Syncope is a clinical condition related to transient loss of consciousness, secondary to cerebral hypoperfusion.1 Its cumulative incidence can be as high as 42% in the general population. Vasovagal syncope (VVS) is the most frequent cause of syncope, and may occur on the basis of factors such as standing position, pain, venous puncture, emotional stress, heat, and dehydration following prodromal symptoms. Although there is still some debate about the pathophysiological background of VVS, reflex mechanism consisting of sympathetic nervous system inhibition and subsequent excessive parasympathetic activity seems to be the most plausible mechanism.2 Demonstration of an increase in sinus rate or atrioventricular conduction properties following various radiofrequency ablation procedures has led to the introduction of several new ideas such that elimination of parasympathetic innervation might be achieved by endocardial radiofrequency ablation and be used in the treatment of conditions associated with parasympathetic hyperactivity.3,4
Knowing the anatomical location of parasympathetic innervation areas and detecting these sites during electrophysiological study are important. In anatomically based studies, two different placement schemes for vagal ganglia have been proposed.5-7 In the first, three main vagal ganglia-based representation schemes were adopted to define functional and anatomical properties of cardiac parasympathetic innervation, whereas a left atrial-based ganglion model was used in the other system. Despite this basic difference in appearance, there are considerable similarities in terms of ganglion settlement in both classification systems.8 Thus, we believe that we should target the following three locations to ablate vagal ganglia: 1) between the superior vena cava and aortic root; 2) the right atrial aspect of the right pulmonary veins; and 3) between the inferior vena cava and left atrium, around the coronary sinus.
At the basis of the theoretical and anatomical background described above, the first attempt was performed by Pachon et al9 on 22 patients, eight with VVS. They defined two different atrial myocardium patterns using the fast Fourier transform (FFT) analysis: 1) compact atrial myocardium consists of normal atrial myocytes connecting to each other by intensive connexin junctions, and demonstrates homogeneous and fast conduction properties on FFT analysis; and 2) fibrillar atrial myocardium contains extensions of neural fibers between cardiac myocytes, and shows fragmented and heterogeneous spectrum with frequencies deviated to the right. The first study specifically investigating effects of vagal ganglia ablation was performed by the same group in 43 cases with VVS (cardioinhibitory type in 95.3% and mix type in 4.7%, respectively).10 After all the points in the left and right atrium having fibrillar myocardium patterns were ablated, empirical additional ablation was performed in predetermined anatomical areas explained above. In a mean follow-up of 45.1 ± 22 months (at least 11 months), spontaneous or head-up tilt table test-induced asystole were not observed. All but three patients had no more new syncopal episodes.
In the second study, 10 patients with VVS without indicating cardioinhibitory or mix type underwent an ablation procedure using high-frequency stimulation (HFS).11 Researchers focused at the regions between the root of the left superior pulmonary vein (PV) and the left atrium or the left auricular appendage, inferior to the left inferior PV, anterior to the right superior PV, and inferior to the right inferior PV. At 30 ± 16 month follow-up, there was no new syncope in any patient, whereas 5 of 10 patients reported transient prodromes.
Lastly, we used a combination of FFT analysis and HFS with additional anatomical ablation.12,13 Our approach consisted of two parts. In the first part, we aimed to investigate whether it is possible to selectively ablate vagal ganglia providing innervation of the atrioventricular node using an isolated right atrial approach in patients with functional atrioventricular block. Our strategy was successful in six of seven patients. In the failed case, the ablation procedure was maintained via the left atrium targeting other possible sites. Although sinus rate increased by almost 50%, 1:1 atrioventricular conduction could not be achieved and 2:1 AVB persisted at the end of procedure. The patient was the oldest included in the study, and demonstrated partial resolution with first-degree atrioventricular block after atropine infusion. So, we speculated that the main underlying cause of failure was the presence of structural damage in the atrioventricular conduction system. In the second part of the study, we investigated the electrophysiological effects of stepwise ablation. In patients with VVS or sinus node dysfunction, the ablation procedures were first performed through the left atrium and then continued with ablation from the right atrial side. Basal cycle length, sinus node recovery time, and corrected sinus node recovery time were decreased after the left atrial ablation. Although all these parameters significantly decreased after the right atrial ablation, it was lower than the previous one. On the contrary, the parameters demonstrating atrioventricular conduction such as atrioventricular Wenckebach point and atrium-His interval showed the most significant improvement after the right atrial ablation. These results may be considered as a clue for individual innervation principles of the sinus and atrioventricular nodes. However, we did not compare an isolated right atrial approach and biatrial approach in any VVS cases. Also, we did not start ablation from the right side in any case of VVS. So, it cannot be speculated that an isolated right atrial ablation is enough for all cases or denervation of sinus and atrioventricular nodes are achieved, selectively.
