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\begin{document}

\title{Sex- Based Differences in Safety and Efficacy of Catheter Ablation for
Atrial Fibrillation}



\author[1]{Ritu Yadav}%
\author[1]{Jenna Milstein}%
\author[1]{Jacob Blum}%
\author[1]{Stefany Lazieh}%
\author[1]{Victor Yang}%
\author[1]{Xiyu Zhao}%
\author[1]{Siam Muquit}%
\author[1]{Jui Malwankar}%
\author[1]{Joseph Marine}%
\author[1]{Ronald Berger}%
\author[1]{Hugh Calkins}%
\author[1]{David Spragg}%
\affil[1]{Johns Hopkins Medicine Division of Cardiology}%


\vspace{-1em}



  
  \date{June 16, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Studies have identified significant sex-based
differences and disparities in the clinical presentation and treatment
of atrial fibrillation (AF). Studies have shown women are less likely to
be referred for catheter ablation, are older at the time of ablation,
and are more likely to have recurrence after ablation. However, in most
studies investigating AF ablation outcomes, the female cohorts were
relatively small. The impact of gender on the outcome and safety of
ablation procedures is still unclear. \textbf{Objective:} To investigate
sex-based differences in outcomes and complications after AF catheter
ablation, with a significant size female cohort \textbf{Method:} In this
retrospective study, patients undergoing AF ablation from January 1,
2014, to March 31, 2021, were included. We investigated clinical
characteristics, duration and progression of AF, number of EP
appointments from diagnosis to ablation, procedural data, and procedure
complications. \textbf{Results:} Total 1346 patients underwent first
catheter ablation for AF during this period, including 896 (66.5\%) male
and 450 (33.4\%) female patients. Female patients were older at the time
of ablation (66.2y vs 62.4y; p\textless{}0.001). Women had higher CHA
\textsubscript{2}DS \textsubscript{2}-VASc scores (3 vs 2;
p\textless{}0.001) than men, expectedly, as the female sex warrants an
additional point. 25.3\% female patients had PersAF at the time of
diagnosis vs 35.3\% male patients (p\textless{}0.001). At the time of
ablation, 31.8\% female patients had PersAF as compared to 43.1\% male
patients (p\textless{}0.001), indicating progression of PAF to PersAF in
both genders. Women tried more AADs than men before ablation (1.13 vs
0.98; p=0.002). Male and female patients had no statistically
significant difference in (a) arrhythmia recurrence at 1-y post ablation
(27.7\% vs 30\%; p=0.38) or (b) procedural complication rate (1.8\% vs
3.1\%; p=0.56). \textbf{Conclusion:} Female patients were older and had
higher CHA \textsubscript{2}DS \textsubscript{2}-VASc scores compared to
males at the time of AF ablation. Women tried more AADs than men prior
to ablation. 1-y arrhythmia recurrence rates and procedural
complications were similar in both genders. No sex- based differences
were observed in safety and efficacy of ablation.%
\end{abstract}%



\sloppy


\textbf{Sex- Based Differences in Safety and Efficacy of Catheter
Ablation for Atrial Fibrillation}

Ritu Yadav, Jenna Milstein, Jacob Blum, Stefany Lazieh, Victor Yang,
Xiyu Zhao, Siam Muquit, Jui Malwankar, Joseph E. Marine, Ronald Berger,
Hugh Calkins, David Spragg

Johns Hopkins Medicine, Division of Cardiology, Baltimore, MD

For correspondence:

David Spragg MD

Johns Hopkins Hospital

Halsted 576

Baltimore, MD 21287

Phone: 410-550-1973

Email: dspragg1@jhmi.edu

Word count:

Running title: Sex- Based Differences in Safety and Efficacy of Catheter
Ablation for Atrial Fibrillation



\textbf{Abstract}

\textbf{Background:~} Studies have identified significant sex-based
differences and disparities in the clinical presentation and treatment
of atrial fibrillation (AF). Studies have shown women are less likely to
be referred for catheter ablation, are older at the time of ablation,
and are more likely to have recurrence after ablation. However, in most
studies investigating AF ablation outcomes, the female cohorts were
relatively small. The impact of gender on the outcome and safety of
ablation procedures is still unclear.

\textbf{Objective:~} To investigate sex-based differences in outcomes
and complications after AF catheter ablation, with a significant size
female cohort

\textbf{Method:} ~In this retrospective study, patients undergoing AF
ablation from January 1, 2014, to March 31, 2021, were included. We
investigated clinical characteristics, duration and progression of AF,
number of EP appointments from diagnosis to ablation, procedural data,
and procedure complications.

