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Vagal denervation and atrial fibrillation inducibility: Epicardial fat pad ablation does not have long-term effects
Abstract
Major epicardial fat pads contain cardiac ganglionated plexi of the autonomic, predominantly vagal nerves. Vagal denervation may improve the success rate of atrial fibrillation (AF) treatment.
The purpose of this study was to elucidate the long-term effects of fat pad ablation on the electrophysiologic characteristics of the atrium and AF inducibility.
Six mongrel dogs were studied. Cervical vagal stimulation was applied to determine effects on the sinus node, AV node, atrial effective refractory period (AERP), and AF inducibility. AERP and AF inducibility were evaluated at both the right atrial and left atrial appendages and at the right atrial and left atrial free walls. Radiofrequency energy was delivered epicardially to the entire areas of two major fat pads: right pulmonary vein fat pad and inferior vena cava-left atrium fat pad. Cervical vagal stimulation then was applied to confirm the acute effects of fat pad ablation. The same evaluation was repeated 4 weeks later.
The effects of vagal stimulation on the sinus node, AV node, and AERP were significantly eliminated immediately after fat pad ablation. However, these denervation effects disappeared after 4 weeks. At baseline, AF inducibility was increased by vagal stimulation (right atrial appendage: 72% +/- 31% vs 4.8% +/- 12%; right atrial free wall: 75% +/- 31% vs 0.0% +/- 0.0%; left atrial appendage: 60% +/- 29% vs 0.0% +/- 0.0%; left atrial free wall: 65% +/- 42% vs 0.0% +/- 0.0%). Fat pad ablation significantly reduced this vagal stimulation effect (8.3% +/- 20%, 10% +/- 22%, 17% +/- 29%, and 25% +/- 29%, respectively). However, similar to baseline, AF inducibility was strongly augmented by vagal stimulation 4 weeks after fat pad ablation (96% +/- 10%, 100% +/- 0.0%, 100% +/- 0.0%, and 95% +/- 11%, respectively).
Radiofrequency fat pad ablation may not achieve long-term suppression of AF induction in this canine model.
... Mazgalev and coworkers reported a Temporary Cardiac Denervation with Human FS in a proof of principle study in canines. 7 An immediate modification of the conduction of electrical impulses through the cardiac ganglia was achieved following injection of 1 mL of the fibrin sealant (FS) Omrix. ...
... 6 In contrast to a permanent destruction of the parasympatic net surrounding the heart, Mazgalev and coworkers reported a temporary cardiac denervation with human FS in a proof of principle study in canines. 7 An immediate modification of the conduction of electrical impulses through the ...
... Histologic assessment of the cardiac fat pad tissue was also observed to be "normal" at 4 weeks post injection, without the development of scared tissue or inflammatory reaction. 7 The aim of this pilot-study was to evaluate the feasibility and safety of a temporary fat pad ablation and its vagal control of the SA node, AV node and the onset and severity of AF after cardiac (mostly coronary bypass) surgery in human beings. ...
... The long-term effects of fat pad ablation were investigated in an animal model. 23) In this study, major epicardial GPs were ablated, but all denervation effects disappeared 4 weeks after the ablation. GP ablation has been adopted in the catheter ablation procedure for AF. ...
Trigger and functional substrate are related to the tone of autonomic nervous system, and the role of the autonomic nerve is more significant in paroxysmal atrial fibrillation (AF) compared to non-paroxysmal AF. We have several options for neuromodulation to help to manage patients with AF. Neuromodulation targets can be divided into efferent and afferent pathways. On the efferent side, block would be an intuitive approach. However, permanent block is hard to achieve due to completeness of the procedure and reinnervation issues. Temporary block such as botulinum toxin injection into ganglionated plexi would be a possible option for post-cardiac surgery AF. Low-level subthreshold stimulation could also prevent AF, but the invasiveness of the procedure is the barrier for the general use. On the afferent side, block is also an option. Various renal denervation approaches are currently under investigation. Auditory vagus nerve stimulation is one of the representative low-level afferent stimulation methods. This technique is noninvasive and easy to apply, so it has the potential to be widely utilized if its efficacy is confirmed.
... Therefore, in future studies, we will consider combining RAGP ablation with other ganglionated plexi for patients with nocturnal paroxysmal atrioventricular block 33 . Several studies in cardiac surgery have suggested that nerve reconnection occurs after autonomic nerve fiber resection 34,35 . It takes an average of 1 to 3 years for vagal nerve reconnection, and about half a year for sympathetic nerve reconnection [36][37][38] . ...
Cardioneuroablation (CNA) is currently considered as a promising treatment option for patients with symptomatic bradycardia caused by vagotonia. This study aims to further investigate its safety and efficacy in patients suffering from vagal bradycardia. A total of 60 patients with vagal bradycardia who underwent CNA in the First Affiliated Hospital of Xinjiang Medical University from November 2019 to June 2022. Preoperative atropine tests revealed abnormal vagal tone elevation in all patients. First, the electroanatomic structures of the left atrium was mapped out by using the Carto 3 system, according to the protocol of purely anatomy-guided and local fractionated intracardiac electrogram-guided CNA methods. The upper limit of ablation power of superior left ganglion (SLGP) and right anterior ganglion (RAGP) was not more than 45W with an ablation index of 450.Postoperative transesophageal cardiac electrophysiological examination was performed 1 to 3 months after surgery. The atropine test was conducted when appropriate. Twelve-lead electrocardiogram, Holter electrocardiogram, and skin sympathetic nerve activity were reviewed at 1, 3, 6 and 12 months after operation. Adverse events such as pacemaker implantation and other complications were also recorded to analyze the safety and efficacy of CNA in the treatment of vagus bradycardia. Sixty patients were enrolled in the study (38 males, mean age 36.67 ± 9.44, ranging from 18 to 50 years old). None of the patients had a vascular injury, thromboembolism, pericardial effusion, or other surgical complications. The mean heart rate, minimum heart rate, low frequency, low/high frequency, acceleration capacity of rate, and skin sympathetic nerve activity increased significantly after CNA. Conversely, SDNN, PNN50, rMSSD, high frequency, and deceleration capacity of rate values decreased after CNA (all P < 0.05). At 3 months after ablation, the average heart rate, maximum heart rate, and acceleration capacity of heart rate remained higher than those before ablation, and the deceleration capacity of heart rate remained lower than those before ablation and the above results continued to follow up for 12 months after ablation (all P < 0.05). There was no significant difference in other indicators compared with those before ablation (all P > 0.05). The remaining 81.67% (49/60) of the patients had good clinical results, with no episodes of arrhythmia during follow-up. CNA may be a safe and effective treatment for vagal-induced bradycardia, subject to confirmation by larger multicenter trials.
... Since the autonomic nervous system crucially regulates heart rhythm and ganglionated plexi are located in EAT ( Figure 2) [52,53], activation of these plexi can cause both parasympathetic and sympathetic stimulation, resulting in shortened action potentials and increased calcium transients, respectively ( Figure 1) [44]. EAT can influence these encased ganglionated plexi contributing to arrhythmogenesis. ...
The epicardial adipose tissue (EAT) or epicardial fat is a visceral fat depot in the heart that contains intrinsic adrenergic and cholinergic nerves, through which it interacts with the cardiac sympathetic (adrenergic) and parasympathetic (cholinergic) nervous systems. These EAT nerves represent a significant source of several adipokines and other bioactive molecules, including norepinephrine, epinephrine, and free fatty acids. The production of these molecules is biologically relevant for the heart, since abnormalities in EAT secretion are implicated in the development of pathological conditions, including coronary atherosclerosis, atrial fibrillation, and heart failure. Sympathetic hyperactivity and parasympathetic (cholinergic) derangement are associated with EAT dysfunction, leading to a variety of adverse cardiac conditions, such as heart failure, diastolic dysfunction, atrial fibrillation, etc.; therefore, several studies have focused on exploring the autonomic regulation of EAT as it pertains to heart disease pathogenesis and progression. In addition, Regulator of G protein Signaling (RGS)-4 is a protein with significant regulatory roles in both adrenergic and muscarinic receptor signaling in the heart. In this review, we provide an overview of the autonomic regulation of EAT, with a specific focus on cardiac RGS4 and the potential roles this protein plays in this regulation.
... The RF-induced injury of GP mainly diminishes vagal tone because parasympathetic fibers predominate in GP and, contrary to the adrenergic nerve endings, can barely regenerate. [9] To date, numerous single case reports, case series and case-control studies using propensity-matching scores have been published, showing promising results. [10][11][12][13][14][15][16][17][18][19][20][21][22] However, randomized, prospective, controlled studies are lacking. ...
Introduction
Treatment of cardioinhibitory vasovagal syncope (VVS) is difficult. Recently, cardioneuroablation (CNA) has emerged as a new therapeutic option.
Aim
To assess the effects of CNA on syncope recurrences in patients with VVS
Methods
We performed a prospective, open, randomized, controlled, investigator-initiated trial comparing CNA vs optimal non-pharmacological therapy in patients with cardioinhibitory VVS. Patients were included if they had documented symptomatic cardioinhibitory or mixed VVS and positive atropine test. CNA was performed using RF ablation of the ganglionated plexi from the left and right atrium. Follow-up lasted 2 years. Primary endpoint was time to first syncope recurrence. Secondary endpoints included changes in sinus rhythm (SR) and heart rate variability (HRV) measured in Holter ECG at baseline and 3, 12 and 24 months after CNA as well as changes in quality of life (QoL) at baseline and after completion of follow-up.
Results
48 patients (17 males, mean age 38±10, 24-CNA group, 24-control group) entered the study. The primary endpoint occurred in 2 (8%) patients from the CNA group vs. 13 (54%) controls (p=0.0004). After CNA the mean SR at 24-hour Holter ECG was significantly faster and HRV parameters significantly changed towards parasympathetic withdrawal compared with baseline values. QoL significantly improved in the CNA group (30±10 vs 10±7 points, p=0.0001) whereas remained stable in controls (31±10 vs 30±10 points, p=0.5501).
Conclusions
This is the first randomized study documenting efficacy of CNA in patients with cardioinhibitory VVS. Larger studies are needed to confirm these findings.
... The atrial effective refractory period (AERP) was used as a surrogate for atrial autonomic tone using similar methods to prior preclinical studies. [30][31][32][33][34] Three separate pacing sites distant to PEF energy delivery were used to assess AERP, as follows: endocardial high right atrium (HRA), distal coronary sinus (CS), and left atrial appendage (LAA). A quadripolar standard curve, 8-Fr, 8-mm tip catheter (Blazer II XP; Boston Scientific Corp., Marlborough, MA, USA) was placed in the HRA position and a 7-Fr deflectable duodecapolar catheter (Orbiter ST; Boston Scientific Corp.) was inserted into the distal CS. ...
This study aimed to evaluate the safety and acute effect on markers of cardiac autonomic tone following pulsed electric fields (PEFs) delivered to epicardial ganglionated plexi (GP) during a cardiac surgical procedure. Ablation of GP as a treatment for atrial fibrillation (AF) has shown promise, but thermal ablation energy sources are limited by the risk of inadvertent collateral tissue injury. In acute canine experiments, median sternotomy was performed to facilitate the identification of 5 epicardial GP regions using an anatomy-guided approach. Each site was targeted with saline-irrigated PEF (1000 V, 100 μs, 10 electrocardiogram [ECG]-synchronized pulse sequences). Atrial effective refractory period (AERP) and local electrogram (EGM) amplitude were measured before and after each treatment. Histology was performed on samples from treatment-adjacent structures. In 5 animals, 30 (n = 2) and 60 (n = 3) pulses were successfully delivered to each of the 5 target sites. There was no difference in local atrial EGM amplitude before and after PEF application at each site (1.83 ± 0.41 vs. 1.92 ± 0.53 mV, P = .72). The mean AERP increased from 97 ± 15 ms at baseline to 115 ± 7 ms following treatment at all sites (18.6% increase; 95% confidence interval, 1.9-35.2; P = .037). There were no sustained ventricular arrhythmias or acute evidence of ischemia following delivery. Histology showed complete preservation of adjacent atrial myocardium, phrenic nerves, pericardium, and esophagus. Use of PEF to target regions rich in cardiac GP in open-chest canine experiments was feasible and effective at acutely altering markers of cardiac autonomic tone.
... Ablation of GP of the intrinsic cardiac nerves with catheter ablation methods may be effective in inhibiting AF (Lu et al., 2008). However, GP ablation may not achieve long-term suppression of AF induction in the canine model (Oh et al., 2006). Clinical evidence shows that GP ablation actually have no benefit on AF suppression in long term (Kim et al., 2021). ...
