The role of the tripartite synapse in the heart: how glial cells may contribute to the physiology and pathophysiology of the intracardiac nervous system.

One of the major roles of the intracardiac nervous system (ICNS) is to act as the final site of signal integration for efferent information destined for the myocardium to enable local control of heart rate and rhythm. Multiple subtypes of neurons exist in the ICNS where they are organized into clusters termed ganglionated plexi (GP). The majority of cells in the ICNS are actually glial cells; however, despite this, ICNS glial cells have received little attention to date. In the central nervous system, where glial cell function has been widely studied, glia are no longer viewed simply as supportive cells but rather have been shown to play an active role in modulating neuronal excitability and synaptic plasticity. Pioneering studies have demonstrated that in addition to glia within the brain stem, glial cells within multiple autonomic ganglia in the peripheral nervous system, including the ICNS, can also act to modulate cardiovascular function. Clinically, patients with atrial fibrillation (AF) undergoing catheter ablation show high plasma levels of S100B, a protein produced by cardiac glial cells, correlated with decreased AF recurrence. Interestingly, S100B also alters GP neuron excitability and neurite outgrowth in the ICNS. These studies highlight the importance of understanding how glial cells can affect the heart by modulating GP neuron activity or synaptic inputs. Here, we review studies investigating glia both in the central and peripheral nervous systems to discuss the potential role of glia in controlling cardiac function in health and disease, paying particular attention to the glial cells of the ICNS.

Emerging importance of satellite glia in nervous system function and dysfunction.

Satellite glial cells (SGCs) closely envelop cell bodies of neurons in sensory, sympathetic and parasympathetic ganglia. This unique organization is not found elsewhere in the nervous system. SGCs in sensory ganglia are activated by numerous types of nerve injury and inflammation. The activation includes upregulation of glial fibrillary acidic protein, stronger gap junction-mediated SGC-SGC and neuron-SGC coupling, increased sensitivity to ATP, downregulation of Kir4.1 potassium channels and increased cytokine synthesis and release. There is evidence that these changes in SGCs contribute to chronic pain by augmenting neuronal activity and that these changes are consistent in various rodent pain models and likely also in human pain. Therefore, understanding these changes and the resulting abnormal interactions of SGCs with sensory neurons could provide a mechanistic approach that might be exploited therapeutically in alleviation and prevention of pain. We describe how SGCs are altered in rodent models of four common types of pain: systemic inflammation (sickness behaviour), post-surgical pain, diabetic neuropathic pain and post-herpetic pain.

Autonomic ganglionic injection of α-synuclein fibrils as a model of pure autonomic failure α-synucleinopathy.

α-Synucleinopathies are characterized by autonomic dysfunction and motor impairments. In the pure autonomic failure (PAF), α-synuclein (α-Syn) pathology is confined within the autonomic nervous system with no motor features, but mouse models recapitulating PAF without motor dysfunction are lacking. Here, we show that in TgM83+/- mice, inoculation of α-Syn preformed fibrils (PFFs) into the stellate and celiac ganglia induces spreading of α-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally. In parallel, the mice develop autonomic dysfunction, featured by orthostatic hypotension, constipation, hypohidrosis and hyposmia, without motor dysfunction. Thus, we have generated a mouse model of pure autonomic dysfunction caused by α-Syn pathology. This model may help define the mechanistic link between transmission of pathological α-Syn and the cardinal features of autonomic dysfunction in α-synucleinopathy.

Ganglionic Acetylcholine Receptor Antibodies and Autonomic Dysfunction in Autoimmune Rheumatic Diseases.

Autonomic neuropathy has been reported in autoimmune rheumatic diseases (ARD) including Sjögren's syndrome, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. However, the pathophysiological mechanism underlying autonomic dysfunction remains unknown to researchers. On the other hand, autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder, which causes dysautonomia that is mediated by autoantibodies against ganglionic acetylcholine receptors (gAChRs). The purpose of this review was to describe the characteristics of autonomic disturbance through previous case reports and the functional tests used in these studies and address the importance of anti-gAChR antibodies. We have established luciferase immunoprecipitation systems to detect antibodies against gAChR in the past and determined the prevalence of gAChR antibodies in various autoimmune diseases including AAG and rheumatic diseases. Autonomic dysfunction, which affects lower parasympathetic and higher sympathetic activity, is usually observed in ARD. The anti-gAChR antibodies may play a crucial role in autonomic dysfunction observed in ARD. Further studies are necessary to determine whether anti-gAChR antibody levels are correlated with the severity of autonomic dysfunction in ARD.

