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\begin{document}

\title{Cardioneuroablation: don't underestimate the posteromedial left atrial
ganglionated plexus.}



\author[1]{Ciro Ascione}%
\author[1]{Léa Benabou}%
\author[1]{Conrado Balbo}%
\author[1]{Tsukasa Kamakura}%
\author[1]{Takamitsu Takagi}%
\author[1]{Philipp Krisai}%
\author[1]{Romain Tixier}%
\author[1]{Hugo Marchand}%
\author[1]{Benjamin Bouyer}%
\author[1]{Clémentine André}%
\author[1]{Remi Chauvel}%
\author[1]{Ghassen Cheniti}%
\author[1]{Thomas Pambrun}%
\author[1]{Nicolas Derval}%
\author[1]{Frederic Sacher}%
\author[1]{Mélèze Hocini}%
\author[2]{Claudio Tondo}%
\author[1]{Pierre Jais}%
\author[1]{Michel Haissaguerre}%
\author[1]{Josselin Duchateau}%
\affil[1]{Centre Hospitalier Universitaire de Bordeaux Hopital Cardiologique}%
\affil[2]{Centro Cardiologico Monzino Istituto di Ricovero e Cura a Carattere Scientifico}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Introduction Cardioneuroablation (CNA) is a technique used to modulate
cardiac parasympathetic tone in patients with sino-atrial (SA) and
atrio-ventricular (AV) vagally mediated syncope. We describe the case of
a patient who developed AV block after a first procedure of CNA,
requiring a second procedure. Case presentation A 47-Year-old man
presented with recurrent syncope (daily episodes) associated with high
vagal tone conditions. An ECG monitoring showed frequent episodes of
sinus bradycardia and sinus arrest, with pauses up to 17 seconds. AV
node conduction impairment was never identified. A CNA procedure
targeting the right superior and posterior ganglionated plexi (GPs),
both from the left and right atrium, was performed with acute success.
The subsequent night, repetitive episodes of AV block with normal sinus
rate were observed. A second procedure was performed targeting the
posteromedial left GP. Follow-up at 4 months showed no recurrent
syncopal event and no bradyarrhythmia episode on the implantable loop
recorder. Conclusion This case report demonstrates that ablation limited
to the right superior and posterior GPs may not be enough for
neurocardiogenic syncope and a more systematic approach, extending the
ablation to the posteromedial left GP, should be considered.%
\end{abstract}%



\sloppy


Cardioneuroablation: don't underestimate the posteromedial left atrial
ganglionated plexus.

Ciro Ascione MD \textsuperscript{1, 2}, L\selectlanguage{ngerman}éa Benabou
MD\textsuperscript{1}, Conrado Balbo MD \textsuperscript{1}, Tsukasa
Kamakura MD \textsuperscript{1}, Takamitsu Takagi MD\textsuperscript{1},
Philipp Krisai MD \textsuperscript{1},Romain Tixier MD
\textsuperscript{1}, Hugo Marchand MD \textsuperscript{1}, Benjamin
Bouyer MD \textsuperscript{1}, Clémentine André MD \textsuperscript{1},
Rémi Chauvel MD \textsuperscript{1}, Ghassen Cheniti
MD\textsuperscript{1}, Thomas Pambrun MD \textsuperscript{1}, Nicolas
Derval MD \textsuperscript{1},Frédéric Sacher MD,
PhD\textsuperscript{1}, Mélèze Hocini MD \textsuperscript{1}, Claudio
Tondo MD, PhD \textsuperscript{2}, Pierre Jaïs MD \textsuperscript{1},
Michel Haïssaguerre MD \textsuperscript{1}, Josselin Duchateau MD,
PhD\textsuperscript{1}

\textsuperscript{1}Hôpital Cardiologique Haut-Lévêque, CHU de Bordeaux,
L'Institut de RYthmologie et modélisation Cardiaque (LIRYC), Université
de Bordeaux, Bordeaux, France.

\textsuperscript{2}Department of Clinical Electrophysiology and Cardiac
Pacing, Centro Cardiologico Monzino, Istituto di Ricovero e Cura a
Carattere Scientifico, Milano, Italy

Corresponding author

Ciro Ascione, division of cardiac electrophysiology, CHU de Bordeaux,
Av. Magellan, 33604 Pessac

Email: ciroascione92@gmail.com

CONFLICT OF INTERESTS

The authors declare that there are no conflict of interests.