Previous studies have indicated that ganglionated plexi (GP) function influences atrial fibrillation (AF) vulnerability, and intermediate-conductance calcium-activated potassium channels (SK4) have a close relationship with cardiomyocyte automaticity and the induction of AF. However, the effects of the SK4 inhibitor on GP function and AF vulnerability are unknown. Eighteen beagles were randomly divided into a control group (n = 6), rapid atrial pacing (RAP) group (n = 6), and triarylmethane-34 (TRAM-34, an SK4 inhibitor) group (n = 6). TRAM-34 (0.3 ml, 15 mmol/L) and saline were locally injected into GPs in the TRAM-34 group dogs and dogs from the other groups, respectively. After that, dogs in the RAP and TRAM-34 groups were subjected to RAP, and the neural activity of anterior right GP (ARGP) and atrial electrophysiology were measured. The levels of inflammatory cytokines and function of macrophages in the ARGP were measured in the three groups. At 10 min after TRAM-34 injection, ARGP activity and atrial electrophysiology did not significantly change. The atrial pacing shortened effective refractory period (ERP) values at all sites and increased the AF vulnerability and ARGP neural activity, while TRAM-34 reversed these changes. The levels of CD68 + cells, induced nitric oxide synthase (iNOS), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the ARGP tissues were higher in the RAP group and TRAM-34 group than they were in the control group. Furthermore, the levels of the CD68 + cells, iNOS, and inflammatory cytokines in the ARGP tissues were higher in the pacing group than those in the TRAM-34 group. Based on these results, administration of TRAM-34 into the atrial GP can suppress GP activity and AF vulnerability during atrial pacing. The effects of TRAM-34 might be related to macrophage polarization and the inflammatory response of GP.
... Ganglionated plexi are considered a further pathway linking EAT with AF development/maintenance. Autonomic nervous system is greatly represented within EAT and GPs located within EAT are likely to exert a role in autonomic tone. 90 cholinergic activity was shown to polarize EAT secretome 92 and epicardial stromal microenvironment towards a pro-inflammatory and lipid accumulating profile. 93 Sympathovagal imbalance would then correlate with EAT thickness in paroxysmal AF and recurrence after catheter ablation, 94-96 although controversial results exist. ...
Obesity is a heterogeneous condition, characterized by different phenotypes and for which the classical assessment with body mass index may underestimate the real impact on cardiovascular (CV) disease burden. An epidemiological link between obesity and atrial fibrillation (AF) has been clearly demonstrated and becomes even more tight when ectopic (i.e. epicardial) fat deposition is considered. Due to anatomical and functional features, a tight paracrine cross-talk exists between epicardial adipose tissue (EAT) and myocardium, including the left atrium (LA). Alongside-and even without-mechanical atrial stretch, the dysfunctional EAT may determine a pro-inflammatory environment in the surrounding myocardial tissue. This evidence has provided a new intriguing pathophysiological link with AF, which in turn is no longer considered a single entity but rather the final stage of atrial remodelling. This maladaptive process would indeed include structural, electric, and autonomic derangement that ultimately leads to overt disease. Here, we update how dysfunctional EAT would orchestrate LA remodelling. Maladaptive changes sustained by dysfunctional EAT are driven by a pro-inflammatory and pro-fibrotic secretome that alters the sinoatrial microenvironment. Structural (e.g. fibro-fatty infiltration) and cellular (e.g. mitochondrial uncoupling, sarcoplasmic reticulum fragmentation, and cellular protein quantity/localization) changes then determine an electrophysiological remodelling that also involves the autonomic nervous system. Finally, we summarize how EAT dysfunction may fit with the standard guidelines for AF. Lastly, we focus on the potential benefit of weight loss and different classes of CV drugs on EAT dysfunction, LA remodelling, and ultimately AF onset and recurrence.
... Oh et al72 observed a recovery of the normal ANS function parameter within 4 months after fat pad radiofrequency ablation and AF returned to be inducible as in the pre-ablation period. In our experience of RA GP ablation,48 we observed.A complete recovery of autonomic function at 12 months in patients undergone anatomical approach and at 6 months in treated with the selective approach.However, even today, we do not know for certain if there is a temporal relationship between reinnervation and the frequency of AF recurrences73 .Finally, as previously mentioned, an extensive endocardial denervation principally targeted to eliminate parasympathetic postganglionic neural bodies placed in the atrial wall and in GP seems to reduce the risk of a significant reinnervation. ...
The autonomic nervous system (ANS) is known to play an important role in the genesis and maintenance of atrial fibrillation (AF). Biomolecular and genetic mechanisms, anatomical knowledges with recent diagnostic techniques acquisitions, both invasive and non‐invasive, have enabled greater therapeutic goals in patients affected by AF related to ANS imbalance. Catheter ablation of ganglionated plexi (GP) in the left and right atrium has been proposed in varied clinical conditions. Moreover interesting results arise from renal sympathetic denervation and vagal nerve stimulation. Despite all this, in the scenario of ANS modulation translational strategies we necessary must consider the treatment or correction of dynamic factors such as obesity, obstructive sleep apnea, lifestyle, food, and stress. Finally, new antiarrhythmic drugs, gene therapy and “ablatogenomic” could be represent exciting future therapeutic perspectives.
... Similarly, selective GP ablation has been linked to the formation of macro-re-entrant atrial tachycardias which may be associated with autonomic reinnervation [139]. Animal studies have linked reinnervation at four weeks post-GP ablation with the selectivity of the regions targeted [140,141]. Therefore, further study must be carried out to understand what may or may not cause this relapse to AF and what changes can be made to increase the denervation time induced by GP ablation, and reduce the occurrence of pro-arrhythmia. Currently sample size is a major limitation in many studies with numbers ranging from individual case studies to research including up to 306 patients [142,143]. ...
Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and is associated with significant morbidity and mortality. The autonomic nervous system (ANS) plays an important role in the initiation and development of AF, causing alterations in atrial structure and electrophysiological defects. The intrinsic ANS of the heart consists of multiple ganglionated plexi (GP), commonly nestled in epicardial fat pads. These GPs contain both parasympathetic and sympathetic afferent and efferent neuronal circuits that control the electrophysiological properties of the myocardium. Pulmonary vein isolation and other cardiac catheter ablation targets including GP ablation can disrupt the fibers connecting GPs or directly damage the GPs, mediating the benefits of the ablation procedure. Ablation of GPs has been evaluated over the past decade as an adjunctive procedure for the treatment of patients suffering from AF. The success rate of GP ablation is strongly associated with specific ablation sites, surgical techniques, localization techniques, method of access and the incorporation of additional interventions. In this review, we present the current data on the clinical utility of GP ablation and its significance in AF elimination and the restoration of normal sinus rhythm in humans.
... 14 Furthermore, ganglionated plexuses are located in EAT, altering the electrophysiological properties of atrial remote areas. 15,16 It remains unclear whether the main pathway underlying the contribution of EAT for the development of AF involves the local or remote effect. ...
Background
Epicardial adipose tissue (EAT) contributes to atrial fibrillation (AF). However, its impact on the efficacy of left atrial posterior wall isolation (LAPWI) is unclear.
Methods
Forty‐four nonparoxysmal AF patients underwent LAPWI after pulmonary vein isolation. EAT overlap on LAPWI was assessed by fusing computed tomography images with electro‐anatomical mapping.
Results
During the 21 ± 7 months of follow‐up, AF recurred in 10 patients (23%). The total and left atrial EAT volumes were 113 ± 36 and 33 ± 12 cm³, respectively. No differences were found between the AF‐free and AF‐recurrent groups regarding EAT volume. The EAT overlaps on LAPWI lines and LAPWI area were 1.2 ± 1.0 and 0.5 ± 0.9 cm² respectively. Although no difference was found between groups regarding the EAT overlap on LAPWI area, the AF‐free group had a significantly larger EAT overlap on LAPWI lines (1.4 ± 1.0 vs 0.6 ± 0.6 cm², P = .014). Multivariate analysis identified EAT overlap on LAPWI lines as an independent predictor of AF recurrence (hazard ratio: 0.399, 95% confidence interval: 0.178‐0.891, P = .025). Kaplan‐Meier analysis revealed that, during follow‐up, 92% of the large EAT overlap group (≥1.0 cm²) and 58% of the small EAT overlap group (<1.0 cm²) remained AF‐free (P = .008).
Conclusions
EAT overlap on LAPWI lines is related to a high AF freedom rate. Direct radiofrequency application to EAT overlap may be necessary to suppress AF.
... Since the autonomic nervous system crucially regulates heart rhythm and ganglionated plexi are located in EAT [50,51], activation of these ganglionated plexi can cause both parasympathetic and sympathetic stimulation, resulting in shortened action potentials and increased calcium transients, respectively ( Fig. 12.2) [42]. Thus, several clinical studies have investigated the role that neuromodulation may have in controlling AF, particularly by ablation of ganglionated plexi of the intrinsic cardiac nervous system. ...
The epicardial adipose tissue (EAT) or epicardial fat, the visceral fat depot in the heart, contains intrinsic adrenergic and cholinergic nerves, which interact with the extrinsic cardiac sympathetic and parasympathetic nervous systems. These EAT nerves represent a significant source of several adipokines and other bioactive molecules, including norepinephrine and epinephrine. The production of these molecules is biologically relevant for the heart, because abnormalities in EAT secretory properties are implicated in the development of pathological conditions, including coronary atherosclerosis, atrial fibrillation, and heart failure. Because sympathetic hyperactivity and parasympathetic (cholinergic) derangement are associated with EAT dysfunction leading to a multitude of adverse cardiac conditions, such as heart failure, diastolic dysfunction, atrial fibrillation, etc., a number of recent studies have focused on exploring the autonomic regulation of EAT as it pertains to heart disease pathogenesis and progression. In this chapter, we provide an overview of these studies, immediately following brief introductions on the regulation of global cardiac function by the two branches of the autonomic nervous system (adrenergic and cholinergic).
... КЛИНИЧЕСКИЕ НАБЛЮДЕНИЯ § В медицинской периодике все чаще встречаются публикации, рассматривающие дисбаланс вегетативной нервной системы (ВНС) в качестве одного из ведущих механизмов развития фибрилляции предсердий (ФП) [1][2][3][4][5]. Нарушение тонуса симпатического и парасимпатического отделов ВНС на уровне её центральных структур, вероятно, имеет пусковое значение в активизации патологической высокочастотной электрической импульсации из аритмогенных зон, локализующихся в области коллекторов легочных вен (ЛВ) и в свободной стенке левого предсердия (ЛП) [6][7][8][9]. ЛП и ЛВ близко прилегают к зонам концентрации интрамуральных ганглионарных сплетений, а постганглионарные нервные окончания последних фактически встраиваются в эти анатомические образования (рис. 1, адаптировано по [10,11]). Тем не менее вопрос о влиянии нейромодуляции на аритмогенез до конца не изучен [12][13][14]. ...
This article describes for the first time in the domestic literature a clinical case of the therapeutic effect of neuromodulation on the permanent form of atrial fibrillation and chronic heart failure in an elderly patient with spinal stenosis which led to the development of pain syndrome and movement disorders. For the treatment of neurological pathology, at the beginning epidural administration of drugs was applied, followed by spinal cord stimulation trial and implantation of permanent neurostimulator. At each stage of treatment conducted by a functional neurosurgeon the patient had a spontaneous restoration of sinus rhythm, and during continuous neurostimulation a stable retention of sinus rhythm and regression of heart failure symptoms have been observed throughout a long observation period. The article also presents the data of a few experimental and clinical studies on the use of neuromodulation in cardiology, describes the method of implantation of spinal electrodes and analyzes possible mechanisms of modulation of the autonomic innervation of the heart, implemented by spinal cord stimulation.
... Such a time course of HRV recovery following ablation of atrial neural targets or GPs agrees with reports from other groups, in which persistence of antiarrhythmic protection also occurred beyond recovery of autonomic chronotropic function [1,2]. In studies conducted in normal canines, the effects of right or bilateral vagus nerve stimulation on sinus cycle length, refractory periods, and vulnerability to AF were abolished immediately after right-sided [20] or bilateral [21] atrial GP ablation; however, such indices showed recovery after 4 weeks, leading the authors to conclude that functional reinnervation had occurred. ...
Outstanding issues concerning the ablative treatment of paroxysmal atrial fibrillation include the identification of target neural tissues, and the perennity of antiarrhythmic protection in relation to possible reinnervation of atrial tissues. This chapter discusses experimental and clinical data to suggest that the extra protective effect against arrhythmia recurrence provided by neuroablation requires spatially extensive interventions on several ganglionated plexuses (GPs), as afforded by an extensive anatomical approach. Anatomical approaches for GP ablation in the clinic are supported by anatomical findings in animal studies, notably the ones derived from the canine heart in situ and corroborated in the human heart. Physiological studies have also played a major role in the identification of neurally active intrinsic cardiac and juxtacardiac loci. The authors concluded that right‐sided GPs as well as central and juxtacardiac mediastinal nerve connections may be involved in generating “vagal” responses to high‐frequency electrical stimulation applied to left‐sided neural elements.
... Ganglionic plexi ablation remains controversial because the additional benefits compared with lone SMI-PVI have never been investigated in a randomized clinical trial. 22 Nonetheless, the combination of techniques has shown good clinical results. 23 Our study shows that, when both AADs and additional transcatheter PVI are considered, 91% of our population is free from atrial arrhythmia. ...
