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\begin{document}

\title{Atrial fibrillation ablation in Athletes vs. non-Athletes: 5-year
experience of a single Italian third-level center.}



\author[1]{Francesca Pizzamiglio}%
\author[1]{Maria Antonietta Dessanai}%
\author[1]{Claudio Tondo}%
\author[1]{Rita Sicuso}%
\author[1]{Gaetano Fassini}%
\author[1]{Alice Bonomi}%
\author[2]{Antonio Dello Russo}%
\author[1]{Daniele Andreini}%
\author[3]{Paolo Zeppilli}%
\author[1]{Sfefania Isabella Riva}%
\affil[1]{Centro Cardiologico Monzino Istituto di Ricovero e Cura a Carattere Scientifico}%
\affil[2]{AOU Ospedali Riuniti di Ancona}%
\affil[3]{Università Cattolica del Sacro Cuore Sede di Roma}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\let\endcenter\endflushleft
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\selectlanguage{english}
\begin{abstract}
Introduction. Few data exist about effectiveness of atrial fibrillation
(AF) catheter ablation (CA) in athletes and feasibility of resuming
vigorous exercise afterwards. Aims of our study were to analyze the
efficacy and safety of AF CA in athletes, to compare AF CA outcomes in
athletes vs Non-Athletes (NA) and to evaluate the feasibility of
resuming vigorous exercise. We additionally analyze the outcome of
patients that underwent concomitant cavo-tricuspid isthmus (CTI) CA.
Methods and results. From January 2015 to October 2019, 38 athletes were
retrospectively matched with 38 NA that underwent first time AF CA.
After a median follow-up of 787 days, 62.5\% of athletes were free from
recurrences after one CA procedure and mostly without antiarrhythmic
drugs (87\%). Seven athletes underwent a redo procedure and all of them
were then free of recurrences with an overall freedom from recurrences
of 84\%. No major complications were observed. After the first year of
follow-up, athletes had a 48\% reduced risk of recurrences than NA
{[}adjusted hazard ratio (HR) on antiarrhythmic drugs, LA volume and AF
subtype, HR 0.52{]}. Athletes that underwent also CTI ablation showed a
positive trend in terms of freedom from recurrences (50\% vs 21\%). Most
(72\%) of the athletes resumed vigorous exercise after at least 3 months
from the CA. Conclusion. AF CA is a safe and efficient therapeutic
option in athletes and it should be considered instead of drugs to early
resume competitive sport activity. Concomitant CTI ablation may have a
favorable role.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Atrial fibrillation (AF) is the most common cardiac arrhythmia in
athletes\textsuperscript{1} and the interaction between sport activity
and AF is now widely accepted, especially in master athletes who
practice long-term endurance sport. Moreover, an association between
physical activity and common atrial flutter (AFL)\textsuperscript{2} has
been described. The mechanism is not fully understood and it is presumed
to be multifactorial. A specific trigger (atrial ectopy, sports
supplements and illicit drug use) in the presence of a suitable
substrate (genetic predisposition, cardiac remodeling with atrium
dilation, inflammation and fibrosis) and a modulator (autonomic
activation, electrolyte abnormalities, acid reflux disease) is the
foundation in onset and maintenance of AF in athletes. Lone AFL seems to
be a right-sided expression of the same pro-arrhythmic changes that lead
to AF in the left atrium.

Effective treatment of symptomatic AF is mandatory for sport
continuation both for European and Italian pre-participation protocols.
However, the management of AF in athletes is challenging. Reduction of
training volume and intensity may be effective, but in clinical practice
most athletes prefer to continue sport at the same level as before.
Rate-control strategy of the episodes is difficult to achieve in
athletes since beta-blockers are poorly tolerated and even prohibited in
some competitive sport. Moreover, pharmacological rhythm-control
strategy is poorly tolerated because of sinus bradycardia and/or
arterial hypotension. Long term antiarrhythmic drug therapy does not
represent the first choice in a young and otherwise healthy population.
Therefore, catheter ablation (CA) should be early considered in
athletes.

Furthermore, any form of anticoagulation can be a challenge due to
increased risk of bleeding with sport activities and it is a
contraindication to all sports with intrinsic risk or interpersonal
contact. There are no data regarding the safety of novel anticoagulants
in athletes with AF. Given the increasing age of athletes, it is not
rare to achieve a CHA\textsubscript{2}DS\textsubscript{2}-VASc score [?] 1
that may indicate the need for stroke prevention, especially when the
arrhythmic burden is high (class IA for score [?] 2, class IIaB for score
of 1). Efficient AF control through CA could also permit to stop
anticoagulant treatment in most athletes.

