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\begin{document}

\title{Acute response and rhythm outcome after the patchy late-gadolinium
enhancement site catheter ablation in patients with persistent atrial
fibrillation}



\author[1]{kunihiko kiuchi}%
\author[1]{Koji Fukuzawa}%
\author[1]{Mitsuru Takami}%
\author[1]{yoshiaki watanabe}%
\author[1]{Yu Izawa}%
\author[1]{Mayumi Shigeru}%
\author[2]{hiroyuki oonishi}%
\author[1]{hideya suehiro}%
\author[1]{tomomi akita}%
\author[1]{makoto takemoto}%
\author[1]{atsusuke yatomi}%
\author[3]{Toshihiro Nakamura}%
\author[1]{jun sakai}%
\author[1]{Kazutaka  Nakasone}%
\author[1]{Yusuke Sonoda}%
\author[1]{Kyoko Yamamoto}%
\author[1]{Hiroyuki Takahara}%
\author[4]{noriyuki negi}%
\author[5]{katsusuke kyotani}%
\author[1]{Atsushi Kono}%
\author[1]{Ken-ichi Hirata}%
\affil[1]{Kobe University Graduate School of Medicine}%
\affil[2]{Kobe Circulation Clinic}%
\affil[3]{Kobe University}%
\affil[4]{Kobe University Hospital}%
\affil[5]{KOBE UNIVERSITY HOSPITAL}%


\vspace{-1em}



  
  \date{May 21, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Computer simulation model demonstrated that atrial
fibrillation (AF) driver attached to the patchy fibrosis assessed by
late gadolinium enhancement magnetic resonance imaging (LGE-MRI).
However, it has not been well elucidated in patients with persistent AF.
The aim of this study is to investigate whether radiofrequency (RF)
application on the patchy LGE site (PLS) could terminate AF or convert
to atrial tachycardia (AT) and improve the rhythm outcome. Methods: A
total of 31consecutive persistent AF patients with PLS were enrolled
(PLS ablation group, mean age: 69 \selectlanguage{ngerman}± 8 years, mean left atrial diameter:
42 ± 6 mm). AF direct termination or AT conversion during RF application
on the PLS were defined as favorable response. The rhythm outcome was
compared between the PLS ablation group and the propensity matched
conventional ablation group. Results: Favorable response was found in 15
(48\%) of 31 patients (AF termination in 7, AT conversion in 8
patients). AF recurrence at 12 months follow-up was significantly less
in the PLS group as compared to the control group (4 (13\%) of 31
patients vs. 11 (35\%) of 31 patients, log-rank p = 0.019). In patients
with favorable response, AT recurred in 1 (7\%) of 15 patients but AF.
Conclusions: The PLS ablation could terminate AF or convert to AT in
half of the patients and improve the rhythm outcome as compared to the
conventional ablation. No AF recurrence was documented in patients with
a favorable response.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Acute response and rhythm outcome after the patchy
late-gadolinium enhancement site catheter ablation in patients with
persistent atrial fibrillation}

Kunihiko Kiuchi, MD, FHRS+, Koji Fukuzawa, MD+, Mitsuru Takami, MD+,
Yoshiaki Watanabe, MD++, Yu Izawa, MD+, Mayumi Shigeru, MD\selectlanguage{ngerman}§,

Hiroyuki Oonishi, RT§, Hideya Suehiro, MD\selectlanguage{english}+, Tomomi Akita, MD\selectlanguage{english}+,

Makoto Takemoto, MD\selectlanguage{english}+, Atsusuke Yatomi MD\selectlanguage{english}+, Toshihiro Nakamura MD\selectlanguage{english}+,

Jun Sakai MD\selectlanguage{english}+, Kazutaka Nakasone, MD\selectlanguage{english}+, Yusuke Sonoda, MD\selectlanguage{english}+,

Kyoko Yamamoto, MD\selectlanguage{english}+, Hiroyuki Takahara, MD\selectlanguage{english}+, Noriyuki Negi, RT~P,

