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\begin{document}

\title{Role of intracardiac defibrillation during the procedure as a predictor
of atrial fibrillation recurrence after catheter ablation}



\author[1]{Shintaro Yao}%
\author[2]{Hideki Koike}%
\author[3]{Tadashi Fujino}%
\author[3]{Ryo Wada}%
\author[4]{Katsuya Akitsu}%
\author[3]{Masaya Shinohara}%
\author[3]{Toshio Kinoshita}%
\author[3]{Takanori Ikeda}%
\affil[1]{Toho University Faculty of Medicine }%
\affil[2]{Toho University Faculty of Medicine}%
\affil[3]{Toho university faculty of medicine}%
\affil[4]{toho university faculty of medicine}%


\vspace{-1em}



  
  \date{May 08, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Introduction: Intracardiac defibrillation (IDF) is performed to restore
sinus rhythm (SR) during radiofrequency catheter ablation (RFCA) of
atrial fibrillation (AF). This study aimed to examine the change in the
IDF threshold before and after RFCA during the procedure, and
furthermore, to evaluate whether the IDF threshold after RFCA was
associated with the AF substrate and recurrence of AF. Method: This
study enrolled 141 consecutive patients with drug-refractory persistent
AF (age 62.5\selectlanguage{ngerman}±10.3 years, 84.4\% male). Before the RFCA, we initially
performed IDF with an output of 1 J. When the defibrillation failed to
restore SR, the output was gradually increased up to 30 J. After RFCA,
we attempted pacing-induced AF to provoke other focuses of AF. When AF
was induced, we again performed IDF to terminate the AF with outputs of
1 to 30 J. The change in the IDF threshold to restore SR before and
after RFCA was assessed. Results: The IDF threshold for restoring SR
significantly decreased after RFCA (from 11.5±8.6 J to 4.0±3.8 J, p
\textless{} 0.001). During the follow-up (24.3±12.2 months), SR was
maintained in 107 patients (75.9\%). A multivariate analysis using a Cox
proportional hazards model revealed that an IDF threshold of
\textgreater{} 5 J after the RFCA was significantly associated with
recurrence of AF (HR, 3.99; 95\% CI 1.93-8.22; p=0.0001). Conclusion:
RFCA decreased the IDF threshold for restoring SR in patients with
persistent AF. IDF outputs of \textgreater{} 5 J after RFCA could be a
predictor of AF recurrence independent of the AF substrate.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

Radiofrequency catheter ablation (RFCA) has been shown to be more
efficacious than drug therapy in restoring sinus rhythm (SR) in patients
with atrial fibrillation (AF). Compared to the other ablation
strategies, pulmonary vein isolation (PVI) is a more basic
strategy.\textsuperscript{1} Furthermore, a trigger ablation is one of
the strategies for AF ablation, which is effective for eliminating
AF.\textsuperscript{2} Isoproterenol (ISP) is often used to induce AF
triggers.\textsuperscript{3} In addition, defibrillation of induced AF
is performed to identify the site of the trigger of spontaneously
occurring AF. In those procedures, intracardiac defibrillation (IDF) is
often performed to restore SR during RFCA of AF.\textsuperscript{4}

There have been many studies about cardioversion of AF, such as
regarding the relationship between the defibrillation threshold and
maintaining SR in patients without RFCA.\textsuperscript{5-11} On the
other hand, many other studies have pointed out the relationship between
AF recurrence after RFCA and the substrate, such as the left atrium (LA)
size and low voltage zones (LVZs). However, a few studies have shown the
relationship between the IDF threshold and recurrence of AF after RFCA.
Furthermore, there have been no studies to assess the relationship
between the IDF and LA substrate. This study aimed to examine the change
in the IDF threshold before and after RFCA for eliminating persistent AF
during the procedure. Additionally, we evaluated whether the IDF
threshold after RFCA was associated with the recurrence of AF and the AF
substrate after the ablation procedure in patients with persistent AF.