AF ablation is therefore an effective and safe therapeutic option and
recent international guidelines strongly recommend CA in paroxysmal AF
patient in whom at least one AAD has failed or is not well tolerated
(class I) and recommend AF ablation as first-line therapy in selected
patients (class IIa)\textsuperscript{3,4}. All guidelines emphasize the
importance of high annual procedure volumes for operators and sites.

However, few data exist about the effectiveness of AF CA in athletes and
feasibility of resuming vigorous exercise afterwards.

Aims of our study were to analyze the efficacy and safety of AF CA in
athletes, to compare AF CA outcomes in athletes vs Non-Athletes (NA) and
to evaluate the feasibility of resuming vigorous exercise. We
additionally analyze the outcome of patients that underwent concomitant
AFL CA.



\textbf{Methods}

\textbf{Study population}

We report a retrospective registry of athletes referred to our Sports
Cardiology Center (Centro Cardiologico Monzino IRCCS) for AF CA in the
last five years. All athletes were previously declared non-eligible to
competitive sport at pre-participation screening because of recurrences
of AF or evidence of persistent asymptomatic AF. Sedentary patients
without any structural heart disease were matched with athletes based on
age and sex.

All patients underwent a complete clinical assessment including ECG,
echocardiogram and thyroid function test. A full medical history and a
query for drug use (especially performance-enhancing drugs) were
included. Additional diagnostic tests were performed if needed.

\textbf{Catheter ablation}

Procedural methods, catheter selection, and post-procedural medication
management followed general practice. All patients underwent isolation
of the pulmonary veins (PVI) either by radiofrequency ablation or
cryoablation. Cavo-tricuspid isthmus ablation (CTI) was performed
discretionally regardless previous documentation of typical AFL.

\textbf{Clinical Follow up and outcomes}

Clinical follow-up of patients was performed through periodic ambulatory
clinical visits with ECG, Holter monitoring and ergometric stress test
before resuming sport activity. Patients were asked in detail about
clinical events occurring during the period of follow-up and
documentation of the events was carefully checked. Recurrences were
defined as reactivation of symptoms and/or any documentation of AF
lasting more than 30 sec. At the end of the follow-up all patients were
asked about resuming sport.

\textbf{Statistical analysis}

To minimize between-group differences at baseline, 38 athletes that
underwent first time CA for paroxysmal AF in our Institution and
Non-Athletes were matched by sex, age (\selectlanguage{ngerman}± 5 y) and year of CA (± 2 y).
Continuous variables are presented as mean ± standard deviation, and
they were compared using \emph{t} test for independent samples.
Non-normally distributed variables are presented as median and
interquartile ranges, and they were compared with the Wilcoxon rank sum
test. Categorical data were compared using \selectlanguage{greek}χ\selectlanguage{english}2 test or Fisher's exact
test, as appropriate

The association of AF recurrences in the two groups were tested by
multivariate Cox regression model and Kaplan Meier excluding any episode
occurred in the first three months (blanking period). Log-rank tests
were used to compare strata. All tests were 2-tailed, and
P\textless{}0.05 was required for statistical significance. All analyses
were performed using SAS version 9.4 (SAS Institute, Cary, NC).



\textbf{Results}

\textbf{Population characteristics}

The main clinical characteristics of patients are shown in \textbf{Table
1} . From January 2015 to October 2019, 38 athletes underwent first time
CA for paroxysmal atrial fibrillation in our Institution and were
matched to 38 NA. Athletes and NA were mostly males (95\%) with a mean
age of 48\selectlanguage{ngerman}±13 years. Non-athletes had significant higher BMI than
athletes {[}respectively, 27.8 (26.3-29.8) kg/m\textsuperscript{2} vs.
24.2 (22.9-26) kg/m\textsuperscript{2}, P \textless{} 0.0001{]} and
suffered more often from dyslipidemia (19\% vs. 3\%, P = 0.0247) and
hypertension (32\% vs. 5\%, P = 0.003) and therefore
CHA\textsubscript{2}DS\textsubscript{2}-VASc score was lower in athletes
(P = 0.0187). In NA AF was more often early-persistent (70\% vs. 21\%, P
= 0.076) than paroxysmal (27\% vs. 76\%, P \textless{} 0.0001) and they
were therefore more often in anticoagulant therapy (86\% vs. 42\%, P
\textless{} 0.0001) but less often in antiarrhythmic drugs (41\% vs.
68\%, P = 0.010). LA volume was significantly higher in NA (43±12 vs.
36±11ml/m2, P = 0.0295).

