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\begin{document}

\title{Left atrial localized low-voltage areas indicate whole left atrial
electrophysiological degeneration in atrial fibrillation patients}



\author[1]{Naoya Kurata}%
\author[1]{Masaharu Masuda}%
\author[1]{Takashi Kanda}%
\author[1]{Mitsutoshi Asai}%
\author[1]{Osamu Iida}%
\author[1]{Shin Okamoto}%
\author[1]{Takayuki Ishihara}%
\author[1]{Kiyonori Nanto}%
\author[1]{Takuya Tsujimura}%
\author[1]{Yasuhiro Matsuda}%
\author[1]{Yosuke Hata}%
\author[1]{Hiroyuki Uematsu}%
\author[1]{Toshiaki Mano}%
\affil[1]{Kansai Rosai Hospital}%


\vspace{-1em}



  
  \date{May 21, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: The efficacy of ablation targeting low-voltage areas (LVAs)
is controversial, although LVA presence is well known to be associated
with AF recurrence after ablation. Atrial fibrillation (AF) substrate
may not localize within LVAs. Methods and results: This observational
study enrolled 405 consecutive patients who underwent an initial AF
ablation procedure. The left atrial voltage map was obtained after
pulmonary vein isolation. LVAs were defined as areas with voltage
\textless{} 0.5 mV. To estimate whole atrial electrophysiological
degeneration, mean regional voltage at each of 6 regions and left atrial
total conduction velocity were measured. LVAs existed in 143 of 405
(35.3\%) patients. Patients with LVAs demonstrated lower mean regional
voltages throughout all 6 regions than those without LVAs (1.3 {[}1.8,
0.8{]} vs. 0.6 {[}1.0, 0.2{]} for anterior wall, p\textless{}0.001). On
the other hand, left atrial conduction velocity was lower in patients
with LVAs than in those without (0.89 {[}1.01, 0.74{]} vs. 0.93 {[}1.03,
0.87{]} m/s, p\textless{}0.001). Multivariate analysis revealed that low
left atrial total conduction velocity and a higher number of regions
with mean voltage reduction were independently associated with AF
recurrence, although LVA presence was not. Conclusion: Patients with
localized left atrial LVAs were characterized by whole left atrial
electrophysiological degeneration as assessed by mean regional voltage
and conduction velocity. In addition, whole left atrial
electrophysiological degeneration parameters were well associated with
AF recurrence.%
\end{abstract}%



\sloppy


\textbf{Left atrial localized low-voltage areas indicate whole left
atrial electrophysiological degeneration in atrial fibrillation
patients.}

\textbf{Short title:} localized LVA and whole atrial
electrophysiological degeneration

Naoya Kurata\textsuperscript{1)} BHS; Masaharu
Masuda\textsuperscript{2)}, MD, PhD; Takashi Kanda\textsuperscript{2)},
MD; Mitsutoshi Asai\textsuperscript{2)}, MD, PhD; Osamu
Iida\textsuperscript{2)}, MD; Shin Okamoto\textsuperscript{2)}, MD;
Takayuki Ishihara\textsuperscript{2)}, MD; Kiyonori
Nanto\textsuperscript{2)}, MD; Takuya Tsujimura\textsuperscript{2)}, MD;
Yasuhiro Matsuda\textsuperscript{2)}, MD; Yosuke
Hata\textsuperscript{2)}, MD; Hiroyuki Uematsu\textsuperscript{2)}, MD;
Toshiaki Mano\textsuperscript{2)}, MD, PhD

\textbf{Authors' affiliations:}

Kansai Rosai Hospital Clinical engineer, 3-1-69 Inabaso, Amagasaki,
Hyogo, Japan

Kansai Rosai Hospital Cardiovascular Center, 3-1-69 Inabaso, Amagasaki,
Hyogo, Japan

\textbf{Funding and conflicts of interest:} Not is all authors.