\textbf{Methods}

\textbf{Study population and study design}

This study enrolled 141 consecutive patients with drug-refractory
persistent AF (age 62.5 \selectlanguage{ngerman}± 10.3 years, 84.4\% male), who underwent RFCA
between January 2013 and December 2015, in our institute. Persistent AF
was defined as AF that was sustained beyond 7 days (including
long-standing persistent AF) according to the
guidelines.\textsuperscript{12} The study patients were followed up for
at least 1 year after the AF ablation.

If AF was terminated before the RFCA, we artificially induced AF by high
rate burst pacing with a high dose ISP infusion (starting at 5 \selectlanguage{greek}µ\selectlanguage{english}g and
increasing it up to 10 \selectlanguage{greek}µ\selectlanguage{english}g and 20 \selectlanguage{greek}µ\selectlanguage{english}g/minute), and we initially performed
IDF to identify the earliest site of the trigger premature atrial
contraction (PAC) with spontaneously occurring AF. Defibrillation was
performed with an output of 1 J. If the defibrillation failed to restore
SR with the low output, the output was gradually increased up to 30 J
(1, 3, 5, 10, 15, 20, and 30 J). After the RFCA, we attempted
pacing-induced AF again to provoke other focuses of AF. When AF was
induced artificially, we performed IDF again to terminate the AF with
outputs of 1 to 30 J after we waited for two minutes. A change of IDF
threshold to restore SR before and after RFCA was assessed. Furthermore,
we investigated the relationship between the IDF threshold and
recurrence of AF after RFCA.

This clinical study was a retrospective analysis of prospectively
collected AF ablation data. The study protocol was approved by the
Institutional Review Board (IRB) of Toho University Medical Center Omori
Hospital (approval number: M20068). This study was a retrospective
observational study, carried out by the opt-out method on our hospital
website.

\textbf{Ablation procedure}

Anti-arrhythmic drug (AAD) therapy was stopped at least five half-lives
before the ablation. Patients on oral anticoagulation stopped their
medications on the day of the ablation. Study patients underwent
transesophageal echocardiography to ensure no thrombus in the atrium or
left atrial appendage 24h before the ablation.

A 7Fr 20-pole 3-site mapping catheter (BeeAT\textsuperscript{}, Japan
Lifeline, Tokyo, Japan) was inserted into the coronary sinus (CS) via
the right jugular vein. IDF could be performed with the a
BeeAT\textsuperscript{} catheter. Further, catheters were introduced
percutaneously through the femoral vein, and a transseptal puncture was
performed after verifying the absence of a patent foramen ovale to
access the LA. After the transseptal access, a bolus of intravenous
heparin (5,000 IU) was administered, with an additional bolus to
maintain an activated clotting time of more than 350
s.\textsuperscript{13} We used propofol and dexmedetomidine during
ablation to obtain deep sedation. We used high dose ISP with a
continuous administration to investigate the trigger of the AF before
the RFCA. If AF was not present, we effectively induced AF artificially
by high rate burst pacing during an ISP infusion. After the AF sustained
for more than two minutes, IDF was performed to restore SR. After that,
we identified the earliest site of the trigger PAC with spontaneously
occurring AF. If reproducible, the trigger was identified as an AF foci.
We performed a PVI in all patients. When we detected non-PV foci, we
added a focal ablation to that site. After the RFCA, we used high dose
ISP and high rate burst pacing to artificially induce AF. After the AF
was artificially induced, we again performed IDF with 1 to 30 J to
restore SR. The endpoint of our ablation was the absence of spontaneous
AF occurring after the ISP infusion.

All the patients underwent an enlarged PVI in order to achieve voltage
abatement of the electrograms in the encircled areas. Radiofrequency
current was delivered with an irrigated-tip ablation catheter
(FlexAbility\textsuperscript{TM}; Abbott, Minneapolis, MN or
Thermocool\textsuperscript{}, Biosense Webster, Inc., Diamond Bar, CA,
USA) through another long sheath under the guidance of a 3-dimensional
(3D) cardiac mapping system (EnSite Precision\textsuperscript{TM},
Abbott or CARTO3, Biosense Webster).

