Intrinsic Cardiac Neuromodulation in Management of Atrial Fibrillation

Intrinsic Cardiac Neuromodulation in Management of Atrial Fibrillation: Comparison

Please note this is a comparison between Version 2 by Conner Chen and Version 3 by Conner Chen.

The intrinsic cardiac autonomic nervous system (ANS) has a significant influence on the structural and electrical milieu, and imbalances in the ANS may contribute to the arrhythmogenesis of atrial fibrillation (AF) in some individuals. There is increasing scientific and clinical interest in various aspects of neuromodulation of intrinsic cardiac ANS, including mapping techniques, ablation methods, and patient selection.

cardioneuroablation
atrial fibrillation
ganglionated plexus

1. Spectral Analysis

By spectral analysis through the fast Fourier transforms, Pachon et al. ^[1][2] defined two types of atrial spectral potentials: (1) compact potentials that work like one isolated cell and present homogeneous, fast conduction with a single high-power fundamental frequency and rapid uniformly decreasing harmonics, and (2) fibrillar potentials that are similar to a group of nerve cells and show a heterogenous and low-power fragmented profile with irregular harmonics of high amplitude and wide distribution. The areas containing fibrillar potentials were named “atrial fibrillation (AF) nests” by the authors and used to define the localization of intrinsic cardiac autonomic nervous system (ANS) or ganglionated plexi (GPs). The investigators found that AF nests were 9.7 times more frequently located in the left atrium (LA) than RA, with the most common locations: the left superior pulmonary vein (PV) insertion (91.1%); interatrial septum (91.1%); RSPV (the right superior PV) (88.2%); left inferior PV (67.6%); right lateral wall of the right atrium (RA) and crista terminalis (47%); and the insertion of the vena cavae (61.7%).

2. High-Frequency Stimulation

According to animal experiments, high-frequency electrical stimulation (HFS) of different parts of the LA causes two types of response: (1) autonomic response and (2) normal or nonspecific response. An autonomic response may occur in three different ways: (1) a vagal response (VR) characterized by immediate sinus bradycardia or atrioventricular block; ^[3] a marked shortening of the atrial RP nearby the stimulated GP; and ^[4] an initiation of sustained AF, either spontaneously or by a single atrial extrastimulus delivered nearby the GP ^[5][6][7]. However, HFS at the remaining LA sites did not induce any significant changes in the PR or RR intervals, decrease in atrial RP, or induction of sustained AF with a single atrial extrastimulus ^[6][7]. Thus, the demonstration of a positive autonomic response may be used to distinguish autonomic innervation sites from uninnervated atrial myocardium. Because each GP has sympathetic and parasympathetic neural elements, autonomic responses to HFS may vary by duration of application, with a tendency for shorter applications to stimulate the parasympathetic fibers. When delivering HFS for longer intervals than 2–5 s, the sympathetic fibers may also be stimulated, potentially blunting the expected parasympathetic response ^[6][8]. Nakagawa et al. ^[6] studied the characteristics of autonomic response and electrogram (EGM) morphology during AF and found that sharp, fractionated atrial potentials are found more frequently in adjacent PVs and LA regions nearby stimulated GP. According to sites exhibiting an autonomic response during HFS and fractionated EGM characteristics during AF, five distinct areas were identified: (1) RSGP (superior right atrial GP; [RSGP]); (2) RIGP (posterior-inferior right atrial GP; [RIGP]); (3) LSGP (superior left atrial GP; [LSGP]); (4) LIGP (posterolateral-inferior left atrial GP; [LIGP]); and (5) MTGP (the Marshall tract GP).

In a recently published study, Kim et al. ^[9] used a slightly different HFS technique and defined two functional classes of GP: an atrioventricular-dissociating GP type and an ectopy-triggering GP type (ET-GP). A probability atlas of ET-GP revealed a 30–40% probability of ET-GP in the areas of the PV ostia (except for the base of the right inferior PV (RIPV) on the posterior wall), roof, mid-anterior wall, the anterior wall near the RSPV, and the posterior wall near the left inferior PV. Smaller isolated patches of ≥40% probability for ET-GP were confined to the peri-PV region: left PV carina, RSPV antrum, and RSPV ostium on the LA roof ^[10]. One potential reason for the discrepant findings between Nakagawa and Kim’s studies may be the stimulation by HFS, not only of the epicardial ganglia, but also the nerve extensions within the atrial myocardium from the epicardial ganglia. In a canine-isolated LSPV model, the HFS of axons originating from the GP led to a marked shortening of action potential duration (APD) and induction of early after depolarizations and firing from the PV sleeve myocardium. Conversely, the response to the HFS was negated with an infusion of tetrodotoxin. These findings suggest HFS may exert its effects through the stimulation of autonomic axons rather than the electrical stimulation of cardiac myocytes ^[11][12].