... 55 A canine study using RF ablation reported that AF inducibility was eliminated immediately after GP ablation, but this denervation effect was reversed within 4 weeks after the ablation. 56 Our laboratory has recently confirmed that after surgical ganglion ablation, there is evidence of reinnervation at 4 weeks. 57 More recently, Katritsis et al 58 used left atrial GP ablation to treat 19 patients with symptomatic paroxysmal AF of which 14 (74%) experienced AF recurrence during the 1-year follow-up period. ...
... Autonomic dysfunction may also contribute, as the autonomic nervous system is thought, to play a crucial role in the initiation and maintenance of AF [39]. Ganglionated plexi are located in the epicardial fat and their dysfunction could lead to AF development as well [40]. ...
Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD) are commonly interconnected, and this coincidence negatively influences patients’ mortality and morbidity. On the basis of the current available data originating mainly from cardiovascular studies epicardial fat (EF) has been proposed as a marker of cardiovascular risk. This review is focused on a potential role of epicardial fat as a new biomarker for risk stratification of COPD patients. Epicardial fat may present an important link between chronic obstructive pulmonary disease and cardiovascular diseases, mainly coronary artery disease.
... On the contrary, GP ablation was associated with significantly more sinus node dysfunction, pacemaker implantations, and periprocedural bleeding. Despite this, it is unknown whether GP ablation exerts intermediate effects that may relate to the reinnervation of the atrium or the absence thereof (14,15). Therefore, we report the 2- ...
Objectives:
The authors report the 2-year follow-up results of the AFACT (Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery) study.
Background:
The AFACT study randomized patients with advanced atrial fibrillation (AF) to thoracoscopic AF ablation with or without additional ganglion plexus (GP) ablation. At 1 year, there was no difference in AF freedom between the groups, but autonomic modification may exert beneficial effects during longer follow-up.
Methods:
Patients underwent thoracoscopic pulmonary vein isolation, with additional left atrial lines in persistent AF patients, and were randomized 1:1 to ablation of the 4 major GP and Marshall ligament or no GP ablation (control). Patients were followed every 3 months up to 18 months and at 24 months. After an initial 3-month blanking period, all antiarrhythmic drugs were discontinued.
Results:
The authors randomized 240 patients (age 59 ± 8 years, 73% men, 68% enlarged left atrium, 60% persistent AF), of whom 228 patients (95%) completed follow-up. Freedom of any atrial tachyarrhythmia did not differ significantly between the GP group (55.6%) and control group (56.1%) (p = 0.91), with no difference in paroxysmal (p = 0.60) or persistent AF patients (p = 0.88). Documented AF recurrences were similar between treatment arms: 11.8% (GP) versus 11.0% (control) had >3 recurrences/year (p = 0.82). More persistent AF patients (17.0%) than paroxysmal (3.2%) had >3 recurrences per year (p < 0.01). Despite this, 78% of patients were off antiarrhythmic drugs after 2 years. No procedural-related complications occurred in the second year.
Conclusions:
Additional GP ablation during thoracoscopic surgery for advanced AF does not affect freedom of AF recurrence. As GP ablation is associated with more major procedural complications, it should not routinely be performed. (Atrial Fibrillation Ablation and Autonomic Modulation via Thorascopic Surgery [AFACT]; NCT01091389).
... 6,7 Additionally, the long-term efficacy of GP ablation remains controversial. [8][9][10] Neuromodulation is a potentially effective way at reducing afferent, efferent, or local circuit neuronal activity and might also affect remodeling in intrathoracic extracardiac ganglia. 11 Yuan et al. 4 and Pauza et al. 12 performed elegant neuroanatomical analysis showing the neuronal distribution in the myocardium and several physiologic studies have suggested the existence of systematic interconnections among GPs. ...
Background
Although ganglionated plexi (GPs) are important in the pathogenesis of arrhythmia, their patterns of atrial innervation have remained unclear. We investigated patterns of GP innervation to cardiac atria and the neuroanatomical interconnections among GPs in an animal model.
Methods
Atrial innervation by GPs was evaluated in 10 mongrel dogs using a retrograde neuronal tracer (cholera toxin subunit B [CTB] conjugated with fluorescent dyes). In Experiment 1, CTB was injected into the atria. In Experiment 2, CTB was injected into the major GP, including the anterior right GP (ARGP), inferior right GP (IRGP), superior left GP (SLGP), and ligament of Marshall (LOM). After 7 days, the GPs were examined for the presence of tracer-positive neurons.
Results
GPs in either right or left-side were innervating to both the same and opposite sides of the atrium. In quantitative analysis, right-sided GPs, especially ARGP, showed numerical predominance in atrial innervation. Based on the proportion of CTB-labeled ganglion in each GP, atrial innervation by GPs showed a tendency of laterality. In Experiment 2, CTB that was injected to a particular GP widely distributed in different GP. ARGP projected the largest number of innervating neurons to the IRGP, SLGP and LOM.
Conclusion
This study demonstrated that GPs project axons widely to both the same and opposite sides of atria. ARGP played a dominant role in atrial innervation. Furthermore, there were numerous neuroanatomical interconnections among GPs. These findings about neuronal innervation and interconnections of GPs could offer useful information for understanding intrinsic cardiac nervous system neuroanatomy.
... On the contrary, GP ablation was associated with significantly more sinus node dysfunction, pacemaker implantations, and periprocedural bleeding. Despite this, it is unknown whether GP ablation exerts intermediate effects that may relate to the reinnervation of the atrium or the absence thereof (14,15). Therefore, we report the 2- ...
... As GPs control anatomically overlapping cardiac Please cite this article in press as: Scridon regions, and cardiac neurons are in constant communication with one another, as well as with more central neurons, it is not surprising that ablation of one or a few GPs does not provide long-lasting effects. It is likely that the complex neural architecture is designed to ensure recovery of function when one of its components becomes damaged [72]. Alternatively, the use of botulinum toxin to interfere with cholinergic neurotransmission may arise as a new strategy for atrial antiarrhythmic neuromodulation [73,74]. ...
A 55-year-old hypertensive patient presents atrial fibrillation after vasovagal syncope. Non-invasive cardiac workup is normal. Without antiarrhythmic therapy, the patient has no recurrence for the next 3years, then presents with a stroke. Echocardiography eventually reveals left atrial dilation. This sequence of events illustrates the well-known links between age, arterial hypertension, atrial fibrillation, atrial neuromyopathy and stroke. A frequently neglected common denominator in this equation is impaired sympathovagal balance. Contrary to what is often stated, autonomic imbalance is not a simple modulation factor of atrial fibrillation; both the trigger and the substrate of atrial fibrillation can be influenced by abnormal cardiac innervation. Here, we review the neurogenic theory of atrial fibrillation, based on literature and original data. We also provide evidence that this concept may help to improve atrial fibrillation prediction, early diagnosis and therapy.
... The long-term influence of GP ablation on the electrophysiology of the AVN is not known. However, the incomplete GP ablation can increase the vulnerability of the atria to atrial fibrillation and denervation is likely transient (4,5). In addition, GP ablation that led to parasympathetic denervation of the AVN could play a role in the high ventricular rate response of atrial tachycardia after atrial fibrillation ablation. ...
... The long-term influence of GP ablation on the electrophysiology of the AVN is not known. However, the incomplete GP ablation can increase the vulnerability of the atria to atrial fibrillation and denervation is likely transient (4,5). In addition, GP ablation that led to parasympathetic denervation of the AVN could play a role in the high ventricular rate response of atrial tachycardia after atrial fibrillation ablation. ...
... Because of multiple feedback circles complex behavior is already existent on this level. Typical for a complex system, its behavior is robust even when some subpopulations are compromised (32,33). ...
Heart-rate variability (HRV) is frequently introduced as mirroring imbalances within the autonomous nerve system. Many investigations are based on the paradigm that increased sympathetic tone is associated with decreased parasympathetic tone and vice versa. But HRV is probably more than an indicator for probable disturbances in the autonomous system. Some perturbations trigger not reciprocal, but parallel changes of vagal and sympathetic nerve activity. HRV has also been considered as a surrogate parameter of the complex interaction between brain and cardiovascular system. Systems biology is an inter-disciplinary field of study focusing on complex interactions within biological systems like the cardiovascular system, with the help of computational models and time series analysis, beyond others. Time series are considered surrogates of the particular system, reflecting robustness or fragility. Increased variability is usually seen as associated with a good health condition, whereas lowered variability might signify pathological changes. This might explain why lower HRV parameters were related to decreased life expectancy in several studies. Newer integrating theories have been proposed. According to them, HRV reflects as much the state of the heart as the state of the brain. The polyvagal theory suggests that the physiological state dictates the range of behavior and psychological experience. Stressful events perpetuate the rhythms of autonomic states, and subsequently, behaviors. Reduced variability will according to this theory not only be a surrogate but represent a fundamental homeostasis mechanism in a pathological state. The neurovisceral integration model proposes that cardiac vagal tone, described in HRV beyond others as HF-index, can mirror the functional balance of the neural networks implicated in emotion–cognition interactions. Both recent models represent a more holistic approach to understanding the significance of HRV.
... However, newer experimental studies bring clear evidence regarding re-innervation also following radiofrequency parasympathetic denervation (vagal denervation). Tests were also performed on canine hearts, the samples were monitored for the period of four weeks following ablation on average [52,53]. Similar results of neural function restitution have also been presented regarding experimental demonstration of administration of cryoenergy on the neural tissue. ...
Background:
The aim of our study was to investigate, whether enhancement of left atrial cryoablation by ablation of the autonomic nervous system of left atrium leads to influencing the outcomes of surgical treatment of atrial fibrillation in patients with structural heart disease undergoing open-heart surgery.
Methods:
The observed patient file consisted of 100 patients, who have undergone a combined open-heart surgery at our department between July 2012 and December 2014. The patients were indicated for the surgical procedure due to structural heart disease, and suffered from paroxysmal, persistent, or long-standing persistent atrial fibrillation. In all cases, left atrial cryoablation was performed in the extent of isolation of pulmonary veins, box lesion, connecting lesion with mitral annulus, amputation of the left atrial appendage and connecting lesion of the appendage base with left pulmonary veins. Furthermore, 35 of the patients underwent mapping and radiofrequency ablation of ganglionated plexi, together with discision and ablation of the ligament of Marshall (Group GP). A control group was consisted of 65 patients without ganglionated plexi intervention (Group LA). The main primary outcome was establishment and duration of sinus rhythm in the course of one-year follow-up.
Results:
Evaluation of the number of patients with a normal sinus rhythm in per cent has shown comparable values in both groups (Group GP - 93.75%, Group LA - 86.67%, p = 0.485); comparable results were also observed in patients with normal sinus rhythm without anti-arrhythmic treatment in the 12th month (Group GP - 50%, Group LA - 47%, p = 0.306). We have not observed any relation between the recurrence of atrial fibrillation and the presence of a mitral valve surgery, or between the presence of a mitral and tricuspid valves surgery and between the left atrial diameter > 50 mm.
Conclusions:
Enhancement of left atrial cryoablation by gangionated plexi ablation did not influence the outcomes of surgical ablation due to atrial fibrillation in our population in the course of 12-month follow-up.
Trial registration:
The study was approved retrospectively by the Ethics Committee of the University Hospital Ostrava ( reference number 867/2016).
... 4 The second-generation CB enables a more efficient ablation of paroxysmal AF and results in shorter procedures. 5 The human ganglionated plexi (GP), which are located in the left atrio-pulmonary junction as a part of the intrinsic cardiac autonomic nervous system (ANS), play a crucial role in the initiation and maintenance of AF. 6,7 An additional GP ablation has been reported to lead to an increased procedural success rate of the PV isolation. 8 Modification of the GP using radiofrequency ablation causes a change in the heart rate variability (HRV) and can also be achieved after CB ablation. ...
Aims
Vagal responses such as marked bradycardia or a rapid blood pressure decrease are often observed during pulmonary vein (PV) isolation of atrial fibrillation (AF) using a cryoballoon (CB). However, the relationship between the marked vagal response and change in the heart rate variability (HRV) as a marker of the autonomic tone is not well understood.
Methods and results
Fifty-four paroxysmal AF patients underwent CB ablation. The CB ablation was started from the right sided PVs in 25 patients (R group) and left sided PVs in 29 (L group). The HRV and haemodynamic status during the procedure were analysed. A vagal response was observed in 16 L group patients (61.5%) during the ablation of the different PVs (RSPV:1, RIPV:5, LSPV:15, LIPV:5), while it was observed in only 2 R group patients (9.5%) (RSPV:0, RIPV:0, LSPV:1, LIPV:1) (P = 0.0002). The HRV in the L group was significantly higher than that in the R group just after the CB ablation especially for the left sided PVs (L group vs. R group, total power of the HRV, median; RSPV, 11184.7 vs. 4360.0, P = 0.21; RIPV, 9044.3 vs. 2115.1, P = 0.01; LSPV, 21186.0 vs. 1314.2, P = 0.0002; LIPV 10265.9 vs. 1236.2, P = 0.0007).
