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\begin{document}

\title{Relationship Between dominant-frequencies/rotors and Low-voltage Areas
Using an Advisor HD Grid Mapping Catheter after Pulmonary Vein Isolation
of Non-paroxysmal Atrial Fibrillation}



\author[1]{Koji Kumagai}%
\author[1]{Yuki Kurose}%
\author[1]{Tsukasa Sato}%
\author[1]{Takenori Sumiyoshi}%
\author[1]{Minoru Yambe}%
\author[1]{Tatsuya Komaru}%
\affil[1]{Tohoku Medical and Pharmaceutical University}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
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\endgroup





\selectlanguage{english}
\begin{abstract}
Background This study aimed to evaluate the relationship between
dominant frequencies (DFs)/rotors and low-voltage areas (LVAs) using the
Advisor HD grid (HDG) after pulmonary vein isolation (PVI) in
non-paroxysmal atrial fibrillation (AF). Methods A total of 73
non-paroxysmal AF patients were prospectively investigated. After
pulmonary vein isolation (PVI), an online real-time phase mapping system
was used to detect the location of rotors with critical non-passively
activated ratios (\%NPs) of[?]50\% in each LA segment, and high-DFs of
[?]7Hz were simultaneously mapped. After recovering sinus rhythm, LVAs
(\textless{}0.5mV) were mapped using the HDG. Results Sixty-eight of 73
(93.2\%) AF patients had minimum to mild LVAs (\textless{}10\%)
regardless of an enlarged LAD and LA volume (45\selectlanguage{ngerman}±6.1mm and 142±30ml).
There were no significant differences in the max and mean DF values and
\%NPs between the patients with and without recurrent AF/AT (atrial
tachycardia). However, LVAs were significantly greater in the patients
with AF/AT than in those without (6.4±8.0\% vs. 2.5±2.6\% P=0.003).
Furthermore, the number of high-DF sites overlapping with LVAs was
significantly greater in the patients with AF/AT than in those without
(0.5±0.8 vs. 0.2±0.7, P=0.019). The AF/AT freedom off anti-arrhythmic
drugs after the PVI was significantly lower in the patients with
high-DFs sites overlapping with LVAs than in those without during
11.6±0.8 months of follow-up (35.7\% vs. 69.5\%, p=0.021). Conclusions
High-DF sites overlapping with LVAs detected accurately by the HDG,
regardless of whether a minimum to mild extent, might be more selective
targets after a PVI in non-paroxysmal AF patients.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Relationship Between dominant-frequencies/rotors and Low-voltage
Areas Using an Advisor HD Grid Mapping Catheter after Pulmonary Vein
Isolation of Non-paroxysmal Atrial Fibrillation}

\textbf{Short title:} Atrial low-voltage areas and rotors/dominant
frequencies

Koji Kumagai, MD, PhD,,Yuki Kurose, Tsukasa Sato, MD, Takenori
Sumiyoshi, MD, PhD, Minoru Yambe, MD, PhD, and Tatsuya Komaru, MD, PhD

Department of Cardiovascular Medicine, Tohoku Medical and Pharmaceutical
University, Miyagi, Japan

Address for Correspondence: Koji Kumagai, 1-15-1 Fukumuro Miyaginoku,
Sendai, Miyagi 983-8536, Japan. Fax 81-22-290-8983; E-mail:
kkumagai4917@yahoo.co.jp

\textbf{Funding}

This work was supported in part by the grant-in-aid for scientific
research from the Japanese Ministry of Education, Culture, Sports,
Science, and Technology, Tokyo, Japan (No. 20K08495).

\textbf{Word Count:} 5,282 words, 3 tables and 4 figures.

\textbf{Abstract}

\textbf{Background} This study aimed to evaluate the relationship
between dominant frequencies (DFs)/rotors and low-voltage areas (LVAs)
using the Advisor HD grid (HDG) after pulmonary vein isolation (PVI) in
non-paroxysmal atrial fibrillation (AF).