3. Electrogram Analysis

Based on the compact and fibrillar atrial EGM principles of Pachon et al. ^[1], Lellouche et al. ^[13] then analyzed the EGM characteristics based on VRs during RF applications. The EGMs from ablation sites were recorded with a 12-bit analog-to-digital amplifier on 977 samples with a 30–500 Hz bandpass filter. A fractionated atrial EGM during sinus rhythm was defined as an EGM with ≥4 deflections plus a duration of ≥40 ms, as those characteristics best predicted the occurrence of a thermal-induced parasympathetic response with RF ablation. Lellouche further distinguished three main types of LA EGMS in sinus rhythm based on the amplitude (Figure 12): (1) normal EGMs: <4 deflections or <40 ms duration; (2) low-amplitude fractionated EGMs: ≥4 deflections and <0.7 mV amplitude; and (3) high-amplitude fractionated EGMs: ≥4 deflections, ≥0.7 mV amplitude, and ≥40 ms duration. Pachon et al. ^[1] demonstrated filter settings may have a great impact on the detection of fractioned potentials. The use of 300–500 Hz filters instead of conventional 30–500 Hz filter settings aided in mapping the “fibrillar” myocardium to target for ablation. Thus, the autonomic ganglia sites were detected through a combination of fast Fourier transform analysis of EGMs and HFS ^[14]. All the EGMs at successful RF ablation sites stimulating an autonomic response demonstrated a fragmented pattern. Based on their superior signal fidelity, the higher high-pass filters improved appreciation of the EGM fragmentation ^[1], and so, in subsequent work, one group used 200–500 Hz bandpass filter settings instead of conventional filter settings to target all the fragmented EGMs in the regions during sinus rhythm, which co-localized with the expected anatomic autonomic innervation sites ^[15]. Indeed, this streamlined electroanatomical mapping-guided approach demonstrated an identical clinical success in comparison to previous combined approaches. Figure 2 3 the anatomical distribution of GPs in accordance with the definition method.

Figure 12. Three bipolar atrial electrogram types for ganglionated plexus mapping. HAFE, high amplitude fragmented electrogram; LAFE, low amplitude fragmented electrogram; Normal, normal atrial electrogram.

Figure 23. Distribution of ablation points in different views. White, pink, and red dots show distribution of ablation points based on fragmented bipolar electrograms. Please see Figure 1 for abbreviations: LL, left lateral; PA, posteroanterior; RAO, right anterior oblique.

In a recent study, Kuniewicz et al. ^[16] attempted to localize fractionated EGMs using a high-density mapping catheter (PentaRay NAV Catheter, Irvine CA) in 35 patients undergoing AF catheter ablation. Using characteristics from Lellouche and one groups ^[13], the duration, amplitude, and number of deflections were determined for each EGM. In a retrospective analysis of case data, the authors identified predominantly six regions exhibiting fragmented EGMs within the LA. Four regions were in nearby PVs: (1) in front of the RSPV; (2) below the RIPV; (3) LSGP, the roof of the LA, and (4) below the LIPV. Two other regions were (5) the MTGP, located along the left atrial appendage (LAA)-LPV ridge; and (6) the inferoposterior fractionated atrial potentials located directly above the coronary sinus between the RIGP and LIGP on the LA posterior wall. Thus, the identification of fractionated bipolar atrial EGMs with or without the use of high-density mapping catheters may facilitate the rapid and feasible identification of GP sites while shortening the ablation procedure time ^[17][18]. Unfortunately, the presence of fractionated atrial EGMs may be less specific for GP sites in the presence of a diseased myocardium, such as areas of fibrosis. In a recent study, one group demonstrated that new operators can successfully achieve acute procedural success using a fragmented EGM-guided GP ablation strategy with low learning ^[19].

