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\begin{document}

\title{Atrial late potentials are associated with atrial fibrillation
recurrence after catheter ablation}



\author[1]{Daiki Saito}%
\author[1]{Hidehira Fukaya}%
\author[1]{Jun Oikawa}%
\author[1]{Tetsuro Sato}%
\author[1]{Gen Matsuura}%
\author[1]{Yuki Arakawa}%
\author[1]{Shuhei Kobayashi}%
\author[1]{Yuki Shirakawa}%
\author[1]{Naruya Ishizue}%
\author[1]{Jun Kishihara}%
\author[1]{Shinichi Niwano}%
\author[1]{Junya Ako}%
\affil[1]{Kitasato Daigaku Igakubu}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
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\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Introduction:} Few non-invasive parameters have been identified
for predicting atrial fibrillation (AF) recurrence after catheter
ablation (CA). This study aimed to assess the association between AF
recurrence and atrial late potentials (ALP) measured using P-wave
signal-averaged electrocardiography (P-SAECG). \textbf{Methods and
results:} Consecutive patients with paroxysmal AF who underwent first CA
at our institution between August 2015 and August 2019 were enrolled.
P-SAECG was performed before CA. Two ALP parameters were evaluated: root
mean square voltage during the terminal 20 ms (RMS \textsubscript{20})
and P-wave duration (PWD). Positive ALP was defined as an RMS
\textsubscript{20} \textless{}2.2 \selectlanguage{greek}µ\selectlanguage{english}V and/or a PWD \textgreater{}115 ms.
Patients were divided into the Recurrence and Non-recurrence groups
based on AF recurrence at the 1-year follow-up after CA. Of 190 patients
(age: 65\selectlanguage{ngerman}±11 years, 37\% women) enrolled in this study, 21 (11\%) had AF
recurrence. Positive ALP rate was significantly higher in the Recurrence
group than in the Non-Recurrence group (86\% vs. 64\%, \emph{P}=0.04)
despite there being no differences in other baseline characteristics
between the two groups. In the multivariate analysis, positive ALP was
an independent predictor of AF recurrence (odds ratio: 3.83, 95\%
confidence interval: 1.05--14.1, \emph{P}=0.04). \textbf{Conclusion:}
Positive ALP on pre-CA P-SAECG was associated with AF recurrence after
CA.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Atrial late potentials are associated with atrial fibrillation
recurrence after catheter ablation}

Daiki Saito, MD\textsuperscript{1)}; Hidehira Fukaya, MD,
PhD\textsuperscript{1)}; Jun Oikawa, MD, PhD\textsuperscript{1)};
Tetsuro Sato, MD\textsuperscript{1)}; Gen Matsuura,
MD\textsuperscript{1)}; Yuki Arakawa, MD, PhD\textsuperscript{1)};
Shuhei Kobayashi, MD, PhD\textsuperscript{1)}; Yuki Shirakawa, MD,
PhD\textsuperscript{1)}; Naruya Ishizue\textsuperscript{1)}, MD, PhD;
Jun Kishihara, MD, PhD\textsuperscript{1)}; Shinichi Niwano, MD,
PhD\textsuperscript{1)}; Junya Ako, MD, PhD\textsuperscript{1)}

Department of Cardiovascular Medicine, Kitasato University School of
Medicine, Sagamihara, Kanagawa, Japan

Funding: This work was supported by JSPS KAKENHI Grant Number
JP18K08113.

Disclosures: There is no conflict of interest.

Corresponding author: Hidehira Fukaya, MD, PhD

Department of Cardiovascular Medicine, Kitasato University School of
Medicine

1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Japan.

Email address: hidehira@med.kitasato-u.ac.jp

Tel: +81-42-778-8111, Fax: +81-42-778-8441

\emph{Abstract}

\textbf{Introduction:} Few non-invasive parameters have been identified
for predicting atrial fibrillation (AF) recurrence after catheter
ablation (CA). This study aimed to assess the association between AF
recurrence and atrial late potentials (ALP) measured using P-wave
signal-averaged electrocardiography (P-SAECG).