\textbf{Results:} Total 1346 patients underwent first catheter ablation
for AF during this period, including 896 (66.5\%) male and 450 (33.4\%)
female patients. Female patients were older at the time of ablation
(66.2y vs 62.4y; p\textless{}0.001). Women had higher
CHA\textsubscript{2}DS\textsubscript{2}-VASc scores (3 vs 2;
p\textless{}0.001) than men, expectedly, as the female sex warrants an
additional point. 25.3\% female patients had PersAF at the time of
diagnosis vs 35.3\% male patients (p\textless{}0.001). At the time of
ablation, 31.8\% female patients had PersAF as compared to 43.1\% male
patients (p\textless{}0.001), indicating progression of PAF to PersAF in
both genders. Women tried more AADs than men before ablation (1.13 vs
0.98; p=0.002). Male and female patients had no statistically
significant difference in (a) arrhythmia recurrence at 1-y post ablation
(27.7\% vs 30\%; p=0.38) or (b) procedural complication rate (1.8\% vs
3.1\%; p=0.56).

\textbf{Conclusion:} Female patients were older and had higher
CHA\textsubscript{2}DS\textsubscript{2}-VASc scores compared to males at
the time of AF ablation. Women tried more AADs than men prior to
ablation. 1-y arrhythmia recurrence rates and procedural complications
were similar in both genders. No sex- based differences were observed in
safety and efficacy of ablation.



\textbf{Introduction}

Atrial fibrillation (AF) is the most common arrhythmia in the world,
associated with an increased risk of stroke, heart failure and
mortality. Data shows a growing incidence and prevalence of AF (1,2,3).
There are notable disparities in the presentation, progression, and
management of AF in men and women.

Women with AF tend to experience more symptoms, poorer quality of life,
and increased functional impairment compared to men (4,5). Although the
lifetime prevalence of AF is similar between men and women (5), women
are at an increased independent risk of stroke and cardiovascular death
due to AF (6,7,8,). In a large population-based cohort, the Copenhagen
City Heart study demonstrated a 4.6-fold increase in independent stroke
risk and 2.5-fold increase in death risk for women with AF compared with
men with AF (6).

Despite this, women are more likely to receive rate control rather than
rhythm control treatments for AF (9,10,). Additionally, women are less
likely to benefit from pharmacological rhythm control medication and are
more likely to experience adverse effects (11,12,). In contrast, men are
more likely to undergo procedures aimed at restoring sinus rhythm, such
as electrical cardioversion and catheter ablation (9,10,). According to
a recent study of the temporal trends in referrals for the first
ablation procedure for AF, catheter ablations have increased almost
sevenfold over the past ten years, but the proportion of women
undergoing this procedure has not increased significantly (13).

Previous studies on the outcomes of AF catheter ablation have primarily
focused on male patients, with women being underrepresented (14-17).
These studies have shown that women are often older (14,15), have a
longer history of AF (16), larger left atrial size, and more
comorbidities at the time of ablation (5,15). There is no clear evidence
on gender-based differences in the outcomes of AF ablation, with some
studies suggesting higher recurrence rates in females (16,18,19) and
others showing no differences (12,14). Furthermore, gender incongruities
have also been described in procedure-related adverse outcomes, but this
too remains unclear due to an underrepresentation of female patients in
clinical trials. The aim of this study is to further investigate gender
differences in the safety and outcomes of catheter ablation for AF
patients with a significant female cohort in the study population.

\textbf{Methods}

\emph{Patient Population}

We conducted a single-center, retrospective observational study of
patients enrolled in a prospectively populated AF ablation database
approved by the Johns Hopkins IRB. The study cohort is comprised of
patients undergoing first catheter ablation from January 1, 2014, to
March 31, 2021. Patient characteristics were systematically recorded,
including demographic, clinical, and echocardiographic parameters. We
also investigated duration and progression of AF, prescribed medication
information, number of electrophysiologist appointments from diagnosis
to ablation, AF types, and procedural data.

\emph{Peri-Procedural Anticoagulation and Imaging}

Catheter ablation was performed with minimal interruption of
anticoagulation. Warfarin was continued throughout the peri-operative
period. DOAC therapy was either uninterrupted, or a single DOAC dose was
held prior to ablation. After ablation, all patients received
anticoagulation for a minimum of 3 months.

Unless clinically contraindicated, patients had either CT or
transesophageal echocardiography (TEE) immediately prior to ablation in
order to exclude LAA thrombus. Data collected during electroanatomic
mapping (EAM) was merged with pre-acquired CT or MRI at the operator's
discretion.