\textbf{Total word count:} 3939

\textbf{Figure and table} : 4 figures and 3 tables

\textbf{Supplemental figure:} 2 figures

\textbf{Corresponding author:}

Masaharu Masuda

Kansai Rosai Hospital Cardiovascular Center

3-1-69 Inabaso, Amagasaki, Hyogo 660-8511, Japan

Tel: +81-6-6416-1221

Fax: +81-6-6419-1870

E-mail:\emph{masuda-masaharu@kansaih.johas.go.jp}

\textbf{1. Abstract}

\textbf{Background:} The efficacy of ablation targeting low-voltage
areas (LVAs) is controversial, although LVA presence is well known to be
associated with AF recurrence after ablation. Atrial fibrillation (AF)
substrate may not localize within LVAs.

\textbf{Methods and results:} This observational study enrolled 405
consecutive patients who underwent an initial AF ablation procedure. The
left atrial voltage map was obtained after pulmonary vein isolation.
LVAs were defined as areas with voltage \textless{} 0.5 mV. To estimate
whole atrial electrophysiological degeneration, mean regional voltage at
each of 6 regions and left atrial total conduction velocity were
measured. LVAs existed in 143 of 405 (35.3\%) patients. Patients with
LVAs demonstrated lower mean regional voltages throughout all 6 regions
than those without LVAs (1.3 {[}1.8, 0.8{]} vs. 0.6 {[}1.0, 0.2{]} for
anterior wall, p\textless{}0.001). On the other hand, left atrial
conduction velocity was lower in patients with LVAs than in those
without (0.89 {[}1.01, 0.74{]} vs. 0.93 {[}1.03, 0.87{]} m/s,
p\textless{}0.001). Multivariate analysis revealed that low left atrial
total conduction velocity and a higher number of regions with mean
voltage reduction were independently associated with AF recurrence,
although LVA presence was not.

\textbf{Conclusion:} Patients with localized left atrial LVAs were
characterized by whole left atrial electrophysiological degeneration as
assessed by mean regional voltage and conduction velocity. In addition,
whole left atrial electrophysiological degeneration parameters were well
associated with AF recurrence.

\textbf{Key words:} atrial fibrillation; low-voltage areas; recurrence;
ablation; conduction velocity; regional voltage

\textbf{Abbreviation}

AF = atrial fibrillation; PVI = pulmonary vein isolation; LVA =
low-voltage areas; Receiver Operating Characteristic = ROC



\textbf{2. Introduction}

Catheter ablation has become a mainstream treatment option for atrial
fibrillation (AF). Electrical pulmonary vein isolation (PVI) is well
established as the cornerstone of AF
ablation.\textsuperscript{1,2}However, frequent AF recurrence after
ablation remains an unsolved problem, with reported 1-year AF recurrence
rates of 20-50\%.\textsuperscript{2-4}

The presence of left atrial low-voltage areas (LVAs) has been reported
to be strongly associated with AF recurrence after
ablation.\textsuperscript{5-7} Nevertheless, several randomized control
trials evaluating the efficacy of LVA ablation in addition to PVI
reported controversial results\textsuperscript{8-11} which suggested
that extra-pulmonary-vein AF substrate does not always localized within
LVAs.

The purpose of this study was to compare whole left atrial
electrophysiological degeneration between patients with and without
localize LVAs, and to explore clinical and mapping data associated with
AF recurrence after ablation.



\textbf{3. Methods}

\emph{3.1 Patients}

This observational study enrolled 405 consecutive patients who underwent
the initial AF ablation procedure at Kansai Rosai Hospital between Aug
2017 to Aug 2019. Patients in whom a voltage map was not obtained due to
unstable cardiac rhythm and those whose 3D mapping was not the CARTO
(CARTO\selectlanguage{ngerman}\textsuperscript{®}; Biosense Webster, Diamond Bar, CA, USA)
system were excluded. This study complied with the Declaration of
Helsinki. Written informed consent for the ablation and for
participation in the study was obtained from all patients, and the
protocol was approved by our institutional review board.