\textbf{Methods and results:} Consecutive patients with paroxysmal AF
who underwent first CA at our institution between August 2015 and August
2019 were enrolled. P-SAECG was performed before CA. Two ALP parameters
were evaluated: root mean square voltage during the terminal 20 ms
(RMS\textsubscript{20}) and P-wave duration (PWD). Positive ALP was
defined as an RMS\textsubscript{20} \textless{}2.2 \selectlanguage{greek}µ\selectlanguage{english}V and/or a PWD
\textgreater{}115 ms. Patients were divided into the Recurrence and
Non-recurrence groups based on AF recurrence at the 1-year follow-up
after CA. Of 190 patients (age: 65\selectlanguage{ngerman}±11 years, 37\% women) enrolled in
this study, 21 (11\%) had AF recurrence. Positive ALP rate was
significantly higher in the Recurrence group than in the Non-Recurrence
group (86\% vs. 64\%, \emph{P} =0.04) despite there being no differences
in other baseline characteristics between the two groups. In the
multivariate analysis, positive ALP was an independent predictor of AF
recurrence (odds ratio: 3.83, 95\% confidence interval:
1.05--14.1,\emph{P} =0.04).

\textbf{Conclusion:} Positive ALP on pre-CA P-SAECG was associated with
AF recurrence after CA.

Keywords: atrial fibrillation; atrial late potentials; catheter
ablation; pulmonary vein isolation; recurrence



\emph{Introduction}

Atrial fibrillation (AF), the most frequently encountered cardiac
arrhythmia,\textsuperscript{1} is associated with high mortality and
morbidity, mainly due to thromboembolic complications and heart failure.
In recent times, catheter ablation (CA) has been found to be effective
for treating AF.\textsuperscript{2,3} However, AF recurs after CA in
10--30\% of patients,\textsuperscript{4.5} and few reports have focused
on the use of electrocardiography (ECG) for predicting AF recurrence
after CA.

Signal-averaged electrocardiography (SAECG) is a technique used for
recording microvolt-potentials from the body surface. QRS-SAECG is
commonly performed, and positive QRS-SAECG findings have been found to
be associated with fatal ventricular arrhythmias and sudden cardiac
death.\textsuperscript{6} In contrast, robust evidence on the use of
P-wave SAECG (P-SAECG) is lacking. Previous reports have demonstrated
that P-SAECG findings of atrial late potentials (ALP) could be
indicative of atrial fibrosis, an arrhythmogenic substrate, in patients
with AF. Therefore, P-SAECG could be useful for identifying patients at
risk of developing new-onset AF\textsuperscript{7,8} and those in whom
conversion from paroxysmal to chronic AF is likely.\textsuperscript{9}

We hypothesized that pre-recorded ALP would differ between patients with
and without AF recurrence after CA, and positive ALP would be associated
with AF recurrence.

\emph{Methods}

Study population

This was a single-center, nonrandomized, observational study.
Consecutive patients with paroxysmal AF who underwent CA between August
2015 and August 2019 at our institution were retrospectively evaluated.
We excluded patients who 1) did not undergo P-SAECG, 2) were receiving a
class I, III, or IV antiarrhythmic drug at the time of P-SAECG, or 3)
were lost to follow-up (Figure 1). This study was approved by the Ethics
Committee of Kitasato University Hospital (No. B18-197).

P-wave signal-averaged electrocardiography

P-SAECG with P-wave triggering was performed before CA using the
FCP-8800 (Fukuda Denshi, Ltd, Tokyo, Japan) with 12 standard ECG leads.
First, the skin at the electrode placement site was cleaned with alcohol
and scrubbed with a rubbing pad because the signals were of relatively
low amplitude. Subsequently, the signals from each lead were ampli\selectlanguage{english}fied
and \selectlanguage{english}filtered between 40 Hz and 300 Hz. A modi\selectlanguage{english}fied X, Y, and Z lead system
was used to trigger signal averaging from the P-wave. The signal was
passed through a P-wave recognition program to eliminate atrial
extrasystole, and a signal of 200 beats with an error vector magnitude
of \textless{}0.4 \selectlanguage{greek}µ\selectlanguage{english}V was obtained. The following two ALP parameters were
evaluated: root mean square voltage during the terminal 20 ms
(RMS\textsubscript{20}) and filtered P-wave duration (PWD).
RMS\textsubscript{20} and PWD data were automatically calculated by the
system. Positive ALP was defined as an
RMS\textsubscript{20}\textless{}2.2 \selectlanguage{greek}µ\selectlanguage{english}V and/or a PWD \textgreater{}115
ms. The standard value was based on an analysis of 120 healthy
individuals.\textsuperscript{10}

Assessment of baseline characteristics

Baseline characteristics such as age, sex, duration of AF history, body
mass index, underlying diseases, and medications used were evaluated.
Additionally, pre-CA 12-lead ECG parameters, echocardiographic
parameters, and blood test findings were evaluated.