Evaluation of effect of Acacia jacquemontii Benth. on blood pressure in normotensive and fructose induced hypertensive sprague dawley rats: An ethnopharmacological approach.

Acacia jacquemontii Benth. is used traditionally to treat hypertension but no scientific literature supports this claim. So, this study was aimed at validating this claim. This was done by injecting various doses of crude extract of Acacia jacquemontii, AJC (5, 10, 20, 30mg/kg) and all fractions (hexane, ethyl acetate, n-butanol and aqueous) (3, 5, 10, 20mg/kg) intravenously in anaesthetized rat. Based on the results, butanol fraction (AJB) at 20mg/kg was found to be the most potent, so it was selected for exploring mechanisms of action. For this purpose, different groups were injected with various pharmacological inhibitors (L-NAME, atropine, captopril, propranolol and hexamethonium) prior to AJB administration. Also, AJB at 20mg/kg was evaluated for prolonged hypotensive effect for the period of 40 min. Results showed a significant dose dependent reduction in BP in normotensive and in hypertensive rats. AJC and AJB produced a decline in SBP, DBP and MAP with p<0.05 - p<0.001 and p<0.001 respectively in normotensive animals. Whereas in hypertensive animals, AJC showed significant reduction at 5mg/kg with p<0.01 and at 10, 20 and 30 mg/kg with p<0.001. AJB produced a decline in hypertensive animals at all tested doses with p<0.001. AJB resulted in hypotensive effect mediated by ß receptors, ganglionic block operating central sympathetic neural responses and renin angiotensin aldosterone system (RAAS). This study supports the ethnomedicinal claim of Acacia jacquemontii Benth. in treating hypertension.

Different effects of additional ganglion plexus ablation on catheter and surgical ablation for atrial fibrillation: a systemic review and meta-analysis.

The effect of ganglion plexus (GP) ablation in addition to pulmonary veins isolation (PVI) for atrial fibrillation (AF) remained controversial between the catheter and surgical-based studies. Eleven studies (five randomized controlled trials and six nonrandomized studies) of 1750 patients were included in a meta-analysis to elucidate the incremental benefit of additional GP ablation in patients undergoing catheter or surgical ablation. Risk ratios were calculated for freedom from AF or AT recurrence after a single procedure. Additional GP ablation was associated with a better rhythm outcome for patients undergone catheter ablation but did not seem to increase freedom from AF/AT for surgical patients. Both paroxysmal and non-paroxysmal AF showed a positive outcome comparing additional GP ablation with PVI alone.

Autoimmune autonomic neuropathies and ganglionopathies: epidemiology, pathophysiology, and therapeutic advances.

Autonomic disorders can be the result of autoimmunity. The classic, well-characterized example is autoimmune autonomic ganglionopathy (AAG), in which antibodies against the ganglionic nicotinic acetylcholine receptor impair autonomic transmission, causing autonomic failure, which responds to immunotherapy. However, a number of other autoimmune disorders cause autonomic failure through a variety of mechanisms. In this article, we review autoimmune disorders causing impairment of the peripheral autonomic nervous system (ganglia and nerves), including AAG, other autoimmune autonomic neuropathies, paraneoplastic autonomic neuropathies, and neuromuscular and rheumatologic diseases with autonomic symptomatology. Awareness of primary autoimmune autonomic disorders and the autonomic manifestations of other autoimmune diseases promotes timely diagnosis and appropriate management, including supportive care for unpleasant or dangerous autonomic dysfunction, a search for underlying malignancy when indicated, and the use of immunotherapy when appropriate. A better understanding of the underlying pathophysiology aids in the judicious use and selection of immunotherapy.

Effect of Lidocaine Injection of Ganglionated Plexi in a Canine Model and Patients With Persistent and Long-Standing Persistent Atrial Fibrillation.