4. Myocardial Innervation Imaging

In 2014, Ben-Haim et al. ^[20] showed for the first time that 123I-metaiodobenzylguanidine (123I-mIBG), which is internalized by the presynaptic nerve endings of postganglionic neurons, can be used to localize GPs. Twelve patients who underwent mIBG-infusion under a solid-state cardiac camera; contrast-enhanced computed tomography (cCT), or cardiac magnetic resonance imaging (CMR) were automatically co-registered. The LA mIBG-uptake in the epicardial fat pads of the LA was projected on the cCT or CMR with the merged data imported into the 3D electroanatomical mapping system (CARTO 3, Biosense Webster). HFS was then performed at these regions to confirm their correspondence to GP locations before ablation was performed. Utilizing the HFS, all except two sites of focal mIBG uptake were confirmed in five patients who underwent AF ablation. Stirrup et al. ^[21] defined a high-resolution Cadmium Zinc Telluride camera SPECT/cCT protocol to identify GPs with high accuracy when compared with HFS at those sites. A total of 73 I-mIBG LA-uptake areas were found, of which 59 (81%) identified sites correlated with HFS responsiveness. Thus, SPECT could enhance or eventually replace HFS techniques for the identification of GPs and assist with procedural planning. Moreover, mIBG SPECT also represents an innovative tool to evaluate the extent of LA denervation and dynamics of reinnervation post-pulmonary vein isolation (PVI). GP ablation may also cause ventricular myocardial denervation in addition to atrial effects. Lemery et al. ^[22] compared pre-ablation mIBG imaging with early and late imaging post-ablation in five AF patients for whom HFS mapping was also performed. The RF ablation targeted GP antral sites with uptake, in addition to the lesion sets required for PVI. Interestingly, ventricular myocardial denervation was documented in all the patients after the atrial ablation.

5. Cardiac Computed Tomography

cCT has been used for a long time to increase confidence in performing LA ablation in cases of complex and variable PV and LA anatomy. In a recently published study to define the ability of cCT to identify epicardial adipose tissue for guiding GP ablation, Markman et al. ^[23] conducted a prospective study of patients who underwent AF catheter ablation. In a total of 15 patients with AF following preprocedural cCT, the atrial anatomy and epicardial adipose tissue near the PVs, coronary sinus, ligament of Marshall (LOM), and superior vena cava (SVC)-aortic area with attenuation <0 Hounsfield Units were segmented and exported using ADAS software (Galgo Inc). The segmentations were then registered to mapping coordinates (CARTOMerge, Biosense Webster). Fractionated EGMs were identified as ≥4 deflections using 100–500 Hz filter settings. HFS was performed with a definition of VR as >50% R-R interval prolongation. The GP ablation in the study was performed targeting epicardial adipose tissue identified by cCT. An heart rate (HR) increase (>10 beats/min) was observed during the ablation of SVC-aortic epicardial adipose sites and also the right superior epicardial adipose tissue sites in 12 (80%) study patients. An HR decrease (>10 beats/min) was observed when ablating left superior epicardial adipose sites in four (27%) study patients. There was, however, substantial variability in the location and expanse of epicardial adipose tissue regions, with >10 mm variability relative to anatomic landmarks between patients.

6. Anatomical Approach

An anatomic ablation strategy can be utilized in two different manners: as adjunctive to EGM analysis or HFS ^[16][24], or both; or it can be utilized as a stand-alone strategy ^[25]. Although the anatomical distribution of GPs is well demonstrated in animal and human experimental studies, the localization of GPs may demonstrate substantial variability from one patient to another. The advantages and disadvantages of this technique have been summarized in Table 1. Despite the existence of highly specialized techniques, it should be noted that the largest randomized controlled study, thus far, examining the role of adjunctive GP ablation to standard PVI used an anatomical-only approach in the GP ablation group ^[26]. Furthermore, anatomical ablation (i.e., targeting areas known to host GP in the LA without using surrogate methods for identification of GP) may yield equivalent or even perhaps superior clinical results to methods utilizing HFS for the identification and ablation of GPs in PAF patients ^[24].

Table 1. Advantages and disadvantages of different ganglionated plexus mapping techniques.