Ablation procedure

Radiofrequency catheter ablation (RFCA) or cryoballoon ablation (CBA)
was performed at the discretion of the operators. CA was performed under
general anesthesia with 0.4 \selectlanguage{greek}μ\selectlanguage{english}g/kg/h of dexmedetomidine, 0.1 mg/kg/h of
propofol, and 0.5--1.0 mg of injected fentanyl with non-invasive or
invasive positive airway pressure for respiratory support. Esophageal
temperature monitoring (Esophastar\selectlanguage{ngerman}®, Japan Lifeline Co., Ltd., Tokyo,
Japan) was performed. Vascular access was obtained and 2000--3000 U of
heparin was intravenously injected, followed by continuous infusion with
a target activated clotting time of 300--350 s. A single transseptal
puncture was performed using intracardiac echocardiography (SOUNDSTAR®,
Biosense Webster, Inc., Diamond Bar, CA, USA or ViewFlex Xtra®, Abbott,
St. Paul, MN, USA). For RFCA, two long sheaths (Agilis and 8.0 Fr SL-0
sheath; Abbott, St Paul, MN, USA) were inserted into the left atrium
(LA). For CBA, a FlexCath Advance Steerable Sheath® (Medtronic, Inc.,
Minneapolis, USA) was inserted into the LA. A detailed 3D model of the
LA was created using a high-density mapping catheter (PENTARAY®,
Biosense Webster Inc., Diamond Bar, CA, USA; HD Grid Mapping Catheter
Sensor Enabled®, Abbott, St. Paul, MN, USA; or IntellaMap Orion®, Boston
Scientific, Inc, Washington DC, USA) and 3D mapping system (CARTO3®,
Biosense Webster, Inc., Diamond Bar, CA, USA; EnSite Velocity\selectlanguage{english}, Abbott,
St. Paul MN, USA; or Rhythmia HDx\selectlanguage{english}, Boston Scientific, Inc, Washington
DC, USA). Extensive circumferential ablation of the ipsilateral
pulmonary veins (PVs) was performed with irrigated-tip ablation
catheters (THERMOCOOL SMARTTOUCH(r) SF, Biosense Webster, Inc., Diamond
Bar, CA, USA; TactiCath\selectlanguage{english}, Abbott, St. Paul, MN, USA; or IntellaNav MiFi
OI, Boston Scientific, Inc, Washington DC, USA) for RFCA. The
radiofrequency energy was 30--35 W, and ablation was performed using
ablation index, lesion size index, and local impedance drop as
indicators of effective lesion formation. Additional procedures such as
posterior wall or superior vena cava isolation were performed at the
operators' discretion. At least 15 min of observation was performed
after pulmonary vein isolation (PVI), and spontaneous reconnection and
dormant conduction were evaluated by administering 2--4 \selectlanguage{greek}μ\selectlanguage{english}g of
isoproterenol followed by rapid injection of 20 mg adenosine
triphosphate to find the electrical gaps. Additional RFCA was performed
at gap areas adjacent to the first-pass ablation line. For CBA,
right-sided phrenic nerve pacing was performed to detect phrenic nerve
injury. A cryoballoon catheter with a 28-mm balloon (Arctic Front
Advance II\selectlanguage{ngerman}®, Medtronic, Inc., Minneapolis, USA) and a PV mapping
catheter (Achieve Mapping Catheter®, Medtronic, Inc., Minneapolis, USA)
were inserted, and freezing for 3 min was performed on each PV.
Additional freezing was performed if the PV was not isolated. After PVI,
exit blocks were confirmed based on the pacing from the circular mapping
catheter in each PV.