Katsusuke Kyotani, RT~P, Atsushi Kono, MD\selectlanguage{english}++, Ken-ichi Hirata, MD\selectlanguage{english}+

\selectlanguage{english}+Section of Arrhythmia, Division of Cardiovascular Medicine, Department
of Internal Medicine, Kobe University Graduate School of Medicine

\selectlanguage{english}++Division of Radiology, Department of Internal Medicine, Kobe University
Graduate School of Medicine

SSKobe Circulation Clinic

PDivision of Diagnostic Imaging, Department of Diagnostic Radiology,
Kobe University Hospital

\emph{7-5-2 Kusunoki-cho}

\emph{Chuo-ku, Kobe city, Japan}

Financial support: none

Short title: LGE-site as AF substrate

Total word count: 4922

Conflicts of Interest

The Section of Arrhythmia was supported by an endowment from Medtronic
JAPAN and Abbott JAPAN. The authors have reported that they have no
relationships relevant to the contents of this paper to disclose.

Address: Kunihiko Kiuchi, MD, FHRS (corresponding author)

Division of Cardiovascular Medicine, Department of Internal Medicine,
Kobe University Hospital

\emph{7-5-2 Kusunoki-cho, Chuo-ku, Kobe city, Japan}

Fax: (81)-78-382-5859

Telephone: (81)-78-382-5846

E-mail:\emph{kunihikokiuchi@yahoo.co.jp}

\textbf{Abstract}

\textbf{Background:} Computer simulation model demonstrated that atrial
fibrillation (AF) driver attached to the patchy fibrosis assessed by
late gadolinium enhancement magnetic resonance imaging (LGE-MRI).
However, it has not been well elucidated in patients with persistent AF.
The aim of this study is to investigate whether radiofrequency (RF)
application on the patchy LGE site (PLS) could terminate AF or convert
to atrial tachycardia (AT) and improve the rhythm
outcome.\textbf{Methods:} A total of 31consecutive persistent AF
patients with PLS were enrolled (PLS ablation group, mean age: 69 +- 8
years, mean left atrial diameter: 42 +- 6 mm). AF direct termination or
AT conversion during RF application on the PLS were defined as favorable
response. The rhythm outcome was compared between the PLS ablation group
and the propensity matched conventional ablation group.\textbf{Results:}
Favorable response was found in 15 (48\%) of 31 patients (AF termination
in 7, AT conversion in 8 patients). AF recurrence at 12 months follow-up
was significantly less in the PLS group as compared to the control group
(4 (13\%) of 31 patients vs. 11 (35\%) of 31 patients, log-rank p =
0.019). In patients with favorable response, AT recurred in 1 (7\%) of
15 patients but AF. \textbf{Conclusions:}The PLS ablation could
terminate AF or convert to AT in half of the patients and improve the
rhythm outcome as compared to the conventional ablation. No AF
recurrence was documented in patients with a favorable response.

\textbf{Key Words} : atrial fibrillation; fibrosis; late-gadolinium
enhancement MRI; catheter ablation; rhythm outcome