Conclusion
A marked increase in the HRV parameters was observed just after the CB ablation. An initial CB ablation of the right PVs decreased the change in the autonomic tone during the right PV ablation and subsequent left PV ablation. It prevented an excessive vagal response during the CB ablation and might be a safe procedure.
... Such interconnectivity implies that predicting the effect of stimulation or ablation of a particular ganglion may be difficult, because each ganglion performs multiple functions. 7,9 Abstract Alterations in resting autonomic tone can be pathogenic in many cardiovascular disease states, such as heart failure and hypertension. ...
Alterations in resting autonomic tone can be pathogenic in many cardiovascular disease states, such as heart failure and hypertension. Indeed, autonomic modulation by way of beta-blockade is a standard treatment of these conditions. There is a significant interest in developing non-pharmacological methods of autonomic modulation as well. For instance, clinical trials of vagal stimulation and spinal cord stimulation in the treatment of heart failure are currently underway, and renal denervation has been studied recently in the treatment of resistant hypertension. Notably, autonomic stimulation is also a potent modulator of cardiac electrophysiology. Manipulating the autonomic nervous system in studies designed to treat heart failure and hypertension have revealed that autonomic modulation may have a role in the treatment of common atrial and ventricular arrhythmias as well. Experimental data on vagal nerve and spinal cord stimulation suggest that each technique may reduce ventricular arrhythmias. Similarly, renal denervation may play a role in the treatment of atrial fibrillation, as well as in controlling refractory ventricular arrhythmias. In this review, we present the current experimental and clinical data on the effect of these therapeutic modalities on cardiac electrophysiology and their potential role in arrhythmia management.
The process of decision-making is quite complex involving different aspects of logic, emotion, and intuition. The process of decision-making can be summarized as choosing the best alternative among a given plethora of options in order to achieve the desired outcome. This requires establishing numerous neural networks between various factors associated with the decision and creation of possible combinations and speculating their possible outcomes. In a nutshell, it is a highly coordinated process consuming the majority of the brain’s energy. It has been found that the heart comprises an intrinsic neural system that contributes not only to the decision-making process but also the short-term and long-term memory. There are approximately 40,000 cells present in the heart known as sensory neurites which play a vital role in memory transfer. The heart is quite a mysterious organ, which functions as a blood-pumping machine and an endocrine gland, as well as possesses a nervous system. There are multiple factors that affect this heart ecosystem, and they directly affect our decision-making capabilities. These interlinked relationships hint toward the sensory neurites which modulate cognition and mood regulation. This review article aims to provide deeper insights into the various roles played by sensory neurites in decision-making and other cognitive functions. The article highlights the pivotal role of sensory neurites in the numerous brain functions, and it also meticulously discusses the mechanisms through which they modulate their effects.
Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia among humans, with its incidence increasing significantly with age. Despite the high frequency of AF in clinical practice, its etiology and management remain elusive. To develop effective treatment strategies, it is imperative to comprehend the underlying mechanisms of AF; therefore, the establishment of animal models of AF is vital to explore its pathogenesis. While spontaneous AF is rare in most animal species, several large animal models, particularly those of pigs, dogs, and horses, have proven as invaluable in recent years in advancing our knowledge of AF pathogenesis and developing novel therapeutic options. This review aims to provide a comprehensive discussion of various animal models of AF, with an emphasis on the unique features of each model and its utility in AF research and treatment. The data summarized in this review provide valuable insights into the mechanisms of AF and can be used to evaluate the efficacy and safety of novel therapeutic interventions.
Background and Objective
Atrial fibrillation (AF) could be induced by different intensity of atrial pacing, however the detail information during these processes have not been fully explored. The aim of this study was to evaluate the effects of different intensity of atrial pacing on atrial electrophysiology.
Methods
Twenty-four dogs were randomly subjected to 16 hours atrial pacing at 500 beats/min (bpm) or 1000 bpm as follows: no stimulation (control, n = 8), 500 bpm stimulation (500 bpm, n = 8) and 1000 bpm stimulation (1000 bpm, n = 8). Programmed and burst atrial pacing were performed at baseline and at the end of every 2 hour to determine AF inducibility, sustained time of AF and atrial effective refractory period (ERP). Moreover, the electrical activities of vagus nerve including discharge frequency, signal area were also recorded. In addition, serum acetylcholine (Ach) was determined by ELISA to explore the relationship with AF and vagus nerve features.
Results
Increased AF inducibility, sustained time of AF and ERP were found in dogs from 1000 bpm group compared to 500 bpm group. Moreover, increased discharge frequency and signal area of vagus nerve were also found in dogs from 1000 bpm group compared to 500 bpm group. Correlation was found between the serum Ach and AF.
Conclusions
Our results demonstrated that different intensity of atrial pacing exerted different effects on atrial electrophysiology and nerve remodeling, while high-frequency electrical stimulation are more prone to autonomic nervous activity induction.
Since its original description in 2005, catheter ablation techniques, commonly called cardioneuroablation, have emerged as a potential strategy for modulating autonomic function. Multiple investigators have provided observational data on the potential benefits of this technique in a variety of conditions associated with or exacerbated by increased vagal tone such as vasovagal syncope, functional atrioventricular block, and sinus node dysfunction. Patient selection, current techniques including the various mapping strategies, clinical experience, and limitations of cardioablation are reviewed. Finally, while cardioneuroablation has potential to be a treatment option for selected patients with symptoms mediated by hypervagotonia, the document outlines the important knowledge gaps that currently exist and the necessary next steps required before this technique can be widely implemented into clinical practice.
Neurocardiogenic syncope is the most common cause of transient loss of consciousness and considerably reduces quality of life. Pharmacological and pacing therapy may not be fully efficacious and complications related to implanted hardware must be considered. In this context, cardioneuroablation (CNA) has been proposed to attenuate the vagal reflex with elimination of cardioinhibition. It has been shown that CNA is able to eliminate recurrences of syncope in over 90% of cases and no major complications are reported in the current literature. Despite these encouraging findings, CNA is only mentioned in current guidelines as a possible alternative treatment and has no real indication class. The diversity of mapping techniques, the absence of direct denervation control, the lack of a precise endpoint, the possible placebo effect, the short follow-up, and the question of the learning curve represent the major limitations of this promising procedure. The aim of this review is to look over the existing literature, analysing the novelties, the limitations, the unresolved issues and the outcome of CNA.
В статье освещена история развития мини-инвазивной эпикардиальной абляции при изолированной форме фибрилляции предсердий. Неоптимальные результаты использования антиаритмических препаратов и антикоагулянтов, невысокая эффективность катетерной абляции при непароксизмальных формах фибрилляции предсердий, травматичность операции Maze на открытом сердце с применением искусственного кровообращения привели к развитию торакоскопической эпикардиальной абляции. Первоначально основанная на изоляции только легочных вен эпикардиальная абляция со временем перешла в формат фрагментации левого предсердия, максимально повторяя операцию Maze. Эффективность торакоскопической эпикардиальной абляции значимо превосходит таковую при катетерной эндокардиальной абляции при непароксизмальных формах фибрилляции предсердий. Появление новых хирургических методов лечения фибрилляции предсердий создало основу для мультидисциплинарного подхода в лечении этой сложной аритмии и способствовало развитию гибридных технологий.
In the article, there is described the history of the development of minimally invasive epicardial ablation in isolated atrial fibrillation. Non-optimal results of the use of antiarrhythmic drugs and anticoagulants, low efficiency of catheter ablation in non-paroxysmal forms of atrial fibrillation, invasiveness of Maze open heart surgery using heart bypass resulted in the development of thoracoscopic epicardial ablation. Epicardial ablation, which was based initially only on isolation of the pulmonary veins, eventually developed into the left atrial fragmentation format, copying the Maze operation as much as possible. The effectiveness of thoracoscopic epicardial ablation significantly exceeds that of catheter endocardial ablation with non-paroxysmal forms of atrial fibrillation. The use of new surgical methods of treatment of atrial fibrillation created the base for multidisciplinary approach in the treatment of this complex arrhythmia and promoted the development of hybrid technologies.
Atrial substrate modification is required for a successful outcome in a minority of patients with paroxysmal atrial fibrillation (AF), and in most patients with persistent AF. Substrate modification is considered when AF persists despite effective elimination of pulmonary vein (PV) arrhythmogenicity by extraostial PV isolation (PVI), antral PVI, or wide area circumferential ablation. Substrate modification strategies are linear ablation, ablation guided by complex fractionated atrial electrograms, and ablation of ganglionic plexi. Termination of AF to sinus rhythm or to an atrial tachycardia is considered the most favorable procedural end point for substrate modification. Complete bidirectional conduction block should be confirmed when linear ablation is performed.
Objective
Circumferential pulmonary vein isolation (CPVI) is a common procedure that is performed on patients with atrial fibrillation (AF). However, AF may recur in some patients after treatment. This study assesses the association between autonomic modulation and late recurrence after CPVI and between autonomic modulation and ablation lesion quality.
Methods
We prospectively enrolled 72 patients with paroxysmal AF who underwent CPVI from January 2017 to January 2018. Pre- and post-ablation 24 h electrocardiograms were performed to document heart rate variability (HRV), which represents cardiac autonomic function. The intraablation force-time integral (FTI) was used to indicate the extent of ablation injury. Patients were followed up for 12 months after the procedure and cases of AF recurrence were recorded.
Results
Changes in HRV decreased after the procedure, which was correlated with FTI (ΔSDNN: r = −0.26, P = 0.03; ΔrMMSD: r = −0.28, P = 0.02; ΔlnHF: r = −0.22, P = 0.04; ΔLnLF: r = −0.29, P = 0.01). Patients without AF recurrence had more pronounced ΔLF (−21.84 ± 33.21% vs. −8.68 ± 34.59%, P = 0.01) and ΔHF (−17.26 ± 16.61% vs. −1.28 ± 9.81%, P = 0.01) than patients with recurrence. Multivariate regression analysis showed that both ΔLF (HR: 1.07, P = 0.04) and ΔHF (HR: 1.11, P = 0.01) were associated with AF recurrence. After adjusting for FTI, ΔLF was no longer associated with AF recurrence (HR: 1.05, P = 0.10). ΔHF remained associated with AF recurrence (HR: 1.08, P = 0.03), but the correlation coefficient was decreased (HR: 1.08, P = 0.03).
Conclusion
Decreased autonomic nerve function is a valid predictor of AF recurrence and is indicated by the extent of ablation injury, which is independently associated with AF recurrence after CPVI.
Background
Endocardial radiofrequency ablation of epicardial 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 ganglionic plexus (GP) without collateral myocardial injury.
Methods
Acute studies and medium‐term terminal studies (mean survival, 1137 days) were performed with 7 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 4‐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 6 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 1 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.
This article is protected by copyright. All rights reserved.
Long-standing persistent atrial fibrillation (L-PeAF) is a category in which rhythm control is attempted while atrial fibrillation (AF) is maintained for more than 1 year. Because AF is a progressive disease and L-PeAF accompanies significant electrical and structural remodeling of atria, it is difficult to restore and maintain sinus rhythm in patients with L-PeAF. Nonetheless, the rhythm outcome is being increasingly improved by the development of sophisticated mapping devices, highly efficient catheters, and evidence-based ablation strategies, and the rational choice of patient selection criteria. This review discusses the evolution of the rhythm control outcome of L-PeAF and its future direction of development.
Atrial fibrillation (AF) is the most challenging rhythm disturbance worldwide. Arrhythmia and its behavior represent complex pathogenesis highly opposing to contemporary curative modalities. Increasing age of patients carries a certain level of risk for AF. Some underlying diseases in concordance with aging actually accelerate the occurrence of AF. Underestimated superimposed risk factors - aging plus any known risk factor or condition (hypertension, diabetes etc.) - elicit great interest and concern. In light of these concerns we offer an elaborated universal hypothesis in attempt to elucidate the genuine origin of AF substrate. Putative chronic toxicity - toxins and/or involution related pseudo-toxins potentially generate micro- and macro-structural changes in atrial myocardium thus inciting both intracellular damage (degeneration of myocites, apoptosis) and extracellular fibrotic proliferation (interstitial fibrosis, formation of matrices, degeneration of cells with fibrotic replacement). The co-products of related underlying diseases in cooperation with cellular senescence, endogenous overproduction of specific lipids/lipoproteins and other pro-atherosclerotic and/or inflammatory components generate a total atrial response - vascular/microvascular damage, intracellular and extracellular injuries. These organizational arrangements covering the entire atrial myocardium and perhaps ganglionated plexi/autonomic branches of the nervous system eventually cause clinical havoc - atrial overstretch, atrial adaptation/maladaptation, electromechanical dysfunction, arrhythmias, heart failure, etc. In essence, valvular heart disease potentially evokes similar changes "violating" thin atrial walls to obey the same scenario. Depicted atriomyodegenerative processes most likely represent the true nature of AF substrate development. Available clinical and morphological evidence potentially designates the atriomyodegenerative or plausible neuro-atriomyodegenerative origin of AF. Deductively fusion of reasons rather than purely heterogeneity is responsible for AF induction. Thus, the uniform approach and synoptic vision of clinical and pathohistological entity may offer an alternative or refreshed viewpoint in AF substrate formation.