Follow-up

Patients were discharged 3±1 days after CA. After CA, we performed
12-lead ECG every 1 or 2 months and 24 h Holter recording at 6 and 12
months post-CA. We defined AF recurrence as any atrial tachyarrhythmia
lasting \selectlanguage{english}[?]30 s detected on ECG after a 3-month blanking period during the
1-year observational period. Patients with AF recurrence were
categorized into the Recurrence group, and those without AF recurrence
were categorized into the Non-Recurrence group.

Statistical analysis

Continuous data are expressed as means +- standard deviations or as
medians with interquartile ranges. Categorical data are presented as
absolute values \selectlanguage{english}\selectlanguage{english}and percentages. Continuous variables were compared
using the t-test or Mann--Whitney \emph{U} test if applicable, and
dichotomous variables were compared using the chi-square test or
Fisher's exact test. A \emph{P-} value of \textless{}0.05 was considered
statistically significant. Univariate and multivariate logistic
regression analyses were performed to determine the clinical factors
associated with AF recurrence. Parameters with \emph{P} -values
\textless{}0.20 were included in the multivariate logistic regression
analysis performed to assess the independent predictors of AF
recurrence. All analyses were performed using JMP 14 software (SAS
Institute, Cary, NC, USA).

\emph{Results}

Comparison of baseline characteristics

Complete bidirectional conduction block of all four PVs was achieved in
all patients. Among the 190 patients enrolled, 21 (11\%) experienced AF
recurrence during the follow-up period. The clinical characteristics of
the enrolled patients are shown in Table 1. There were no significant
differences between the two groups in echocardiographic parameters,
including LA dimension; 12-lead electrocardiographic parameters;
underlying diseases; medications; CHADS\textsubscript{2} score; and CA
procedure performed.

P-SAECG findings and AF recurrence

The P-SAECGs of representative patients are shown in Figure 2. The left
and right panels show the P-SAECGs of one patient each from the
Recurrence (RMS\textsubscript{20}: 1.6 \selectlanguage{greek}μ\selectlanguage{english}V, PWD: 128 ms) and
Non-Recurrence (RMS\textsubscript{20}: 3.1 \selectlanguage{greek}μ\selectlanguage{english}V, PWD: 91 ms) groups,
respectively. The representative patient from the Recurrence group met
both the criteria for ALP positivity. Table 2 shows positive ALP rates
of both groups. The rate of positive ALP was significantly higher in the
Recurrence group than in the Non-Recurrence group (85.7\% vs.
63.9\%,\emph{P} =0.04).

Predictors of AF recurrence

Sex, PVI alone, and positive ALP were included in the multivariate
analysis because they had \emph{P-} values \textless{}0.20 in the
univariate analysis. In the multivariate analysis, positive ALP was an
independent predictor of AF recurrence (odds ratio: 3.83, 95\%
confidence interval: 1.05--14.1, \emph{P} =0.04, Table 3).

\emph{Discussion}

This study showed that the rate of positive ALP before CA was
significantly higher in the Recurrence group than in the Non-recurrence
group despite there being no significant differences in baseline
characteristics, including the LA dimensions. Furthermore, multivariate
analysis showed that positive ALP was an independent factor associated
with AF recurrence after CA.

P-SAECG and atrial remodeling

PWD is an electrophysiological parameter that reflects complete atrial
conduction. Studies\textsuperscript{11-13} have reported that P-SAECG
findings are closely related to AF recurrence after CA. Okumura et
al.\textsuperscript{12} performed P-SAECG before and after CA (n=51) in
patients with paroxysmal and persistent AF. Patients with successful CA
had a more significant shortening of the PWD (from 146 \selectlanguage{ngerman}± 13 to 136 ± 12
ms; \emph{P} \selectlanguage{english}<0.01) than those in whom recurrence occurred (from 167 +-
15 to 157 +- 15 ms; \emph{P=} 0.18). Ogawa et
al.\textsuperscript{11}reported a significant reduction in PWD (from 161
+- 7 to 151 +- 8 ms; \selectlanguage{greek}Δ\selectlanguage{english}PWD 10 \selectlanguage{ngerman}± 7 ms; \emph{P} \textless{}0.0001) after CA
in patients with paroxysmal and persistent AF (n\selectlanguage{english}=27), although they
observed no significant shortening in PWD in patients with AF
recurrence. Masuda et al.\textsuperscript{13} performed P-SAECG before
and 1 day after CA (n=88) in patients with paroxysmal AF. Although there
were no differences in pre-CA P-SAECG findings, AF recurrence was
significantly more common in patients with a long PWD and low
RMS\textsubscript{20} 1 day after CA than those without them (54\% vs.
19\%, P=0.001). These reports suggest that improvement in atrial
conduction parameters could be associated with a reduced recurrence rate
after CA because ALP is a marker of abnormal atrial electrical
properties such as intra-atrial or inter-atrial conduction disturbance.