\emph{Ablation Procedure}

Ablation was performed under general anesthesia in all patients. A
detailed electro-anatomical map (EAM) using either CARTO or ESI mapping
systems was performed in all patients after vascular and left atrial
access, prior to and following ablation. Patients presenting in AF
underwent cardioversion to sinus rhythm prior to EAM. In all cases, PVI
was the primary ablative strategy and any additional non-PV targets
(linear lesions; low-voltage areas) were ablated at the operator's
discretion.

Ablation was performed using either an irrigated, contact force-sensing
RF ablation system (Biosense Webster, etc., or Abbott/ESI) or a
cryoballoon ablation catheter (Arctic Front Advance and Arctic Front,
Medtronic Inc.). For patients undergoing RF ablation, target power
delivery to the anterior and posterior LA walls was 35--45 and 25--35 W,
respectively. Patients undergoing cryo-balloon ablation underwent
fluoroscopic positioning of a 28- or 23mm cryo-balloon to achieve
complete PV occlusion as assessed by contrast injection. A minimum of
two freeze-thaw cycles (3 min duration) were applied to each vein,
sufficient to achieve PV isolation as assessed by a multipolar mapping
catheter.

An esophageal temperature probe was placed in all patients during
ablation, with temporary cessation of lesion application if significant
temperature deviation occurred. During cryoballoon ablation of
right-sided pulmonary veins, phrenic nerve pacing was performed, and
ablation was terminated if diaphragmatic contractions diminished.

In all cases, PV isolation was determined by demonstrating an entrance
block to each vein during sinus rhythm on post-ablation EAM after a
20-minute waiting period. Exit block was demonstrated at the operator's
discretion, as was occult PV reconnection during adenosine infusion.

\emph{Follow-up}

Following ablation, all patients were either monitored in the
Post-anesthesia Care Unit for 4h or admitted to the hospital for
overnight observation. Routine follow-up (history, exam, and
electrocardiography) was performed at the outpatient clinic or by a
local cardiologist at 3, 6, and 12 months, and additionally, if prompted
by symptoms. Mean follow-up duration was 12 months. During the
post-blanking follow-up period, Holter or event monitors were arranged
for patients who developed symptoms suggestive of AF. When available,
pacemaker interrogation records and mobile technology rhythm devices
(Apple Watch; Kardia) were also used for arrhythmia recurrence
monitoring. Antiarrhythmic drug (AAD) therapy, if present at the time of
ablation, was discontinued prior to the 3-month follow-up visit.
Arrhythmia recurrence was defined on the basis of the 2017 Heart Rhythm
Society consensus document as any AF/atrial tachycardia/atrial flutter
sustained for more than 30 seconds recorded by a surface ECG or rhythm
monitoring device after a 90-day blanking period. One-year outcomes were
assessed in all patients, either at clinic follow-up, electronic health
record review, or phone interview.

\emph{Statistical Analysis}

Continuous data were analyzed using the student's t-test for normally
distributed data and the Mann-Whitney test for non-normally distributed
data. Categorical data were analyzed using the \selectlanguage{greek}χ\selectlanguage{english}2 test. Values are
presented as mean \selectlanguage{ngerman}± standard deviation or median and interquartile range
(Q1-Q3) according to distribution for continuous data and count and
percentage for categorical data unless otherwise stated. The cumulative
probability of survival free from atrial arrhythmia was displayed
according to the Kaplan--Meier method, with comparisons of cumulative
event rates by the log-rank test. Follow-up for all patients was
censored one year after ablation. A p-value of \textless{}0.05 was
considered statistically significant. Analyses were performed using SPSS
Statistics version 23.0 (IBM Corporation, Armonk, New York) and STATA
Version 13 (Stata Corp, College Station, TX).

\textbf{Results}

\emph{Patient Characteristics}

A total of 1346 patients underwent first catheter ablation for AF during
this period, including 896 (66.5\%) male patients and 450 (33.4\%)
female patients. Table 1 shows comparison of baseline characteristics of
men and women. The female patient group was older at the time of
ablation (66.2y vs 62.4y; p\textless{}0.001{]} compared to male
patients. Women had higher CHA\textsubscript{2}DS\textsubscript{2}-VASc
scores (3 vs 2; p\textless{}0.001) than men at the time of ablation,
expectedly, given that female gender in the current guidelines confers a
CHA\textsubscript{2}DS\textsubscript{2}-VASc point. There was no
statistically significant difference in two groups in terms of BMI, DM,
HTN, hyperlipidemia, CHF, stroke history, or CKD. In our study
population, women had smaller LA diameter as compared to men (4.3 vs
4.5cm; p=0.024), and slightly reduced left-ventricular ejection fraction
(LVEF) values (55.9\% vs 58.4\%; p\textless{}0.001).