\emph{3.2 Ablation procedure}

Electrophysiological studies and catheter ablation were performed by
three experienced operators (M.M, T.K, and Y.M) with the patient under
intravenous sedation with dexmedetomidine. The operator performed the
mapping and ablation under guidance with an electroanatomical mapping
system (CARTO 3\textsuperscript{®}). First, PVI was performed using an
open-irrigated ablation catheter (Thermocool
SmartTouch\textsuperscript{®}, Biosense Webster), a cryoballoon (Arctic
Front Advance\textsuperscript{®}, Medtronic, Minneapolis, MN, USA), or a
laser balloon (HeartLight\textsuperscript{®}, CardioFocus, Marlborough,
MA, USA). Radiofrequency application was set at 30 W using a dragging
technique with a maximum temperature of 42 °C and an irrigation rate of
17 ml/min. The operator attempted to maintain an appropriate contact
force between the catheter and endocardium of 5 to 20 g. In cases using
a cryoballoon, 180-sec freezing was applied. The laser balloon was
inflated with the goal of complete occlusion of the PV ostium. Laser
lesions were created with a 30--50\% lesion overlap. Where very good
tissue contact was obtained, maximal power (12 W for 20 seconds) was
chosen. At regions with moving blood, laser energy was applied at 7 W
for 30 seconds. PV electrograms were recorded using a 20-pole circular
mapping catheter (LassoNaV\textsuperscript{®}, Biosense Webstar). PVI
was considered complete when both entrance and exit blocks were created.

\emph{3.3 Left atrial voltage mapping}

Following PVI, detailed voltage mapping using a 20-pole circular
catheter with 1-mm electrodes (LassoNaV\textsuperscript{®}, Biosense
Webstar) or a 20-pole multielectrode catheter arranged in 5 soft
radiating spines (Pentaray\textsuperscript{®}, Biosense Webster) was
performed during 100-beat-per-minute paced rhythm from the high right
atrium. Mapping points were automatically acquired using the CARTO
confidence module with the following settings: cycle length filtering,
±30 msec; localize activation time stability, \textless{} 3 msec;
position stability, \textless{} 2 mm; and density, \textless{} 1 mm.
Left atrial geometry was created using the fast-anatomical mapping
module. Mapping was continued to fill all color gaps on the voltage map
with an interpolation threshold of 17 mm for fill threshold and 10 mm
for color threshold. If poor contact between the circular mapping
catheter and endocardium surface was suspected, mapping using the
ablation catheter was added with a point acquisition setting of contact
force \selectlanguage{english}[?] 5 g. The band pass filter was set at 30 to 500 Hz.

LVAs were defined as areas with a bipolar peak-to-peak voltage
\textless{} 0.50 mV covering \textgreater{} 5 cm\textsuperscript{2} of
left atrium. On the voltage map, the bipolar voltage color bar was set
to range from 0.10 to 0.50 mV and scar level was set at \textless{} 0.05
mV. The left atrium was divided into six regions - septal, anterior,
roof, posterior, inferior, and lateral - as reported
previously.\textsuperscript{5}

After this procedure, constant burst pacing was performed for 5 s at
each cycle length, starting with 300 ms and a subsequent decrement of 20
to 200 ms or the shortest cycle length that resulted in 1:1 atrial
capture. This was followed by a high-dose isoproterenol provocation test
(infusion of 5, 10, and 20 \selectlanguage{greek}µ\selectlanguage{english}g/min isoproterenol for 2 min each) to
induce AF or atrial tachycardia. If atrial flutters or non-PV AF
triggers were observed spontaneously or induced by atrial burst stimuli
or isoproterenol infusion, additional ablation were performed. Ablation
of induced and spontaneously developing AF-triggering ectopies and
atrial tachycardia was attempted at the earliest activation site for AF
trigger or centrifugal atrial tachycardia, and across the reentrant
circuit for macro-reentrant atrial tachycardia. Ablation targeting LVAs,
linear ablations and/or ablation guided by complex fractionated
electrograms were performed at the discretion of attending operators.