\textbf{Abbreviations}

AF = atrial fibrillation

AT = atrial tachycardia

BNP = brain natriuretic peptide

CE-MRA = contrast enhancement magnetic resonance angiography

FFE = fast field echo

LA = left atrium

LAA = left atrium appendage

LAD = left atrial diameter

LVEF = left ventricular ejection fraction

LGE MRI = late-gadolinium enhancement magnetic resonance imaging

PLS = patchy late-gadolinium enhancement site

PV = pulmonary vein

PVI = pulmonary vein isolation

RFCA = radiofrequency catheter ablation

SM = substrate modification

\textbf{Introduction}

STAR AF II clinical trial demonstrated no benefit of either linear
ablation or ablation of complex fractionated electrograms in addition to
pulmonary vein isolation (PVI).\textsuperscript{1} However, the impact
of PVI on the rhythm outcome was not enough in patients with persistent
atrial fibrillation (AF). AF termination was considered the factor
predicting freedom from arrhythmia recurrence in patients with
persistent AF during long-term follow-up, but it was still in
debate.\textsuperscript{2} The rate of AF termination during the
procedure could range from 10 to 40\%, which depended on the ablation
strategy such PVI alone, PVI plus ablation of complex fractionated
atrial electrograms (CFAEs), PVI plus a liner ablation or FIRM-guided
ablation.\textsuperscript{2-5} Late gadolinium enhancement magnetic
resonance imaging (LGE-MRI) based computer simulation model has
demonstrated that meandering re-entrant AF driver attached to patchy
\selectlanguage{english}fibrosis.\textsuperscript{6} Boyle and Trayanova et al. have recently
introduced a technology for the targeted ablation of persistent AF
patients with atrial fibrosis, and demonstrated the feasibility of the
technology to guide patient treatment in a prospective study of 10
patients. Although it was a proof-of -concept feasibility study of the
technology, the AF termination rate and rhythm outcome were likely
excellent.\textsuperscript{7} This indicated that the importance of
targeting of the fibrotic tissue specifically associating with AF
driver. We hypothesized that radiofrequency (RF) application on the
patchy LGE site (PLS ablation) could eliminate the possible AF driver
which resulted in AF termination and improving the rhythm outcome. The
primary goal of this study was to determine whether the PLS ablation
could terminate AF. The secondary goal was to determine whether the PLS
ablation could improve the rhythm outcome as compared to the
conventional ablation in patients with persistent AF.

\textbf{Methods}

\emph{Patient population}

A total of 31 consecutive persistent AF patients with patchy LGE site
were enrolled in this study (PLS group). The chronic kidney disease
patients were excluded from this study, because no LGE-MRI could be
performed before ablation. As a control group, propensity matched 62
patients with or without the patchy LGE site were selected from Kobe
University AF registry including a total 241 persistent AF patients who
underwent conventional catheter ablation (31 in the control group with
the patchy LGE site, 31 in the control group without the patchy LGE
site). The study design and flowchart were shown in Figure 1. The study
was approved by the local ethics committee and complied with the
Declaration of Helsinki (Committee of 2020.7.21., Approval No. B200121).

\emph{Late-Gadolinium enhancement MRI acquisition}

All patients underwent contrast enhanced MR imaging using a 1.5-T MR
system (Achiva, Philips Medical, Best, The Netherlands) equipped with a
5-channel cardiac coil one to three months before the AF ablation. This
scan technique has been established, and the acquired images were used
for the AF ablation procedure.\textsuperscript{8,9}First, contrast
enhancement--magnetic resonance angiography (CE-MRA) of the PV--LA
anatomy was acquired with a breath-hold 3D fast field echo (FFE)
sequence in the coronal plane during the first pass of a contrast agent
(gadobutrol, Gadovist; Bayer Yakuhin, Osaka, Japan) injection at a dose
of 0.1 mmol/kg. The purpose of the scanning in the coronal plane was to
reduce the number of acquisition slices and shorten the breath holding
time. Then the LGE-MRI of the LA with the PVs was acquired using a 3D
inversion recovery, respiration navigated, electrocardiogram-gated,
T1-FFE sequence in the transverse plane 15 minutes after the contrast
injection, which has been previously reported. The typical parameters
were as follows: repetition time /echo time = 4.7 / 1.5 ms, voxel size =
1.43 x 1.43 x 2.40 mm (reconstructed to 0.63 x 0.63 x 1.20 mm), flip
angle = 15deg, SENSE = 1.8, and 80 reference lines. The inversion time
(TI) was set at 280 -- 320 ms, using a Look-Locker scan. In case of AF,
the data acquisition was performed with the shortest trigger delay of
cardiac synchronization.\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}In case of sinus rhythm, the data acquisition
was performed during the mid-diastolic phase of the left ventricle. The
typical scan time for the LGE-MRI study was 7 to 12 minutes depending on
the patient's heart rate and respiration pattern. The images of the
CE-MRA, and LGE-MRI were transferred to customized software (MRI LADE
Analysis; PixSpace Inc, Fukuoka, Japan) for a further image post
processing and image analysis.