\emph{AF Characteristics}

A comparison of AF history and procedural characteristics between
genders is shown in Table 2. At the time of initial diagnosis, 25.3\%
patients in female group had persistent AF (PersAF) vs 35.3\% patients
in male group (p\textless{}0.001). The mean duration of AF, from initial
diagnosis to ablation, was 44.4 months for the study population, and was
similar for men and women (44.6 vs 44.1; p=0.91). At the time of
ablation, 31.8\% female patients had PersAF as compared to 43.1\%
patients in male group (p\textless{}0.001), suggesting progression of
paroxysmal AF (PAF) to PersAF in both genders.

The number of electrophysiologist appointments by women during the
period leading up to catheter ablation was similar to that of men (5.35
vs 4.95; p=0.37), but women tried more AADs than men before presenting
for catheter ablation (1.13 vs 0.98; p=0.002). In the female group,
92.2\% of patients received anticoagulation before the ablation
procedure as compared to 88.6\% patients in male group (p=0. 012).

\emph{Procedural Characteristics}

There were no significant differences in ablation strategy in men and
women. Radiofrequency ablation was performed in 60.5\% of males and
60.9\% of females, whereas cryoballoon ablation was used in 33.1\% of
males and 31.8\% of females. Combined cryoballoon and RF was used in
6.4\% men and 7.3\% women (p=0.74). Men underwent more cardioversions
during ablation then women (34.2\% vs 27.6\%; p=0.014), likely due to
greater prevalence of persistent AF.

\emph{Outcomes}

There was no significant difference in 1-year arrhythmia recurrence rate
between men and women (27.7\% vs 30\%; p=0.38). Redo ablation rates were
similar between the two groups (11.7\% vs 9.3\%; p=0.19).

A total 29 out of 1350 patients developed procedure related
complications (2.1\%). Adverse events included vascular complications,
phrenic nerve injury, neurological complications, and pericardial
effusion (Table 3). There was no significant difference in procedure
related complication rate between men and women (1.9\% vs 3.1\%;
p=0.56).

\textbf{Discussion}

\emph{Main findings}

We conducted a single center, retrospective analysis of 1346 patients
undergoing index AF ablation, with a significant size female cohort in
the study population, to investigate gender differences in outcomes and
complications following catheter ablation of AF. We found that:
diagnosis-to-ablation time for both groups was similar; although the
number of EP appointments leading up to ablation was similar in men and
women, women tried and failed more AADs than men prior to ablation;
there were no gender-based differences in one-year arrhythmia recurrence
rates; and procedure-related complication rates between men and women
were similar.

Studies have shown that women with AF have a worse prognosis, including
an increased risk of stroke, heart failure, and death, as well as more
severe symptoms, a worse quality of life, and diminished functional
capacity (5). Despite these facts, women are less likely to receive
rhythm control through catheter ablation and cardioversion.
Consequently, women often undergo ablation procedures at an older age
and later in their disease course, often having experienced AF for a
longer period with advanced cardiac remodeling resulting from the
disease (5). While some studies suggest that females have a higher
post-ablation arrhythmia recurrence rate than males, other studies like
the CASTLE-AF trial did not show a gender difference in the
effectiveness of ablation procedures. There remains ambiguity regarding
gender-based differences in outcomes and complications related to AF
ablation, partly because of the underrepresentation of women in these
studies. Our study aimed to investigate gender-based disparities in the
management of AF and as well as the outcome and complication rate of AF
ablation procedures.

In contrast to most previous studies investigating gender impact on AF
ablation, our study included a relatively large cohort of patients with
a significantly higher proportion of female patients (n=450, 33.4\% of
total study patients). In accordance with existing studies, women were
older at the time of ablation (66.2 vs 62.4 years; p\textless{}0.001).
Compared to their male counterparts, women also tried and failed more
anti-arrhythmic drugs before presenting for ablation procedure (1.13 vs
0.98; p=0.002). These results may indicate female patients' apprehension
towards procedural intervention, referral bias, or some other delaying
factor. In contrast to previous studies (6), however, we found no
significant difference in the duration of AF between men and women from
initial diagnosis to ablation (44.6 months versus 44.1 m; p=0.97). At
the time of diagnosis, it was observed that 25.3\% of female patients
had PersAF compared to 35.3\% of male patients (p\textless{}0.001).
Similarly, at the time of ablation, 31.8\% of female patients had PersAF
as opposed to 43.1\% of male patients (p\textless{}0.001), suggesting a
similar rate of progression from paroxysmal to PersAF in both genders.