\textbf{Methods} A total of 73 non-paroxysmal AF patients were
prospectively investigated. After pulmonary vein isolation (PVI), an
online real-time phase mapping system was used to detect the location of
rotors with critical non-passively activated ratios (\%NPs) of[?]50\% in
each LA segment, and high-DFs of [?]7Hz were simultaneously mapped. After
recovering sinus rhythm, LVAs (\textless{}0.5mV) were mapped using the
HDG.

\textbf{Results} Sixty-eight of 73 (93.2\%) AF patients had minimum to
mild LVAs (\textless{}10\%) regardless of an enlarged LAD and LA volume
(45\selectlanguage{ngerman}±6.1mm and 142±30ml). There were no significant differences in the
max and mean DF values and \%NPs between the patients with and without
recurrent AF/AT (atrial tachycardia). However, LVAs were significantly
greater in the patients with AF/AT than in those without (6.4±8.0\% vs.
2.5±2.6\% P=0.003). Furthermore, the number of high-DF sites overlapping
with LVAs was significantly greater in the patients with AF/AT than in
those without (0.5±0.8 vs. 0.2±0.7, P=0.019). The AF/AT freedom off
anti-arrhythmic drugs after the PVI was significantly lower in the
patients with high-DFs sites overlapping with LVAs than in those without
during 11.6±0.8 months of follow-up (35.7\% vs. 69.5\%, p=0.021).

\textbf{Conclusions} High-DF sites overlapping with LVAs detected
accurately by the HDG, regardless of whether a minimum to mild extent,
might be more selective targets after a PVI in non-paroxysmal AF
patients.

\textbf{Key words:} atrial fibrillation; catheter ablation; dominant
frequencies; low-voltage areas; pulmonary vein isolation; rotors.

\textbf{Abbreviations}

AF = atrial fibrillation

AT = atrial tachycardia

DFs = dominant frequencies

PVI = pulmonary vein isolation

\%NP \textbf{=} non-passively activated ratio

\textbf{INTRODUCTION}

Pulmonary vein isolation (PVI) has been the cornerstone of atrial
fibrillation (AF) ablation. However, the single procedure success rates
are limited, particularly in persistent and longstanding persistent
AF.\textsuperscript{1} However, additional strategies including linear
ablation and ablation of complex fractionated atrial electrograms
(CFAEs) \textsuperscript{2,3} have not indicated any efficacy benefit
over a PVI alone in non-paroxysmal AF patients. \textsuperscript{4}

A strategy based on low-voltage areas (LVAs) as detected by left atrial
(LA) voltage mapping during sinus rhythm (SR) has recently been reported
because LVAs are a predictor of AF recurrence after AF
ablation.\textsuperscript{5,6,7} Furthermore, the recent utility of the
Advisor HD grid HD (HDG) mapping catheter (Abbott Technologies, St Paul,
Minnesota, USA) might lead to new and unique mapping techniques. The HDG
contributes to the bipolar recording of activation parallel and
perpendicular to the splines, which differs from conventional
mapping.\textsuperscript{8} Therefore, the HDG can create high density
maps to define anatomical substrates regardless of the direction of the
activation.

High-DF sites may be potential selective targets for localized sources
maintaining AF in non-paroxysmal AF
patients.\textsuperscript{9,10,11}However, high-DF areas change
spatiotemporally and the DF based ablation is still
controversial.\textsuperscript{12} Therefore, we previously reported the
importance of high-DF sites overlapping with present LVAs using a
conventional mapping catheter after the PVI.\textsuperscript{13}
Recently, the areas in which rotational activations are frequently
observed are automatically detected by a novel phase mapping system
among some ablation strategies targeting AF
drivers.\textsuperscript{14-16} This study aimed to evaluate the
relationship between the DFs/rotors and LVAs detected using the HDG
after PVI in non-paroxysmal AF.