\textbf{IDF}

We used the BeeAT\textsuperscript{} catheter and a dedicated
defibrillator (Shock AT\textsuperscript{}, Japan Lifeline, Tokyo,
Japan). which together constituted the IDF system approved for use in
Japan (\emph{Figure 1} ). The BeeAT\textsuperscript{} catheter has 20
poles consisting of a distal set of 8 poles, middle set of 8 poles, and
proximal set of 4 poles. The distal 8 poles are positioned in the distal
CS and middle 8 poles along the lateral wall of the right atrium (RA).
The proximal 4 poles are positioned in the superior vena cava (SVC) and
record the SVC activity during the procedure. We selected the catheter
sizes (S, M, and L) to fit the LA and RA size of the patients.
Cardioversion was effective with a current delivery between those distal
and middle sets of electrodes, but they were also able to record the
local electrograms.

For cardioversion, a biphasic direct current was delivered between the
distal set and the middle set of electrodes synchronized to the R wave
of the body surface electrocardiogram. If cardioversion was not
possible, we changed the lead of the body surface electrocardiogram to
detect and synchronize to any R wave. We started the IDF output at 1 J
and went up to 3, 5, 10, 15, 20, and 30 J. The maximum energy output was
30 J with this system. We performed IDF under deep sedation with
propofol and dexmedetomidine. When the blood pressure was low, we used
phenylephrine.

\textbf{Long-term follow-up}

All patients were followed up for at least 12 months. We saw all
patients at every 0.5, 1, 2, 3, 4, and 6 months, and every 6 months
thereafter. Anticoagulation drugs were also used for at least 3 months
and were continued based on the patients' risk for thrombus embolisms
determined using the CHADS\textsubscript{2} or
CHA\textsubscript{2}DS\textsubscript{2}-VASc
score.\textsuperscript{12}Each doctor decided whether or not to use
AADs. The 12-lead electrocardiogram (ECG) and clinical assessments were
performed at each visit. Further, 24h-Holter monitoring was performed at
0.5, 1, 2, 3, and 6 months after the initial ablation and every 6 months
thereafter. The study patients were asked to record all episodes of any
symptoms suggestive of arrhythmias such as palpitations, dizziness, or
shortness of breath and report that to us as soon as possible. In such
cases, an immediate ECG and 24 h Holter monitoring at the nearest clinic
during the symptomatic period were suggested. Recurrence was defined as
atrial arrhythmia episodes including AF, atrial flutter, and other
atrial tachycardias lasting more than 30s after the first 3-month
blanking period.

\textbf{Statistical analysis}

All continuous data were expressed as means \selectlanguage{ngerman}± standard deviation,
medians (quartile: 25-75\%), or numbers (expressed as percentage, \%).
The comparison between groups was analyzed using univariate (unpaired
Student's \emph{t} -test and Fisher's exact test) and multivariate
analyses with a Cox hazard model. A \emph{p} -value of \textless{} 0.05
was considered statistically significant. Recurrence curves were plotted
using the Kaplan-Meier method. All statistical analyses were performed
with R commander, which is a graphical user interface for R (Saitama
Medical Center, Jichi Medical University, Saitama, Japan).

\textbf{Results}

\textbf{Baseline characteristics and AF recurrence after RFCA}

The mean age was 62.5 ± 10.3 years, 119 (84.4\%) were male, and the body
mass index (BMI) was 24.6 ± 3.3 kg/m\textsuperscript{2}. The mean
CHADS\textsubscript{2} and CHA\textsubscript{2}DS\textsubscript{2}-VASc
scores were 1.3 ± 1.1 and 2.1 ± 1.5, respectively. The mean left atrial
diameter (LAD) was 43.2 ± 6.3 mm, and the left ventricular ejection
fraction (LVEF) was 64.6 ± 10.5\%. Those baseline characteristics are
listed in \emph{Table 1} .