With regards to procedural success, we found no significant difference
in AF recurrence at 1-year post-ablation between male and female
patients (27.7\% vs 30\%; p=0.38). This is consistent with previous
studies (4,12,14) that have reported equal rates of procedural success
and low recurrence rates in both genders. We believe it is more likely
that the procedural results are primarily influenced by the consistency
in timing of ablation from the time of diagnosis, regardless of gender.
Timing of ablation is one of the major predictive factors of ablation
outcomes due to advancement of atrial substrate. The study by Bunch et
al. demonstrated that increasing time between diagnosis of atrial
fibrillation and catheter ablation adversely affects long-term outcomes
(20).

In prior research, it has been suggested that sex differences in
outcomes can be partly explained by women having more advanced AF
disease at the time of ablation (16). The prospective multicenter DECAAF
study found a linear relationship between the degree of atrial fibrosis
as identified by LGE-CMR and AF recurrence rates post-ablation (21) and
another study by Chelu and colleagues correlated higher levels of atrial
fibrosis with longer AF duration (22). Recent clinical trials EARLY- AF,
CASTLE-AF, STOP-AF strongly advocate for early rhythm control using
catheter ablation as a first line treatment for AF to reduce morbidity
and mortality (23,24,25). With the growing evidence for early ablation,
our study supports a uniform approach for all patients with regards to
early ablation. Given a greater tendency to use antiarrhythmic drug
therapy in women with AF, greater attention to counseling on therapeutic
choices may be needed in this population (5).

In addition, no gender-related differences were observed in procedural
complications, including vascular injury (7 males, 5 females; p=0.55),
phrenic nerve injury (1 male, 1 female), pericardial effusion (6 males,
7 females; p=0.12), esophageal fistula (0 males, 0 females), or
stroke/TIA (3 males, 1 female; p=0.71), supporting the recommendation
that both men and women should be offered catheter ablation for atrial
fibrillation on an equal basis.~It should be acknowledged, however, that
unlike most other studies in this area (15), our population did not
demonstrate significant gender-based differences in the rates of
comorbidities such as diabetes, hypertension, heart failure, chronic
kidney disease, which may also be contribute to the lack of gender
differences in procedural complications.

One of the key gender disparities in the management of AF is in the use
of anticoagulation therapy. Studies have shown that women with AF are
less likely to receive anticoagulation therapy compared to men, despite
having similar or higher risk for stroke (3, 26). It is worth
emphasizing, however, that women in our study were adequately treated
with oral anticoagulants (92.2\% females, 88.6\% males; p=0.012), and
that may partly explain the reduction in neurological adverse events.

\emph{Future directions}

Despite a growing body of evidence supporting early catheter ablation
for treatment of AF, gender disparities in AF care persist. To address
gender disparities and improve the care of women with AF, several
campaigns have been launched to raise awareness and educate both the
general public and healthcare providers alike about gender equity in
cardiac care. These include the AHA -- Go Red for Women and other
similar campaigns. Continued efforts to educate healthcare providers and
the general public about the need for gender-specific treatment are
essential to ensure that women with AF receive the care they need to
manage this condition effectively.

\textbf{Conclusions}

One year arrhythmia recurrence rate and procedural complication rates
were similar in men and women undergoing index AF ablation. These
findings support equal and early treatments for all procedure candidates
regardless of their gender.

\textbf{Limitations}

Due to the single-center, retrospective, observational nature of this
study, it has several inherent limitations. There is a possibility of
selection bias. Second, a lack of continuous ECG monitoring after
ablation could have resulted in the underestimation of arrhythmia
recurrence. That, and the limited (12m) follow-up period of our study,
could result in under-reporting of AF recurrence. Due to retrospective
nature of study, it is not possible to determine the extent of fibrosis.
Additionally, it should be noted that, despite the clear duration from
initial diagnosis to ablation, it is not possible to determine the
duration of time patients suffered from arrhythmia prior to diagnosis.
In the present study, data regarding the frequency of ablation of
non-pulmonary vein foci was not included. Greater diligence in targeting
these foci may have contributed to improved gender equity in procedural
effectiveness.