\textbf{METHODS}

\textbf{Study Population}

The present study was a prospective observational study that included 81
consecutive patients with non-paroxysmal AF who underwent catheter
ablation at our institution between November 2018 and April 2020. Five
patients were excluded due to having no multidetector computed
tomography (MDCT) images and 3 patients for undergoing additional LA
ablation other than the PVI. Finally, a total of 73 persistent and
longstanding persistent AF patients were investigated in this study.
Persistent AF was defined as AF lasting \selectlanguage{english}[?]7 days but \textless{}1 year,
and longstanding persistent AF as continuous AF lasting \selectlanguage{english}[?]1
year.\textsuperscript{17} All antiarrhythmic drugs were discontinued for
at least 5 half-lives and one patient received oral amiodarone therapy
before the catheter ablation. The protocol for this research project was
approved by a suitably constituted Ethics Committee of Tohoku Medical
and Pharmaceutical University (Date of IRB approval: February 25, 2019;
Approval number, 2018-2-104) and it conformed to the provisions of the
Declaration of Helsinki. All patients provided written informed consent
for the ablation procedure, and the use of their anonymized data in this
study.

\textbf{Catheter Ablation Procedure}

The catheter ablation procedure was performed using a NavX system (St.
Jude Medical, St. Paul, MN, USA) as described
previously.\textsuperscript{10,13,18} A 5-french deflectable catheter
was inserted into the coronary sinus (CS) via the right femoral vein.
After a single transseptal procedure under intracardiac echocardiography
guidance, an 8-F SL0 sheath and Agilis sheath (St. Jude Medical, St.
Paul, MN, USA) were advanced into the LA. After the transseptal
procedure, a single bolus of 5,000U of heparin was administered. A
continuous infusion with heparinized saline was delivered to maintain an
activated clotting time of 300 to 350s. The 3D LA geometry was created,
and sequential contact mapping was performed using a 7-F decapolar
circular catheter (EPstar Libero, Japan-lifeline Co.,Ltd., Tokyo,
Japan). The whole LA was divided into eight areas (PVs, roof, left
atrial appendage {[}LAA{]}, septum, lateral, anterior, inferior, and
posterior) for a location analysis of the AF substrate.
\textsuperscript{10,13,18} The mapping points in each region were
similar in number and nearly equally distributed (LA mean mapping
points: 1843+- 501).

The PVI was performed guided by a 7-F decapolar circular catheter
positioned at the PV ostia as described
previously.\textsuperscript{10,13,18} Each radiofrequency (RF) energy
application was delivered for 40s. A 3.5mm irrigated tip RF catheter
(FlexAbility \textsuperscript{TM}, St. Jude Medical Inc.) was used with
the temperature limited to 42\selectlanguage{english} and power to 30W (25W to sites near the
esophagus) with a flow rate of 13 mL/min. After the elimination or
dissociation of the PV potentials, exit block was confirmed by pacing
from the circular catheter placed within the PVs. After the PVI, DF
mapping and rotor mapping were simultaneously performed in the same
mapping area as follows. Finally, a LA voltage map was performed during
pacing from the distal CS after external cardioversion.

Once in SR, decremental pacing (10 milliseconds steps from 250 to 200
miliseconds, over a period of 10 seconds) at an output of 10mA and 2ms
pulse width was performed from the distal CS once, in an attempt to
induce an atrial tachyarrhythmia without an isoproterenol injection. An
induced AF/atrial tachycardia (AT) was defined as that sustained for at
least 2 minutes.\textsuperscript{17} When AF/AT continued, external
cardioversion was performed. When cavotricuspid isthmus (CTI) dependent
AFL was induced, a CTI ablation was performed.