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. This article is protected by copyright. All rights reserved
The autonomic nervous system (ANS) is complex and plays an important role in cardiac arrhythmia pathogenesis. A deeper understanding of the anatomy and development of the ANS has shed light on its involvement in cardiac arrhythmias. Alterations in levels of Sema-3a and NGF, both growth factors involved in innervation patterning during development of the ANS, leads to cardiac arrhythmias. Dysregulation of the ANS, including polymorphisms in genes involved in ANS development, have been implicated in sudden infant death syndrome. Disruptions in the sympathetic and/or parasympathetic systems of the ANS can lead to cardiac arrhythmias and can vary depending on the type of arrhythmia. Simultaneous stimulation of both the sympathetic and parasympathetic systems is thought to lead to atrial fibrillation whereas increased sympathetic stimulation is thought to lead to ventricular fibrillation or ventricular tachycardia. In inherited arrhythmia syndromes, such as Long QT and Catecholaminergic Polymorphic Ventricular Tachycardia, sympathetic system stimulation is thought to lead to ventricular tachycardia, subsequent arrhythmias, and in severe cases, cardiac death. On the other hand, arrhythmic events in Brugada Syndrome have been associated with periods of high parasympathetic tone. Increasing evidence suggests that modulation of the ANS as a therapeutic strategy in the treatment of cardiac arrhythmias is safe and effective. Further studies investigating the involvement of the ANS in arrhythmia pathogenesis and its modulation for the treatment of cardiac arrhythmias is warranted.
Background:
Skin sympathetic nerve activity (SKNA) is useful in estimating sympathetic tone in humans OBJECTIVE: To test the hypothesis that (1) increased SKNA is associated with the onset and termination of paroxysmal atrial tachycardia (AT) and AF and (2) The sinoatrial node (SAN) response to SKNA is reduced in patients with more frequent of AT or AF.
Methods:
SKNA and electrocardiogram were recorded in 11 patients (4 males and 7 females, average age 66?10 years), including 3 patients with AT (11?18 episodes/patient) and 8 patients with AF (24?26 episodes/patient).
Results:
The average SKNA (aSKNA, in ?V) 10 s prior to AT onset were 1.07?0.10; 10 s after termination were 1.27?0.10, both were significantly (p=0.032, p<0.0001) higher than that during sinus rhythm (0.97?0.09). The aSKNA 10 s prior to AF onset were 1.34?0.07 and 10 s after termination were 1.31?0.07. Both were significantly (p<0.0001) higher than that during sinus rhythm (1.04?0.07). The aSKNA before onset (p<0.0001) and after termination (p= 0.0011) were both higher in AF than in AT. The sinus rate correlated (p<0.0001) with aSKNA in each patient (average r: 0.74, 95% confidence interval (CI): 0.65-0.84). The r in each patient negatively correlated with the number of AT and AF episodes (r= - 0.6493, 95% confidence interval:-0.8990 to -0.08073, p=0.0306).
Conclusions:
Increased SKNA was observed both at onset and termination of AT and AF. The patients with more frequent AT and AF episodes had less of a correlation between sinus rate and aSKNA, suggesting SAN remodeling by tachycardia.
Introduction:
Radiofrequency isolation of pulmonary vein can be accompanied by transient sinus bradycardia or atrioventricular nodal (AVN) block, suggesting an influence on vagal cardiac innervation. However, the importance of the atrial fat pads in relation with the vagal innervation of AVN in humans remains largely unknown. This article is protected by copyright. All rights reserved The aim of this study was to evaluate the role of ganglionated plexi (GP) in the innervation of the AVN by the right vagus nerve.
Methods and results:
Direct epicardial high frequency stimulation (HFS) of the GP (20 patients) and the right vagus nerve (10 patients) was performed before and after fat pad exclusion or destruction in 20 patients undergoing thoracoscopic epicardial ablation for the treatment of persistent AF. Asystole longer than 3s or acute R-R prolongation over 25% was considered as a positive response to HFS. Prior to the ablation, positive responses to HFS were detected in three GPs in 7 patients (35%), two GP in 5 patients (25%), and one GP in 8 patients (40 %). After exclusion of the fat pads, all patients had a negative response to HFS. All the patients who exhibited a positive response to right vagus nerve stimulation (n = 10) demonstrated negative responses after the ablation.
Conclusion:
The integrity of the GP is essential for the right vagus nerve to exert physiological effects of on AVN in humans.
Atrial fibrillation (AF) is the most common sustained arrhythmia disturbance and is associated with significant morbidity and mortality. In recent years, the pulmonary veins (PVs) and posterior left atrium (PLA) have been shown to play a significant role in the genesis of AF.
Positron emission tomography in combination with the newly introduced catecholamine analogue [11C]hydroxyephedrine ([11C]HED) enables the noninvasive delineation of sympathetic nerve terminals of the heart. To address the ongoing controversy over possible reinnervation of the human transplant, 5 healthy control subjects and 11 patients were studied after cardiac transplant by this imaging approach. Regional [11C]HED retention was compared to regional blood flow as assessed by rubidium-82. Transplant patients were divided into two groups. Group I had recent (less than 1 yr, 4.4 +/- 2.3 mo) surgery, while group II patients underwent cardiac transplantation more than 2 yr before imaging (3.5 +/- 1.3 yr). [11C]HED retention paralleled blood flow in normals, but was homogeneously reduced in group I. In contrast, group II patients revealed heterogeneous [11C]HED retention, with increased uptake in the proximal anterior and septal wall. Quantitative evaluation of [11C]HED retention revealed a 70% reduction in group I and 59% reduction in group II patients (P less than 0.001). In group II patients, [11C]HED retention reached 60% of normal in the proximal anterior wall. These data suggest the presence of neuronal tissue in the transplanted human heart, which may reflect regional sympathetic reinnervation.
The presence of cardiac reinnervation in humans after cardiac transplantation has been widely debated, based on the application of differing methods for the assessment of neuronal function. Some of these techniques have been rather indirect; consequently, the time course and extent of cardiac reinnervation remains uncertain.
To test for the presence of cardiac reinnervation after transplantation, we examined neurochemical (radiolabeled norepinephrine [NE] kinetics) and functional markers (power spectral analysis, heart rate response to exercise) of cardiac sympathetic nerve integrity in 15 cardiac transplantation recipients and 25 healthy control subjects of similar age. Cardiac transplantation subjects were studied 9 weeks to 8 years after cardiac transplantation (10 "early" patients < 18 months and 5 "late" patients > 2 years after cardiac transplantation). At rest, cardiac NE spillover was markedly attenuated early after transplantation (11.2 +/- 18.3 pmol/min) compared with subjects late after transplantation (105 +/- 11 pmol/min, P < .01) or in healthy control subjects (103 +/- 15 pmol/min, P < .01). Heart rate variability (measured by total spectral power) was significantly reduced in cardiac transplantation recipients compared with control subjects (59.4 +/- 30 vs 1673 +/- 516 milliseconds squared; P < .05), with evidence of a trend toward increasing spectral power late after transplantation. During exercise, the cardiac NE spillover was significantly lower in early cardiac transplantation recipients when compared with control subjects (163 +/- 50 vs 1876 +/- 418 pmol/min, P < .01). Late cardiac transplantation subjects showed a response intermediate (1080 +/- 254 pmol/min) between that of the early cardiac transplantation and control groups. However, measurements of the neuronal reuptake process for NE (assessed by the fractional extraction of plasma labeled NE across the heart and tritiated dihydroxyphenylglycol release) were significantly depressed in both early and late cardiac transplantation subjects.
The present study demonstrates a partial restoration of cardiac sympathetic nerve function in humans up to 8 years after heart transplantation.
Previous work has shown that spontaneous and stimulated vagal activity is diminished in heart failure (HF) despite upregulation of functional postsynaptic cholinergic mechanisms. We therefore examined function of the postganglionic neuron in the paced canine model of HF as a possible site for diminished control.
We measured sinus cycle length changes in response to electrical stimulation of preganglionic and postganglionic parasympathetic neurons innervating the sinoatrial node in control and HF dogs (both, n=8). Cervical vagus stimulation (preganglionic) demonstrated attenuated responses in the HF group at all levels of stimulation (P<0.05). Stimulation of the right atrial fat pad, containing both postganglionic nerves and terminals of preganglionic neurons, showed no such difference between control and HF (200+/-25 versus 192+/-18 ms). To ensure that preganglionic input and different levels of baseline sympathetic activity did not contribute to the group difference, similar stimulations were done in the presence of ganglionic and beta-adrenergic blockade. Under these conditions, postganglionic stimulation showed smaller changes in sinus cycle length, but the HF group response remained significantly higher than in controls (76+/-10 versus 20+/-2 ms; P<0. 01), indicating that the difference was independent of preganglionic input and sympathetic activity.
A component of attenuated parasympathetic control in HF is located within the peripheral efferent limb. This defect is located within the parasympathetic ganglion. Future work should be focused on determining mechanisms of attenuated ganglionic transmission so that means targeted at restoring vagal activity can be developed.
Nicotinic acetylcholine receptors (nAChRs) mediate ganglionic transmission in the peripheral autonomic nervous system in mammals. Functional neuronal nAChRs have been shown to assemble from a combination of alpha and beta subunits, including alpha3, alpha5, alpha7, beta2, and beta4 in RNA-injected oocytes, but the subunit composition of functional neuronal nAChRs in vivo in mammals remains unknown. We examined the subunit composition of functional nAChRs in the intracardiac parasympathetic ganglion in a physiologically intact system in vivo. We report here that localized perfusion of the canine intracardiac ganglion in situ with an antagonist specific for nAChRs containing an alpha3/beta2 subunit interface (alpha-conotoxin MII 100-200 nm) resulted in reversible attenuation of the sinus cycle length (SCL) response by approximately 70% to electrical stimulation of the preganglionic vagus nerve. Perfusion with antagonist specific for receptors containing an alpha3/beta4 subunit interface (alpha-conotoxin AuIB 1 micrometer) resulted in attenuation in SCL responses (approximately 20%) compared with baseline when applied by itself, but not in animals pretreated with alpha-conotoxin MII. Perfusion of the ganglion with alpha-bungarotoxin (1 micrometer, which blocks alpha7 receptors) caused a reduction in SCL response by approximately 30% compared with baseline when perfused on its own and when added after blockade with MII and AuIB. Perfusion with hexamethonium bromide resulted in complete blockade of ganglionic transmission, confirming total perfusion of the ganglion and the nicotinic nature of ganglionic transmission at this synapse. Immunohistochemistry using monoclonal antibodies against specific nicotinic subunits confirmed the presence of alpha3, alpha7, beta2, and beta4 subunits. We conclude that functional ganglionic transmission in the canine intracardiac ganglion is mediated primarily by receptors containing an alpha3/beta2 subunit interface, with a smaller contribution by receptors containing alpha7 nAChRs. Despite the presence of beta4 subunits in functional channels, a contribution of a distinct alpha3/beta4 receptor population that does not include an alpha3/beta2 subunit interface was less clear.
The purpose of this article is to review the nerve sprouting hypothesis of sudden cardiac death. It is known that sympathetic stimulation is important in the generation of sudden cardiac death. For example, there is a diurnal variation of sudden death rate in patients with myocardial infarction. Beta blockers, or drugs with beta blocking effects, are known to prevent sudden cardiac death. It was unclear if the cardiac nerves in the heart play only a passive role in the mechanisms of sudden death. To determine if nerve sprouting and neural remodeling occur after myocardial infarction, we performed immunocytochemical studies of cardiac nerves in explanted native hearts of transplant recipients. We found that there was a positive correlation between nerve density and a clinical history of ventricular arrhythmia. Encouraged by these results, we performed a study in dogs to determine whether or not nerve growth factor (NGF) infusion to the left stellate ganglion can facilitate the development of ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD). The results showed that augmented myocardial sympathetic nerve sprouting through NGF infusion plus atrioventricular (AV) block and MI result in a 44% incidence (four of nine dogs) of SCD and a high incidence of VT in the chronic phase of MI. In contrast, none of the six dogs (with AV block and MI) without NGF infusion died suddenly or had frequent VT episodes. Based on these findings, we propose the nerve sprouting hypothesis of ventricular arrhythmia and SCD. The hypothesis states that MI results in nerve injury, followed by sympathetic nerve sprouting and regional (heterogeneous) myocardial hyperinnervation. The coupling between augmented sympathetic nerve sprouting with electrically remodeled myocardium results in VT, VF and SCD. Modification of nerve sprouting after MI may provide a novel opportunity for arrhythmia control.