\textbf{Funding}

Funding for this research was provided in part by the Edward St. John
Fund for AF Research, the Roz and Marvin H. Weiner and Family
Foundation, the Dr. Francis P. Chiaramonte Foundation, the Marilyn and
Christian Poindexter Arrhythmia Research Fund, Norbert and Louise
Grunwald Cardiac Arrhythmia Research Fund, and the Mr. \& Mrs. Larry
Small AF Research Fund.

\textbf{Conflict of Interest}

All other authors have reported that they have no relationships relevant
to the contents of this paper to disclose.

\textbf{Acknowledgement:} None.

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  stratification schemes for predicting stroke and thromboembolism in
  patients with atrial fibrillation: Nationwide cohort study.\emph{BMJ}
  , \emph{342} (jan31 1),
  d124--d124.\emph{https://doi.org/10.1136/bmj.d124}
\item
  Fang, M. C., Singer, D. E., Chang, Y., Hylek, E. M., Henault, L. E.,
  Jensvold, N. G., \& Go, A. S. (2005). Gender differences in the risk
  of ischemic stroke and peripheral embolism in atrial
  fibrillation.\emph{Circulation} , \emph{112} (12),
  1687--1691.\emph{https://doi.org/10.1161/circulationaha.105.553438}
\item
  Westerman, S., \& Wenger, N. (2019). Gender differences in atrial
  fibrillation: A review of Epidemiology, management, and
  outcomes.\emph{Current Cardiology Reviews} , \emph{15} (2),
  136--144.\emph{https://doi.org/10.2174/1573403x15666181205110624}
\item
  Piccini, J. P., Simon, D. J. N., Steinberg, B. A., Thomas, L., Allen,
  L. A., Fonarow, G. C., Gersh, B., Hylek, E., Kowey, P. R., Reiffel, J.
  A., Naccarelli, G. V., Chan, P. S., Spertus, J. A., \& Peterson, E. D.
  (2016). Differences in clinical and functional outcomes of atrial
  fibrillation in women and men. \emph{JAMA Cardiology} , \emph{1} (3),
  282.\emph{https://doi.org/10.1001/jamacardio.2016.0529}
\item
  Rienstra, M., Van Veldhuisen, D. J., Hagens, V. E., Ranchor, A. V.,
  Veeger, N. J. G. M., Crijns, H. J. G. M., \& Van Gelder, I. C.
  (2005).Gender-related differences in rhythm control treatment in
  persistent atrial fibrillation. \emph{Journal of the American College
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  1298--1306.\emph{https://doi.org/10.1016/j.jacc.2005.05.078}
\item
  Forleo, G. B., Tondo, C., De Luca, L., Russo, A. D., Casella, M., De
  Sanctis, V., Clementi, F., Fagundes, R. L., Leo, R., Romeo, F., \&
  Mantica, M. (2007). Gender-related differences in catheter ablation of
  atrial fibrillation. \emph{EP Europace} , \emph{9} (8),
  613--620.\emph{https://doi.org/10.1093/europace/eum144}
\item
  Avgil Tsadok, M., Gagnon, J., Joza, J., Behlouli, H., Verma, A.,
  Essebag, V., \& Pilote, L. (2015). Temporal trends and sex differences
  in pulmonary vein isolation for patients with atrial
  fibrillation.\emph{Heart Rhythm} , \emph{12} (9),
  1979--1986.\emph{https://doi.org/10.1016/j.hrthm.2015.06.029}
\item
  Takigawa, M., Kuwahara, T., Takahashi, A., Watari, Y., Okubo, K.,
  Takahashi, Y., Takagi, K., Kuroda, S., Osaka, Y., Kawaguchi, N.,
  Yamao, K., Nakashima, E., Sugiyama, T., Akiyama, D., Kamiishi, T.,
  Kimura, S., Hikita, H., Hirao, K., \& Isobe, M. (2013). Differences in
  catheter ablation of paroxysmal atrial fibrillation between males and
  females. \emph{International Journal of Cardiology} , \emph{168} (3),
  1984--1991.\emph{https://doi.org/10.1016/j.ijcard.2012.12.101}
\item
  Kaiser, D. W., Fan, J., Schmitt, S., Than, C. T., Ullal, A. J.,
  Piccini, J. P., Heidenreich, P. A., \& Turakhia, M. P. (2016). Gender