\textbf{Frequencies Analysis}

After the PVI, DF mapping during AF in each area was performed using the
fast Fourier transform (FFT) method described
previously.\textsuperscript{10,13,18,19} Recordings at each site for 5
seconds were performed using a deflectable 20-pole spiral-shaped
catheter with a diameter of 2.5 cm (Reflexion HDTM, St. Jude Medical).
Signals were truncated to 5 seconds at a sampling rate of 1,000Hz,
providing 4,096 points for analysis (resolution 0.50Hz). The signals
were rectified and processed by a Hanning window function and filtered
from 2 to 20Hz. The DF analysis was done by an offline FFT analysis
using the software implemented in the polygraph (RMC-5000; Nihon Kohden
Co., Tokyo, Japan) in real-time and then the DF values were input
manually into the NavX system. The DF value was determined as the
frequency associated with the maximum peak power of the spectrum. Only
DF points with a regularity index \selectlanguage{english}[?]0.2 were
included.\textsuperscript{10,13,18,19} The high-DF sites were defined as
DFs of \selectlanguage{english}[?]7Hz. The highest value of the DF in each mapping area in the LA
was measured and calculated.

\textbf{Real-Time Phase Mapping}

In the same areas where the DF mapping was performed, mapping during AF
was simultaneously performed using an online real-time phase mapping
system (ExTRa MappingTM, Nihon Kohden Co., Tokyo, Japan) as described
previously.\textsuperscript{16} This mapping system was based on 41
bipolar intraatrial electrograms (including 9 virtual electrograms)
recorded by a deflectable 20-pole spiral-shaped catheter with a diameter
of 2.5 cm. The contact was confirmed by the recorded electrograms,
fluoroscopy, and 3D geometry. The distance between a mapping point and
the geometry surface created by the EnSite NavX was set at 5 mm. The
data sampling was adopted as good contact in areas where sufficient
electrograms could be recorded from the vast majority of the electrodes.
Based on the 5-s wave dynamics during AF, each phase map was
automatically created by ExTRa Mapping. Non-passively activated areas,
in which rotational activations were frequently observed, were
automatically detected by ExTRa Mapping. The value of the
``non-passively activated ratio'' (\%NP), which is the ratio of the form
of rotors and multiple wavelets assumed to contain AF drivers to the
recording time, was automatically calculated from the 5-s real-time
phase map created by ExTRa Mapping.\textsuperscript{16} Of the 5-s map,
the activation sequences during 720 ms (60 msx12 consecutive time
windows) of representative episodes were depicted as images.

\textbf{LVA mapping and analysis}

After external cardioversion, a detailed bipolar LA voltage map was
constructed during pacing from the distal CS in all patients. The LVA
mapping method has been described previously.\textsuperscript{5,6,7} The
mapping points were systematically acquired with the HDG, which has 16
electrodes and 3 mm equidistant electrode spacing to create a high
density contact voltage map via the Ensite Velocity 3D mapping system.
The algorithm displays the signals amalgamated from orthogonal
recordings of each bipole and displays the highest amplitude signal (HD
wave solution). An interpolation threshold of 10 mm on the NavX system
was used for the surface color projection. Adequate endocardial contact
was evaluated by stable electrograms and consideration of the distance
to the geometry surface. Only true sinus beats were selected. Bipolar
electrograms were filtered by a bandpass of frequencies between 30 and
500Hz. In accordance with the previous studies \textsuperscript{5,6,7},
an LVA was defined as an area with a bipolar peak-to-peak electrogram
amplitude of \textless{}0.5mV and electrical scar areas as
\textless{}0.1mV. The LA surface area was defined as the LA body area
without the PV antrum regions inside the PVI line. The registration for
evaluating the MDCT image with the NavX map consisted of an AF image
imported (pre-ablation) with a post cardioversion SR map in all patients
in order to obtain the anatomical information, and the overlap between
the LVAs and high-DF sites was evaluated manually by 2 independent
blinded observers.