Distribution between type of sport is illustrated in \textbf{Figure 1} .



\textbf{Table 1.}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{Athletes (n=38)} & \textbf{Non-athletes (n=38)} &
\textbf{P-value}\tabularnewline
\midrule
\endhead
Age at CA & 48\selectlanguage{ngerman}±13 & 50\selectlanguage{ngerman}±10 & 0.3908\tabularnewline
Male & 36 (95) & 36 (97) & 0.9847\tabularnewline
Hypertension & 2 (5) & 12 (32) & 0.0030\tabularnewline
Diabetes mellitus & 0 (0) & 1 (3) & 0.3140\tabularnewline
Dyslipidemia & 1 (3) & 7 (19) & 0.0247\tabularnewline
BMI (kg/m\textsuperscript{2}) & 24.2 (22.9-26) & 27.8 (26.3-29.8) &
\textbf{\textless{}.0001}\tabularnewline
\textbf{CHA\textsubscript{2}DS\textsubscript{2}-VASc score} & 0 (0-0) &
0 (0-1) & 0.0187\tabularnewline
EHRA symptoms score & 2 (1-2) & 1 (1-2) & 0.3305\tabularnewline
\textbf{AAD} & 26 (68) & 15 (41) & 0.0101\tabularnewline
Class Ic at CA & 18 (69) & 11 (73) & 0.1166\tabularnewline
Class II at CA & 7 (27) & 1 (7) & 0.0247\tabularnewline
Class III at CA & 4 (15) & 3 (20) & 0.7189\tabularnewline
\textbf{Anticoagulant at CA} & 16 (42) & 32 (86) &
\textless{}.0001\tabularnewline
Acenocumarol/warfarin & 3 (19) & 10 (31) & 0.0286\tabularnewline
Direct anticoagulants & 13 (81) & 22 (69) & 0.0284\tabularnewline
\textbf{AF subtype} & & &\tabularnewline
Paroxysmal & 29 (76) & 10 (27) & \textless{}.0001\tabularnewline
Early-persistent & 8 (21) & 26 (70) & 0.0760\tabularnewline
Long-persistent & 1 (3) & 1 (3) & 1\tabularnewline
AF diagnosis prior CA (years) & 2 (1-4) & 2 (1-4,5) &
0.8097\tabularnewline
\textbf{Echocardiogram} & & &\tabularnewline
LVEF (\%) & 61\selectlanguage{ngerman}±5 & 56\selectlanguage{ngerman}±9 & 0.0133\tabularnewline
LA Vol (ml/m\textsuperscript{2}) & 36\selectlanguage{ngerman}±11 & 43\selectlanguage{ngerman}±12 & 0.0295\tabularnewline
\bottomrule
\end{longtable}

Data are presented as mean \selectlanguage{ngerman}± standard deviation, n (\%), or median
(interquartile range).

AAD, antiarrhythmic drugs; AF, atrial fibrillation; BMI, body mass
index; CA, catheter ablation; EHRA, European Heart Rhythm Association;
LA, left atrium; LVEF, left ventricular ejection fraction.

\textbf{Figure 1.}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Distribution between type of sport.

\textbf{Procedural characteristics}

The main procedural characteristics are shown in \textbf{Table 2} .
Athletes were treated almost 1:1 with cryo and RF ablation, while in NA
RF was chosen in most of cases {[}RF 21 (55\%) vs 35 (92\%), P=0.00057;
cryo 17 (45\%) vs 3 (8\%), P = 0.00012{]}. LA target different from
pulmonary veins was ablated only in NA {[}8 (21\%) vs 0, P = 0.0129{]},
while CTI was performed significantly more often in athletes {[}16
(42\%) vs 5 (13\%), P = 0.0047{]}.

\textbf{Table 2.}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{Athletes (n=38)} & \textbf{Non-athletes (n=38)} &
\textbf{P-value}\tabularnewline
\midrule
\endhead
\textbf{1st CA procedure} & & &\tabularnewline
PVI & 38 (100) & 38 (100) & 1\tabularnewline
CTI & 16 (42) & 5 (13) & 0.0047\tabularnewline
Other LA target & 0 (0) & 8 (21) & 0.0129\tabularnewline
SAE & 0 (0) & 0 (0) & 1\tabularnewline
RF & 21 (55) & 35 (92) & 0.00057\tabularnewline
Cryo & 17 (45) & 3 (8) & 0.00012\tabularnewline
\textbf{Redo CA procedure} & 5 (13) & 6 (16) & 0.74440\tabularnewline
Redo before 1 year & 1 (20) & 2 (33\%) & 0.55579\tabularnewline
Redo after 1 year & 4 (80) & 4 (77\%) & 1\tabularnewline
\bottomrule
\end{longtable}

Data are presented as n (\%).