\emph{3D visualization of LGE site}

The method of the 3D visualization for the LGE site was as follows.
First, the LA was segmented semi-manually by contouring the endocardial
and epicardial borders of the atrium, including the PVs. Second, the
mean value and SD of the voxel intensity was measured on the ``healthy''
LA wall where no hyper-enhanced areas in the LGE-MRI were involved.
Third, a voxel intensity histogram analysis of the LA wall identified
LGEs as intensities \textgreater{}2 SD on the ``healthy'' LA wall.
Furthermore, the degree of the intensity was categorized by color-coded
scaling (green: \textgreater{} 1SD: yellow: 2 -- 3SD; and red:
\textgreater{} 3SD). Finally, a 3D reconstruction of the color-coded LGE
and volume-rendered LA and PV image generated from the CE-MRA were fused
semi-automatically. The LGE site was defined as a site with a signal
intensity of \textgreater{} 1SD.

\emph{Definition of the `patchy' LGE site}

The LGE site was classified into the dens or patchy LGE site. An animal
study reported that the maximum gap length with conduction block was 4
mm.\textsuperscript{10} According to the result, the patchy LGE site was
defined as the site where the at least two small LGE could distributed
within 5mm diameter (Figure 2). Based on this definition, the patchy LGE
site appeared inhomogeneous infiltration of atrial tissue by LGE, while
the dense LGE site appeared homogenous and strong infiltration of atrial
tissue by LGE.

\emph{PLS ablation and conventional ablation}

Prior to the procedure, transesophageal echocardiography was performed
to exclude any thrombus formation. Patients were studied under
dexmedetomidine hydrochloride sedation while breathing spontaneously.
Standard electrode catheters were placed in the right ventricular apex
and coronary sinus after which a single transseptal puncture was
performed. Unfractionated heparin was administered in a bolus form
before the transseptal puncture to maintain an activated clotting time
of \textgreater{}350 s.

Mapping and ablation were performed using a NavX system (Abbott,
Chicago, IL) or CARTO3 (Biosense Webster, Diamond Bar, CA, USA) as a
guide after integration of a three-dimensional (3D) model of the anatomy
of the LA and PVs obtained from pre-interventional computed tomography
(CT) or magnetic resonance imaging (MRI). Prior to the ablation, the
circular mapping catheter (Optima, Abbott, Chicago, IL; Carto Lasso,
Biosense Webster, Diamond Bar, CA) and ablation catheter-reconstructed
LA posterior anatomies were aligned with the MRI.

RF alternating current was delivered in a unipolar mode between the
irrigated tip electrode of the ablation catheter
(TactiCath\textsuperscript{TM}, Abbott, Chicago, IL; SmartTouch
ThermoCool, Biosense Webster) and an external back-patch electrode. The
initial RF generator setting consisted of maximal RF power of 30 to 35W.
All patients underwent an extensive encircling pulmonary vein isolation.
RF applications were performed in a ``point by point'' manner. For each
RF application, the target CF was 5 -- 30 g, and the target lesion size
index (LSI) or ablation index (AI) was 5.2 or 500,
respectively.\textsuperscript{9} The RF application time was routinely
limited 10s when ablating the posterior wall according to the esophageal
temperature measured with an esophageal temperature probe (SensiTherm,
Abbott, Chicago, IL). Catheter navigation was performed with a steerable
sheath (Agillis, Abbott, Chicago, IL). Conventional ablation strategy
including the PVI, non-PV foci ablation, linear ablation, CFAE ablation
and low voltage area (LVA) ablation depended on the operator discussion.