Background This study assessed the effect of blockading neural transmission in the ganglionated plexi by injecting lidocaine into fat pads in the vagal nerve stimulation canine model and patients with persistent atrial fibrillation ( AF ). Methods and Results An efficacy test of lidocaine injection was performed in 7 canines. During vagal nerve stimulation, AF was sustained for >5 minutes. The lidocaine was injected into ganglionated plexi during sinus rhythm and reinduction of AF was attempted. Six patients with persistent AF were studied at open heart surgery. Lidocaine was injected into ganglionated plexi. Atrial electrograms were recorded from 96 epicardial electrodes covering Bachmann's bundle and atrial appendages. In the canine vagal nerve stimulation AF model, AF was not inducible in 4 of 7 after lidocaine injection. In patients with persistent AF , during baseline AF , there was a left atrium ( LA )-to-right atrium ( RA ) frequency gradient ( LA , mean cycle length [ CL ] 175±17 ms; RA , mean CL 192±17 ms; P<0.01). After lidocaine injection, AF persisted in all patients, and the LA -to- RA frequency gradient disappeared ( LA , mean CL 186±13 ms; RA , mean CL 199±23 ms; P=0.08). Comparison of mean CL s before and after lidocaine demonstrated prolongation of LA CL s ( P<0.05) with no effect on RA CL s. Conclusions In the canine vagal nerve stimulation AF model, lidocaine injection decreased inducibility of AF . In patients with persistent AF , atrial electrograms from the LA had shorter CL s than RA , indicating an LA -to- RA frequency gradient. Lidocaine injection significantly prolonged only LA CL s, explaining disappearance of the LA -to- RA frequency gradient. The mechanism of localized atrial electrogram CL prolongation in patients with persistent AF is uncertain.

Epicardial injection of nanoformulated calcium into cardiac ganglionic plexi suppresses autonomic nerve activity and postoperative atrial fibrillation.

BACKGROUND: Imbalanced activation of the cardiac autonomic nervous system triggers postoperative atrial fibrillation (POAF). Neuronal calcium overload induces apoptosis. We hypothesize that epicardial injection of timed-release nanoformulated CaCl2 (nCaCl2) into left atrial ganglionic plexi (GP) modulates autonomic function and suppresses POAF. OBJECTIVE: The purpose of this study was to determine whether nCaCl2 GP therapy suppresses POAF. METHODS: We used a novel canine model of POAF with implanted radiotelemetry to record nerve activity (NA) from the left stellate ganglion (SNA), left cardiac vagus nerve, and GP. At week 3, nCaCl2 (n = 7) or vehicle control (sham; n = 3) was injected into left pulmonary vein GP (LGP), followed by right pulmonary vein GP at week 4. Atrial effective refractory period (AERP) and atrial fibrillation vulnerability (AFV) were assessed in vivo. Resting and exercise NA and heart rate (HR) were assessed before and after LGP treatment. RESULTS: AERP decreased (P < .0001) and AFV increased (P = .008) at week 3 vs baseline. However, nCaCl2-LGP treatment reversed these changes and restored them to baseline after 1 week (P = .04). Subsequent nCaCl2-right pulmonary vein GP treatment further reduced AFV (P = .03). In contrast, AFV increased (P = .001) and AERP remained decreased (P = .01) 1 week after sham-LGP treatment vs baseline. nCaCl2-LGP treatment reduced NA from GP (P < .02) and NA from the left cardiac vagus nerve (P < .05) and increased SNA (P < .02). Despite increased SNA, HR was decreased (P < .01) with loss of HR-SNA correlation (R = 0.62). After sham-LGP treatment, NA was unchanged and HR-SNA remained correlated (R = 0.95). Histology confirmed nCaCl2-GP colocalization, apoptosis, and loss of immunoreactivity in nCaCl2-treated somas. CONCLUSION: Epicardial injection of nCaCl2 into left atrial GP induced neuroapoptosis and modulated autonomic function. This reversed a postoperative reduction in AERP and suppressed POAF.

Electroporation of epicardial autonomic ganglia: Safety and efficacy in medium-term canine models.