From right thoracotomy (T4-T5), the canine heart was suspended in its pericardium to expose its major venous inputs. Vagal and sympathetic trunks were prepared for electrical stimulation (10-20 Hz, 5.0 ms, 3-5 V) before and after each separate denervation procedure. Vagal stimulation was instituted with and without concurrent atrial pacing. The following surgical interventions were performed. 1) The superior vena cava was cleared of connective and nervous tissues from the pericardial reflection caudally to the level of the right pulmonary artery. 2) The azygos vein was cleared, tied, and sectioned. 3) The right pulmonary veins were isolated and cleared intrapericardially. 4) The dorsal surface of the atria was dissected between the right and left pulmonary veins and painted with phenol. Each step in the procedure elicited successive stepwise deletion of parasympathetic influences on sinoatrial tissues of the canine heart with only minor ablation of sympathetic inputs. 5) Dissection of the triangular fat pad at the junction of the inferior vena cava and inferior left atrium eliminated the remaining parasympathetic efferent input to the heart with dramatic deletion of atrioventricular block during either left or right vagal stimulation, again with preservation of most of the sympathetic innervation. These experiments clearly demonstrate differential and selective inputs of parasympathetic pathways to sinoatrial (SAN) and atrioventricular (AVN) regions of the dog heart but relatively little interference with sympathetic distributions. The inputs may be selectively interrupted to produce highly restricted denervation of either SAN or AVN function for study in both anesthetized and chronic unanesthetized dog models, thus allowing for separate evaluation of reflex effects on chronotropic (SAN) or dromotropic (AVN) regions of the heart.
Background — Mechanisms favoring the occurrence of paroxysmal atrial fibrillation (PAF) are complex and poorly defined. This study was designed to analyze dynamic changes in autonomic tone preceding the onset of PAF in a large group of patients.
Methods and Results — Holter tapes from 77 unselected consecutive patients (63 men and 14 women aged 58±12 years) with PAF were analyzed. A total of 147 episodes of sustained AF (>30 minutes) were recorded and submitted to time-domain and frequency-domain heart rate variability analyses; 6 periods were studied using repeated measures ANOVA: the 24-hour period, the hour preceding PAF, and the 20 minutes before PAF divided into four 5-minute periods. In the time-domain analyses, a linear decrease in mean RR interval from 925±16 to 906±16 ms ( P <0.0002) was observed before the onset of PAF, together with a significant increase in the standard deviation of NN intervals from 65±4 to 70±4 ms ( P <0.02). In the frequency-domain analyses, a significant increase in high-frequency (HF, HF-NU) components was observed before PAF ( P <0.001 and P <0.0001, respectively), together with a progressive decrease in low-frequency components (LF, LF-NU) ( P <0.0001 and P <0.004, respectively). The low/high frequency ratio showed a linear increase until 10 minutes before PAF, followed by a sharp decrease immediately before PAF, suggesting a primary increase in adrenergic tone followed by a marked modulation toward vagal predominance. No difference was observed in these heart rate variability changes between patients with “lone” PAF and patients with structural heart disease.
Conclusions — The occurrence of PAF greatly depends on variations of the autonomic tone, with a primary increase in adrenergic tone followed by an abrupt shift toward vagal predominance.
The purpose of this article is to review the nerve sprouting hypothesis of sudden cardiac death. It is known that sympathetic stimulation is important in the generation of sudden cardiac death. For example, there is a diurnal variation of sudden death rate in patients with myocardial infarction. Beta blockers, or drugs with beta blocking effects, are known to prevent sudden cardiac death. It was unclear if the cardiac nerves in the heart play only a passive role in the mechanisms of sudden death. To determine if nerve sprouting and neural remodeling occur after myocardial infarction, we performed immunocytochemical studies of cardiac nerves in explanted native hearts of transplant recipients. We found that there was a positive correlation between nerve density and a clinical history of ventricular arrhythmia. Encouraged by these results, we performed a study in dogs to determine whether or not nerve growth factor (NGF) infusion to the left stellate ganglion can facilitate the development of ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD). The results showed that augmented myocardial sympathetic nerve sprouting through NGF infusion plus atrioventricular (AV) block and MI result in a 44% incidence (four of nine dogs) of SCD and a high incidence of VT in the chronic phase of MI. In contrast, none of the six dogs (with AV block and MI) without NGF infusion died suddenly or had frequent VT episodes. Based on these findings, we propose the nerve sprouting hypothesis of ventricular arrhythmia and SCD. The hypothesis states that MI results in nerve injury, followed by sympathetic nerve sprouting and regional (heterogeneous) myocardial hyperinnervation. The coupling between augmented sympathetic nerve sprouting with electrically remodeled myocardium results in VT, VF and SCD. Modification of nerve sprouting after MI may provide a novel opportunity for arrhythmia control.
The purpose of this study was to investigate the electrophysiologic profile of the pulmonary veins (PVs) and left atrium (LA) in response to autonomic manipulation.
The parasympathetic innervation of the PVs and posterior left atrium (PLA) is thought to contribute to focal atrial fibrillation (AF). We hypothesized that autonomic effects would be more prominent in these regions.
In 14 dogs, epicardial mapping was performed in the PVs, PLA, and left atrial appendage (LAA) under the following conditions: baseline, 20-Hz cervical vagal stimulation (VS), propranolol (P), P + VS, and P + atropine. Effective refractory periods (ERPs) were measured, and conduction vectors were computed at multiple sites. Western blotting and immunostaining were performed for IKAch (Kir3.1/3.4).
The VS and P + VS caused more ERP shortening in the PV and PLA than in the LAA. The P + atropine caused greatest ERP prolongation in the LAA. Cumulative ERP change (ERP difference between P + VS and P + atropine) was greatest in the LAA and corresponded with expression of Kir3.1/3.4 (LAA > PLA > or = PV). The ERP change in response to vagal manipulation was most heterogeneous in the PLA; this corresponded with a pronounced heterogeneity of Kir3.1 distribution in the PLA. With VS and/or P, there was evidence of regional conduction delay in the PVs with a significant change in activation direction. Similar activation changes were not seen in the PLA and LAA.
The PVs and PLA demonstrate unique activation and repolarization characteristics in response to autonomic manipulation. The heterogeneity of vagal responses correlates with the pattern of IKAch distribution in the LA. The peculiar autonomic characteristics of the PVs and PLA might create substrate for re-entry and AF.
Cardiac transplantation (CT) causes total cardiac denervation.
To test directly for sympathetic reinnervation in humans, we measured the cardiac release of norepinephrine (NE) in response to tyramine (an agent that causes NE release from intact sympathetic nerve terminals) and sustained handgrip exercise (a reflex sympathetic stimulus) in 12 patients less than 5 months after CT, in 50 patients 1 year or more after CT, and in eight patients without CT. Plasma [NE] was measured in the aorta [( NE]Ao) and coronary sinus [( NE]CS) at rest, after tyramine administration (55 micrograms/kg, i.v.), and during sustained handgrip exercise. Cardiac NE release was determined by subtracting [NE]Ao from [NE]CS [( NE]CS-Ao). NE release was defined as [NE]CS-Ao during the intervention-[NE]CS-Ao at rest (delta [NE]CS-Ao). In patients studied within 5 months of CT, no significant NE release occurred after tyramine administration (delta [NE]CS-Ao, 33 +/- 18 pg/ml; range, -98 to 117 pg/ml) or handgrip exercise (delta [NE]CS-Ao, -34 +/- 10 pg/ml; range, -46 to 8 pg/ml; n = 10). Conversely, in 39 of 50 patients studied 1 year or more after CT, tyramine administration caused a significant cardiac NE release (delta [NE]CS-Ao, 500 +/- 59 pg/ml; range, -11 to 1,918 pg/ml), and handgrip exercise caused a significant NE release in 17 of 41 patients (delta [NE]CS-Ao, 189 +/- 34 pg/ml; range, -211 to 949 pg/ml). In normally innervated patients, tyramine caused an even larger NE release (delta [NE]Ao-CS, 1,943 +/- 210 pg/ml; range, 1,152 to 2,977 pg/ml), and handgrip exercise caused a significant NE release in two of seven patients (delta [NE]CS-Ao, 143 +/- 51 pg/ml; range, -15 to 338 pg/ml).
Early after CT, neither tyramine nor handgrip exercise caused a significant cardiac release of NE, suggesting sympathetic denervation. Late after CT, most patients had a significant, but subnormal, NE release in response to pharmacological or reflex stimuli, suggesting that limited sympathetic reinnervation occurs in most patients after orthotopic CT.
Parasympathetic pathways mediating chronotropic and dromotropic responses to cervical vagal stimulation were determined from sequential, restricted, intrapericardial dissection around major cardiac vessels. Although right cervical vagal input evoked significantly greater bradycardia, supramaximal electrical stimulation of either vagus produced similar ventricular rates, both with and without simultaneous atrial pacing. Dissection of the triangular fat pad at the junction of the inferior vena cava-inferior left atrium (IVC-ILA) invariably eliminated all vagal input to the atrioventricular (AV) nodal region. Yet IVC-ILA dissection had minimal influence on evoked-chronotropic responses to either cervical vagal or stellate ganglia stimulation. Respective intrapericardial projection pathways, from either right or left vagi, are sufficiently distinct to allow unilateral parasympathetic denervation of the sinoatrial (SA) and atrioventricular (AV) nodal regions. Left vagal projections to the SA and AV nodal regions course primarily along and between the right pulmonary artery and left superior pulmonary vein. Right vagal projections to the SA and AV nodal regions are somewhat more diffuse but concentrate around the right pulmonary vein complex and adjacent segments of the right pulmonary artery. We conclude there are parallel, yet functionally distinct, inputs from right and left vagi to the SA and AV nodal regions.
Supersensitivity of the sinus (SAN) and atrioventricular (AVN) nodes to acetylcholine (ACh) after parasympathetic denervation has not been demonstrated conclusively. In this study, we denervated the SAN and AVN by surgically removing parasympathetic ganglia and painting the area with phenol. Sham dogs underwent thoracotomy without denervation. Four to 9 days later, vagal denervation was proved by supramaximal bilateral vagal stimulation, which prolonged the sinus cycle length (SCL) only 32 +/- 7% (mean +/- SE) and the AVN conduction time (AH interval) 15 +/- 7% in denervated dogs. We tested for supersensitivity by obtaining dose-response curves to ACh (1 ml, 10(-8.0) to 10(-4.0) M in 10(0.5) steps) infused over 15 s into the sinus nodal and posterior septal arteries in open chest-denervated (Den) dogs and in sham-operated (Sham) dogs that were anesthetized with alpha-chloralose. ACh concentration (Log[ACh], M) required to prolong SCL 50, 100, and 300% was -5.7 +/- 0.1, -5.6 +/- 0.1, and -5.4 +/- 0.1 in 10 Sham dogs vs. -6.4 +/- 0.1 (P less than 0.001), -6.3 +/- 0.1 (P less than 0.001) and -6.1 +/- 0.1 (P less than 0.001) in 11 Den dogs. ACh concentration necessary to produce second degree and complete AV block was -5.7 +/- 0.1 and -5.3 +/- 0.1 in 11 Sham dogs vs. -6.3 +/- 0.1 (P less than 0.001) and -5.8 +/- 0.1 (P less than 0.01) in 10 Den dogs. Because significantly lower doses of ACh prolonged SCL or produced AV block in Den compared with Sham dogs, we conclude that dogs with vagally denervated SAN and AVN develop a supersensitive response to ACh.
AUTHORS' SYNOPSIS: This study reports results of selective right and left vagosympathetic trunk (VST) and stellate ganglion stimulation (supra-maximal intensity) on atrial refractory period (ARP) in dogs. The effect of selective stellate stimulation on A-V conduction was also evaluated. During right and left VST stimulation, the region of the sinus node exhibited greater ARP shortening than most of the tested sites on the right atrium and all of the tested sites on the left atrium. The right VST exerted a greater effect on the right atrium than on the left atrium. Right VST stimulation shortened ARP at most tested right atrial sites more than did left VST stimulation. Selective vagal stimulation could result in three-fold difference in ARPs at the same electrode site. During right or left stellate ganglion stimulation, the refractory period change at any atrial site was usually minimal and often did not change at all. Supra-maximal right or left stellate stimulation shortened A-H (nodal) conduction by 50% or more in some experiments but shortened conduction time distal to the bundle of His by only 1 to 3 msec.
This study attempted to determine whether cardiac sympathetic reinnervation occurs late after orthotopic heart transplantation.
Metaiodobenzylguanidine (MIBG) is taken up by myocardial sympathetic nerves. Iodine-123 (I-123) MIBG cardiac uptake reflects intact myocardial sympathetic innervation of the heart. Cardiac transplant recipients do not demonstrate I-123 MIBG cardiac uptake when studied < 6 months from transplantation. However, physiologic and biochemical studies suggest that sympathetic reinnervation of the heart can occur > 1 year after transplantation.
We performed serial cardiac I-123 MIBG imaging in 23 cardiac transplant recipients early (< or = 1 year) and late (> 1 year) after operation. In 16 subjects transmyocardial norepinephrine release was measured late after transplantation.