In the PLS group, PVI or PVI plus Box lesion were predefined based on
the LGE-MRI. If the patchy LGE was found at the PV antrum or left atrial
posterior wall, PVI plus Box lesion was attempted. If not, only PVI was
performed. After complete PVI or PVI plus Box was confirmed, RF
application at the patchy LGE site in a point by point manner. Even
though AF could be terminated during the PLS ablation, RF application
continued till it covered the all patchy LGE sites. If AF could convert
to AT during the PLS ablation, mapping and ablation was performed for
the AT termination. AF termination or AT conversion during PLS ablation
were defined as a favorable response positive. If no favorable respond
could be achieved, cardio version was performed. After the procedure, we
performed a stimulation protocol (burst pacing from the CS with 300 ms,
250 ms, and 200 ms for 10s each) to test the inducibility. Holter ECGs
were performed immediately after the procedure and after 6, and 12
months for all patients. If symptoms occurred outside the recording
period, patients were requested to contact our institution or the
referring physician to obtain ECG documentation. AF and AT episodes
lasting \textgreater{}30 s was considered recurrences.

\emph{Ablation strategies promising AF termination and eliminating
recurrence}

To determine the ablation strategy associated with terminating AF and
maintaining SR, a total of 241 persistent AF patients who underwent
catheter ablation were recruited from the Kobe University AF registry
database. Based on the ablation summary, the patients were classified
into the following four groups: 1) PVI group, 2) PVI plus substrate
modification including linear, CFAE and LVZ ablation group (PVI plus SM
group), 3) PVI plus Box lesion group (Box lesion group) and 4) PLS
ablation group. The ratio of AF termination and AF recurrence during the
follow-up period were assessed among four groups.

\emph{Statistical analysis}

Continuous data were presented as the mean\selectlanguage{ngerman}± standard deviation.
Continuous variables were compared by means of 1-way ANOVA and post hoc
analysis with Bonferroni correction for multiple comparisons of data if
normally distributed, or the Kruskal-Wallis test, if skewed. Categorical
variables were analyzed with the Fisher's exact test. To compare the
rhythm outcome between the PLS ablation and conventional ablation, age,
gender, left atrial diameter (LAD), left ventricular ejection fraction
(LVEF) and creatinine level matched conventional ablation group were
selected as a conventional ablation group. The cumulative incidence of
AF recurrence was determined by the Kaplan-Meier method. The survival
analysis between PLS ablation group and conventional ablation group was
performed using a log-rank test. Cox proportional hazards regression
models were used to estimate hazard ratios and 95\% CIs for AF
recurrence. Variables in the multivariable Cox proportional hazards
regression model included each ablation strategy, age, gender, LAD and
LVEF with P\textless{}0.05 using unadjusted Cox proportional hazard
regression analysis. Multivariate logistic regression models were used
to estimate hazard ratios and 95\% CIs for AF termination. A value of
p\textless{}0.05 was considered statistically significant. All
statistical analyses were performed using EZR on R commander, version
1.36 or SPSS, Release 24 software (SPSS, Chicago, IL, USA).

\textbf{Results}

\emph{Patient and procedural characteristics}

The patient and procedural characteristics are shown in Table 1.
Although age, gender, left atrial diameter (LAD) and left ventricular
ejection fraction (LVEF), creatinine level was matched, the other
patient characteristics including CHADS2 score, brain natriuretic
peptide (BNP) level were also comparative between the PLS and the
control. As for the ablation procedure in the control group with patchy
LGE site, pulmonary vein isolation (PVI), PVI plus substrate
modification including linear ablation, complex fractionated atrial
electrograms (CFAE) ablation, low-voltage area (LVA) ablation and PVI
plus Box lesion were performed in 17 (55\%), 4 (13\%) and 10 (32\%) of
31 patients, respectively. In the control group without patchy LGE site,
pulmonary vein isolation (PVI), PVI plus substrate modification
including linear ablation, complex fractionated atrial electrograms
(CFAE) ablation, low-voltage area (LVA) ablation and PVI plus Box lesion
were performed in 27 (88\%), 2 (6\%) and 2 (6\%) of 31 patients,
respectively. As for the procedural characteristics, the procedure time
were comparative among the groups, but the fluoroscopy time was
significantly longer in the PLS group than that in the control group
without patchy LGE site (fluoroscopic time: 22 ± 11 min and 16 ± 4 min,
p = 0.01).

