Review ArticleCatheter Ablation of Bradyarrhythmia: From the Beginning to the Future☆
Introduction
Increased parasympathetic tone or an imbalance between sympathetic and parasympathetic systems may cause several significant clinical conditions such as functional atrioventricular block (AVB), some forms of sinus node dysfunction (SND) and neurally mediated reflex syncope.1 Although the most common cause of SND or AVB is fibrosis of the sinus node or atrioventricular conducting system, excessive vagal tone may be the only underlying cause, especially in intermittent forms. Vasovagal syncope (VVS) is the most common form of neurally mediated reflex syncope and traditionally refers to a heterogeneous group of conditions in which cardiovascular reflexes that are normally useful in controlling the circulation become intermittently inappropriate, in response to a trigger, resulting in vasodilatation or bradycardia, or both, thereby a fall in global cerebral perfusion and syncope.2
After the demonstration that a significant number of parasympathetic autonomic ganglia (PAG) are located subepicardially and surround regions of the sinus and AV nodes, the potential therapeutic role of elimination of these structures by endocardial radiofrequency catheter ablation (RFCA) was investigated by various groups in different patient populations.3, 4, 5 The technique was attempted by Pachon et al6 for the first time and termed cardioneuroablation (CNA).
The current review article is dedicated to finding answers to the following questions: (1) Is there any difference between parasympathetic and sympathetic systems according to innervation principles? (2) Where are the true locations of PAG (according to anatomists or electrophysiologists)? (3) Do we need any alternative modality to define the locations of PAG? (4) How can we select suitable candidates for the procedure? (5) What is the best ablation approach? (6) What should be the endpoints?
Section snippets
Is There Any Difference Between Parasympathetic and Sympathetic Systems According to Innervation Principles?
Cardiac innervation consists of parasympathetic and sympathetic systems as well as sensory system. For better understanding, cardiac autonomic nervous system (ANS) can be divided into extrinsic and intrinsic parts according to the course of nerve fibers and localization of ganglia and neuron bodies.
Extrinsic Part
The extrinsic part of cardiac ANS is also divided into following 2 components: the sympathetic system and the parasympathetic system (Figure 1). The sympathetic fibers are largely derived from major autonomic ganglia along the cervical and thoracic spinal cord (the “stellate” or “cervicothoracic” ganglia).7 The parasympathetic preganglionic fibers originate from the medulla oblongata and are carried almost entirely within the vagus nerve.
Intrinsic Part
In ANS, fibers from the ganglion to the effector organ are called postganglionic fibers.7, 8, 9, 10 The axons of presynaptic parasympathetic neurons extend from the central nervous system to PAG, which are either very close to or embedded in the heart. Therefore, the postsynaptic parasympathetic nerve fibers are very short, whereas the neural body of the postganglionic sympathetic and sensory neurons is located far from the heart. The intrinsic cardiac ANS thus forms a complex network composed
Where Are the True Locations of the PAG?
Theoretically, if we can determine exact locations of PAG, our RFCA application on these sites may permanently damage postganglionic neuronal bodies of the parasympathetic system, whereas sympathetic and sensory systems will not be permanently affected because they only have postganglionic nerve fibers in this region and may be repaired by the axonal regeneration process in the long term.11, 12
High Frequency Stimulation
Animal experiments revealed several endocardial localizations that contain parasympathetic nerves innervating the sinus node, AV node and atria. These areas can be stimulated electrically using HFS.13, 14, 15, 16, 17 HFS application causes 2 types of response in atria: (1) a vagal response (VR), which is defined as a significant prolongation of the PR or RR intervals (Figure 4A); (2) a normal response characterized by the absence of any effect or nonsignificant changes on the PR or RR
Spectral Analysis
In 2004, Pachon et al22 used SA of the atrial potentials through the fast Fourier transforms to go beyond the time domain to the frequency domain of them using a software program which works with a 32 channel-polygraph. In a conventional electrophysiology system, the amplitudes of electrical potentials are recorded against time, whereas fast Fourier transforms analysis, which is a simplified mathematical tool that allows the visualization of the frequency spectrum (the frequencies of sinus
Anatomic Approach
Empiric anatomic ablation has been used in 2 different ways, so far adjunctive to SA or HFS or both; or as a stand-alone strategy. Pachon et al6, 23, 24 performed empirical ablation in the presumed areas of ganglion A-C after completion of ablation in the areas determined by SA (Figure 2). We used a combination of SA and HFS for guidance in finding the target areas. Then, we similarly extended our ablation in ganglion A-C sites.19, 20 After ablation of left atrial areas demonstrating positive
Do We Need Any Alternative Modality to Define the Locations of PAG?
The constraints mentioned below suggest that we need an alternative modality to define exact localization of PAG.