BACKGROUND: Endocardial radiofrequency ablation of epicardial ganglionic plexus (GP) for atrial fibrillation (AF) is complicated by myocardial damage. OBJECTIVES: We hypothesized that an epicardial approach with a novel nitinol catheter system capable of causing irreversible electroporation (IRE) with direct current (DC) could selectively and permanently destroy GP without collateral myocardial injury. METHODS: Acute studies and medium-term terminal studies (mean survival, 1137 days) were performed with seven dogs. In the acute studies, DC was used to target epicardial GP within the transverse sinus, oblique sinus, vein of Marshall, and right periaortic space. Successful electroporation was defined as the presence of ablative lesions in the GP without collateral myocardial damage. A four-point integer system was used to classify histologic changes in tissue harvested from the ablation sites. Atrial effective refractory period (AERP) was measured during the acute and medium-term studies. RESULTS: For six dogs in the medium-term studies, the postablation period was uneventful without complications. Lesions were successfully created at 20 of 21 sites (95.2%) with more than minimal myocardial damage in one dog. An increase in AERP occurred in both atria during the acute studies but was maintained only in the right atrium at medium-term follow-up (5032 milliseconds). No dog had damage to the esophagus, adjacent great arteries, or pulmonary veins. CONCLUSIONS: This proof-of-concept study suggests that safe, effective, and selective epicardial ablation of GP can be performed with DC by IRE with minimal collateral myocardial damage.

Selective ablation of atrial ganglionated plexus attenuates vasovagal reflex in a canine model.

BACKGROUND: Atrial ganglionated plexus (GP) ablation was proved to have therapeutic effects on vasovagal syncope. The study aimed to investigate whether selective ablation of only right anterior GP (ARGP) and right inferior GP (IRGP) was effective in a canine model of vasovagal syncope. METHODS: Seventeen mongrel dogs were divided into control (N = 10) and ablation group (N = 7). Bilateral thoracotomy was performed at the fourth intercostal space and ARGP and IRGP were ablated in the ablation group. A bolus of veratridine (15 ug/kg) was injected into the left atrium to induce vasovagal reflex. Surface electrocardiogram and blood pressure (BP) were continuously monitored. Heart rate (HR) variability was calculated to represent cardiac autonomic tone. RESULTS: Veratridine injection induced vasovagal reflex in all dogs. HR decreased from 149 ± 17 to 89 ± 33 beats/min (P < 0.001) in the control group, while in the ablation group HR decreased from 141 ± 35 to 125 ± 34 beats/min (P = 0.032). The postveratridine HR in the ablation group was significantly higher than that in the control group (P = 0.045). A significantly less intense HR decrease was observed in the ablation group compared with control (-17 ± 16 vs -61 ± 34 beats/min, P = 0.006). Significant BP decreases were induced in both the groups (all P < 0.01), while no evident differences in postveratridine BP and the extent of BP decreases were found between the groups. HR variability revealed significant decrease in cardiac vagal tone after ablation [high-frequency power, 0.50 (0.17-1.05) vs 6.28 (0.68-8.99) ms2 , P = 0.005]. CONCLUSIONS: Selective ablation of ARGP + IRGP weakened cardiac parasympathetic control and significantly attenuated the cardioinhibitory response in an animal model of vasovagal reflex. This ablation strategy might be effective for vasovagal syncope with evident cardioinhibitory response.

Electrophysiological effects of nicotinic and electrical stimulation of intrinsic cardiac ganglia in the absence of extrinsic autonomic nerves in the rabbit heart.

BACKGROUND: The intrinsic cardiac nervous system is a rich network of cardiac nerves that converge to form distinct ganglia and extend across the heart and is capable of influencing cardiac function. OBJECTIVE: The goals of this study were to provide a complete picture of the neurotransmitter/neuromodulator profile of the rabbit intrinsic cardiac nervous system and to determine the influence of spatially divergent ganglia on cardiac electrophysiology. METHODS: Nicotinic or electrical stimulation was applied at discrete sites of the intrinsic cardiac nerve plexus in the Langendorff-perfused rabbit heart. Functional effects on sinus rate and atrioventricular conduction were measured. Immunohistochemistry for choline acetyltransferase (ChAT), tyrosine hydroxylase, and/or neuronal nitric oxide synthase (nNOS) was performed using whole mount preparations. RESULTS: Stimulation within all ganglia produced either bradycardia, tachycardia, or a biphasic brady-tachycardia. Electrical stimulation of the right atrial and right neuronal cluster regions produced the largest chronotropic responses. Significant prolongation of atrioventricular conduction was predominant at the pulmonary vein-caudal vein region. Neurons immunoreactive (IR) only for ChAT, tyrosine hydroxylase, or nNOS were consistently located within the limits of the hilum and at the roots of the right cranial and right pulmonary veins. ChAT-IR neurons were most abundant (1946 ± 668 neurons). Neurons IR only for nNOS were distributed within ganglia. CONCLUSION: Stimulation of intrinsic ganglia, shown to be of phenotypic complexity but predominantly of cholinergic nature, indicates that clusters of neurons are capable of independent selective effects on cardiac electrophysiology, therefore providing a potential therapeutic target for the prevention and treatment of cardiac disease.