In our study, we evaluated a large number of patients with paroxysmal AF
and focused on the prediction of AF recurrence based on positive ALP
before CA. Consequently, the rate of positive ALP before CA (a long PWD
and a low RMS\textsubscript{20}) was significantly higher in the
Recurrence group than in the Non-recurrence group. These results suggest
that the parameter of positive ALP on P-SAECG could be used to detect
the electrical remodeling.

Prediction of AF recurrence after CA using P-SAECG

Structural and electrical remodeling have been reported as the causes of
arrhythmias.\textsuperscript{14} Findings suggestive of dilatation on
non-invasive modalities such as echocardiography or computed tomography
could indicate structural remodeling of the atrium. Preoperative left
atrial diameter (LAD) has been reported to be associated with AF
recurrence after CA.\textsuperscript{15,16} Structural remodeling in the
form of LA enlargement is the most common arrhythmogenic substrate.
P-wave duration on surface 12-lead ECG has also been associated with AF
recurrence after CA.\textsuperscript{17,18} A long P-wave duration is
associated with an enlarged LA\textsuperscript{19} and atrial conduction
disturbance.\textsuperscript{20} We demonstrated that positive ALP was
an independent predictor of AF recurrence after CA, and there were no
significant differences in the LAD and P-wave duration on surface
12-lead ECG between the Recurrence and Non-Recurrence groups. This may
be because our study population only consisted of patients with
paroxysmal AF who had a short disease duration and in whom structural
remodeling might not have progressed. ALP could reflect subtle changes
in the atria that are not structural changes and do show up as changes
in the P-wave on 12-lead ECG. Based on the results of our study, we
speculate that ALP can reveal the progression of electrical remodeling
in patients without structural remodeling.

Limitations

Several limitations of this study need to be acknowledged. First, this
was a single\selectlanguage{english}-center retrospective study that included a limited number
of patients, which resulted in the possibility of selection bias.
Second, P-SAECG is sometimes difficult to perform because of irregular
cardiac rhythms such as atrial or ventricular premature beats,
environmental noise causing electrocardiogram interference, or overlap
between the end of the P-wave and the beginning of the QRS complex.
Third, asymptomatic recurrence during the follow-up period could not be
fully identified; therefore, the recurrence rate may be underestimated.
Fourth, the cause of AF recurrence, such as PV reconnection or other
non-PV foci, could not be identified. Finally, P-SAECG can only be
performed in patients with sinus rhythm; therefore, it might be
challenging to apply our findings to patients with non-paroxysmal AF.
Further prospective studies are needed to ascertain the relationship
between AF recurrence and ALP.

\emph{Conclusion}

Positive ALP on pre-CA P-SAECG was associated with AF recurrence after
CA.

\emph{Disclosure}

This work was supported by JSPS KAKENHI Grant Number JP18K08113.

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14. Wang YS, Chen GY, Li XH, Zhou X, Li YG. Prolonged P-wave duration is
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\textbf{Figure legends}

\emph{Figure 1. Patient enrolment flow chart.}

This figure shows the flowchart of enrolment of patients in this study.
The enrolment procedure has been described in detail in the main text.

AF: atrial fibrillation, P-SAECG: P-wave signal-averaged
electrocardiography.

\emph{Figure 2. Representative P-SAECG findings}

P-SAECGs of representative patients are shown. Solid perpendicular lines
indicate the start and end of the P-wave. Dotted perpendicular lines
indicate the point preceding the end of the P-wave by 20 ms. Positive
ALP was defined as an RMS\textsubscript{20} \textless{}2.2 \selectlanguage{greek}µ\selectlanguage{english}V or a PWD
\textgreater{}115 ms.

P-SAECG: P-wave signal-averaged electrocardiography,
RMS\textsubscript{20}: root mean square voltage during the terminal 20
ms, PWD: P-wave duration.

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