Technique	Setting	Advantages	Disadvantages
Spectral analysis ^[1]^[2]	Time to amplitude-based electrograms are converted to frequency spectrum through the fast Fourier transforms The software (Pachón-TEB2002) works with a customized 32-channel polygraph Fibrillar potentials (AF nests) with a highly fragmented, heterogeneous, and right-skewed spectral distribution show vagal innervation sites	Depending on the filters applied during the recordings, all desired frequency spectra can be studied A concise method for the qualitative and quantitative assessment of the proportion of high-frequency components within atrial electrogram	No integration with current 3D mapping systems No chance for online analysis of electrogram
High frequency Stimulation (HFS)	20 Hz, 10–30 V, and pulse width of 1–10 ms, for 2–5 s ^[6]^[8] 20 Hz, 10 V, up to 10 s to detect the atrioventricular dissociating-GPs and 40 Hz, 10 V for 80 ms to detect the ectopy-triggering-GPs ^[9]^[10] A positive vagal response, which is defined as a transient sinus bradycardia or atrioventricular block, shows vagal innervation sites	A well-studied method on both atrial fibrillation ablation and cardioneuroablation ^[6]^[8]^[9]^[10]^[14]^[15] Can be used to evaluate vagal denervation in each GP site	Need stimulators with high-frequency capability (e.g., Grass stimulator S-88 and Micropace EPS320) No consensus for proper protocol No consensus for definition of positive vagal response Conscious patients may not tolerate more than 15 V and general anesthesia is usually needed Induction of atrial fibrillation HFS-based strategy has not demonstrated an advantage over empirical anatomic ablation ^[24] Vagal response characteristics can be differentially affected by conscious and sedation deep sedation ^[27]
Electrogram analysis	Bipolar endocardial atrial electrograms are evaluated for number of deflections at filter settings of 200–500 Hz ^[15] * The electrograms demonstrating greater or equal to 3–4 deflections in regions which are anatomically consistent with GP sites are tagged as ablation targets ^[17]^[18]^[24]^[27]	A readily available method for the semi-quantitative assessment of high-frequency components (can be considered a simplified variant of spectral analysis) does not require any specific technology and can be used in all electrophysiology centers No extra costs Related to shorter procedure time than combination of spectral analysis and high-frequency stimulation with a similar success rate ^[15] Reproducible by first-time operators ^[19]	The fragmented electrograms may also be found at the sites with complex architecture of atrial myocardium, (e.g., at the pulmonary veins ostia, at ridges, multiple layers (coronary sinus), and most likely at the interatrial septum sites where GPs important for cardioneuroablation are also located The assessment might be less concise compared to spectral analysis Fibrosis may also cause fragmentation due to slow conduction Decisions made by humans based on visualizations of data may demonstrate low reproducibility
Anatomical Approach	The technique can be used as adjunctive to spectral analysis, high-frequency stimulation, or fragmented electrograms; or as a stand-alone strategy ^[16]^[24]^[25] Empirical ablation is performed in the presumed areas of GPs ^[28]	No extra costs does not require any specific technology and can be used in all electrophysiology centers Easily applicable Better results than high-frequency stimulation-based approach ^[24]	No definition for ablation target No definition for ablation endpoint Reproducibility by first-time operators?
Computed Tomography (CT) imaging		It might be used to define posteroseptal part of the superior vena cava to avoid transseptal puncture if it is properly performed and correctly merged with an electroanatomical map ^[23] It may increase the confidence in performing left atrial or bi-atrial cardioneuroablation, in case of complex and variable pulmonary vein and left atrium anatomy It may disclose major anatomical abnormalities that could interfere with successful cardioneuroablation	The benefit of registering the CT anatomic images to the electroanatomical map has not been reliably proven for the success of cardioneuroablation as well as for other complex ablation procedures for cardiac arrhythmias. It might be associated with non-necessary additional costs. Another concern in young patients is the radiation exposure which is multi-fold higher than that during cardioneuroablation itself that can be performed in a near-to-zero fluoro manner. Improper use of image registration may be misleading in non-experienced hands.
123I-metaiodobenzylguanidine (mIBG)	Imaging is performed following injection of 123I-mIBG on a dedicated cardiac solid-state SPECT camera Images are acquired for 20 min with the region of interest ^[21] All patients undergo cardiac CT After manual corrections to the segmentation, a representative 3D surface mesh file is created for each chamber that is then used for co-registration with SPECT tomograms	mIBG LA uptake areas are usually correlated with HFS ^[21] Left atrial innervation imaging by SPECT may integrate with invasive HFS and provide the planning of the ablation procedure	Mapping parameters are not standardized the technique needs validation against High-frequency stimulation or visual electrogram analysis No integration with current 3D mapping systems

* This setting is available in WorkMate Claris system (St Jude Medical, Abbott, St. Paul, MN, USA). In Prucka Cardiolab system (GE Healthcare, Wauwatosa, WI), 100–500 Hz can be selected as default setting ^[2].AF, atrial fibrillation; GP, ganglionated plexus.

References

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