\textbf{Post-procedure Care and Follow-up}

Antiarrhythmic medications were continued for at least 3 months to
prevent any early recurrences. A clinical interview, surface ECG, and
24-h Holter monitoring were performed 1 day after the procedure and
repeated 1, 3, 6 and 12 months after the catheter ablation. AF/AT
recurrence was defined as sustained AF/AT lasting more than 30s, which
occurred more than 3 months after the catheter
ablation.\textsuperscript{17}

\textbf{Statistical Analysis}

The continuous variables are presented as the mean +- standard deviation
together with the 95\% confidence intervals. Categorical variables were
expressed as numbers and percentages. The significance of any
differences between the two groups was analyzed with an unpaired\emph{t}
-test and Mann-Whitney U test for continuous variables, and with a
Fisher's exact probability test for categorical variables. A predictive
analysis of AF recurrence during the follow-up period was assessed using
multivariate Cox proportional hazard regression models. A multivariate
analysis with multivariate Cox proportional hazard regression models was
performed to isolate the independent criteria of AF recurrence after
ablation. Only the variables with significant P-values in the univariate
analysis were included in the multivariate Cox proportional hazard
regression. A Kaplan-Meier event-free survival analysis was conducted to
assess the cumulative freedom from AF recurrence. A value of
P\textless{}0.05 was considered statistically significant.

\textbf{Results}

\textbf{Patient Characteristics}

The AF patients were divided into two groups: patients without AF/AT
recurrence (n=46) and those with AF/AT recurrence (n=27). The patient
characteristics are shown in \textbf{Table 1} . The patients included 19
with persistent AF and 54 with longstanding persistent AF (mean duration
25+-18 months). The mean LA diameter (LAD) and LA volume were 45+-6.1 mm
and 142+-30 ml, respectively. The patient characteristics and laboratory
data except for the LV ejection fraction did not significantly differ
between the two groups. None except for 6 (2 with hypertrophic
cardiomyopathy, 3 with mitral regurgitation, and 1 with old myocardial
infarctions) had structural heart disease.

\textbf{Procedural Characteristics}

The procedural characteristics are shown in \textbf{Table 2} . Though
the total procedure time significantly differed between the two groups,
the RF time for the PVI did not differ between the two groups. There
were no patients with AF termination. Therefore, all patients finally
needed external cardioversion after the PVI.

\textbf{Frequencies and Phase mapping Analysis}

According to the frequencies and phase mapping analysis, all mapping
sites (n=835, 11.4 sites per patient) were divided into 4 types
(\textbf{Table 3} ). However, there were no significant differences
among the 4 types between the patients with and without recurrent AF
(\textbf{Table 2} ). The max-DF value and max-\%NP per patient were
6.7+-0.9 Hz and 65+-11 \% after the PVI, respectively. There were no
significant differences between the patients with and without recurrent
AF in the max-DF value, max-\%NP, mean DF value, and mean \%NP
(\textbf{Table 2} ). The number of high-DF sites\selectlanguage{english}[?]7Hz in the LA was
2.4+-3.7 per patient after the PVI, and the number of \%NPs\selectlanguage{english}[?]50\% was
9.1+-4.7 per patient after the PVI (\textbf{Table 2} ). A \%NP\selectlanguage{english}[?]50\% and
high-DF sites\selectlanguage{english}[?]7Hz were frequently identified in the inferior and
anterior regions of the LA, respectively (\textbf{Figure 1A} ).

\textbf{LVA mapping and analysis}

Two different voltage maps were created using the 2 HDG bipolar
configurations (along the spline and HD wave solution). There was a
significant difference in the LVAs/LA surface between that using the HD
wave solution and that along the spline (3.9+-11\% vs. 7.3+-14\%,
P\textless{}0.001) (\textbf{Figure 2} ). The extent of the LVZ was
calculated as the percentage of the LA surface area and was categorized
into stages 1 (minimum LVA, \textless{}5\%), 2 (mild, \selectlanguage{english}[?]5\% to
\textless{}20\%), 3 (moderate, \selectlanguage{english}[?]20\% to \textless{}30\%), and 4
(extensive, \selectlanguage{english}[?]30\%). Sixty-eight of 73 (93.2\%) patients with AF had
minimum to mild LVAs (\textless{}10\%) using the HDG with the HD wave
solution regardless of an enlarged LAD and LA volume.

