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\begin{document}

\title{Repeat Cardioneuroablation for Recurrent Syncope}



\author[1]{Clinton Thurber}%
\author[1]{Nathaniel Steiger}%
\author[2]{Davis R. Sneider}%
\author[1]{Sunil Kapur}%
\affil[1]{Brigham and Women's Hospital}%
\affil[2]{Abbott Laboratories}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\selectlanguage{english}
\begin{abstract}
Introduction: Some patients suffer recurrent syncope following
cardioneuroablation (CNA) for vasovagal syncope (VVS), yet no cases of
repeat CNA have been described in detail. Methods and Results: Our
present patient suffered a recurrence seven months following successful
CNA and wished for a repeat CNA. Pre-procedurally, she lacked an
atropine response. During CNA, high-frequency stimulation (HFS) at
ganglionated plexi (GP) would not trigger cardioinhibitory events.
Ablation was delivered based on anatomy and fractionation mapping,
producing characteristic tachycardia at 2 GP sites. Conclusion: Repeat
CNA is feasible and safe, and characterized by unique physiology.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Cardioneuroablation (CNA) is emerging as a compelling new management
option for vasovagal syncope (VVS), one which has grown increasingly
prevalent since the first US case was described only three years ago
(1,2). The largest CNA cohorts have reported promising success,
describing recurrent syncope at rates ranging from only 0-27\% on
long-term follow up (3-6). Many patients suffering from VVS are young,
and standard-of-care management is often ineffective or overly
burdensome. CNA may be a promising new option for this segment of the
VVS population; however, the question of how to treat the minority who
faint again post-CNA must be confronted. To this point, there have been
no published reports in the literature describing in detail a repeat CNA
procedure in patients with recurrent syncope post-CNA. Herein we
describe such a case, our diagnostic findings, and procedural approach.

\textbf{Case Report}

A 20-year-old woman with VVS suffered recurrent cardioinhibitory syncope
seven months after successful CNA (see Fig 1), the details of which are
published elsewhere (7). Evaluation of her ILR data at the time of
recurrence revealed both HRV and average ventricular rate gradually
trending back toward baseline pre-CNA levels, after having initially
dropped off following CNA (see Fig 2). On her subsequent clinic visit, a
thorough discussion was held with the patient and her mother, during
which time she expressed a strong desire to re-attempt CNA.

She presented to the EP suite again in a fasting state, and the same
preparations were made. She was administered atropine 0.5 mg; however,
her HR increased from 51 beats per minute (BPM) to only 60 BPM. After
ruling out administration errors and waiting approximately 20 minutes, a
second dose of atropine 0.5 mg was administered, and again no
significant HR response was observed. These findings were in stark
contrast to those of her index procedure, when a single dose of atropine
0.4 mg increased her HR by 81\% (7). A transseptal puncture was
performed in the usual fashion. Fractionation mapping was then
undertaken, resulting in the same annotated fractionation areas as in
the first CNA (see Fig 3A). High-frequency stimulation (HFS) was applied
to each of the ganglionated plexi (GP); however, this time, slow
junctional responses could not be reliably elicited from any GP sites,
except for a single junctional beat following HFS from the posterior RA
GP. Ablation at both the posterior RA GP and along the anterior RSPV
acutely increased the HR by approximately 10 BPM, suggestive of further
vagal denervation (see Fig 3B). Of note, the anterior RSPV lesions
covered a broader area than in the index CNA. RF ablation was applied at
each of the GP sites, due to sparse new diagnostic data in support of
any given site, and with cognizance that this was a repeat procedure
(see Fig 3C). Atropine was again administered at the end of ablation,
and the patient's HR paradoxically dropped from 78 BPM to 40 BPM in
response. Isoproterenol 10 mcg was given as a bolus, and HR increased to
\textgreater{}100 BPM. A 12-lead ECG obtained in the post-procedural
recovery area recorded normal sinus rhythm, HR 65 BPM, with all measured
intervals within normal range.