FUNDING

None

DATA AVAILABILITY STATEMENT

Data of this study are available upon reasonable request from the
corresponding author.

ABSTRACT

Introduction

Cardioneuroablation (CNA) is a technique used to modulate cardiac
parasympathetic tone in patients with sino-atrial (SA) and
atrio-ventricular (AV) vagally mediated syncope. We describe the case of
a patient who developed AV block after a first procedure of CNA,
requiring a second procedure.

Case presentation

A 47-Year-old man presented with recurrent syncope (daily episodes)
associated with high vagal tone conditions. An ECG monitoring showed
frequent episodes of sinus bradycardia and sinus arrest, with pauses up
to 17 seconds. AV node conduction impairment was never identified. A CNA
procedure targeting the right superior and posterior ganglionated plexi
(GPs), both from the left and right atrium, was performed with acute
success. The subsequent night, repetitive episodes of AV block with
normal sinus rate were observed. A second procedure was performed
targeting the posteromedial left GP. Follow-up at 4 months showed no
recurrent syncopal event and no bradyarrhythmia episode on the
implantable loop recorder.

Conclusion

This case report demonstrates that ablation limited to the right
superior and posterior GPs may not be enough for neurocardiogenic
syncope and a more systematic approach, extending the ablation to the
posteromedial left GP, should be considered.

Keywords: Cardioneuroablation, catheter ablation, syncope, vagal
denervation, ganglionated plexi.

CASE

A 47-year-old man, with a medical history of OSAS and gastric bypass
surgery for obesity presented repetitive episodes of reflex syncope.
These episodes first appeared in 2010 and were associated with
vegetative symptoms. Tilt table testing in another institution was able
to reproduce the reflex syncope and demonstrated a VASIS type 1 profile
(mixed response with drop in blood pressure and bradycardia, no
asystole). In 2018 episodes progressively increased in frequency, and
additional neurological investigation with an EEG and a brain MRI were
performed, without any abnormal findings. Syncopal episodes became
extremely frequent and recurred on a daily basis by the end of 2021. In
November 2021 the patient underwent a video EEG, during which vasovagal
sinus arrest was shown to precede the syncopal event (Figure 1 in the
data supplement). The patient was then referred to our institution.

Physical examination was completely normal, blood pressure was 120/80
mmHg. The ECG showed sinus rhythm at 67 bpm, normal AV and IV conduction
without repolarization alterations. Blood tests were unremarkable. He
was under budesonide/formoterol and salbutamol inhalation therapy for
asthma. During the ECG monitoring, different episodes of sinus
bradycardia and symptomatic sinus pauses were documented, lasting up to
17 seconds at night. Since all the episodes were concomitant to high
vagal status conditions and associated with parasympathetic signs and
symptoms, a CNA procedure under general anaesthesia was scheduled.

The patient was brought to the EP laboratory on January 26th, 2022. He
was in sinus rhythm at 59 bpm. A preliminary EP study showed borderline
SA nodal function (after a 1 minute of atrial pacing at 600 ms SNRT was
1460 ms, cSNRT was 420 ms). AV and HV intervals were respectively 50 and
46 ms, and the AV Wenckebach point (WP) was 540 ms.

The vagal nerve stimulation with a quadripolar catheter placed at the
level of the right jugular vein (Micropace system, frequency: 30 Hz,
pulse width: 0,5 ms, current intensity: 25 mA) elicited a moderate
response with a heart rate drop of 17 bpm (from 63 bpm to 46 bpm).

A map of both right and left atria (Figure 1) was obtained using a
multipolar catheter (PentaRay, Biosense Webster Inc, Diamond Bar, CA).
Ablation of the right superior and posterior ganglionated plexi (GP) was
performed using a CT-guided anatomical approach, both from left and
right atria. The CT segmentation was merged with the bi-atrial
electro-anatomical map.

After the ablation, the EP parameters were tested again, with an
improvement of SNRT (1060 ms, pacing at 600 ms) and WP at 360 ms. Right
vagal stimulation no longer elicited a significant heart rate drop.