\emph{The distribution of the PLS}

A total of 69 PLS were found in 31 patients. The distribution of the PLS
was shown in Figure 3. 23 (33\%) and 22 (32\%) of the 69 PLS were found
around PV antrum and left atrial appendage (LAA) base, respectively.
Subsequently, 9 (13\%), 6 (9\%), 5 (7\%), 4 (6\%) of the 69 PLS were
found around the left atrial septum, left atrial posterior wall, left
atrial roof and left atrial bottom, respectively.

\emph{Favorable response and rhythm outcome}

Favorable response was found in 15 (48\%) of the 31 patients in the PLS
group, while no favorable response in the control group. Of the patients
with favorable response, AF termination could be documented in 7 (23\%)
patients and AT conversion in 8 (26\%) patients. AT could be mapped and
terminated by the RF application. At the end of the procedure, AF
inducibility by burst pacing could be reduced in in 26 (84\%) patients.

The AF/ AT recurrence at 12 months after the procedure was significantly
less in the PLS groups as compared to the control group with patchy LGE
site (4 {[}13\%{]} vs. 11 {[}36\%{]}, log-rank test p = 0.034) (Figure
4A). AF/AT recurrence was likely less in the patients with favorable
response as compared to those without one (1 (7\%) of 15 vs. 3 (19\%) of
16 patients, p = 0.090). Of note, the patient with a favorable response
had AT recurrence but not AF. Representative case was shown in Figure 5.
The PLS could be found at the LA septum and LAA base where RF
application could terminate AF. Of interest, AF/AT recurrence were
comparative between the PLS ablation group and the conventional ablation
group without the patchy LGE site (4 {[}13\%{]} vs. 5 {[}16\%{]},
log-rank test p = 0.710) (Figure 4B).

\emph{Ablation strategies promising AF termination and eliminating
recurrence}

As for the AF termination, unadjusted logistic regression analysis
identified 2 ablation strategies associated with favorable response: PLS
ablation and PVI. Of interest, the PLS ablation and PVI were positively
and negatively associated with favorable response, respectively.
According to the multivariate logistic regression analysis, the most
predictive model of favorable response consisted of the PLS ablation
(Table 2).

As for the AF/AT recurrence, unadjusted Cox proportional hazard
regression analysis identified 2 factors associated with AF/AT
recurrence: PLS ablation and LVEF. According to the multivariate Cox
proportional hazard regression analysis, the most predictive model of
AF/AT recurrence consisted of the PLS ablation (Table 3).

\textbf{Discussion}

\emph{Main findings}

The study presented here demonstrated that significant impact of the PLS
ablation in patients with persistent AF. With the primary goal of our
study to determine whether the PLS ablation could terminate AF, we
concluded that the ratio of AF termination during the PLS ablation was
almost 50\%. The secondary goal was to assess whether the rhythm outcome
after the PLS ablation could be improved as compared to that after
conventional ablation. During a median 9 months follow-up, the AF
recurrence was significantly less in the PLS ablation group as compared
to the conventional ablation group. Furthermore, we concluded by means
of multivariate analysis that the PLS ablation was only associated with
a freedom from the AF recurrence.

\emph{Distribution of AF substrate}

To date, atrial fibrosis, LVA, CFAE, AF rotor were considered as AF
substrates.\textsuperscript{3,11-14}The left atrial fibrosis was
visualized by the LGE-MRI and the LGE site was heterogeneously
distributed in AF patients. Higuchi et al. reported that the LGE site
was highly distributed in the left PV antrum near the posterior wall
side and spread on the posterior and anterior wall with AF
progression.\textsuperscript{15} The LGE was more widely distributed in
patients with persistent AF compared with patients with paroxysmal AF,
especially on the posterior and anterior wall. Notably, the LGE site was
likely distributed around LAA on the anterior wall in the progressed AF
patients. Our study also demonstrated that the patchy LGE site was
predominantly distributed at PV antrum and LAA base, which was
completely consistent with their results.