The mean follow-up period after the procedure was 24.3 ± 12.2 months.
One hundred seven patients (75.9\%) were in SR and 34 (24.1\%) developed
an AF recurrence. As shown in \emph{Table 1} , the AF recurrence group
had a longer duration of AF, higher use rate of AADs after the RFCA, and
higher IDF threshold after the RFCA as compared to that in the
no-recurrence group (\emph{p} \textless{} 0.05). However, there were no
significant differences in the age, sex distribution, BMI,
CHADS\textsubscript{2} score, Creatinine, brain natriuretic peptide
(BNP), LAD, LVEF, non-PV foci, and IDF threshold before the RFCA between
the two groups.

\textbf{RFCA and IDF}

AF was induced artificially in all patients after the RFCA to provocate
AF triggers. The IDF threshold to restore SR was significantly decreased
after the RFCA (from 11.5 ± 8.6 J to 4.0 ± 3.8 J, \emph{p} \textless{}
0.001). There was no difference in the IDF threshold between the
recurrence and no-recurrence groups before the RFCA (\emph{Table 1} ),
however, the threshold in the no-recurrence group was significantly
lower than that in the recurrence group after the RFCA as shown
in\emph{Figure 2} . A cut-off point analysis showed that as IDF
threshold after the RFCA of \textgreater{} 5 J was the optimal point
that discriminated those with AF recurrence from the rest of the
participants as shown in \emph{Figure 3} (sensitivity 68.0\% and
specificity 65.2\%). We divided the patients into two groups according
to IDF outputs of \selectlanguage{english}[?] 5 J or \textgreater{} 5 J. Of all the patients, the
number of patients whose IDF output that restored SR was \selectlanguage{english}[?] 5 J was 117.
\emph{Table 2}shows that the IDF threshold before the RFCA, LAD, and BNP
in the patients with an output of \selectlanguage{english}[?] 5 J were significantly lower than
those in the patients with an output of \textgreater{} 5 J. On the other
hand, there were no significant differences in the LVEF, duration of AF,
and non-PV foci between the two groups. The presence of an LVZ in the LA
significantly differed between the two groups (17 patients, 14.5\% vs. 8
patients, 33.3\%, \emph{p} = 0.039).

The recurrence rate of AF was significantly higher in the patients with
an output of \textgreater{} 5 J than in those with an output of \selectlanguage{english}[?] 5 J
(22 patients, 18.8\% vs. 12 patients, 50\%, \emph{p} = 0.003). Further,
the Kaplan-Meier model showed that an IDF threshold after RFCA of
\textgreater{} 5 J was associated with a recurrence of AF
(\emph{p}\textless{} 0.001) as shown in \emph{Figure 4} .

A multivariate analysis using Cox proportional hazards models (models 1
and 2) after adjusting for the patient background, LAD, duration of AF,
and use rate of AADs after the RFCA, revealed that an IDF threshold of
\textgreater{} 5 J after the RFCA (HR, 3.99; 95\% CI 1.93 -
8.22;\emph{p} = 0.0001) was significantly associated with recurrence of
AF (\emph{Table 3} ).

\textbf{Discussion}

\textbf{Main Findings}

The main findings were as follows. First, the IDF threshold to restore
SR in patients with persistent AF was significantly decreased after the
RFCA. Second, the IDF threshold in the no-recurrence group was
significantly lower than that in the AF recurrence group, however,
before the RFCA, there was no difference in the IDF threshold between
the recurrence and no-recurrence groups. Third, the outputs of the IDF
(threshold \textgreater{} 5 J) after RFCA were an independent predictor
of a recurrence of AF.

\begin{CJK}{UTF8}{gbsn}\textbf{IDF and AF　}

\end{CJK}\selectlanguage{english}Some reports have assessed the efficacy and safety of transvenous
internal atrial cardioversion performed in patients with persistent
AF.\textsuperscript{14, 15} The IDF is an effective procedure for
restoring SR in patients with AF.\textsuperscript{6} Further, there are
few complications with IDF. Boriani G etc. reported myocardial injury
following repeated internal atrial
defibrillations.\textsuperscript{16}Although, minor elevations in the
troponin I level were detected, it suggested minor asymptomatic
myocardial injury. There was no relationship between an elevated
troponin I level and the number of shocks or amount of energy delivered.
Therefore, the BeeAT\textsuperscript{} catheter and dedicated
defibrillator could be used multiple times for IDF, and because of that
they are useful for checking triggers. The maximum energy output of this
system was 30 J. Although the mean number of IDFs was 9.1 \selectlanguage{ngerman}± 7.5 times
(max 28 times) per RFCA procedure, there were no complications
associated with the IDF in our study. All patients were restored to
sinus rhythm by the IDF with an output of less than 30 J.