CA, catheter ablation; CTI, cavo-tricuspid isthmus; LA, left atrium;
PVI: pulmonary vein isolation; RF, radiofrequency; SAE, serious adverse
event.



\textbf{Outcomes}

\emph{Outcomes in athletes.} After a median follow-up of 787 days,
62.5\% of athletes were free from recurrences after one CA procedure and
mostly without antiarrhythmic drugs (87\%). Seven athletes underwent a
redo procedure and all of them were then free of recurrences with an
overall freedom from recurrences of 84\% (\textbf{Figure 2} ). No major
complication was observed. Athletes practicing endurance sports showed a
negative trend in terms of recurrences (p = ns).

\textbf{Figure 2.}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Kaplan-Meyer of AF recurrences in athletes.

Most (72\%) of the athletes resumed vigorous exercise after at least 3
months from the CA, successfully passed preparticipation screening and
could be eligible again for competitive sport activities in agreement
with Italian sport protocols.

\emph{Ouctomes in athletes vs non-athletes.} After the first year of
follow-up, athletes had a 48\% reduced risk of recurrences than NA
{[}adjusted hazard ratio (HR) on antiarrhythmic drugs, LA volume and AF
subtype, HR 0.52{]}. These data were confirmed and more significant in
an age-related analysis in which young patients (\textless{} 49 years
old) were compared to old patients (\textgreater{} 49 years old) of both
groups. Young athletes had a risk of AF recurrences 4 times lower (HR
3.98) than young NA, while elderly athletes had a 46\% reduced risk of
AF recurrences (HR 1.46) than elderly NA. These differences were not
statistically significant due to low sample size, but showed a positive
trend in athletes vs NA (\textbf{Figure 3} ).

\textbf{Figure 3.}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Kaplan-Meyer of AF recurrences in athletes vs non-athletes. Adjusted on
antiarrhythmic drugs, LA volume and AF subtype.

\emph{Outcomes with concomitant CTI ablation.} CTI ablation was
performed in 16 athletes (43\%). Athletes that underwent also CTI
ablation showed a positive trend in terms of freedom from recurrences
(50\% recurrences in AF CA only vs 21\% in CTI plus AF CA,\textbf{Figure
4} ). The statistical significance was borderline due to small sampling
size (p = 0.06, Kaplan-Meier log-rank 3.3587).

\textbf{Figure 4.}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Kaplan-Meyer of arrhytmia recurrences after AF ablation vs concomitant
CTI ablation.



\textbf{Discussion}

The main finding of this study is the higher propensity of athletes
population of remaining free from AF recurrences after a single AF
ablation procedure compared with Non-athletes population, especially
when CTI ablation was associated with PVI. Furthermore, the majority of
our athletes population quickly resumed competitive sport activity.

Data from the literature suggest that freedom from AF is between 50-80\%
in patients with either persistent or paroxysmal
AF\textsuperscript{5-10}. However, there are few and conflicting
long-term data available in athletes and no difference in long-term
freedom from AF has been observed between athletes and NA.

In 2008 Furlanello et al. reported in a small population of 20 athletes
(mean age 44.4\selectlanguage{ngerman}±13 years) 90\% freedom from AF at 36.1±12.7 months after
PVI\textsuperscript{11}. Another study including 182 subjects undergoing
PVI reported similar arrhythmia-free survival at one year in the lone AF
sport group versus controls (59\% vs 48\%, p=0.44), and similar rates of
procedure related complications (7.1\% vs. 4.3\%; p=0.45). The frequency
of redo PVI procedures was similar between the lone AF sport group and
controls (40.5\% vs 37.3\%, p=0.5)\textsuperscript{12}. Koopman et al.
studied 94 endurance athletes and reported similar AF recurrence after
first PVI procedure\textsuperscript{13}: both groups showed similar
arrhythmia free survival at 3 years (87 vs. 85\%, p=0.88).

More recently, the case-control study by Decroocq et
al.\textsuperscript{14} showed the same AF recurrences rates at 1-year
follow-up after CA between 73 athletes and 73 matched sedentary
patients. After 5-year follow-up, AF recurrences rates did not differ
statistically between 38 (52\%) athletes and 35 (47.9\%) NA who
recurred. Finally, Mandsager et al.\textsuperscript{15} reported no
difference in arrhythmia recurrence between athletes and a matched
cohort of NA who underwent PVI. Single-procedure freedom from arrhythmia
was 75\%, 68\%, and 33\% at 1 year for paroxysmal, persistent, and
long-standing persistent AF, respectively. Multiple-procedure freedom
from arrhythmia off antiarrhythmic drugs was 86\%, 76\% and 56\% in
respective group at the end of follow-up (mean 1.4 ± 0.7 ablation per
athletes).