As shown in \textbf{Figure 1B,} LVAs were found in 194 (23.2\%) sites
out of 835. LVAs were frequently identified in the septal, anterior, and
posterior regions of the LA. There was a significant difference in the
LVA (\textless{}0.5mV)/LA surface area between the patients with and
without recurrent AF/AT (6.4+-8.0\% vs. 2.5+-2.6\% P=0.003) as shown in
Table 3. In addition, though there was no significant difference in the
number of \%NPs\selectlanguage{english}[?]50\% that overlapped with LVAs between the two groups
(0.9+-1.1 vs. 0.6+-1.0, P=0.178), there were a significant difference in
the number of high-DF sites \selectlanguage{english}[?]7Hz that overlapped with LVAs between the
two groups (0.5+-0.8 vs. 0.2+-0.7, P=0.026). Further, high-DF sites \selectlanguage{english}[?]7Hz
overlapping with LVAs were frequently identified in the septal, roof,
and inferior regions of the LA and the \%NPs\selectlanguage{english}[?]50\% overlapping with LVAs
in the anterior and septal regions (\textbf{Figure 1C} ). Furthermore,
the number of sites that overlapped with all regions (LVAs, high-DF
sites \selectlanguage{english}[?]7Hz and \%NPs\selectlanguage{english}[?]50\%) included only 6 (0.7\%) out of 835 sites (1
anterior, 2 posterior, 1 septal, 1 roof, and 1 LAA). A representative
case is shown in \textbf{Figure 3} .

\textbf{Outcome of the Catheter Ablation}

A Kaplan-Meier event-free survival analysis was conducted to assess the
cumulative freedom from AF/AT recurrence. One patient had AT recurrences
after one procedure. The atrial arrythmia freedom off anti-arrhythmic
drugs after the PVI was significantly lower in the patients with
high-DFs sites \selectlanguage{english}[?]7Hz overlapping with LVAs than in those without high-DFs
sites overlapping with LVAs during 11.6+-0.8 months of follow-up (35.7\%
vs. 69.5\%, p=0.008). (\textbf{Figure 4A} ). However, there was no
significant difference in the \%NPs\selectlanguage{english}[?]50\% overlapping with LVAs between
the two groups (\textbf{Figure 4B} ). The number of patients receiving
post ablation anti-arrhythmic drugs (AADs) during the follow-up was 16
(22\%) among those with recurrent AF. There were no cases of cerebral
infarctions, cardiac tamponade, PV stenosis, or atrial-esophageal
fistulae.

\textbf{Predictors of AF recurrence}

A univariate Cox proportional hazard regression analysis, including of
the AF duration, LA diameter, EF, LA volume, CHA2DS2-VASc score, LVA/LA
surface area after the PVI, max-DF value, max-\%NP value, high-DF sites
overlapping with LVAs, and \%NP\textgreater{}50\% sites overlapping with
LVAs, indicated that the LVA/LA surface area after the PVI (hazard ratio
{[}HR{]} 1.066; confidence interval {[}CI{]}, 1.017-1.117, P=0.007) and
high-DF sites overlapping with LVAs (HR 1.031; CI, 1.083-5.381, P=
0.031) were significantly associated with AF/AT recurrence. In a
multivariate analysis, the LVA/LA surface area after the PVI (HR 1.079;
CI, 1.026-1.134, P=0.003) and high-DF sites overlapping with LVAs (HR
2.842; CI, 1.238-6.527, P= 0.014) were independent predictors of AF
recurrence.

\textbf{Discussion}

\textbf{Major findings}

The major findings of the present study were: (1) Most AF patients had
minimum to mild LVAs using the HDG (HD wave solution) regardless of an
enlarged LAD and LA volume. (2) There were no significant differences in
the max and mean DF values and \%NP after the PVI between the patients
with and without recurrent AF/AT. (3) The LVAs, regardless of a minimum
to mild extent, were significantly indicated to be greater in the
patients with recurrent AF/AT than in those without. (4) The number of
high-DFs sites overlapping with LVAs was significantly greater in
patients with recurrent AF/AT than in those without. (5) The atrial
arrythmia freedom off AADs after the PVI was significantly lower in the
patients with high-DF sites overlapping with LVAs than in those without
during 11.6+-0.8 months of follow-up.