  differences in clinical outcomes after catheter ablation of atrial
  fibrillation. \emph{JACC: Clinical Electrophysiology} , \emph{2} (6),
  703--710.\emph{https://doi.org/10.1016/j.jacep.2016.04.014}
\item
  Santangeli, P., Di Biase, L, Pelargonio, G, \& Natale, A. (2010).
  Outcome of invasive electrophysiological procedures and gender: Are
  males and females the same? \emph{Journal of Cardiovascular
  Electrophysiology} , \emph{22} (5),
  605--612.\emph{https://doi.org/10.1111/j.1540-8167.2010.01920.x}
\item
  Schnabel, R. B., Pecen, L., Ojeda, F. M., Lucerna, M., Rzayeva, N.,
  Blankenberg, S., Darius, H., Kotecha, D., Caterina, R. D., \&
  Kirchhof, P. (2017). Gender differences in clinical presentation and
  1-year outcomes in atrial fibrillation. \emph{Heart} , \emph{103}
  (13), 1024--1030.\emph{https://doi.org/10.1136/heartjnl-2016-310406}
\item
  Cheng, X., Hu, Q., Gao, L., Liu, J., Qin, S., \& Zhang, D. (2019).
  Sex-related differences in catheter ablation of atrial fibrillation: A
  systematic review and meta-analysis. \emph{EP Europace} ,\emph{21}
  (10), 1509--1518.\emph{https://doi.org/10.1093/europace/euz179}
\item
  Park, Y. J., Park, J.-W., Yu, H. T., Kim, T.-H., Uhm, J.-S., Joung,
  B., Lee, M.-H., \& Pak, H.-N. (2022). Sex difference in atrial
  fibrillation recurrence after catheter ablation and antiarrhythmic
  drugs. \emph{Heart}
  .\emph{https://doi.org/10.1136/heartjnl-2021-320601}
\item
  Bunch TJ, May HT, Bair TL, et al. Five-year outcomes of catheter
  ablation in patients with atrial fibrillation: is atrial fibrillation
  a curable disease? J Am Coll Cardiol. 2011;57(2):137-146.
  doi:10.1016/j.jacc.2010.05.061.
\item
  Marrouche NF, Wilber D, Hindricks G, Jais P, Akoum N, Marchlinski F,
  Kholmovski E, Burgon N, Hu N, Mont L, Deneke T, Duytschaever M,
  Neumann T, Mansour M, Mahnkopf C, Herweg B, Daoud E, Wissner E,
  Bansmann P, Brachmann J. Association of atrial tissue fibrosis
  identified by delayed enhancement MRI and atrial fibrillation catheter
  ablation: the DECAAF study. JAMA. 2014 Feb 5;311(5):498-506. doi:
  10.1001/jama.2014.3. Erratum in: JAMA. 2014 Nov 5;312(17):1805. PMID:
  24496537.
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  Chelu MG, King JB, Kholmovski EG, Ma J, Gal P, Marashly Q, AlJuaid MA,
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  4;7(23):e006313. doi: 10.1161/JAHA.117.006313. PMID: 30511895; PMCID:
  PMC6405558.
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  Kirchhof P, Camm AJ, Goette A, Brandes A, Eckardt L, Elvan A, Fetsch
  T, van Gelder IC, Haase D, Haegeli LM, Hamann F, Heidbüchel H,
  Hindricks G, Kautzner J, Kuck KH, Mont L, Ng GA, Rekosz J, Schoen N,
  Schotten U, Suling A, Taggeselle J, Themistoclakis S, Vettorazzi E,
  Vardas P, Wegscheider K, Willems S, Crijns HJGM, Breithardt G;
  EAST-AFNET 4 Trial Investigators. Early Rhythm-Control Therapy in
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  PMID: 32865375.
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  Packer DL, Kowal RC, Wheelan KR, Irwin JM, Champagne J, Guerra PG,
  Dubuc M, Reddy V, Nelson L, Holcomb RG, Lehmann JW, Ruskin JN; STOP AF
  Cryoablation Investigators. Cryoballoon ablation of pulmonary veins
  for paroxysmal atrial fibrillation: first results of the North
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  21. PMID: 23500312.
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  OpinPharmacother. 2018;19:365\selectlanguage{english}-374.7.
\end{enumerate}