No subject had visible I-123 MIBG uptake on imaging < 1 year after transplantation. However, 11 (48%) of 23 subjects developed visible cardiac I-123 MIBG uptake 1 to 2 years after transplantation. Only 3 (25%) of 12 subjects with a pretransplantation diagnosis of idiopathic cardiomyopathy demonstrated I-123 MIBG uptake compared with 8 (73%) of 11 with a pretransplantation diagnosis of ischemic or rheumatic heart disease (p = 0.04). All 10 subjects with a net myocardial release of norepinephrine had cardiac I-123 MIBG uptake; all 6 subjects without a net release of norepinephrine had no cardiac I-123 MIBG uptake.
Sympathetic reinnervation of the transplanted human heart can occur > 1 year after operation, as assessed by I-123 MIBG imaging and the transmyocardial release of norepinephrine. Reinnervation is less likely to occur in patients with a pretransplantation diagnosis of idiopathic cardiomyopathy than in those with other etiologies of congestive heart failure.
The purpose of this study was to investigate the functional pathways of efferent vagal innervation to the atrial myocardium and sinus and atrioventricular (AV) nodes.
Using vagally induced atrial effective refractory period shortening, slowing of spontaneous sinus rate, and prolongation of AV nodal conduction time as end points of vagal effects, we determined the actions of phenol and epicardial radiofrequency catheter ablation (RFCA) applied to different sites at or near the atrial myocardium to inhibit these responses. We found that efferent vagal fibers to the atria are located both subepicardially and intramurally or subendocardially. Most efferent vagal fibers to the atria appear to travel through a newly described fat pad located between the medial superior vena cava and aortic root (SVC-Ao fat pad), superior to the right pulmonary artery, and then project onto two previously noted fat pads at the inferior vena cava-left atrial junction (IVC-LA fat pad) and the right pulmonary vein-atrial junction (RPV fat pad) and to both atria. A few vagal fibers may bypass the SVC-Ao fat pad and go directly to the IVC-LA or RPV fat pad and then innervate the atrial myocardium. Vagal fibers to the sinus and AV nodes also converge at the SVC-Ao fat pad (a few fibers to the sinus node go directly to the RPV fat pad) before projecting to the RPV and IVC-LA fat pads. Long-term vagal denervation of the atria and sinus and AV nodes can be produced by RFCA of these fat pads and results in vagal denervation supersensitivity. Vagal denervation prevents induction of atrial fibrillation in this model.
The newly described SVC-Ao fat pad receives most of the vagal fibers to the atria and sinus and AV nodes. Elimination of the fat pads with RFCA selectively vagally denervated the atria and sinus and AV nodes.
Although sympathetic activation is believed to promote atrial fibrillation (AF), the effects of sympathetic stimulation on AF have not been systematically studied. In seven morphine-chloralose-anesthetized dogs, autonomic decentralization increased atrial effective refractory period (ERP) and reentrant wavelength (WL) and decreased the duration of AF induced by burst atrial pacing. Graded bilateral stellate ansa stimulation decreased ERP and WL to values similar to those before decentralization but did not return AF duration to predecentralization values. Sympathetic and bilateral vagal stimulation were adjusted in six additional dogs to produce similar effects on ERP and WL. Despite comparable effects on mean WL, the duration of AF was increased by vagal stimulation from 14 +/- 5 (control) to 372 +/- 96 s (P < 0.001) but was not altered significantly (26 +/- 10 s) by sympathetic stimulation. Vagal stimulation increased the variability in atrial refractoriness, as indicated by the standard deviation of ERP at seven atrial sites and of activation frequency during AF at 112 recording sites, whereas sympathetic stimulation had no significant effect on these indexes of ERP heterogeneity. We conclude that sympathetic stimulation is much less effective than vagal stimulation in promoting AF and that heterogeneity in atrial ERP may be important in determining the ability to sustain AF.
The response to sinoatrial parasympathetic nerve stimulation (shortened atrial refractoriness) was used to determine the atrial distribution of these nerve fibers in humans. We hypothesized that, in humans, parasympathetic nerves that innervate the sinoatrial node also innervate the right atrium and that the greatest density of innervation is near the sinoatrial nodal fat pad.
Temporary epicardial wire electrodes were sutured in pairs in the sinoatrial nodal fat pad, high right atrium, and right ventricle by direct visualization during coronary artery bypass surgery in nine patients. Appropriate electrode placement was confirmed by electrically stimulating the fat pad in the operating room to prolong sinus cycle length by 50%. Experiments were performed in the electrophysiology laboratory 1 to 5 days after surgery. Programmed atrial stimulation was performed via an endocardial electrode catheter advanced to the right atrium. The catheter tip electrode was moved in 1-cm concentric zones around the epicardial wires by fluoroscopic guidance. Atrial refractoriness was determined in the presence and absence of sinoatrial parasympathetic nerve stimulation at each catheter site. In 8 of 9 patients, parasympathetic nerve stimulation reproducibly prolonged sinus cycle length by 50%. There was no effect on AV nodal conduction (no prolongation of PR interval) and no change in AV nodal refractoriness. Atrial effective refractory periods reproducibly shortened in response to parasympathetic nerve stimulation in 1-cm zones up to 3 cm surrounding the fat pad, by a mean (+/- SEM) of 26.6+/-4.3 msec (zone 1), 11.4+/-1.8 msec (zone 2), and 10.0+/-2.5 msec (zone 3), respectively (P = 0.0001). At distances > 3 cm from the fat pad, the effective refractory period did not shorten.
Stimulation of parasympathetic nerves that innervate the sinoatrial node shortened atrial refractoriness in humans.
Vagal stimulation shortens the atrial effective refractory period (AERP) and maintains atrial fibrillation (AF). This study investigated whether the parasympathetic pathways that innervate the atria can be identified and ablated by use of transvenous catheter stimulation and radiofrequency current catheter ablation (RFCA) techniques.
In 11 dogs, AERPs were determined at 7 atrial sites during bilateral cervical vagal nerve stimulation (VNS) and electrical stimulation of the third fat pad (20 Hz) in the right pulmonary artery (RPA). VNS shortened the AERP at all sites (from 123+/-4 to 39+/-4 ms, P<0.001) and increased the covariance of AERP (COV-AERP) (from 9+/-3% to 27+/-13%, P<0.001). RPA stimulation shortened the AERP at all sites from 123+/-4 to 66+/-13 ms (P<0.001) and increased the COV-AERP from 9+/-3% to 30+/-12% (P<0.001). In 7 dogs, transvascular RFCA of the parasympathetic pathways along the RPA was performed, and in 3 dogs, additional RFCA of parasympathetic fibers along the inferior (n=2) or superior (n=1) vena cava was performed. RFCA blunted the AERP shortening at all sites during VNS (114+/-4 ms after RFCA), abolished the increase of COV-AERP during VNS (12+/-7% after RFCA), and led to an increase of the baseline AERP (123+/-4 ms before versus 127+/-3 ms after RFCA, P=0.002). Before RFCA, AF could be induced and maintained as long as VNS was continued, whereas after RFCA, AF was no longer inducible during VNS.
-Transvascular atrial parasympathetic nerve system modification by RFCA abolishes vagally mediated AF. This antifibrillatory procedure may provide a foundation for investigating the usefulness of neural ablation in chronic animal models of AF and eventually in patients with AF and high vagal tone.
Long-term rapid atrial pacing may result in atrial fibrillation (AF) in dogs. Whether there is histological evidence for neural remodeling is unclear.
We performed rapid right atrial pacing in 6 dogs for 111+/-76 days to induce sustained AF. Tissues from 6 healthy dogs were used as controls. Immunocytochemical staining of cardiac nerves was performed using anti-growth-associated protein 43 (GAP43) and anti-tyrosine hydroxylase (TH) antibodies. In dogs with AF, the density of GAP43-positive and TH-positive nerves in the right atrium was 470+/-406 and 231+/-126 per mm(2), respectively, which was significantly (P:<0.001) higher than the nerve density in control tissues (25+/-32 and 88+/-40 per mm(2), respectively). The density of GAP43-positive and TH-positive nerves in the atrial septum was 317+/-36 and 155+/-85 per mm(2), respectively, and was significantly (P:<0.001) higher than the nerve density in control tissues (9+/-13 and 30+/-7 per mm(2), respectively). Similarly, the density of GAP43-positive and TH-positive nerves in the left atrium of dogs with AF was 119+/-61 and 91+/-40 per mm(2), respectively, which was significantly (P:<0.001) higher than the nerve density in control tissues (10+/-15 and 38+/-39 per mm(2), respectively). Furthermore, in dogs with AF, the right atrium had a significantly higher nerve density than the left atrium. Microscopic examinations revealed an inhomogeneous distribution of cardiac nerves within each sampling site.
Significant nerve sprouting and sympathetic hyperinnervation are present in a canine model of sustained AF produced by prolonged right atrial pacing. The magnitude of nerve sprouting and hyperinnervation was higher in the right atrium than in the left atrium.
This study was designed to analyze dynamic changes in autonomic tone preceding the onset of sustained atrial arrhythmias in patients with focal atrial fibrillation (AF) to determine why patients with frequent discharge from the arrhythmogenic foci develop sustained AF.
Holter tapes from 13 patients (10 men and 3 women; mean age 53 +/- 5 years) with paroxysmal "lone" AF (mean 18 +/- 13 episodes per week) and a proven focal origin (pulmonary veins in all cases) were analyzed. A total of 38 episodes of sustained (>30 min) were recorded and submitted to frequency-domain heart rate variability analysis. Six periods were studied using repeated measures analysis of variance: the 24-hour period, the hour preceding AF, and the 20 minutes before AF divided into four 5-minute periods. A significant increase in high-frequency (HF, HF-NU) components was observed during the 20 minutes preceding AF (P = 0.003 and 0.002, respectively), together with a progressive decrease in normalized low-frequency (LF-NU) components (P = 0.035). An increase in LF/HF ratio followed by a linear decrease starting 15 minutes before sustained AF also was observed, indicating fluctuations in autonomic tone, with a primary increase in adrenergic drive followed by a marked modulation toward vagal predominance immediately before AF onset.
In patients with focal ectopy originating from the pulmonary veins, sustained episodes of atrial arrhythmias are mainly dependent on variations of autonomic tone, with a significant shift toward vagal predominance before AF onset.
Atrial tachyarrhythmias are the most common arrhythmias in the general population. The abundant experimental evidence suggests that the autonomic nervous system plays an important role in the occurrence of atrial arrhythmias. However, complex interactions of the autonomic nervous system with the arrhythmogenic substrate make it difficult to correlate human arrhythmias with the laboratory data. Development of new methods to explore the subtle modulation of the autonomic nervous system may have implications for understanding the arrhythmogenic mechanism and providing an effective therapy.
Mechanisms favoring the occurrence of paroxysmal atrial fibrillation (PAF) are complex and poorly defined. This study was designed to analyze dynamic changes in autonomic tone preceding the onset of PAF in a large group of patients.
Holter tapes from 77 unselected consecutive patients (63 men and 14 women aged 58+/-12 years) with PAF were analyzed. A total of 147 episodes of sustained AF (>30 minutes) were recorded and submitted to time-domain and frequency-domain heart rate variability analyses; 6 periods were studied using repeated measures ANOVA: the 24-hour period, the hour preceding PAF, and the 20 minutes before PAF divided into four 5-minute periods. In the time-domain analyses, a linear decrease in mean RR interval from 925+/-16 to 906+/-16 ms (P<0.0002) was observed before the onset of PAF, together with a significant increase in the standard deviation of NN intervals from 65+/-4 to 70+/-4 ms (P<0.02). In the frequency-domain analyses, a significant increase in high-frequency (HF, HF-NU) components was observed before PAF (P<0.001 and P<0.0001, respectively), together with a progressive decrease in low-frequency components (LF, LF-NU) (P<0.0001 and P<0.004, respectively). The low/high frequency ratio showed a linear increase until 10 minutes before PAF, followed by a sharp decrease immediately before PAF, suggesting a primary increase in adrenergic tone followed by a marked modulation toward vagal predominance. No difference was observed in these heart rate variability changes between patients with "lone" PAF and patients with structural heart disease.
The occurrence of PAF greatly depends on variations of the autonomic tone, with a primary increase in adrenergic tone followed by an abrupt shift toward vagal predominance.
We hypothesized that in humans there is an epicardial fat pad from which parasympathetic ganglia supply the AV node. We also hypothesized that the parasympathetic nerves innervating the AV node also innervate the right atrium, and the greatest density of innervation is near the AV nodal fat pad.
An epicardial fat pad near the junction of the left atrium and right inferior pulmonary vein was identified during cardiac surgery in seven patients. A ring electrode was used to stimulate this fat pad intraoperatively during sinus rhythm to produce transient complete heart block. Subsequently, temporary epicardial wire electrodes were sutured in pairs on this epicardial fat pad, the high right atrium, and the right ventricle by direct visualization during coronary artery bypass surgery in seven patients. Experiments were performed in the electrophysiology laboratory 1 to 5 days after surgery. Programmed atrial stimulation was performed via an endocardial electrode catheter advanced to the right atrium. The catheter tip electrode was moved in 1-cm concentric zones around the epicardial wires by fluoroscopic guidance. Atrial refractoriness at each catheter site was determined in the presence and absence of parasympathetic nerve stimulation (via the epicardial wires). In all seven patients, an AV nodal fat pad was identified. Fat pad stimulation during and after surgery caused complete heart block but no change in sinus rate. Fat pad stimulation decreased the right atrial effective refractory period at 1 cm (280 +/- 42 msec to 242 +/- 39 msec) and 2 cm (235 +/- 21 msec to 201 +/- 11 msec) from the fat pad (P = 0.04, compared with baseline). No significant change in atrial refractoriness occurred at distances >2 cm. The response to stimulation decreased as the distance from the fat pad increased.