\textbf{LVAs detected using the HDG}

An increased amount of fibrosis as detected by LA voltage mapping has
been shown to be a predictor of AF/AT recurrence after AF
ablation.\textsuperscript{5,6,7} The extent of the LVAs was categorized
on the basis of the LA fibrosis grade evaluated by delayed-enhancement
magnetic resonance imaging (MRI).\textsuperscript{20,21} However, the
definition of the LVAs and their correlation with histological fibrosis
remains controversial, because the bipolar voltage amplitudes depend on
the electrode orientation relative to the direction of the wavefront,
electrode length, interelectrode spacing, and tissue
contact.\textsuperscript{22} Furthermore, the HDG when used for bipolar
recording can record not only the parallel but also the perpendicular
activation to the splines, which differs from conventional
mapping.\textsuperscript{23} Therefore, the HD grid could create high
density maps to define anatomical substrates regardless of the direction
of the activation. In this study, the HDG drastically decreased the
extent of the LVA. The HDG may improve the directional sensitivity and
exclude any false low-voltages, and can detect the AF substrate more
accurately, which would lead to a more effective ablation
strategy.\textsuperscript{23}

\textbf{Frequencies and rotor mapping after a PVI}

Atrial sites that represent local electrograms with high-DFs may be
associated with AF maintenance.\textsuperscript{10,13,18} In addition,
Sakata et al.\textsuperscript{16} demonstrated that real AF drivers are
contained in the non-passively activated areas where rotors and/or
multiple wavelets are most frequently observed during a short recording
time (5-s) with high reproducibility of the \%NP. The distribution of
the high-DF sites in the LA was similar to that of the \%NP\selectlanguage{english}[?]50\% after
the PVI in this study. In the previous report, the highest DF and rotor
positions were robust markers of the driver location during AF using a
computational study.\textsuperscript{24} However, in this study there
were no significant differences in the DF, \%NP value, and combination
of the DF and \%NP between the patients with and without recurrent
AF/AT. An index such as the DF or \%NP may not always reflect the
critical AF drivers. Furthermore, a combination of the DF and LVA may be
needed for the detection of the critical targets for an atrial substrate
modification.

\textbf{The sites overlapping with LVAs}

In the previous study, 77\% of the high-DF sites overlapped with LVAs in
the LA\textsuperscript{13} using conventional mapping catheters, while
only 2.6\% (22 sites out of 835) overlapped using the HDG in this study.
However, there was a significant difference in the number of high-DF
sites overlapping with LVAs between the patients with and without
recurrent AF/AT. The HDG might drastically exclude false LVAs, which
would help detect the AF substrate more accurately.

Furthermore, though the number of \%NP\selectlanguage{english}[?]50\% sites overlapping with LVAs
in the LA was greater, there was no significant difference in that
number between the patients with and without recurrent AF/AT. The \%NP
indicated the frequency of the presence of rotors within a relatively
large mapping area (diameter of 2.5 cm), and the area overlapping with
LVAs may not always reflect the exact overlapping sites between the
rotors and LVAs.

High-DF areas change spatiotemporally and the DF based ablation is still
controversial.\textsuperscript{12} However, drivers are harbored
within/in the vicinity of LVAs, and fractionated activity, rotational
activity, and discrete rapid local activity during AF in LVAs may
contribute to the formation of high-DFs.\textsuperscript{7,15} The
selection of high-DF sites overlapping with LVAs as targets may correct
the shortcoming of an ablation based on the DF.\textsuperscript{13} In
this study, a combination of frequency mapping and LVA mapping using the
HDG could detect the critical selective atrial substrate necessary to
maintain AF. Therefore, this strategy using the HDG could avoid any
excessive RF applications as compared to that using conventional
mapping.