(1) For HFS, due to concomitant afferent autonomic nerve stimulation, it may cause the sensations of discomfort and this discomfort may increase with increasing nerve stimulation voltage. Furthermore, the discomfort may occur predominantly at stimulation sites at which negative dromotropic or chronotropic effects are achieved, which may be related with a specific excitation of
How Can We Select Suitable Candidates?
Selection of suitable candidates for CNA procedure is not only the most important, but also the most confusing part of the path to success, because there are significant differences between studies for patient selection criteria. Furthermore, some of the studies consist of mixed patient groups. To clarify patient selection criteria, we divided relevant literature (case reports, case series and trials) into 3 groups: studies consisting of mixed patient groups, studies consisting only of cases
Studies Consisting of Mixed Patient Groups
After demonstration of an increase in sinus rate following various RFCA procedures, it was hypothesized that elimination of parasympathetic innervation might be achieved by endocardial RFCA and be used in the treatment of conditions associated with excessive vagal activation.33, 34 This hypothesis was introduced by Pachon et al.6 Twenty-one patients with VVS in 6, functional high degree AVB in 7, and SND in 13 were studied. The inclusion and exclusion criteria are not specified for each group
Studies Consisting Only of Cases With VVS
Patient selection criteria were more clearly defined in these studies (Table 1). In the first homogenous study, Pachon et al23 evaluated the clinical efficieny of CNA in 43 VVS cases. They included not only cases with cardioinhibitory response, but also with mixed reponse (4.7%). In case of no symptom reproduction after 30 minutes, patients were sensitized with sublingual isosorbide dinitrate (2.5 mg) during tilt testing. Mean number of syncope episodes was 4.7 ± 2 syncope/patient and all
Studies Consisting Only of Cases With SND
As mentioned before and seen in Table 2, potential usage of CNA therapy in patients with SND was studied in 3 different studies consisting of heterogenous patient groups.6, 20, 28 The main limitation of these studies is the marked variation in patient inclusion criteria. So, we have to consider the results of 1 study consisting solely of cases with SND, for a clear judgment about selection of suitable candidates.18 In that study, Zhao et al18 performed a CNA procedure in 11 patients presenting
Studies Consisting Only of Cases With AVB
To date, there are no clinical studies consisting only of cases with AVB. Therefore, our data were restricted to 3 clinical studies consisting of mixed case groups and 3 case reports (Table 3).6, 19, 20, 24, 25, 28 Since limitations and features of studies with mixed case groups have been discussed previously, patient characteristics of case reports will be discussed in the following section.
In the first case report, the procedure was performed in a 23-year-old woman presenting with recurrent
What is the Best Ablation Approach?
In the first study, Pachon et al6 used 2-stage ablation approach in both atria by using fluoroscopy guidance. In the first part of ablation, they obtained spectral mapping and targeted the sites demonstrating right-shifted spectra on SA. In the second part, ablation was performed on estimated location of ganglion A-C. Despite this preprocedural planning, the procedure was accomplished only via RA due to unknown reasons. A similar ablation scheme was successfully used in the second study of
Selective or Stepwise Ablation Approach
The anatomical relationships of PAG may allow elimination of either parasympathetic or sympathetic nerve supplies to either (or both) sinus and atrioventricular node regions by careful epicardial or even endocardial intervention. In an animal study, Randall et al4 demonstrated that the great majority of PAG supplying sinus nodes reside in the PV fat pad (ganglion A and B) and associated adipose tissues. In contrast, PAG supplying atrioventricular nodes are found within a smaller fat pad
What Should be the Endpoints?
Definition of reasonable procedural endpoints seems to the assessment of the success of the procedure is the most complicated issue and seems to be the Achilles’ heel of CNA as several significant variables may each have a major impact on the outcome and should be considered. The endpoints of the procedure may be divided into 2 groups: (1) elimination of the all targeted EGMs which should change according to the method used for determination of PAG; (2) electrophysiological evidence of vagal
Ethical and Economic Aspects of the Procedure
On the basis of all the evidence, ablation of PAG may markedly improve health and quality of life in patients with pronounced symptoms and who cannot be treated effectively with drugs or refuse permanent pacemaker implantation. However, the procedure carries some risk of serious complications, such as as septal puncture. Hence, it is important that patients who are candidates for treatment receive comprehensive and objective information concerning the risks and the expected benefits of the
Conclusions
Ablation of PAG may be a feasible and valuable adjunctive therapy in patients with VVS, functional AVB and SND. However, the procedure is complex with considerable variability in methods and end-points. It is also a very invasive and aggressive approach to a problem that is resolved very effectively with a pacemaker. Considering PAG are epicardial structures, their ablation via endocardial approach may not always be possible as seen in atrial fibrillation studies. Furthermore, the results of
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The authors have no financial or other conflicts of interest to disclose.