabilization of ICN local circuit neurons by SCS or the local circuit and autonomic efferent neurons with hexamethonium reduces the arrhythmogenic potential.

Neuromodulation of the intrinsic cardiac nervous system attenuates the formation of neurally‐induced atrial arrhythmias

The objective was to determine whether neurally‐induced atrial fibrillation (AF) differentially activates intrinsic cardiac neurons (ICN) and whether electrical or pharmacological modulation of ICN activity can reduce the arrhythmogenic potential. Trains of 5 electrical stimuli (1ms) were delivered during the atrial refractory period to mediastinal nerves (MSNS) on the right atria at the pericardial reflection to evoked AF. Recordings of neuronal activity were obtained from right atrial ganglionated plexus (RAGP) in response to MSNS prior to and following neuromodulation involving either pre‐emptive spinal cord stimulation (SCS) or ganglionic blockade (hexamethonium). MSNS evoked a ~4‐fold increase in RAGP neuronal activity, which SCS reduced by 43%. Hexamethonium blocked the MSNS evoked increase in RAGP neuronal activation. MSNS evoked atrial fibrillation/flutter in 78% of right‐sided nerve sites stimulated, which SCS reduced to 33% and hexamethonium reduced to 7%. MSNS induced bradycardia was maintained with SCS, but mitigated by hexamethonium. We conclude that MSNS activates subpopulations of intrinsic cardiac neurons resulting in the formation of atrial arrhythmias leading to atrial fibrillation. Stabilization of ICN local circuit neurons with SCS or local circuit and autonomic efferent projections with hexamethonium reduces the arrhythmogenic potential. (HL71830)

Multiple Schwannomas of the Bilateral Mediastinal Vagus Nerves

Multiple schwannomas arising from the mediastinal vagus nerve are very rare, but herein we report a case with such lesions involving the bilateral intrathoracic vagus nerves. A 43-year-old man presented with multiple mediastinal tumors during a check-up. A chest computed tomographic scan revealed multiple lesions that appeared strung together like beads along the right vagus nerve. Three small tumors were also evident on the left side of the esophagus. We performed a complete resection of the bilateral mediastinal tumors through right thoracoscopic surgery. The pathologic diagnosis for each of these tumors was a schwannoma without malignant components.

Longterm effects of cardiac mediastinal nerve cryoablation on neural inducibility of atrial fibrillation in canines

In canines, excessive activation of select mediastinal nerve inputs to the intrinsic cardiac nervous system induces atrial fibrillation (AF). Since ablation of neural elements is proposed as an adjunct to circumferential pulmonary vein ablation for AF, we investigated the short and long-term effects of mediastinal nerve ablation on AF inducibility. Under general anesthesia, in 11 dogs several mediastinal nerve sites were identified on the superior vena cava that, when stimulated electrically during the atrial refractory period, reproducibly initiated AF. Cryoablation of one nerve site was then performed and inducibility retested early (1–2 months post Cryo; n = 7) or late (4 months post Cryo; n = 4). Four additional dogs that underwent a sham procedure were retested 1 to 2 months post-surgery. Stimulation induced AF at 91% of nerve sites tested in control versus 21% nerve sites early and 54% late post-ablation (both P < 0.05). Fewer stimuli were required to induce AF in controls versus the Early Cryo group; this capacity returned to normal values in the Late Cryo group. AF episodes were longer in control versus the Early or Late Cryo groups. Heart rate responses to vagal or stellate ganglion stimulation, as well as to local nicotine infusion into the right coronary artery, were similar in all groups. In conclusion, focal damage to intrinsic cardiac neuronal inputs causes short-term stunning of neuronal inducibility of AF without major loss of overall adrenergic or cholinergic efferent neuronal control. That recovery of AF inducibility occurs rapidly post-surgery indicates the plasticity of intrathoracic neuronal elements to focal injury.