The LVA was reported to be mainly found in LA septum, anterior LA and LA
posterior.\textsuperscript{16} Of interest, Chen et al. reported that
LGE sites were present at 61\% of LVAs, whereas LVAs were present at
28\% of LGE sites.\textsuperscript{17} Those findings indicated that the
distribution of the LGE sites could not completely overlapped with that
of the LVAs. The LVA distribution could depend on the mapping
resolution, pacing site, cardiac rhythm or use of the cardioversion.
Furthermore, the patchy LGE site was sometimes underestimated which
depended on the visualization method. This might be the reason why the
distribution of the LVA were not completely concordant with that of the
LGE.

The distribution of CFAE were most commonly located in the LA posterior
and PV antral region.\textsuperscript{18}The distribution of
spatiotemporal electrogram dispersion area were equally distributed at
PV, LAA, LA posterior, LA anterior and LA roof. The distribution was
unlikely similar to that of the patchy LGE site. The relationship
between CFAE, spatiotemporal electrogram dispersion area, LVA and atrial
fibrosis were complex and it was still in debate.

AF driver detected by a 252-electrode vest for body surface mapping were
predominantly located in the PV antrum and LA bottom, subsequently
around the LAA.\textsuperscript{19} Their results were likely consistent
with our results. Cochet et al. concluded that the number of AF driver
related to the extent of LGE, with the location of AF driver clustering
to LGE sites.\textsuperscript{20} This strongly indicated that the LGE
site could be one of the possible AF substrates and it was considered as
an ablation target, which strongly supported our ablation strategy.

\emph{AF termination and rhythm outcome}

The importance of AF termination as a procedural endpoint that
correlates positively with rhythm outcome is still in debate. AF termed
in 51\% of catheter ablation using a sequential biatrial linear
defragmentation approach. Miyazaki et al. reported that AF termination
was the sole factor predicting freedom from both arrhythmia recurrence
and crossover to rate control strategies during long-term
follow-up.\textsuperscript{2} While, in the subgroup analysis of STAR AF
II, AF termed in 8\% of the PVI, 45\% in the PVI plus CFAE ablation and
22\% of the PVI plus linear ablation and the AF termination could not
predict the better rhythm outcome.\textsuperscript{4} This discrepancy
might be caused by 1) multiple procedure or single procedure, 2)
follow-up period (60 months vs. 18 months). CFAE ablation was associated
with a high likelihood of AT as the mode of arrhythmia recurrence.
Actually, linear ablation was mainly performed for macro-reentrant ATs
in the 2\textsuperscript{nd} procedure. Of note, the AF recurrence was
significantly less after eliminating AT after index procedure when
2\textsuperscript{nd} or 3\textsuperscript{rd} session was mainly
performed from 4 to 28 months after the initial procedure. In our study,
the mode of the arrhythmia recurrence was perimitral AT in one patient
with a favorable response. Thus, no AF recurrence was found in patients
with a favorable response. We speculated that AF termination during RF
application could reduce the AF recurrence, however, additional RF
application could have a potential risk of increasing the AT substrate.
The PLS ablation provide the relatively high AF termination and the
excellent outcome, however, the ablation target area should have been
more specifically focused and we should have used the time for creating
a durable PVI and linear lesion. Recently, Ashihara et al. had developed
a novel online real-time phase mapping system: ExTRa
Mapping.\textsuperscript{13} By using this novel system, we reported the
case in which RF application at the AF rotor area overlapped with the
PLS could convert AF to common atrial flutter.\textsuperscript{21} We
would like to hope that this real-time mapping system and LGE-MRI
assessment could make it possible to intervention on the specific AF
substrate.

