Abstract
Background: Atrial ganglionated plexus (GP) ablation was proved to have therapeutic effects on vasovagal syncope. The study aimed to investigate whether selective ablation of only right anterior GP (ARGP) and right inferior GP (IRGP) was effective in a canine model of vasovagal syncope.
Abstract
Seventeen mongrel dogs were divided into control (N = 10) and ablation group (N = 7).
Abstract
Bilateral thoracotomy was performed at the fourth intercostal space and ARGP and IRGP were ablated in the ablation group. A bolus of veratridine (15 ug/kg) was injected into the left atrium to induce vasovagal reflex. Surface electrocardiogram and blood pressure (BP) were continuously monitored. Heart rate (HR) variability was calculated to represent cardiac autonomic tone. Results: Veratridine injection induced vasovagal reflex in all dogs. HR decreased from 149 ± 17 to 89 ± 33 beats/min (P < 0.001) in the control group, while in the ablation group HR decreased from 141 ± 35 to 125 ± 34 beats/min (P = 0.032). The postveratridine HR in the ablation group was significantly higher than that in the control group (P = 0.045). A significantly less intense HR decrease was observed in the ablation group compared with control (-17 ± 16 vs -61 ± 34 beats/min, P = 0.006). Significant BP decreases were induced in both the groups (all P < 0.01), while no evident differences in postveratridine BP and the extent of BP decreases were found between the groups. HR variability revealed significant decrease in cardiac vagal tone after ablation [highfrequency power, 0.50 (0.17-1.05) vs 6.28 (0.68-8.99) ms 2 , P = 0.005].
Abstract
Conclusions: Selective ablation of ARGP + IRGP weakened cardiac parasympathetic control and significantly attenuated the cardioinhibitory response in an animal model of vasovagal reflex. This ablation strategy might be effective for vasovagal syncope with evident cardioinhibitory response.
INTRODUCTION
As a most common cause of syncope, vasovagal syncope accounts for approximately 30-50% in syncopal patients 1 named the Bezold-Jarisch reflex, which was first introduced by Albert von Bezold and Adolf Jarisch. 4 Based on the theory, therapies focusing on the initiating factors and the afferent or efferent limb of Bezold-Jarisch reflex have been used to treat vasovagal syncope. However, therapies with satisfying effects are rare. For instance, fludrocortisone, a synthetic corticosteroid which can enhance sodium and fluid retention, has been used to treat vasovagal syncope. However, it did not reduce the long-term overall syncope occurrence. 5 Beta-blockers, which might suppress the initiating sympathetic activation, was also found to be ineffective in preventing vasovagal syncope in a clinical trial. 6 In recent years, cardiac vagal denervation emerges as a novel therapy for vasovagal syncope, which shows better efficacy when compared with pharmacological therapies. Pachon et al. have performed catheter ablation of atrial ganglionated plexus (GP) in patients with cardioinhibitory or mixed-type vasovagal syncope. 7 The cardioinhibitory response was significantly eliminated and symptoms of most patients were improved. Later, Yao et al. and Sun et al. used a highfrequency stimulation-guided technique to ablate four major atrial GPs in patients with vasovagal syncope and significantly improved the symptoms. 8, 9 Note that 91.2% of syncopal patients remained syncopefree after an average follow-up of 3 years. 9 The rationale for GP ablation in treating vasovagal syncope is that it could weaken the efferent cardioinhibitory limb in the vasovagal reflex.
INTRODUCTION
The four major atrial GPs include right anterior GP (ARGP), right inferior GP (IRGP), superior left GP (SLGP), and inferior left GP (ILGP), [10] [11] [12] among which ARGP and IRGP were regarded as the main vagal input into the sinoatrial and atrioventricular nodes. 13, 14 Thus, it might also be effective to ablate only ARGP and IRGP, which could be simpler and safer than ablation of all four GPs. The present study aims to investigate the effects of selective ablation of ARGP and IRGP on vasovagal reflex in a canine model of Bezold-Jarisch reflex, thus providing evidence for the eligibility of selective ARGP+IRGP ablation in the treatment of vasovagal syncope.
METHODS

Animal preparation
The experiment was approved by the Animal Care and Use Commit- 
Ablation of ARGP and IRGP
The heart was exposed by right thoracotomy performed at the fourth intercostal space in both groups. The pericardium was then opened to expose right atrial GPs. As reported previously, GP was identified by both anatomical localization and electrical stimulation. 15 
Induction and recording of the Bezold-Jarisch reflex
Left thoracotomy was performed at the fourth intercostal space to expose the heart. After the pericardium was opened, Bezold-Jarisch reflex was induced by a bolus of veratridine (15 
HR variability analysis
HR variability was analyzed to represent the cardiac autonomic tone. The power spectrum densities of 5-minute segments free of extrasystoles before and after GP ablation were computed using the HR variability module of the LabChart 7.2 software. HR variability indices including total power (TP), high-frequency component (HF) (0.15-0.4 Hz), low-frequency component (LF) (0.04-0.15 Hz), and mean intervals of normal sinus beats (NN) were calculated. TP represented the overall autonomic control of the heart, HF was used as an index of parasympathetic activity, and the LF-to-HF ratio (LF/HF) was used to reflect sympathetic modulations. 18 
Data analysis
Data analysis was performed using SPSS version 17.0 (IBM Corp., Armonk, NY, USA). All continuous variables were tested for normality of distribution using the Kolmogorov-Smirnov test. Data with normal distribution were expressed as mean ± standard deviation. 