Effects of Transcutaneous Electrical Nerve Stimulation in Autonomic Nervous System of Hypertensive Patients: A Randomized Controlled Trial.

BACKGROUND: Patients with hypertension have altered autonomic nervous system function, which are increased sympathetic activity. Transcutaneous Electrical Nerve Stimulation (TENS) is a useful modality for pain control and has also been shown to be effective in the reduction of sympathetic activity in healthy subjects and individuals with cardiovascular diseases. OBJECTIVE: The aim of this study was to verify the effects of transcutaneous electrical nerve stimulation by the evaluation of heart rate variability (HRV) in patients with essential hypertension. METHOD: Twenty-eight patients received an application of low-frequency TENS(4 Hz) n=8, highfrequency TENS (100 Hz) n=10 or placebo TENS n=10 in paravertebral ganglionar region during thirty minutes. RESULTS: After 4 Hz TENS, there was a decrease in the low-frequency (LFn.u.) component (57.71±9.46 vs 45.58±13.51, p<0.026) and an increase in the high-frequency (HFn.u.) component (33.03±13.83 vs 45.83±20.19, p <0.05) of HRV. After 100 Hz TENS and placebo, there were no changes in the LF and HF components. No significant differences were found in systolic blood pressure with low-frequency TENS (129.37± 15.48 vs 126.69 ± 15.21, p<0.490). There was an increase, although not significant, with high-frequency TENS (131.00 ± 15.97 vs 138.75 ± 25.79, p<0.121) and placebo (133.80 ± 29.85 vs 134.80 ± 29.72, p< 0.800). No differences were found in the diastolic blood pressure with low-frequency TENS and placebo, but there was a significant increase in high-frequency TENS (81.00 ± 11.78 vs 85.65 ± 13.68, p< 0.018). CONCLUSION: Low-frequency TENS decreases sympathetic nervous system activity and increases parasympathetic nervous system activity and high-frequency TENS increases diastolic blood pressure, when applied on the paravertebral ganglionar region in the hypertensive patients.

Clinical Problem Solving: A Tobacco Merchant Who Can't Spit.

BACKGROUND: A 47 year old man presented with a combination of dry mouth and lightheadedness while standing. His medical background was unremarkable except for cigarette smoking and hyperlipidemia. Sjögren's syndrome was ruled out, and he was referred for evaluation of orthostatic hypotension, which by then included syncopal episodes and injuries. Additional symptoms included dry eyes, constipation, reduced sweating, and erectile dysfunction. After excluding medications and structural cardiac abnormalities as causes of orthostatic hypotension, a clinical autonomic evaluation was performed. The pattern of beat-to-beat blood pressure associated with performance of the Valsalva maneuver, and a low plasma norepinephrine level that did not increase in response to standing, established that the orthostatic hypotension was neurogenic. Treatment with an alpha-adrenoceptor agonist and fludrocortisone yielded partial improvement. After systemic diseases involving autonomic failure were excluded, cardiac sympathetic neuroimaging was performed by 123I-metaliodobenzylguanidine (MIBG) scanning. The normal uptake seen in the heart indicated intact post ganglionic sympathetic innervation. There were no signs of central neurodegeneration or peripheral neuropathy. Because of symptoms and signs of both parasympathetic and sympathetic failure without denervation, an autonomic ganglionopathy was considered. A high titer of antibody to the neuronal nicotinic receptor, which mediates ganglionic neurotransmission, was obtained. The diagnosis of autoimmune autonomic ganglionopathy (AAG) was made, and the management strategy shifted to first lowering the antibody burden by plasma exchanges and then instituting chronic anti-autoimmune treatment with rituximab and a low dose of cortiosteroid. The patient showed remarkable improvement.