For the first time in humans, an epicardial fat pad was identified from which parasympathetic nerve fibers selectively innervate the AV node but not the sinoatrial node. Nerves in this fat pad also innervate the surrounding right atrium.
Cervical vagal stimulation shortens the atrial effective refractory period (ERP) primarily in the high right atrium (HRA) and facilitates induction of atrial fibrillation (AF) by single premature HRA extrastimuli. We hypothesized that vagal denervation of the HRA prevents both ERP shortening in the HRA and AF induction during vagal stimulation.
Vagal denervation of the HRA was achieved using radiofrequency catheter ablation (RFA) of the fat pad at the right pulmonary vein-atrial junction (RPV fat pad). Programmed stimulation was performed at each of four atrial sites to measure ERP and inducibility of AF during vagal stimulation. RPV fat pad RFA increased only the HRA ERP during vagal stimulation (70 +/- 8.7 vs 117 +/-14.8, P < 0.05). RPV fat pad RFA increased measures of dispersion of refractoriness, the standard deviation of ERP (24 +/- 2.1 vs 33 +/- 2.0, P < 0.01), and the standard deviation of AF cycle length (11 +/- 0.8 vs 22 +/- 1.7, P < 0.001) during vagal stimulation. RPV fat pad RFA increased the incidence of AF (15/28 vs 24/28, P < 0.05) and the vulnerability (22 +/- 4.7 vs 39 +/- 5.6, P < 0.01) to AF induction during vagal stimulation, particularly from left atrial premature beats. After RPV fat pad RFA, premature beats induced AF by causing conduction block primarily in the HRA and macroreentrant activation around the block.
Partial right atrial vagal denervation facilitated rather than prevented initiation of vagally mediated AF.
The refractory period (RP) was measured at several points on the right atrial surface in anesthetized dogs. Under control conditions with vagi cut the values recorded at various points varied by no more than 40 msec. During stimulation of the vagus nerves, singly or together, the RP varied widely. At some points marked effects were observed, while at others little or no effect was apparent. Reflex excitation of the vagi, induced by increased arterial pressure, yielded similar results. It was concluded that the effects of vagal stimulation are not uniformly distributed.
Atrial arrhythmias are a common complication of cardiac surgery. Reports describing pericardiac neurogenic tissue led us to hypothesize that removal of the aortic fat pad could cause an autonomic imbalance and contribute to atrial arrhythmias following cardiac surgery.
A randomized prospective pilot study (n =131) was conducted to test our hypotheses. Patients underwent conventional cardio-pulmonary bypass surgery (CPB) or off pump coronary bypass surgery (OPCAB). The fat pad was either left intact or removed. The incidence of de novo atrial arrhythmias during the patient's hospital stay was tabulated. Patients with peri-operative myocardial infarction or pre-existing atrial or supraventricular arrhythmias were excluded. The randomization schedule was made subservient to clinical judgment at surgery. After promising preliminary results, an extension study (n =189 patients, total patients =320) was performed which employed the same definitions and interventions but was a sample of convenience. The data of this second study have not been previously published.
In the pilot study, in demographically similar groups, logistic regression demonstrated a significantly elevated atrial arrhythmia incidence when the fat pad was removed (Odds ratio 3.49, 95% confidence intervals 1.09 to 11.18). A chi-square analysis of these same data, however, (4 fibrillations in 58 patients with fat pad intact versus 15 fibrillation in 73 patients with fat pad removed; P = 0.051) suggested that the importance of the fat pad status was not definite. Overall, atrial arrhythmias were present in 19 of 131 patients (14.5%). In the extension study, in contrast to the pilot data, the data did not demonstrate any contribution of fat pad status to the incidence of atrial fibrillation.
Although we feel that our hypothesis remains viable, retention of the aortic fat pad during coronary artery bypass surgery may not be related to a decreased incidence of post operative atrial arrhythmias.
There are no data to evaluate the relationship between autonomic nerve function modification and recurrent atrial fibrillation (AF) after circumferential pulmonary vein ablation (CPVA). This study assesses the incremental benefit of vagal denervation by radiofrequency in preventing recurrent AF in a large series of patients undergoing CPVA for paroxysmal AF.
Data were collected on 297 patients undergoing CPVA for paroxysmal AF. Abolition of all evoked vagal reflexes around all pulmonary vein ostia was defined as complete vagal denervation (CVD) and was obtained in 34.3% of patients. Follow-up ended at 12 months. Heart rate variability attenuation, consistent with vagal withdrawal, was detectable for up to 3 months after CPVA, particularly in patients with reflexes and CVD, who were less likely to have recurrent AF than those without reflexes (P=0.0002, log-rank test). Only the percentage area of left atrial isolation and CVD were predictors of AF recurrence after CPVA (P<0.001 and P=0.025, respectively).
This study suggests that adjunctive CVD during CPVA significantly reduces recurrence of AF at 12 months.
Because the autonomic nervous system is an important determinant in the appearance of atrial fibrillation, we have assessed the role of ventral cardiac denervation for its prevention.
Patients undergoing low-risk coronary artery surgery were enrolled. No routine antiarrhythmic drugs were administered before or after the operation. Ventral cardiac denervation was performed in 207 patients, and 219 patients were used as control subjects. Denervation was performed before cardiopulmonary bypass. The groups were comparable regarding demographic, clinical, and operative variables.
The additional time for the denervation was 5 +/- 2 minutes, and there were no associated complications. Postoperative atrial fibrillation was present in 15 (7%) patients undergoing ventral cardiac denervation (95% confidence interval, 4%-12%) and in 56 (27%) control subjects (95% confidence interval, 18%-35%). Patients submitted to ventral cardiac denervation had fewer and less severe episodes of atrial fibrillation, and no patient had atrial fibrillation after discharge. Ventral cardiac denervation was the most significant predictor of postoperative atrial fibrillation (odds ratio, 0.42; confidence interval, 0.23-0.78; P =.006). Age of greater than 65 years (odds ratio, 1.67; confidence interval, 0.96-2.9; P =.067) was a highly suggestive predictor. The analysis of the effect of ventral cardiac denervation correlated with the patient's age showed a more pronounced effect in patients younger than 70 years (odds ratio, 0.43; confidence interval, 0.22-0.86; P =.022)
Ventral cardiac denervation is a fast and low-risk procedure. Its use significantly reduces the incidence and severity of atrial fibrillation after routine coronary artery bypass surgery. Patients younger than 70 years of age are expected to have a higher success rate than those older than 70 years.
The goal of this study was to determine if parasympathetic nerves in the anterior fat pad (FP) can be stimulated at the time of coronary artery bypass surgery (CABG), and if dissection of this FP decreases the incidence of postoperative atrial fibrillation (AF).
The human anterior epicardial FP contains parasympathetic ganglia and is often dissected during CABG. Changes in parasympathetic tone influence the incidence of AF.
Fifty-five patients undergoing CABG were randomized to anterior FP preservation (group A) or dissection (group B). Nerve stimulation was applied to the FP before and after surgery. Sinus cycle length (CL) was measured during stimulation. The incidence of postoperative AF was recorded.
Of the 55 patients enrolled, 26 patients were randomized to group A, and 29 patients were randomized to group B. In all of the 55 patients, the FP was identified before initiating cardiopulmonary bypass by CL prolongation with stimulation (865.5 +/- 147.9 ms vs. 957.9 +/- 155.1 ms, baseline vs. stimulation, p < 0.001). In group A, stimulation at the conclusion of surgery increased sinus CL (801.8 +/- 166.4 ms vs. 890.9 +/- 178.2 ms, baseline vs. stimulation, p < 0.001). In group B, repeat stimulation failed to increase sinus CL (853.6 +/- 201.6 ms vs. 841.4 +/- 198.4 ms, baseline vs. stimulation, p = NS). The incidence of postoperative AF in group A (7%) was significantly less than that in group B (37%) (p < 0.01).
This is the first study demonstrating that direct stimulation of the human anterior epicardial FP slows sinus CL. This parasympathetic effect is eliminated with FP dissection. Preservation of the human anterior epicardial FP during CABG decreases incidence of postoperative AF.
Cardiac nerve sprouting and sympathetic hyperinnervation after myocardial infarction (MI) both contribute to arrhythmogenesis and sudden death. However, the mechanisms responsible for nerve sprouting after MI are unclear. The expression of nerve growth factor (NGF), growth associated protein 43 (GAP43), and other nerve markers were studied at the infarcted site, the noninfarcted left ventricle free wall (LVFW), and the left stellate ganglion (LSG) at several time points (30 minutes to 1 month) after MI. Transcardiac (difference between coronary sinus and aorta) NGF levels were also assayed. Acute MI resulted in the immediate elevation of the transcardiac NGF concentration within 3.5 hours after MI, followed by the upregulation of cardiac NGF and GAP43 expression, which was earlier and more pronounced at the infarcted site than the noninfarcted LVFW. However, cardiac nerve sprouting and sympathetic hyperinnervation were more pronounced in the noninfarcted than the infarcted LVFW site and peaked at 1 week after MI. The NGF and GAP43 protein levels significantly increased in the LSG from 3 days (P<0.01 for all) after MI, without a concomitant increase in mRNA. There was persistent elevation of NGF levels in aorta and coronary sinus within 1 month after MI. We conclude MI results in immediate local NGF release, followed by upregulation of NGF and GAP43 expression at the infarcted site. NGF and GAP43 are transported retrogradely to LSG, which triggers nerve sprouting at the noninfarcted LVFW. A rapid and persistent upregulation of NGF and GAP43 expression at the infarcted site underlies the mechanisms of cardiac nerve sprouting after MI.
To evaluate the efficacy of ventral cardiac denervation as a prophylaxis against post-coronary artery bypass grafting (CABG) atrial fibrillation (AF).
Seventy consecutive patients who underwent CABG (group A) were compared to 70 consecutive subsequent patients who underwent CABG + ventral cardiac denervation (group B). Both groups were well-matched for age, gender, disease severity, LV function, Euro scores, Parsonnet scores, preoperative beta-blockers, Ca-channel blockers, digoxin, and angiotensin converting enzyme inhibitors. The same cardioplegia, bypass, and operation techniques were used in all cases. Denervation before initiating bypass increased operation time by approximately 5 minutes. Heart rate and rhythm were monitored by continuous telemetry until postoperative day 5 and then 4- hourly until discharge.
The cross-clamp time (p = 0.6), bypass time (p = 0.1), number of grafts (p = 0.9), inotrope usage (p = 0.4), reexploration rate (p = 1), postoperative myocardial infarction (none in either group), blood loss (p = 0.7), and length of stay (p = 0.8) were comparable in both groups. There was no significant difference in the incidence of AF; 34% in group A versus 29% in group B (p = 0.3).
Ventral cardiac denervation failed to significantly reduce the incidence of AF following coronary revascularization in our study.
Experimental Studies: Anesthetized dogs were subjected to a right then left thoracotomy. Two modes of electrical stimulation were used to activate ganglionated plexi (GP) on the epicardium of the atria: (1) Near the base of each pulmonary vein (PV), trains of high frequency stimuli (HFS) were coupled to each atrial paced beat so as to fall within the refractory period to achieve nerve stimulation without atrial excitation; and (2) Continuous HFS was applied via plaque electrodes sutured to epicardial fat pads (containing a GP) near the right superior (RS) and left superior (LS) PVs. The chest was then closed. An ablation catheter, inserted percutaneously, was positioned fluoroscopically in the right atrium across from the epicardial plaque electrode near the RSPV. Transeptal puncture was used to place an ablation catheter at the LSPV-left atrial junction. HFS applied to each of the epicardial fat pads induced atrial fibrillation (AF) and also caused high grade AV block due to a strong parasympathetic effect on the AV node. Radiofrequency ablation from the right and left atrial endocardium abolished the vagal response to HFS delivered to the plaque electrodes on the fat pads close to the RSPV and LSPV, respectively.
Clinical Studies: Sixty (60) patients with paroxysmal or persistent AF underwent PV antrum isolation (27 patients) or PV antrum isolation plus left atrial GP ablation (33 patients). Endocardial HFS at the border of the PV antra near the 4 GPs produced AF and high grade AV block (vagal response) during AF. RFA at these sites abolished the vagal response. Testing in a small number of patients with very short follow-up suggests that adding GP ablation to PV antrum isolation may increase ablation success (absence of AF recurrence) from 70% to 91%.
Conclusions: These basic and clinical studies suggest that localized cardiac autonomic ganglia (GPs) may play a critical role in the initiation and maintenance of AF.