\emph{3.4 Whole left atrial electrophysiological degeneration}

Whole left atrial electrophysiological degeneration was assessed by the
mean regional voltage at each region and left atrial total conduction
velocity.\textsuperscript{12}

Mean regional voltage was calculated by averaging 10 points evenly
selected across the region. ROC analysis was used to estimate a best
cut-off value of mean regional voltage to predict AF recurrence. The
extension of mean regional voltage reduction was assessed by the number
of regions with a mean regional voltage \textless{} the region-specific
cut-off value.

Left atrial conduction velocity was calculated as left atrial anterior
conduction distance divided by conduction time between the start
(septum) and end of the propagation wave front (lateral mitral annulus)
in the left atrium, as reported previously.\textsuperscript{12} Anterior
conduction distance was measured manually by tracing the pathway of the
propagation wave front from the start point to the end point in the
anterior left atrium.

\emph{3.5 Post-procedure follow-up}

Patients were discharged two days after ablation if their clinical
status was stable. Following a blanking period of 3 months, they
completed outpatient clinical visits and 12-lead ECG monitoring at 1, 3,
6 and 12 months, and 24 h-Holter ECG monitoring every 6 months.
Additional Holter monitoring was performed if arrhythmic symptoms
occurred. Either of the following events following the initial 3 months
after ablation (blanking period) was considered to indicate AF
recurrence: (1) atrial tachyarrhythmias recorded on routine or
symptom-triggered ECG during an outpatient visit; or (2) atrial
tachyarrhythmias of at least a 30 seconds' duration on ambulatory ECG
monitoring. All antiarrhythmic drugs were discontinued 3 months after
the procedure, unless AF recurrence was diagnosed.

\emph{3.6 Statistical analysis}

Categorical values are expressed as absolute values and relative
frequencies. Continuous variables are expressed as mean \selectlanguage{ngerman}± SD. Tests for
significance were conducted using the unpaired t-test or nonparametric
test (Mann-Whitney U-test) for continuous variables and the chi-squared
test or Fisher's exact test for categorical variables. The cutoff value
of the voltage in each region was examined using the Receiver Operating
Characteristic (ROC) curve. The score below the cutoff value was set as
1 point each, and the relationship with the recurrence of atrial
fibrillation was examined by a chi-square test. Clinical factors
associated with AF recurrence were determined using univariate and
multivariate Cox proportional hazard models and logistic regression
analyses. All statistical analyses were performed using commercial
software (SPSS version 25 ®, SPSS, Chicago, IL, USA), and statistical
significance was defined as p \textless{}0 .05.



\textbf{4. Results}

\emph{4.1 Baseline and procedure characteristics}

Patient characteristics are shown in Table 1. LVAs existed in 143 of 405
(35.3\%) patients. Patients with LVAs were older, more likely to be
female, had a higher CHA\textsubscript{2}DS\textsubscript{2}-VASc score,
and larger left atrial diameter. Heart failure, pacemaker implantation,
and non-paroxysmal AF were more common in patients with LVAs than in
those without.

Ablation lesions created during the initial ablation are shown in Table
2. PVI was completed in all patients. There was no difference in
modalities used for PVI between patients with and without LVAs
(radiofrequency catheter, 68\% vs. 78\%; cryoballoon catheter, 31\% vs.
20\%; laser balloon catheter, 1\% vs. 1\%; p=0.06). No severe
procedure-related complications such as cardiac tamponade, stroke,
esophageal injury, or major bleeding were observed. Patients with LVAs
more frequently underwent additional ablations such as LVA ablation and
left atrial linear ablations.

\emph{4.2 LVA presence and whole left atrial electrophysiological
degeneration}

Total LVA size among the 143 patients with LVAs was 12.8 ± 8.6
cm\textsuperscript{2}. The distribution of LVAs was the anterior region
in 75\%; septal region in 69\%; roof region in 41\%; posterior region in
32\%; bottom region in 46\%, and lateral region in 7\%.