The electrode position for the outcome of the IDF was very important.
Thus, low-energy biphasic shocks positioned between the RA and CS were
effective for cardioverting AF. The distal 8 poles of the
BeeAT\selectlanguage{english}\textsuperscript{} catheter were positioned in the distal CS and
the middle 8 poles along the lateral wall of the RA. We selected the
different catheter sizes (S, M, and L) to fit the LA and RA size of the
patients. Therefore, an appropriate IDF could be performed in this
study. Furthermore, the IDF was less affected by the LA size than by an
external defibrillation catheter that fit the LA
size.\textsuperscript{6}

\textbf{IDF and AF substrate}

The factors for the persistence of AF are regarded as trigger factors
and arrhythmogenic substrate factors, which play a role as an AF
perpetuator.\textsuperscript{17, 18} The triggers generally initiate AF
and the substrate plays a critical role in AF persistence. Therefore, as
the AF duration prolongs, LA remodeling proceeds, and the AF substrates
increase. Thus, the success rate of AF cardioversion is inversely
correlated to the LA size, because the fibrosis accompanying atrial
dilatation increases the AF substrate.\textsuperscript{19} There are
many reports about predictors associated with recurrence of AF after
electrical cardioversion, such as the LA size, age, and
BNP.\textsuperscript{20-22} However, there are few reports on
cardioversion after AF ablation.

In the present study, RFCA significantly decreased the IDF threshold for
restoring SR (Figure 1). The conditions for IDF were the same before and
after the RFCA; we induced AF artificially with high rate burst pacing
and ISP. After the AF sustained for more than two minutes, IDF was
performed to detect any AF triggers. Although the main strategy for RFCA
in our institute is an AF trigger ablation, an extensive encircling PVI
or posterior wall isolation might decrease the AF substrate. That
suggests that RFCA could eliminate or decrease both AF triggers and the
substrate, and further, it could decrease the cardioversion threshold.
Thus, the difference in the cardioversion threshold before and after
RFCA may reflect the elimination of the AF substrate and triggers. There
were some cases with LA enlargement but without a low voltage area in
our study. In those cases, the IDF threshold could reflect the AF
substrate, which could not be assessed by electrophysiology.
Additionally, our study revealed that the lower output IDF (\selectlanguage{english}[?] 5 J) group
after the RFCA was associated with a lower recurrence of AF. In fact, in
patients with an output \textgreater{} 5 J, the LAD was larger, and
there was a greater presence of an LVZ in the LA. Thus, the LA
remodeling proceeded in those patients. An IDF threshold of
\textgreater{} 5 J was a strong predictor of AF recurrence in a
multivariate analysis after adjusting for the patient background, LAD,
LVZ, duration of AF, and administration of AADs after the RFCA.
Furthermore, the presence of an LVZ disappeared in the multivariate
analysis model 1. Additionally, the ablation strategies (such as an SVC
isolation, posterior wall isolation, and focal ablation) did not have
any significant value for detecting AF recurrence or the IDF threshold
(\emph{Tables 1 and 2} ). The IDF method was useful for assessing
whether RFCA could decrease the AF substrate during the RFCA procedure.