In a recently published study, Sun et al14 compared HFS-guided ablation with an anatomical approach in 57 patients with VVS. In the HFS-guided group, the previously defined locations11 were checked for vagal response after HFS application and the sites demonstrating positive response were ablated. In the anatomically guided group, left atrial vagal ganglion and the previously defined four vagal ganglia were ablated empirically without using HFS. Electrophysiological parameters and clinical endpoints were similar between groups.
To define whether there is any difference between vagal ganglia determination methods during electrophysiological study, we conducted a meta-analysis and compared recurrence rates between different approaches in patients with VVS.15 A Kaplan-Meier survival analysis was done with the available follow-up data. From the survival plot, we demonstrated that the methodologies incorporating HFS into the procedure are associated with the lowest recurrence rates. Furthermore, empirical anatomic ablation was associated with worse outcomes. There are certain limitations of all of the above methods used in the determination of vagal ganglia. We aimed to develop a simple technique that demonstrates parasympathetic innervation sites using conventional electrophysiology equipment. A case study below details use of this new technique in a patient with VVS.
A 32-year-old male with refractory VVS, a sinus pause of six seconds during head-up tilt table testing, and documented paroxysmal atrial fibrillation, was referred to our clinic for pulmonary vein isolation and implantation of a permanent pacemaker. He had eight episodes of syncope within one year. Conventional therapies consisting of optimal fluid intake and counterpressure maneuvers failed to prevent syncope. After creating three-dimensional electroanatomic mapping of both atria (using Abbott’s EnSite Precision™ Cardiac Mapping System), bipolar endocardial electrograms divided the following subgroups at filter settings of 300-500 Hz and a sweep speed of 400 mm/s: 1) normal electrogram, which demonstrates deflections less than 4; 2) low-amplitude fractionated electrogram (LAFE), which demonstrates greater or equal to 4 deflections and amplitude of less than 0.7 mV; and 3) high-amplitude fractionated electrogram (HAFE), which demonstrates greater or equal to 4 deflections and amplitude of greater or equal to 0.7 mV (Figure 1). A similar technique was previously defined by Lellouche et al16 and investigated in patients with paroxysmal atrial fibrillation during sinus rhythm. The sites demonstrating HAFE or LAFE pattern in a region that is compatible with the probable location of the vagal ganglia were tagged as ablation targets. The other sites demonstrating LAFE pattern were accepted as scar tissue and excluded from the assessment. Ablation endpoint was almost complete elimination of atrial electrical potentials (<0.1 mV) in all targeted sites.
For pulmonary vein isolation, circumferential radiofrequency lesions were placed at least 2 cm outside of the pulmonary vein ostia to encircle and electrically isolate ipsilateral pairs of the pulmonary vein antra using the FlexAbility™ Ablation Catheter, Sensor Enabled™ (Abbott). Radiofrequency ablation was performed point-by-point at a power of 35 W (maximum 40 W) and applied in temperature-controlled mode. The target temperature was 40°C, with a cooling rate of 18 mL/min. Continuous flow during mapping was 2 mL/min. After completion of pulmonary vein isolation, all targeted areas as vagal ganglia were successfully ablated first from the left atrial side and then from the right atrial side (Figure 2). As of 12-month follow-up, the patient is completely asymptomatic. There was no new syncopal or atrial fibrillation episodes. Follow-up tilt tests and Holter recordings were negative at 1 and 6 months after the ablation.