During the first night after the procedure, the patient had a recurrent
episode of syncope with high grade AV block (Figure 2 in the data
supplement). Sinus bradycardia or arrest was no longer recorded.

The patient was brought back to the EP laboratory the next day for a
second procedure, this time under conscious sedation. Basal HR was 83
bpm. AH, HV, and PR intervals were respectively 50, 54, and 138 ms, the
AV WP was 320 ms and AV ERP was 250 ms for a baseline cycle length of
600 ms. Since general anaesthesia was not available vagal nerve
stimulation was not performed. The posteromedial left atrial GP was
targeted this time, at the level of the coronary sinus ostium, from the
right and left atria (Figure 2). After the ablation there was no
sensible change in basal HR, the PR interval was slightly reduced to 120
ms (AH 32 ms, HV 56 ms), the WP decreased to 290 ms and AVN ERP
decreased to below 200 ms.

A loop recorder (Biotronik BIOMONITOR) was implanted before discharge.
At 4 months of follow-up, no bradyarrhythmias or recurrent syncopal
episode were documented, and the patient has had no recurrent syncope.

LEARNING OBJECTIVES

To define the effect of different GPs on SA and AV function.

To understand the importance of ablating ganglia converging both on the
SA node and AV node.

To not overestimate the acute success indicators of CNA.

DISCUSSION

Cardioneuroablation is a treatment for neurocardiogenic syncope,
consisting of autonomic denervation via catheter ablation of GPs in both
left and right atria\textsuperscript{1}. Mainly described as a technique
to modulate sinoatrial bradyarrhythmia, recent evidence has also shown
efficacy for the treatment of vagally mediated AV
block\textsuperscript{2}.

GPs are embedded in epicardial fat pads\textsuperscript{3} and there is
no general consent on nomenclature. The ones commonly targeted,
according to the classification made by Armour et al\textsuperscript{3},
are the superior right atrial GP (SRGP) and the posterior right atrial
GP (PRGP), also referred as a single element, the right atrial GP
(RAGP), respectively on the posterior superior surface of the right
atrium adjacent to the superior vena cava and on the posterior surface
of the right atrium adjacent to the interatrial groove, the superior
left GP (SLGP) on the posterior surface of the left atrium between the
pulmonary veins, the inferior left GP (ILGP) located in the
inferoposterior area around the root of the left inferior pulmonary
vein, the posterior right atrial GP (PRGP) on the posterior surface of
the right atrium adjacent to the interatrial groove and the
posteromedial left atrial GP (PMLGP) located between coronary sinus
ostium and lower part of the LA\textsuperscript{3,4}.

In canine models, there was a predominance of right vagal projections
ending on SA nodal tissue\textsuperscript{5}. The posterior and superior
right GPs have been demonstrated to mediate vagal influences
preferentially via the SA node \textsuperscript{5,6}, and SRGP
stimulation in humans has shown to affect the SA node activity without
AH interval prolongation \textsuperscript{7,8}. In animal models, the
sole ablation of the SRGP has been shown to mitigate both the right and
left vagal nerve stimulation-induced bradycardia, but to reduce only
right vagal nerve mediated AH interval prolongation, without significant
effect on the left vagal nerve influence\textsuperscript{9}. In humans,
there were no statistical differences in heart rate modification after
SLGP, ILGP, and RIGP ablation, whereas heart rate increased
significantly after SRGP (which was referred as right anterior GP)
ablation\textsuperscript{10}. For this reason, Right Superior and Right
Posterior GPs are considered by some authors as the primary targets of
cardioneuroablation.

On the other hand, stimulation of the left vagus nerve elicited a
greater change in AV conduction time than did right vagal
stimulation\textsuperscript{11}. In addition, supramaximal left vagal
stimulation is more likely to produce severe AV block than right vagal
stimulation\textsuperscript{12}. Based on different canine studies, this
effect seems to be mediated through the Postero-Medial Left GP (PMLGP),
located at the inferior vena cava - left atrial junction, in close
proximity to the CS ostium\textsuperscript{5,6}.