\textbf{AF recurrence and other factors}

AADs after RFCA were a strong confounding factor for an AF recurrence.
In our study, the LA size in the patients with an output of
\textgreater{} 5 J was larger than that in those with an output of \selectlanguage{english}[?] 5
J. However, the IDF threshold remained as an independent predictor of an
AF recurrence. These findings suggested that a greater AF substrate
remained in the patients with an output \textgreater{} 5 J after the
RFCA. On the other hand, there was no significant difference in the
presence of non-PV foci between the patients with an output of \selectlanguage{english}[?] 5 J and
those with an output \textgreater{} 5 J. In addition, the LA size was
not associated with AF recurrence, however, the LA size was larger in
the patients with an output of \textgreater{} 5 J. Those findings
suggested that not only eliminating AF triggers but also approaching the
LA substrate were important, because those patients with an output of
\textgreater{} 5 J had a higher rate of AF recurrence and greater AF
substrate. Recent studies have demonstrated that the efficacy of
substrate ablation is questionable.\textsuperscript{23, 24} In our
study, AADs after the RFCA could not prevent AF recurrence especially in
patients with an output of \textgreater{} 5 J. Therefore, further
studies are need to study those patients with an output of
\textgreater{} 5 J.

\textbf{Limitations}

This study had some potential limitations. First, it was a retrospective
and observational study at a single institute. We did not have many
patients with persistent AF, which might have caused a statistical bias.
Second, we did not perform a substrate ablation such as a line, complex
fractionated atrial electrogram (CFAE), rotor, and LVZ ablation.
However, recent studies have revealed that only the efficacy of the PVI
has been proven.\textsuperscript{25-28} In this study, there was no
significant difference in the non-PV foci between the two groups. Third,
we also considered the effects of the confounding predictors for AF
recurrence. However, the IDF threshold was a useful predictor for AF
recurrence because the IDF remained after a multivariate analysis after
adjusting for the patient factors.

\textbf{Conclusion}

RFCA decreased the IDF threshold for restoring SR in patients with
persistent AF. Outputs of the IDF of \textgreater{} 5 J after RFCA could
be a predictor of a recurrence of persistent AF independent of an AF
substrate. IDF is useful for assessing whether RFCA could decrease the
AF substrate during the procedure.

\textbf{Conflict of Interest}

This research received no grants from any funding agencies in the
public, commercial, or not-for-profit sectors. The authors declare that
there is no conflict of interest.

\textbf{Acknowledgments}

We thank Mr. John Martin for his help with the preparation of the
manuscript.

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\textbf{Tables and Figure Legends}

\textbf{Table 1:} Patient characteristics of those with and without
atrial fibrillation recurrence

\textbf{Table 2:} Patient characteristics between intracardiac
defibrillation output groups of \selectlanguage{english}[?] 5 J and \textgreater{}5 J

\textbf{Table 3:} Clinical factors for atrial fibrillation recurrence
determined by univariate and multivariate analyses

\textbf{Figure 1} : (A) A 7Fr 20-pole 3-site mapping catheter
(BeeAT\selectlanguage{english}\textsuperscript{}, Japan Lifeline, Tokyo, Japan) and (B)
dedicated defibrillator (Shock AT\selectlanguage{english}\textsuperscript{}, Japan Lifeline,
Tokyo, Japan)

\textbf{Figure 2:} The change in the intracardiac defibrillation
threshold before and after RFCA

There was no difference in the IDF threshold between the no-recurrence
group and recurrence group before the RFCA, however, the threshold in
the no-recurrence group was significantly lower than that in the
recurrence group after the RFCA. The red colored line and words show the
recurrence group, and the black colored lines and words show the no
recurrence group. RFCA = radiofrequency catheter ablation, IDF =
Intracardiac defibrillation

\textbf{Figure 3:} The ROC curve for recurrence and intracardiac
defibrillation threshold after RFCA

Cut-off point analysis show that an intracardiac defibrillation
threshold after the RFCA of \textgreater{} 5J was the optimal point that
discriminated those with AF recurrence from the rest of the participants
(sensitivity 68.0\% and specificity 65.2\%).

\textbf{Figure 4} : Kaplan-Meier curve for the recurrence of atrial
fibrillation

Kaplan-Meier survival analysis for long-term sinus rhythm maintenance
after RFCA.

Patients with an intracardiac defibrillation threshold after the RFCA of
\textgreater{} 5J had a higher risk of recurrence than those with an
intracardiac defibrillation threshold after the RFCA of \selectlanguage{english}[?] 5J.

\textbf{Hosted file}

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