RESULTS
Veratridine injection successfully induced the Bezold-Jarisch reflex in all dogs. In the control dogs, immediate decreases in HR and BP were observed a few seconds after veratridine injection (Figure 2A ). In the ablation group, veratridine injection also resulted in evident decrease of BP. However, the veratridine-induced HR decrease was significantly blunted when compared with the control group ( Figure 2B ).
Veratridine-induced changes in HR
As revealed in Table 1 , there were no significant differences in baseline HR between the control group and ablation group (149 ± 17 vs 141 ± 35, P = 0.540). Veratridine caused significant HR decreases in both the control and ablation groups. In the control group, HR decreased from 149 ± 17 to 89 ± 33 beats/min (P < 0.001), while in the ablation group the HR decrease was from 141 ± 35 to 125 ± 34 beats/min (P = 0.032). The postveratridine HR in the ablation group was significantly higher than that in the control group (125 ± 34 vs 89 ± 33 beats/min, P = 0.045). A significantly less intense HR decrease was observed in the ablation group compared with the control group (HR change, -17 ± 16 vs -61 ± 34 beats/min, P = 0.006; percentage HR change, -12 ± 11% vs -40 ± 21%, P = 0.005). In addition, the longest RR interval after veratridine injection in the ablation group tended to be shorter than that in the control group 
Veratridine-induced changes in arterial pressure
As shown in Table 2 , there were no significant difference in baseline systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP) between the control group and ablation group. Veratridine injection induced significant decreases of SBP, DBP, and MAP in both the groups (all P < 0.01). However, no evident differences in postveratridine SBP, DBP, and MAP were found between the two groups. And the extent of BP decreases (expressed as percentage change of SBP, DBP, and MBP) showed no significant difference between the control group and ablation group (all P > 0.05). Note: RR max is expressed as median (interquartile range) and the other data are shown as mean ± standard deviation. * P < 0.05, ** P < 0.01 versus control; # P < 0.05, ### P < 0.001 versus baseline. GPA = ganglionated plexus ablation; HR = heart rate; ΔHR = changes in HR; ΔHR (%) = percentage change of HR; RR max = the longest RR interval after veratridine injection.
Effects of ARGP+IRGP ablation on cardiac autonomic tone
Changes of HR variability indices after ARGP+IRGP ablation were shown in Figure 3 . TP, an indice for the overall cardiac autonomic showing that HR was decreased after ARGP+IRGP ablation. Besides, LF/HF was not significantly changed after ablation, which might reflect sympathetic activity. These results showed that the parasympathetic control of the heart was significantly weakened by ARGP+IRGP ablation. and CO appears and BP variability is increased. In phase 3, syncope occurs after a rapid drop of HR and SBP, which coincides with symptoms of vagal activation. The Bezold-Jarisch reflex is considered a possible mechanism for the hemodynamic changes during phase 3. 19, 20 As shown in Figure 4 , the vigorous contraction of the hypovolemic heart is considered to stimulate the ventricular receptors and the signals are relayed to the central nervous system through unmyelinated vagal fibers (C fibers). 21, 22 These signals are then integrated in the cardiovascular centers in the medulla oblongata (e.g., solitary tract) 23, 24 and reflexly cause an increase in vagal outflow and/or an inhibition of sympathetic activity.
DISCUSSION
The increase of vagal activity is found to cause bradycardia, 16 while sympathetic withdrawal is considered to result in decreases in peripheral vascular resistance and BP. 25 The atrial GPs, clusters of cardiac parasympathetic neurons which receive the input of vagus nerve, modulate the interactions between extrinsic and intrinsic cardiac autonomic nervous system and comprise the key elements of cardiac vagal control. As mentioned before, there are four major atrial GPs including ARGP, IRGP, SLGP, and ILGP. [10] [11] [12] Ablation of these GPs were found to be effective in treating patients with vasovagal syncope, especially for patients with evident cardioinhibitory response. [7] [8] [9] The rationale for GP ablation in the treatment of vasovagal syncope was considered to be the weakening of the efferent cardioinhibitory limb involved in vasovagal reflex through vagal denervation. 7 Since the vasodepressor element in vasovagal reflex is probably due to sympathetic inhibition, it is reasonable that GP ablation may not be effective for BP decrease in vasovagal reflex, which has been found in our results.
DISCUSSION
The role of these major atrial GPs on the function of sinoatrial and atrioventricular nodes has been systematically studied by Hou ARGP and IRGP locate in the superoanterior area around the root of the right superior pulmonary vein and the inferoposterior area around the root of the right inferior pulmonary vein, respectively. Anatomically, these two GPs can be accessed through the right atrium and venae cavae. 7, 26, 27 Ablation of only ARGP and IRGP may not need interatrial septal puncture and will be less time-consuming. And risks for left atrium ablation (e.g., systemic embolism) will be avoided. It is also reported that ablation of four major GPs could increase ventricular arrhythmogenesis in ischemic hearts 15 ; thus, it is reasonable to ablate fewer GPs if possible. Selective ablation of ARGP and IRGP might be a better strategy of cardioneuroablation in the treatment of vasovagal syncope.
Study limitations
Although the veratridine-induced Bezold-Jarisch reflex is a classical model for vasovagal response, it may not accurately mimic vasovagal syncope of humans, which can be induced by many complicated factors. In addition, the present study only observed the acute effects of selective ARGP and IRGP ablation on vasovagal reflex; further studies should be performed to evaluate the long-term effects of this ablation strategy.
CONCLUSIONS
Selective ablation of ARGP and IRGP weakened cardiac parasympathetic control and significantly attenuated the cardioinhibitory response in an animal model of vasovagal reflex. This ablation strategy might be effective for vasovagal syncope with evident cardioinhibitory response.

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