\textbf{Table 1. Patient characteristics in male and female groups.}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Characteristic}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Total (1346)}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Male (N=896)} \textbf{66.5\%}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Female (N=450)} \textbf{33.5\%}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{p-value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Age\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
63.7\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
62.4\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
66.2\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Race\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.43\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
White\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1,239 (92.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
832 (92.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
407 (90.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
African American\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
57 (4.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
33 (3.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
24 (5.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Asian\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
18 (1.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10 (1.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (1.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hispanic\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6 (0.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (0.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (0.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Other\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
25 (1.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
17 (1.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (1.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
BMI\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
32.01\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
32.24\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31.51\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.52\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CHADSVASC\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 (1-3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 (1-3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (2-4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
DM\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
185 (13.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
132 (14.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
53 (11.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.14\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
HTN\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
802 (59.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
538 (60.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
264 (58.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.63\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CHF\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
201 (14.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
134 (15.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
67 (14.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.97\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Stroke or TIA\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
109 (8.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
64 (7.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
45 (10.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.070\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
OSA\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
269 (20.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
205 (22.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
64 (14.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CKD\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
54 (4.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
33 (3.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
21 (4.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.38\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hyperlipidemia\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
483 (35.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
324 (36.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
159 (35.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.77\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Asthma or COPD\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
96 (7.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
51 (5.7\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
45 (10.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0.004}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Smoking History\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
335(24.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
174(19.4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
97(21.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.074\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Anticoagulant\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1209(89.8\%0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
794(88.6\%0\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
415(92.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0.012}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ACEi\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
246(18.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
194(21.6\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
52(11.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
ARB\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
259(19.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
163(18.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
96(21.3\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.74\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LA diameter (cm)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4.41\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4.47\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4.31\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0.024}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
LVEF by TEE (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
56.7\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
55.9\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
58.4\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2. Procedural characteristics in male and female groups.}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Characteristic} & \textbf{Total(N=1346)} & \textbf{Male(N=896)}
& \textbf{Female(N=450)} & \textbf{p-value}\tabularnewline
\midrule
\endhead
Mean Duration of AF (months) & 44.4 & 44.6 & 44.1 & 0.91\tabularnewline
total no. of AAD used & 1 (1-1) & 1 (1-1) & 1 (1-2) &
\textbf{0.002}\tabularnewline
No. of Electrophysiologist appointment & 5.08 (7.76) & 4.95 (7.47) &
5.35 (8.30) & 0.37\tabularnewline
AF Type at Diagnosis & & & & \textbf{\textless{}0.001}\tabularnewline
Paroxysmal & 916(68.1\%) & 580(64.7\%) & 336 (74.7\%) &\tabularnewline
Persistent & 430 (31.9\%) & 316 (35.3\%) & 114 (25.3\%) &\tabularnewline
AF Type at Ablation & & & & \textbf{\textless{}0.001}\tabularnewline
Paroxysmal & 817 (60.7\%) & 510 (56.9\%) & 307 (68.2\%) &\tabularnewline
Persistent & 529 (39.3\%) & 386 (43.1\%) & 143 (31.8\%) &\tabularnewline
Ablation Type & & & & 0.74\tabularnewline
Cryo & 440 (32.7\%) & 297 (33.1\%) & 143 (31.8\%) &\tabularnewline
RF & 816 (60.6\%) & 542 (60.5\%) & 274 (60.9\%) &\tabularnewline
Cryo and RF & 90 (6.7\%) & 57 (6.4\%) & 33 (7.3\%) &\tabularnewline
Recurrence in 1 year & 383 (28.5\%) & 248 (27.7\%) & 135 (30.0\%) &
0.38\tabularnewline
DCV during ablation & 430 (31.9\%) & 306 (34.2\%) & 124 (27.6\%) &
\textbf{0.014}\tabularnewline
Redo ablation & 147 (10.9\%) & 105 (11.7\%) & 42 (9.3\%) &
0.19\tabularnewline
Duration from first ablation to redo ablation (in months) & 9.20
(5.22-16.36) & 8.51 (5.13-16.36) & 9.76 (6.90-14.49) &
0.69\tabularnewline
\bottomrule
\end{longtable}



\textbf{Table 3. Procedural complications in male and female groups.}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Complications} & \textbf{Total (n = 1346)} & \textbf{Men (n =
896)} & \textbf{Women (n = 450)} & \textbf{P-value}\tabularnewline
\midrule
\endhead
Overall, n (\%) & 29 (2.1\%) & 17(1.9\%) & 14(3.1\%) &
0.56\tabularnewline
Vascular Complication, n (\%) & 12 & 7 & 5 & 0.55\tabularnewline
Phrenic Nerve Injury, n (\%) & 2 & 1 & 1 & 0.62\tabularnewline
Pericardial Effusion, n (\%) & 13 & 6 & 7 & 0.12\tabularnewline
Esophageal Injury, n (\%) & 0 & 0 & 0 & NA\tabularnewline
Stroke/TIA, n (\%) & 4 & 3 & 1 & 0.71\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{english}
\FloatBarrier
\end{document}