On follow up 2 months after her repeat CNA, she reported feeling quite
well, with no further syncope events. Her ILR again demonstrated an
abrupt decrease in HRV, although its ensuing ascent was steeper than the
pattern following her initial procedure (see Fig 2B). Further, there was
not a sustained increase in her average ventricular rate, unlike her
spike following her first CNA (7).

\textbf{Discussion}

While VVS in young patients represents a management challenge, recurrent
VVS post-CNA poses an even greater dilemma. Repeat CNA has not yet been
reported in the nascent literature on this novel approach; the present
case is the first such report to our knowledge.

The first interesting aspect of the present case was the inability to
pharmacologically suppress vagal tone in pre-procedural testing, despite
both her ILR data and clinical recurrence demonstrating its return (see
Figs 1 and 2). This ``reinnervation'' phenomenon has been previously
described in AF populations treated via GP ablation, including the same
HRV trend back to pre-procedural values (8). However, AF suppression in
these patients remained durable despite recovery of GP inputs. The
underlying mechanism is not well understood; indeed, our present patient
was autonomically denervated, after which her ILR data exhibited gradual
reinnervation (Fig 2). Unlike the AF cohorts, however, she suffered
clinical relapse.

As such, one might expect to find at least one endocardial site behaving
similarly to her GP in the initial procedure, perhaps suggesting that
ablation had been incomplete, or that some GP connections had been
missed. Yet after she failed to generate a tachycardic response to
serial doses of atropine, she could not reproduce her junctional
responses to HFS at GP sites. The significance of this finding is not
entirely clear, although one explanation is that her reinnervation
process may have been characterized by a ``re-growth'' of injured vagal
inputs, perhaps with altered functional properties, or possibly a
scenario where alternative plexi gradually took over cardiac vagal
function. Yet during the RF phase of the procedure, in which her GP were
largely targeted anatomically due to lack of a response to HFS, it was
notable that two of her GP (posterior RA and right anterior GP)
exhibited accelerated sinus rates in response to RF. During her first
procedure, all five GP had clearly accelerated.

One limitation of our present report is that current protocols favoring
atropine administration for vagal testing may be fallible, and one
practice favors administration of atropine 1-2 days in advance of the
procedure. Given her lack of chronotropic response to atropine on this
second CNA, it is not clear that advance administration would have
changed the responses, nor is it clear that the absent junctional
responses to HFS at previously-responsive GP were simply blunted
pharmacologically, by the same rationale. One promising albeit primitive
alternative to atropine testing is extracardiac vagal stimulation
(ECVS), performed by applying high-amplitude, high-frequency pulses from
within the lumen of the right internal jugular vein to achieve transient
asystole or atrioventricular block. A report from a Brazilian group
found GP-ablated patients significantly less responsive to the maneuver
at the end of the procedure than a control group, suggesting significant
vagal denervation (9). It is of course theoretically possible that, had
our present patient been tested either at the end of her first CNA or
the beginning of her second, ECVS might have revealed some lingering
vagal inputs, perhaps at the GP which produced HR increases on second
CNA, although this is only speculative.

A second limitation in the present case may have been simply related to
patient selection, the optimal approach to which is widely acknowledged
to be an enigma in CNA. Early work in a post-CNA population with
recurrent syncope found nocturnal deceleration capacity, calculated from
interval differences in R waves from signal-averaged ECGs, to be
predictive of recurrent VVS in post-CNA patients (6).

The pace of progress in CNA is encouraging; however, larger prospective
studies are needed to better understand the post-CNA population with
recurrent VVS.

\textbf{Conclusion}

Herein we report the first detailed case of repeat CNA in a patient with
recurrent VVS despite successful CNA seven months prior. Repeat CNA
after recurrent VVS is both feasible and safe. It may be characterized
by a blunted chronotropic response to atropine and a failure to
redemonstrate bradycardic responses to HFS. It may reproduce
chronotropic evidence of vagal denervation after prior post-CNA recovery
of the same. Repeat CNA lacks well-defined patient selection criteria
and consensus procedural protocols, including optimal means of vagal
denervation testing. The present case underscores the importance of
elucidating these measures.