Our patient had repetitive episodes of SA bradycardia and SA block,
without AV conduction alterations. There is currently no consensus on
how to perform CNA, hence our initial approach was conservative, and
anatomically guided ablation\textsuperscript{13} was restricted to the
Right Superior and Right Posterior GPs, which innervate the SAN. For the
same principle and the mentioned physiological reasons, vagal
stimulation was performed only from the right side.

This case report demonstrates that ablation restricted to the SRGP/PRGP
may not be enough for neurocardiogenic syncope due to sinus arrest, even
after what could be considered a good acute outcome. Functional AV block
may be masked by the concomitant SA bradyarrhythmia. A more systematic
approach, extending the ablation to the PMLGP, should be considered.

REFERENCES

1. Pachon M., J. C. \emph{et al.} `Cardioneuroablation' - New treatment
for neurocardiogenic syncope, functional AV block and sinus dysfunction
using catheter RF-ablation. \emph{Europace} \textbf{7} , 1--13 (2005).

2. Aksu, T., Gopinathannair, R., Bozyel, S., Yalin, K. \& Gupta, D.
Cardioneuroablation for Treatment of Atrioventricular Block. \emph{Circ.
Arrhythmia Electrophysiol.} 841--850 (2021)
doi:10.1161/CIRCEP.121.010018.

3. Armour, J. A., Murphy, D. A., Yuan, B. X., Macdonald, S. \& Hopkins,
D. A. Gross and microscopic anatomy of the human intrinsic cardiac
nervous system. \emph{Anat. Rec.} \textbf{247} , 289--298 (1997).

4. Pauza, D. H., Skripka, V., Pauziene, N. \& Stropus, R. Morphology,
distribution, and variability of the epicardiac neural ganglionated
subplexuses in the human heart. \emph{Anat. Rec.} \textbf{259} ,
353--382 (2000).

5. Ardell, J. L. \& Randall, W. C. Selective vagal innervation of
sinoatrial and atrioventricular nodes in canine heart. \emph{Am. J.
Physiol. - Hear. Circ. Physiol.} \textbf{251} , 3--5 (1986).

6. Lazzara, R., Scherlag, B. J., Robinson, M. J. \& Samet, P. Selective
in situ parasympathetic control of the canine sinoatrial and
atrioventricular nodes. \emph{Circulation research} vol. 32 393--401
(1973).

7. Carlson, M. D. \emph{et al.} Selective stimulation of parasympathetic
nerve fibers to the human sinoatrial node. \emph{Circulation}\textbf{85}
, 1311--1317 (1992).

8. Quan, K. J. \emph{et al.} Characterization of sinoatrial
parasympathetic innervation in humans. \emph{J. Cardiovasc.
Electrophysiol.} \textbf{10} , 1060--1065 (1999).

9. Hanna, P. \emph{et al.} Innervation and Neuronal Control of the
Mammalian Sinoatrial Node a Comprehensive Atlas. \emph{Circ.
Res.}1279--1296 (2021) doi:10.1161/CIRCRESAHA.120.318458.

10. Hu, F. \emph{et al.} Right anterior ganglionated plexus: The primary
target of cardioneuroablation? \emph{Hear. Rhythm} \textbf{16} ,
1545--1551 (2019).

11. Irisawa, H., Caldwell, W. M. \& Wilson, M. F. Neural regulation of
atrioventricular conduction. \emph{Jpn. J. Physiol.} \textbf{21} ,
15--25 (1971).

12. Hamlin, R. L. \& Smith, C. R. Effects of vagal stimulation on S-A
and A-V nodes. \emph{Am. J. Physiol.} \textbf{215} , 560--568 (1968).

13. Piotrowski, R., Baran, J. \& Ku\selectlanguage{polish}ł\selectlanguage{english}akowski, P. Cardioneuroablation
using an anatomical approach: A new and promising method for the
treatment of cardioinhibitory neurocardiogenic syncope. \emph{Kardiol.
Pol.} \textbf{76} , 1736--1738 (2018).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1

Three-dimensional mapping of the right and left atria at the time of the
first procedure. White dots represent phrenic nerve capture at high
output pacing, red dots represent ablation sites.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure
2

Three-dimensional mapping of the right and left atria at the time of the
second procedure. Red dots represent ablation sites.

\selectlanguage{english}
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