Heart rate variability after radiofrequency ablation of epicardial ganglionated plexuses on the ovine left atrium.

BACKGROUND: Ganglionated plexuses (GP) are terminal parts of cardiac autonomous nervous system (ANS). Radiofrequency ablation (RFA) for atrial fibrillation (AF) possibly affects GP. Changes in heart rate variability (HRV) after RFA can reflect ANS modulation. METHODS: Epicardial RFA of GP on the left atrium (LA) was performed under the general anesthesia in 15 mature Romanov sheep. HRV was used to assess the alterations in autonomic regulation of the heart. A 24 - hour ECG monitoring was performed before the ablation, 2 days after it and at each of the 12 following months. Ablation sites were evaluated histologically. RESULTS: There was an instant change in HRV parameters after the ablation. A standard deviation of all intervals between normal QRS (SDNN), a square root of the mean of the squared differences between successive normal QRS intervals (RMSSD) along with HRV triangular index (TI), low frequency (LF) power and high frequency (HF) power decreased, while LF/HF ratio increased. Both the SDNN, LF power and the HF power changes persisted throughout the 12 - month follow - up. Significant decrease in RMSSD persisted only for 3 months, HRV TI for 6 months and increase in LF/HF ratio for 7 months of the follow - up. Afterwards these three parameters were not different from the preprocedural values. CONCLUSIONS: Epicardial RFA of GP's on the ovine left atrium has lasting effect on the main HRV parameters (SDNN, HF power and LF power). The normalization of RMSSD, HRV TI and LF/HF suggests that HRV after epicardial RFA of GPs on the left atrium might restore over time.

Plastics and cardiovascular health: phthalates may disrupt heart rate variability and cardiovascular reactivity.

Plastics have revolutionized medical device technology, transformed hematological care, and facilitated modern cardiology procedures. Despite these advances, studies have shown that phthalate chemicals migrate out of plastic products and that these chemicals are bioactive. Recent epidemiological and research studies have suggested that phthalate exposure adversely affects cardiovascular function. Our objective was to assess the safety and biocompatibility of phthalate chemicals and resolve the impact on cardiovascular and autonomic physiology. Adult mice were implanted with radiofrequency transmitters to monitor heart rate variability, blood pressure, and autonomic regulation in response to di-2-ethylhexyl-phthalate (DEHP) exposure. DEHP-treated animals displayed a decrease in heart rate variability (-17% SD of normal beat-to-beat intervals and -36% high-frequency power) and an exaggerated mean arterial pressure response to ganglionic blockade (31.5% via chlorisondamine). In response to a conditioned stressor, DEHP-treated animals displayed enhanced cardiovascular reactivity (-56% SD major axis Poincarè plot) and prolonged blood pressure recovery. Alterations in cardiac gene expression of endothelin-1, angiotensin-converting enzyme, and nitric oxide synthase may partly explain these cardiovascular alterations. This is the first study to show an association between phthalate chemicals that are used in medical devices with alterations in autonomic regulation, heart rate variability, and cardiovascular reactivity. Because changes in autonomic balance often precede clinical manifestations of hypertension, atherosclerosis, and conduction abnormalities, future studies are warranted to assess the downstream impact of plastic chemical exposure on end-organ function in sensitive patient populations. This study also highlights the importance of adopting safer biomaterials, chemicals, and/or surface coatings for use in medical devices.NEW & NOTEWORTHY Phthalates are widely used in the manufacturing of consumer and medical products. In the present study, di-2-ethylhexyl-phthalate exposure was associated with alterations in heart rate variability and cardiovascular reactivity. This highlights the importance of investigating the impact of phthalates on health and identifying suitable alternatives for medical device manufacturing.

Ganglionated plexi as neuromodulation targets for atrial fibrillation.