Whole left atrial electrophysiological degeneration was assessed by mean
regional voltages and left atrial total conduction velocity. Patients
with LVAs demonstrated lower mean regional voltages throughout all 6
regions than those without LVAs (Figure 1). Example cases showing the
absence or presence of LVAs (\textless{}0.5 mV) and whole left atrial
voltage reduction are presented in Supplementary Figure 1. In contrast,
a longer left atrial total conduction time and lower left atrial total
conduction velocity were demonstrated in patients with LVAs than in
those without (Figure 2).

\emph{4.3 AF recurrence using left atrial regional voltage value}

During a mean follow-up period of 16 ± 8 months, 126 (31\%) patients
experienced AF recurrence. Patients with AF recurrence had LVAs more
frequently than those without (53\% vs. 27\%, p\textless{}0.001).

Associations between AF recurrence and mapping parameters representing
whole left atrial electrophysiological degeneration were explored. Mean
regional voltages were significantly lower in patients with AF
recurrence than in those without in all 6 regions (Figure 3). Cut-off
values of regional voltage obtained by ROC analysis for the prediction
of AF recurrence were 0.9 mV for the anterior and septal regions, 1.0 mV
for the roof region, 1.2 mV for the posterior region, 1.4 mV for the
bottom region, and 1.8 mV for the lateral region) (Supplementary Figure
2). Regions with a mean voltage \textless{} the region-specific cut-off
value were defined as a mean regional voltage reduction. AF recurrence
rates stratified according to the number of regions with mean voltage
reduction are presented in Figure 4. AF recurrence rates became higher
as the number of regions with a mean voltage reduction increased. On the
other hand, left atrial total conduction velocity was significantly
lower in patients with AF recurrence than in those without (0.84 ± 0.15
vs. 0.98 ± 0.17 m/s, p \textless{}0.005).

Predictors of AF recurrence are presented in Table 3. On the univariate
analysis, patients with AF recurrence more frequently had non-paroxysmal
AF and left atrial LVAs, and demonstrated a higher left atrial diameter,
lower left ventricular ejection fraction, lower left atrial anterior
conduction velocity, and higher number of regions with mean voltage
reduction. Multivariate analysis revealed that low left ventricular
ejection fraction, low left atrial conduction velocity, and a high
number of regions with mean voltage reduction were independently
associated with AF recurrence.



\textbf{5. Discussion}

In this observational study, we evaluated 405 patients who underwent
initial AF ablation, and compared whole left atrial electrophysiological
degeneration assessed by electroanatomical mapping parameters between
patients with and without LVAs. We then explored clinical and mapping
parameters predicting AF recurrence. The main findings were (1) patients
with left atrial LVAs had a lower mean regional voltage throughout all 6
regions, and regional mean voltage reduction was more extensive than
those without LVAs; (2) left atrial total conduction velocity was lower
in patients with LVAs than in those without; and (3) mapping parameters
representing whole left atrial electrophysiological degeneration such as
left atrial total conduction velocity and the extension of mean regional
voltage reduction independently predicted AF recurrence. To our
knowledge, this is the first clinical study to explore the association
between the presence of localized LVAs and whole left atrial
electrophysiological degeneration.

\emph{5.1 Association between localized LVA presence and whole left
atrial electrophysiological degeneration.}

Patients with localized LVAs demonstrated whole left atrial
degeneration, represented by an extensive mean regional voltage
reduction and a low left atrial total conduction velocity. Several
upstream factors causing atrial fibrosis have been reported, including
atrial stretch, aging, AF burden, hypertension, heart failure, alcohol,
obesity, and obstructive sleep apnea.\textsuperscript{13-17} These
upstream factors would promote atrial fibrosis not only at localized
areas, but also across the entire atrial myocardium. Therefore, when the
voltages at some portions of the left atrium were below 0.50mV - which
is a commonly used cut-off value of LVA - voltages at other areas likely
decreased in parallel, even if not below 0.50 mV.