\textbf{Study limitations}

The present study was limited in several ways. First, this was a
single-center, nonrandomized observational study. Second, missed brief
or silent AF episodes may have been underestimated in the present study
because of noncontinuous monitoring during the follow-up. Third, LVA
mapping in the RA could not be performed due to the long procedure.
Fourth, there may have been the possibility that the voltage mapping and
phase mapping may not have been adequately performed with sufficient
catheter contact with the atrial tissue because we did not use a contact
force sensing catheter for the mapping. Finally, we could not evaluate
the efficacy of the ablation of the high-DF sites that overlapped with
LVAs.

\textbf{Conclusions}

Most AF patients had only minimum to mild LVAs using the HDG regardless
of an enlarged LAD and LA volume. However, the minimum to mild LVAs were
significantly greater in the patients with recurrent AF/AT than in those
without. The HDG might drastically exclude false LVAs, which would help
detect the AF substrate more accurately. Furthermore, high-DFs sites
overlapping with LVAs detected by the HDG might be more selective
targets after the PVI in non-paroxysmal AF patients.

\textbf{Conflicts of Interest}

All authors declare no conflict of interest related to this study

\textbf{Funding}

This work was supported in part by the grant-in-aid for scientific
research from the Japanese Ministry of Education, Culture, Sports,
Science, and Technology, Tokyo, Japan (No. 20K08495).

\textbf{Acknowledgments}

We would like to thank John Martin for his linguistic help in preparing
this manuscript.

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\textbf{Figure Legends}

\textbf{Figure 1.}

\textbf{Voltage maps created using the2 HDG bipolar configurations. A.
along the spline B. HD wave solution.}

The low voltage areas (LVAs)/left atrial (LA) surface was 20.5\% (A) and
14.3\% (B), respectively. The red tags show the PVI ablation points. The
color-coding was defined as follows: \textless{}0.1mV=scar (gray), 0.1
to 0.5mV=diseased atrial tissue, and \textgreater{}0.5mV=healthy atrial
myocardium (purple).

\textbf{Figure 2.}

\textbf{The distribution of the DFs, rotors and LVAs in the LA after the
PVI}

A. The \%NPs\selectlanguage{english}[?]50\% and high-DF sites\selectlanguage{english}[?]7Hz were frequently identified in
the inferior and anterior regions of the LA, respectively. B. LVAs were
frequently identified in the septal, anterior, and posterior regions of
the LA. C. High-DF sites \selectlanguage{english}[?]7Hz overlapping with LVAs were frequently
identified in the septal, roof, and inferior regions of the LA and
\%NPs\selectlanguage{english}[?]50\% overlapping with LVAs in the anterior and septal regions.

\textbf{Figure 3.}

(A) A voltage map in the left atrium (LA) after the PVI. Minimum low
voltage areas (LVAs) (LVAs/LA: 2.3\%) were found in the posterior LA.
The red tags show the PVI ablation points. (B) The spectrum of high-DF
sites overlapping with LVAs in the posterior LA (7.2Hz with RI 0.72)
(pink tag). (C) Electrograms in the posterior LA after the PVI.
Intra-atrial bipolar electrograms recorded by a 20-pole spiral-shaped
catheter during atrial fibrillation (AF) are shown. The mean AF cycle
length is 148 ms. (D) ExTRa Mapping of the posterior LA after the PVI.
The activation sequences during 720ms of data (60-msx12 consecutive time
windows) are shown. The white lines indicate the head of the wavefronts
and white arrows the direction of the wavefronts. In this case, a
wavefront traveling in the posterior LA forms a rotor lasting for 3
rotations. The nonpassively activated ratio (\%NP) is 53\%.

\textbf{Figure 4.}

\textbf{Kaplan-Meier event-free survival analysis for the cumulative
freedom from AF /AT recurrence.}

A. The atrial arrythmia freedom off anti-arrhythmic drugs after the PVI
was significantly lower in the patients with high-DFs sites \selectlanguage{english}[?]7Hz
overlapping with LVAs than in those without during 11.6+-0.8 months of
follow-up (35.7\% vs. 69.5\%, p=0.008). B. There was no significant
difference in the \%NP sites \selectlanguage{english}[?]50\% overlapping with LVAs between the two
groups.

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