In this case study, we demonstrated that vagal ganglia ablation may be a good alternative modality for a patient with VVS who cannot be adequately treated by conventional modalities and who refuses pacemaker implantation. Targeting of fractionated electrogram sites may be used to define parasympathetic innervation sites instead of FFT analysis or HFS. However, designed trials with large numbers of patients as well as further observations about long-term efficacy and safety are required for determining a final conclusion.
Disclosures: The authors have no conflicts of interest to report regarding the content herein.
- Task Force for the Diagnosis and Management of Syncope., European Society of Cardiology (ESC), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA), Heart Rhythm Society (HRS), Moya A, Sutton R, Ammirati F, et al. Eur Heart J. 2009;30(21):2631-2671.
- Medow MS, Stewart JM, Sanyal S, et al. Pathophysiology, diagnosis, and treatment of orthostatic hypotension and vasovagal syncope. Cardiol Rev. 2008;16(1):4-20.
- Soejima K, Akaishi M, Mitamura H, et al. Increase in heart rate after radiofrequency catheter ablation is mediated by parasympathetic nervous withdrawal and related to site of ablation. J Electrocardiol. 1997;30:239-246.
- Pappone C, Stabile G, Oreto G, et al. Inappropriate sinus tachycardia after radiofrequency ablation of para-Hisian accessory pathways. J Cardiovasc Electrophysiol. 1997;8:1357-1365.
- Chiou CW, Eble JN, Zipes DP. Efferent vagal innervation of the canine atria and sinus and atrioventricular nodes. The third fat pad. Circulation. 1997;95:2573-2584.
- Armour JA, Murphy DA, Yuan BX, et al. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec. 1997;247:289-298.
- Yuan BX, Ardell JL, Hopkins DA, et al. Gross and microscopic anatomy of the canine intrinsic cardiac nervous system. Anat Rec. 1994;239:75-87.
- Aksu T, Güler TE, Mutluer FO, et al. Vagal denervation in atrial fibrillation ablation: A comprehensive review. Anatol J Cardiol. 2017;18:142-148.
- Pachon JC, Pachon EI, Pachon JC, et al. “Cardioneuroablation”—New treatment for neurocardiogenic syncope, functional AV block and sinus dysfunction using catheter RF ablation. Europace. 2005;7:1-13.
- Pachon JC, Pachon EI, Cunha Pachon MZ, et al. Catheter ablation of severe neurally meditated reflex (neurocardiogenic or vasovagal) syncope: cardioneuroablation long-term results. Europace. 2011;13:1231-1242.
- Yao Y, Shi R, Wong T, et al. Endocardial autonomic denervation of the left atrium to treat vasovagal syncope: an early experience in humans. Circ Arrhythm Electrophysiol. 2012;5:279-286.
- Aksu T, Golcuk E, Yalin K, et al. Simplified Cardioneuroablation in the Treatment of Reflex Syncope, Functional AV Block, and Sinus Node Dysfunction. Pacing Clin Electrophysiol. 2016;39:42-53.
- Aksu T, Golcuk SE, Erdem Guler T, et al. Functional permanent 2:1 atrioventricular block treated with cardioneuroablation: Case report. HeartRhythm Case Rep. 2015;1:58-61.
- Sun W, Zheng L, Qiao Y, et al. Catheter Ablation as a Treatment for Vasovagal Syncope: Long-Term Outcome of Endocardial Autonomic Modification of the Left Atrium. J Am Heart Assoc. 2016;5. pii: e003471.
- Aksu T, Güler TE, Bozyel S, et al. Cardioneuroablation in the treatment of neurally mediated reflex syncope: a review of the current literature. Turk Kardiyol Dern Ars. 2017;45:33-41.
- Lellouche N, Buch E, Celigoj A, et al. Functional characterization of atrial electrograms in sinus rhythm delineates sites of parasympathetic innervation in patients with paroxysmal atrial fibrillation. J Am Coll Cardiol. 2007;50:1324-1331.