Atrial Tachyarrhythmias and Repolarization Changes Induced by Discrete Activation of Dorsal Mediastinal Cardiac Nerves in Canines

Chronotropic "vagal responses" elicited by high-frequency stimulation have been used to identify atrial targets for ablative treatment of atrial tachyarrhythmias (AT), whereas an anatomic approach consisting of extensive ablation of the ganglionated plexus areas has been proposed as an alternative. Therefore, there is a need for precise delineation of juxtacardiac nerves involved in AT initiation and clarification of their regional influences throughout the atria in relation to AT sites of origin, beyond chronotropic effects related to sinus node modulation. Unipolar electrograms were recorded from 191 biatrial epicardial sites in 13 anesthetized canines, with concomitant left atrial endocardial recording from 63 sites in 5 of 13 animals. When electric stimuli were delivered to dorsal mediastinal nerves during the atrial refractory period, atrial premature depolarizations initiating AT were elicited in all animals, most frequently without prior sinus cycle length modification. Among 63 episodes, the sites of origin of early AT beats were localized to (1) the posterolateral left atrial wall in the pulmonary vein region (33%), (2) superior left atrial loci along the Bachmann bundle (55%), and (3) the region of Bachmann bundle insertion into the superior right atrial wall (11%). Moreover, the AT sites of origin were spatially concordant with regional waveform changes during the repolarization phase of unipolar recordings. AT induction and repolarization changes were abolished after atropine administration. Activation of individual dorsal mediastinal nerves induces AT arising from distinct sites of origin which are spatially concordant with regional atrial repolarization changes.

α-Adrenoceptor blockade modifies neurally induced atrial arrhythmias

Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by alpha-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (alpha(1)-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (alpha(2)-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined alpha-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by alpha(1,2)-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal alpha-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that alpha-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system.

Stabilization of intrinsic cardiac neuronal processing mitigates neurally induced atrial arrhythmias

Our objective was to determine whether neuronally‐induced atrial arrhythmias can be suppressed by stabilizing the intrinsic cardiac nervous system. In anaesthetized dogs, trains of 5 electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 right and left atrial epicardial unipolar electrodes. Mediastinal nerve sites that reproducibly initiated atrial arrhythmias were identified. These sites were re‐stimulated following hexamethonium (1 mg/kg, iv) blockade or pre‐emptive spinal cord stimulation (SCS: the dorsal aspect of the T1–T3 spinal cord was stimulated electrically at 50 Hz; 0.2 ms; 90% of motor threshold) with parameters sufficient to reduce intrinsic cardiac neuronal activity by 70% for up to 1 hour. Stimulating select mediastinal nerves sites consistently elicited atrial tachyarrhythmias (85% of which progressed to atrial fibrillation, AF) with dispersion of epicardial breakthrough sites. Either hexamethonium or pre‐emptive SCS reduced the incidence of mediastinal nerve‐induced AF (to 11% and 40%, respectively) while increasing pacemaker stability. We conclude that excessive and heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias. The anti‐arrhythmic effects of stabilizing intrinsic cardiac neuronal processing, via either pharmacological or electrical neuromodulation, indicates a potential novel therapeutic approach to atrial arrhythmia suppression. Supported by the CIHR, the Québec Heart &amp; Stroke Foundation and the NIH.

NEURALLY INDUCED ATRIAL ARRHYTHMIAS ARE MODIFIED BY ALPHA‐ADRENOCEPTOR BLOCKADE.

Objective: To determine whether neurally induced atrial arrhythmias can be modified by α-adrenergic receptor blockade. Methods: In 24 anaesthetized dogs, trains of 5 electrical stimuli were delivered during the atrial refractory period to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were characterized using multiple unipolar electrodes. Active neural sites which induce atrial arrhythmias were identified and then re-stimulated following administration of naftopidil (α1-adrenergic blocker: 0.2 mg/kg iv) and/or yohimbine (α2-adrenergic blocker: 1 mg/kg iv). Results: Stimulation of select mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Combined α-adrenergic blockade eliminated atrial tachydysrythmia induction in every animal. Naftopidil or yohimbine alone mitigated atrial arrhythmia induction. Conclusions: Excessive activation of select intrinsic cardiac neural components induces atrial arrhythmia. This neurally based arrhythmic substrate can be suppressed by α-adrenoceptor blockade. Treatment targeting select neural elements with ICN has potential therapeutic benefits for atrial arrhythmias management. Supported by the CIHR, the Québec Heart & Stroke Foundation and the NIH.