\emph{PLS as AF substrate}

LGE-MRI based computer simulation model demonstrated that meandering
re-entrant AF driver was localized in boundary zones between fibrotic
and non-fibrotic tissue characterized with high fibrosis density and
entropy where the lower local conduction velocity was
documented.\textsuperscript{20,22}Furthermore, they has demonstrated
that the residual fibrosis after catheter ablation might be attributable
to preserved re-entrant drivers and the emergence of new re-entrant
driver.\textsuperscript{23} This strongly indicated that the all
fibrosis with high density and entropy were possible ablation targets.
Therefore, the RF application at the PLS was continued, even in cases
where AF termination was achieved during the procedure. Recently, Boyle
et al. had presented the computationally guided personalized targeted
ablation as a proof-of -concept feasibility study.\textsuperscript{7}
Furthermore, they suggested that LGE-MRI based computationally guided
ablation could provide not only accurate prediction of AF ablation
targets but could overcome the prolonged procedure time and higher
radiation exposure due to the difficulty of a conventional mapping of
atrial electrical activity. In our study, both procedure time and
fluoroscopy time ware acceptable as compared to that of conventional
ablation procedure, because additional target site was predefined by the
preprocedural LGE-MRI and no further mapping was necessary during the
procedure. We would hope that the PLS ablation could improve the rhythm
outcome in persistent AF patients without increasing of the procedure
time and radiation exposure.

\textbf{Study limitations}

Our study had several limitations. First, the sample size was small and
the follow-up period was relatively short. Second, the PLS was assessed
on the LA but not the right atrium (RA). Further PLS ablation at the RA
could influence the rhythm outcome. To clarify this issue, further study
should be needed.

\textbf{Conclusions}

The PLS ablation could terminate AF or convert to AT in half of the
patients and no AF recurrence in patients with a favorable response. The
rhythm outcome could be improved without compromising both procedure
time and radiation exposure as compared to conventional catheter
ablation.

\textbf{Acknowledgements}

We would like to thank Mr. Tsuyoshi Sakamoto for his development of the
specially customized software (MRI LADE Analysis, PixSpace Inc.,
Fukuoka, Japan).

\textbf{Figure Legends}

\textbf{Figure 1. Study design and flowchart}

AF = atrial fibrillation, LGE = late-gadolinium enhancement

\textbf{Figure 2.} \textbf{Definition of the PLS}

A: patchy and dense LGE pattern. B: 3D LGE-MRI fused with CE-MRA. Lower
panel depicted the patchy and dense LGE sites. Of note, ablation targets
were the patchy LGE sites but the dense one. MA = mitral annulus,
LGE-MRI = late-gadolinium enhancement magnetic resonance imaging, CE-MRA
= contrast enhancement magnetic resonance angiography

\textbf{Figure 3.} \textbf{Distribution of the PLS}

The left and right panels illustrated the distribution of the PLS in the
posterior-anterior view and anterior -- posterior view. The PLS was
predominantly found around PV antrum and LAA base.

PLS = patchy late-gadolinium enhancement site, PV = pulmonary vein, LAA
= left atrium appendage

\textbf{Figure 4.} \textbf{Kaplan-Meier curve of freedom from AF/AT for
each group}

AF = atrial fibrillation, AT = atrial tachycardia, PLS = patchy LGE site

\textbf{Figure 5.} \textbf{PLS ablation in the representative case}

A: The left panel showed the LGE-MRI. The right panel showed the 3D
LGE-MRI fused with CE-MRA using by specially customized software. The
white arrow and red dotted circle indicated the PLS around LAA base.

B: RF application at the PLS by using NavX system. The light blue
electrogram indicated the atrial signal recorded by the ring catheter in
the LAA. The LAA electrograms were organized and terminated during RF
application. The 3D tags indicated the RF application points. The yellow
one indicated AF termination points.

LGE-MRI = late-gadolinium enhancement magnetic resonance imaging, CE-MRA
= contrast enhancement magnetic resonance angiography, PLS = patchy LGE
site, LAA = left atrial appendage, RF = radiofrequency

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\emph{Cardiovasc Res.}2019;115(12):1757-1765.\selectlanguage{english}
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