Myocardial degeneration of the entire atrium in AF patients has also
been reported. Teh et al showed that AF patients had lower mean voltage,
slower conduction, and more prevalent complex signals at a majority of
left atrial regions than controls.\textsuperscript{13}

\emph{5.2 AF substrate extending to the whole left atrium}

In this and our previous study,\textsuperscript{12} whole left atrial
electrophysiological abnormalities such as an extensive mean regional
voltage reduction and a slow left atrial total conduction velocity were
shown to be reliable predictors of AF recurrence.

In addition to the previously reported limited efficacy of LVA
ablation,\textsuperscript{8,11} these results suggest the important
clinical implication that AF substrate is not always limited to LVAs.
Several substrate-based ablations using different ablation targets have
been proposed. One study reported that the cut-off value of voltage for
the prediction of fibrosis differs between
regions,\textsuperscript{18}and others have shown that the use of
different voltage criteria improves the efficacy of LVA
ablation.\textsuperscript{19,20} The efficacy of ablation targeting
fractionated electrograms during sinus rhythm using an ultra-high
resolution mapping system has also been proposed.\textsuperscript{21}

The management of AF based on therapies for upstream factors which
promote atrial degeneration, such as hypertension, diabetes mellitus,
and heart failure, will likely benefit by considering that the AF
substrate extends across the whole atria rather than being localized to
specific portions.

\emph{5.3 Clinical implications}

The presence of a low-voltage area is a marker of myocardial damage, and
in the left atrium where this findings is also locally observed,
electrophysiological degeneration may already be present throughout the
left atrium. Localized LVA suggests that it is a good maker of AF
substrate, but may not always be an optimal ablation target.

\textbf{6. Study limitations}

Several limitations of the present study warrant mention. First, data
analyses were not performed at independent facilities blinded to patient
characteristics, which may have resulted in bias in mapping-data
collection. In particular, mean regional voltage was obtained using
arbitrarily selected mapping points within the region, possibly
resulting in biased values. Second, the study did not investigate data
from repeat procedures, and did not examine the reconnection rate of
isolated pulmonary vein. Accordingly, AF recurrence does not necessarily
mean that the patient had an extra-pulmonary-vein AF substrate. Third,
ablation strategies were at the discretion of attending physician,
possibly affecting rhythm outcomes. Fourth, AF recurrence after
discharge was quantified on the basis of intermittent ECG monitoring,
giving rise to the possibility that asymptomatic episodes of AF might
have been missed. Finally, the study was conducted under a
single-center, observational design. Confirmation awaits a prospective
multicenter study.

\textbf{7. Conclusion}

Patients with localized left atrial LVAs had whole left atrial
electrophysiological degeneration as assessed by regional mean regional
voltages and total left atrial conduction velocity. In addition, whole
left atrial electrophysiological degeneration parameters were well
associated with AF recurrence. These findings suggest that localized LVA
is an excellent maker of AF substrate, but may not always be an optimal
ablation target.

\textbf{Author disclosure}

None.

\textbf{Acknowledgements}

We wish to express our sincerest appreciation to our staff colleagues
for their continuing support and constant encouragement of these works.