The autonomic nervous system plays an important role in the genesis of atrial fibrillation and is one of the candidate targets for atrial fibrillation therapy. This review focuses on the role of the autonomic nervous system in atrial fibrillation development and discusses the results of the ganglionated plexi catheter and surgical ablation in preclinical and clinical studies. The heart is innervated by the extrinsic and intrinsic autonomic nervous systems. The intrinsic autonomic nervous system consists of multiple ganglionated plexi and axons, which innervate the neighboring atrial myocardium and control their electrophysiological properties. Abnormal autonomic innervation has been observed in an animal model of atrial fibrillation and in humans. Direct recordings of autonomic nerve activity in canine models showed that atrial tachyarrhythmia episodes were invariably preceded by intrinsic cardiac autonomic nerve activity, thus supporting the importance of intrinsic cardiac autonomic nerve activity as the triggers for atrial tachyarrhythmia. Targeting ganglionated plexi with catheter ablation improves the outcomes of paroxysmal atrial fibrillation ablation in addition to pulmonary vein antrum isolation. Ablation of ganglionated plexi alone without pulmonary vein isolation is also useful in controlling paroxysmal atrial fibrillation in some patients. However, surgical ganglionated plexi ablation in patients with a large left atrium, persistent atrial fibrillation, and/or a history of prior catheter ablation does not result in additional benefits. These different outcomes suggest that ganglionated plexi ablation is effective in managing patients with paroxysmal atrial fibrillation, but its effects in patients with persistent atrial fibrillation and advanced atrial diseases might be limited.

Increase of Autonomic Nerve Factors in Epicardial Ganglionated Plexi During Rapid Atrial Pacing Induced Acute Atrial Fibrillation.

BACKGROUND The cardiac autonomic nervous system plays an essential role in epicardial ganglionated plexi (GP) regulation of atrial fibrillation onset and progression. To date, the activity of GP and the function of the cardiac autonomic nervous system are not well understood. The aim of this study was to determine alterations in epicardial GP cholinergic nerve, adrenergic nerve, and nerve growth factor expression using rapid atrial pacing to induce atrial fibrillation in canines. MATERIAL AND METHODS Nine healthy adult beagles were divided into two groups: the pacing experimental group (n=6) and the sham-operation control group (n=3). For the pacing group, high frequency pacing of the left atrial appendage was performed for eight hours. In the control group, electrodes were implanted without rapid atrial pacing. Immunocytochemistry was used to identify neurons positively expressing tyrosine hydroxylase, choline acetyl transferase, nerve growth factor and neurturin. RESULTS After successfully establishing a rapid atrial pacing of the left atrial appendage induced atrial fibrillation model, we found that expression of choline acetyl transferase, tyrosine hydroxylase, nerve growth factor, and neurturin was significantly higher in the rapid atrial pacing group than the control group (p<0.05). CONCLUSIONS In our model, incremental excitability of both the adrenergic and cholinergic nerves led to frequent incidents of atrial fibrillation, which were possibly due to an imbalance of autonomic nerve factors in the epicardial GP during acute atrial fibrillation.

Spatial relationship of organized rotational and focal sources in human atrial fibrillation to autonomic ganglionated plexi.

BACKGROUND: One approach to improve ablation for atrial fibrillation (AF) is to focus on physiological targets including focal or rotational sources or ganglionic plexi (GP). However, the spatial relationship between these potential mechanisms has never been studied. We tested the hypothesis that rotors and focal sources for AF may co-localize with ganglionated plexi (GP). METHODS: We prospectively identified locations of AF rotors and focal sources, and correlated these to GP sites in 97 consecutive patients (age 59.9±11.4, 73% persistent AF). AF was recorded with 64-pole catheters with activation/phase mapping, and related to anatomic GP sites on electroanatomic maps. RESULTS: AF sources arose in 96/97 (99%) patients for 2.6±1.4 sources per patient (left atrium: 1.7±0.9 right atrium: 1.1±0.8), each with an area of 2-3cm2. On area analyses, the probability of an AF source randomly overlapping a GP area was 26%. Left atrial sources were seen in 94 (97%) patients, in whom ≥1 source co-localized with GP in 75 patients (80%; p<0.05). AF sources were more likely to colocalize with left vs right GPs (p<0.05), and colocalization was more likely in patients with higher CHADS2VASc scores (age>65, diabetes; p<0.05). CONCLUSIONS: This is the first study to demonstrate that clinically detected AF focal and rotational sources in the left atrium often colocalize with regions of autonomic innervation. Studies should define if the role of AF sources differs by their anatomical location.