\textbf{Acknowledgements:} none

\textbf{References:}

\begin{enumerate}
\item
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  Ablation for Refractory Vasovagal Syncope: First U.S. Report. JACC
  Case Rep. 2020 Jun 10;2(8):1161-1165. doi:
  10.1016/j.jaccas.2020.04.022. PMID: 34317439; PMCID: PMC8311716.
\item
  Aksu T, De Potter T, John L, et al. Procedural and short-term results
  of electroanatomic-mapping-guided ganglionated plexus ablation by
  first-time operators: A multicenter study. J Cardiovasc
  Electrophysiol. 2022 Jan;33(1):117-122. doi: 10.1111/jce.15278. Epub
  2021 Oct 25. PMID: 34674347.
\item
  Pachon JC, Pachon EI, Cunha Pachon MZ, Lobo TJ, Pachon JC, Santillana
  TG. Catheter ablation of severe neurally meditated reflex
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  results. Europace. 2011 Sep;13(9):1231-42. doi:
  10.1093/europace/eur163. Epub 2011 Jun 28. PMID: 21712276.
\item
  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 Jul
  8;5(7):e003471. doi: 10.1161/JAHA.116.003471. PMID: 27402231; PMCID:
  PMC5015383.
\item
  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 Jan;7(1):1-13.
  doi: 10.1016/j.eupc.2004.10.003. PMID: 15670960.
\item
  Tu B, Wu L, Hu F, et al. Cardiac deceleration capacity as an indicator
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  10.1016/j.hrthm.2021.12.007. Epub ahead of print. PMID: 34896621.
\item
  Thurber CJ, Sneider DR, Sauer WH, Kapur S. Recurrent Vasovagal Syncope
  Following Successful Cardioneuroablation. HeartRhythm Cas Rep; 2022.
  doi: 10.1016/j.hrcr.2022.04.001
\item
  Stavrakis S, Po S. Ganglionated Plexi Ablation: Physiology and
  Clinical Applications. Arrhythm Electrophysiol Rev. 2017
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  PMC5739885.
\item
  Pachon-M EI, Pachon-Mateos JC, Higuti C, et al. Relation of
  Fractionated Atrial Potentials With the Vagal Innervation Evaluated by
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\item
\end{enumerate}

\textbf{Figures and Legends}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1: Syncopal events.} A) \emph{Pre-cardioneuroablation
(CNA) syncope:} The patient's implantable loop recorder (ILR) recorded
gradual sinus slowing followed by 13 seconds of sinus arrest with
asystole, causing syncope. B) \emph{Post-CNA syncope:} 7 months after
successful CNA, the ILR recorded gradual sinus slowing leading to
junctional beats followed by 7 seconds of sinus arrest with asystole,
causing syncope.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2: Ventricular Rate and Heart Rate Variability (HRV).}The
patient's implantable loop recorder (ILR) recorded an abrupt increase in
her average ventricular rate and an abrupt decrease in her HRV upon
initial cardioneuroablation (CNA). In the months following, the
patient's ILR recorded a gradual regression to pre-procedural values in
both average ventricular rate and heart rate variability, culminating in
her recurrent syncopal event over 7 months later. On repeat CNA, she
again exhibited an abrupt drop in HRV, though without a sustained rise
in her average ventricular rate.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3:} \textbf{Procedural Data.} A) \emph{Fractionation
maps:} The ganglionated plexi (GP) were found in the same locations as
in her first cardioneuroablation (CNA), at the posterior right atrial
(RA) GP, posteromedial RA GP, left anterior GP, left inferior GP, and
right anterior GP, correlating with expected anatomy.
B)\emph{Radiofrequency (RF) ablation:} At the posterior RA GP, she
exhibited a tachycardic response to RF characteristic of vagal
denervation. C) \emph{Final lesion set:} Due to a lack of high-frequency
stimulation (HFS) responses, repeat CNA was performed based on anatomy
and fractionation mapping.

\textbf{Hosted file}

\verb`Redo CNA - figures combined_DS.pptx`  available at \url{https://authorea.com/users/487255/articles/571896-repeat-cardioneuroablation-for-recurrent-syncope}

\selectlanguage{english}
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