\textbf{References}

\begin{enumerate}
\tightlist
\item
  Di Biase L, Elayi CS, Fahmy TS, et al. Atrial fibrillation ablation
  strategies for paroxysmal patients: randomized comparison between
  different techniques. Circ Arrhythm Electrophysiol 2009; 2: 113--119.
\item
  Takahashi A, Iesaka Y, Takahashi Y, et al. Electrical connections
  between pulmonary veins: implication for ostial ablation of pulmonary
  veins in patients with paroxysmal atrial fibrillation. Circulation
  2002; 105: 2998--3003.
\item
  Calkins H, Hindricks G, Cappato R,et al. 2017
  HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and
  surgical ablation of atrial fibrillation. Heart Rhythm 2017; 14:
  e275--e444.
\item
  Verma Atul, Jiang Chen-yang, Betts Timothy R, et al. Approaches to
  catheter ablation for persistent atrial fibrillation. N Engl J Med
  2015; 372: 1812--1822.
\item
  Rolf S, Kircher S, Arya A, Eitel C, Sommer P, Richter S, Gaspar T,
  Bollmann A, Altmann D, Piedra C, et al. Tailored atrial substrate
  modification based on low-voltage areas in catheter ablation of atrial
  fibrillation. Circ Arrhythm Electrophysiol 2014; 7: 25-833.
\item
  Masuda M, Fujita M, Iida O, et al. Left atrial low-voltage areas
  predict atrial fibrillation recurrence after catheter ablation in
  patients with paroxysmal atrial fibrillation. Int J Cardiol 2018; 257:
  97-101.
\item
  Vlachos K, Efremidis M, Letsas KP, et al. Low-voltage areas detected
  by high-density electroanatomical mapping predict recurrence after
  ablation for paroxysmal atrial fibrillation. J Cardiovasc
  Electrophysiol 2017; 28: 1393-1402.
\item
  Masuda M, Asai M, Iida O, et al. Additional Low-Voltage-Area Ablation
  in Patients With Paroxysmal Atrial Fibrillation: Results of the
  Randomized Controlled VOLCANO Trial. J Am Heart Assoc 2020; 9:
  e015927.
\item
  Kircher S, Arya A, Altmann D, et al. Individually tailored vs.
  standardized substrate modification during radiofrequency catheter
  ablation for atrial fibrillation: a randomized study. Europace 2018;
  20: 1766-1775.
\item
  Yang B, Jiang C, Lin Y, et al. STABLE-SR (Electrophysiological
  Substrate Ablation in the Left Atrium During Sinus Rhythm) for the
  Treatment of Non paroxysmal Atrial Fibrillation: A Prospective,
  Multicenter Randomized Clinical Trial. Circ Arrhythm Electrophysiol.
  2017; 10. pii: e005405. doi:10.1161/CIRCEP.117.005405.
\item
  Kumagai K, Toyama H, Zhang B. Effects of additional ablation of
  low-voltage areas after Box isolation for persistent atrial
  fibrillation. J Arrhythmia 2019; 35:737-738.
\item
  Kurata N, Masuda M, Kanda T, et al. Slow whole left atrial conduction
  velocity after pulmonary vein isolation predicts atrial fibrillation
  recurrence. J Cardiovasc Electrophysiol 2020; 31: 1942-1949.
\item
  Teh A, Kistler P, Lee G,et al. Electroanatomic remodeling of the left
  atrium in paroxysmal and persistent atrial fibrillation patients
  without structural heart disease. J Cardiovasc Electrophysiol 2012;
  23: 232-238.
\item
  Kistler P, Sanders P, Fynn S, et al. Electrophysiologic and
  electroanatomic changes in the human atrium associated with age. J Am
  Coll Cardiol 2004; 44: 109-116.
\item
  Wong CX, Abed HS, Molaee P, et al. Pericardial fat is associated with
  atrial fibrillation severity and ablation outcome. J Am Coll Cardiol
  2011; 57: 1745-1751.
\item
  Shahar E, Whitney CW, Redline S, et al. Sleep\selectlanguage{english}-disordered breathing and
  cardiovascular disease: cross\selectlanguage{english}-sectional results of the Sleep Heart
  Health Study. Am J Respir Crit Care Med 2001; 163: 19--25.
\item
  Voskoboinik A, Prabhu S, Ling LH, Kalman JM, Kistler PM. Alcohol and
  Atrial Fibrillation: A Sobering Review. J Am Coll Cardiol 2016; 68:
  2567-2576.
\item
  Kapa S, Desjardins B, Callans DJ, Marchlinski FE, Dixit S. Contact
  electroanatomic mapping derived voltage criteria for characterizing
  left atrial scar in patients undergoing ablation for atrial
  fibrillation. J Cardiovasc Electrophysiol 2014; 25:1044-1052.
\item
  Yagishita A, Gimbel JR, DE Oliveira S, et al. Long-Term Outcome of
  Left Atrial Voltage-Guided Substrate Ablation During Atrial
  Fibrillation: A Novel Adjunctive Ablation Strategy. J Cardiovasc
  Electrophysiol 2017; 28: 147-155.
\item
  Jadidi AS, Duncan E, Miyazaki S, et al. Functional nature of
  electrogram fractionation demonstrated by left atrial high-density
  mapping. Circ Arrhythm Electrophysiol 2012; 5: 32-42.
\item
  Hirokami J, Hiroshima K, Yamaji K, et al. Relationship between
  fractionated signal areas in the atrial muscle during sinus rhythm and
  atrial pacing and non-pulmonary vein foci: novel mapping strategy.
  Circ Arrhythm Electrophysiol 2020; 13: e008667.
\end{enumerate}

\textbf{Figure legends}

\textbf{Figure 1. Comparison of mean regional voltage between patients
with and without low-voltage areas}

Mean regional voltages between patients with and without low-voltage
areas were compared. Low-voltage areas indicated localized areas with
bipolar voltage \textless{} 0.50 mV. Mean regional voltage was
calculated by averaging evenly selected 10 points at the region. The
left atrium was divided into 6 regions. Patients with localized
low-voltage areas at any portion of the left atrium had significantly
lower mean regional voltage throughout all regions than those without.

\textbf{Figure 2. Comparison of left atrial whole conduction time and
velocity between patients with and without low-voltage areas}

Left atrial whole conduction time and velocity between patients with and
without low-voltage areas were compared. Conduction time was defined as
the time difference between the start (septum) and end of the left
atrial propagation wave front (lateral mitral annulus) during right
atrial pacing or sinus rhythm. Left atrial conduction velocity was
calculated as left atrial anterior conduction distance divided by
conduction time. Anterior conduction distance was measured manually by
tracing the pathway of the propagation wave front from the start point
to the end point in the anterior left atrium. Patients with localized
low-voltage areas at any portion of the left atrium demonstrated longer
conduction time and a slower conduction velocity than those without.

\textbf{Figure 3. Comparison of mean regional voltage between patients
with and without recurrence of atrial fibrillation}

Mean regional voltages between patients with and without recurrence of
atrial fibrillation were compared. Mean regional voltage was calculated
by averaging 10 evenly selected points in the region. The left atrium
was divided into 6 regions. Patients with recurrence of atrial
fibrillation demonstrated lower mean regional voltages throughout all
regions than those without.

\textbf{Figure 4.Recurrence rates of atrial fibrillation stratified
according to the number of regions with mean voltage reduction}

Recurrence rates of atrial fibrillation stratified according to the
number of regions with mean voltage reduction were compared. A region
with mean voltage reduction was defined as a region with a mean voltage
\textless{} the region-specific cut-off value obtained using
receiver-operator characteristics analysis for the prediction of atrial
fibrillation recurrence (0.9 mV for anterior and septal, 1.0 mV for
roof, 1.2 mV for posterior, 1.4 mV for bottom, and 1.8 mV for lateral).
Recurrence rates became higher as the number of regions with mean
voltage reduction increased.

\textbf{Supplementary Figure 1. Representative cases showing the
extension of voltage reduction with and without low-voltage areas}

Left atrial voltage maps using various voltage thresholds with and
without localized low-voltage areas are shown. Low-voltage areas
indicated localized areas with bipolar voltage \textless{} 0.50 mV. A
patient without low-voltage areas (Upper) demonstrated no or smaller
areas with reduced voltage even using a relatively high voltage
threshold (\textless{} 1.0mV, and \textless{} 1.5mV) than a patient with
localized low-voltage areas (lower).

\textbf{Supplementary Figure 2. Receiver-operator characteristics curves
of mean regional voltages for the prediction of recurrence of atrial
fibrillation}

The best cut-off value of mean regional voltage at each region for the
prediction of recurrence of atrial fibrillation was calculated using the
receiver-operator characteristics curve. AUC indicates area under the
curve; CI, confidence interval.\selectlanguage{english}
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