In our study, after a median follow-up of 787 days, 62.5\% of athletes
were free from recurrences after one CA procedure and mostly without
antiarrhythmic drugs (87\%), while after a redo procedure the overall
freedom from recurrences was 84\%. However, in contrast with previous
data, our study showed a higher propensity of athletes of remaining free
from AF recurrences after a single AF ablation procedure compared with
NA population. After the first year of follow-up, athletes had, in fact,
a 48\% reduced risk of recurrences than NA, especially in an age-related
analysis. Young athletes had a risk of AF recurrences 4 times lower than
young NA, while elderly athletes had a 46\% reduced risk of AF
recurrences than elderly NA. These differences were not statistically
significant due to low sample size, but showed a positive trend in
athletes.

Different reasons may explain a better outcome of CA in athletes
compared to NA. First of all, athletes were slimmer than NA and the
correlation between BMI and AF is clearly
demonstrated\textsuperscript{16-18}. Moreover, in NA LA volume was
significantly higher and persistent AF significantly more prevalent,
suggesting the presence of atrial remodelling and more advanced electric
LA disease. It has been demonstrated, in fact, that even small
difference in LA volume is an independent predictor of increased odds of
AF recurrence\textsuperscript{19}. The negative trend showed in
endurance athletes may be correlated with atrial remodelling described
in this subpopulation of athletes\textsuperscript{20}. Endurance
training leads to a harmonic enlargement of all four cardiac chambers as
an adaptation to exercise conditioning; however, the atrial walls are
significantly thinner than the ventricular walls and the higher stress
during episodes of training-related volume overload may contribute to
progressive LA enlargement and remodelling. Repetitive episodes of
atrial stretching and chronic inflammation secondary to excessive
endurance training may be contributing factors for atrial fibrosis and
AF, especially in aging athletes\textsuperscript{21,22}.

Furthermore, in our study concomitant CTI ablation in athletes seemed to
be associated with an additional positive trend in terms of freedom from
recurrences, regardless previous documentation of typical AFL. AFL often
precedes or coexists with AF in athletes as a consequence of
exercise-induced enlargement of the atria\textsuperscript{23} and it may
also be life-threatening during exertion due to 1-to-1 conduction to the
ventricles under high sympathetic tone. Our results are in contrast with
available data from literature in NA population showing that
prophylactic CTI ablation irrespective of the previous documentation of
typical AFL is not associated with improvement in recurrence of atrial
arrhythmia compared with PVI alone. After the small randomized
controlled trial by Pontoppidan et al. in 2009\textsuperscript{24}, more
recently Mesquita et al.\textsuperscript{25} compared the outcomes of
patients without any previous documentation of typical AFL who underwent
PVI alone vs. PVI + prophylactic CTI ablation using a registry dataset
of more than 1900 consecutive patients who underwent a first AF CA. CTI
ablation remained unassociated with AF-free survival. The same results
were obtained by Lee et al. in 2019 in their retrospective study of 139
patients\textsuperscript{26} and they were confirmed also by the
meta-analysis by Romero et al. in 2020\textsuperscript{27}. Ongoing
randomized control trials in general population may give further
evidence to support or refuse prophylactic CTI ablation. Increased vagal
tone and structural atrial changes (i.e. fibrosis) associated with high
intensity sport practice may have a causative role in the development of
typical AFL in athletes and it may explain our results. However, further
data are requested. Recent recommendations for participation in
leisure-time physical activity and competitive sports suggest that in an
athlete presenting with AFL, there should be a very low threshold to
ablate the CTI, given the efficacy and safety of the procedure versus
the risk for recurrences during sports. European recommendations even
advice that CTI should be ablated prophylactically in athletes with AF
who want to engage in intensive exercise, especially when drug treatment
is considered or concomitantly with PVI\textsuperscript{28}.

Lastly, the high success rate of AF CA obtained in our study confirmed
the possibility to permanently abolish AF in athletes, offering a unique
option for resume competitive sport. Most of our athletes were, in fact,
declared eligible to competitive sport activity after at least 3 months
from the CA as per Italian sport protocol.

\textbf{Limitations}

The main limitation of the study is an observational, non-randomized,
retrospective, low sample size design. The low sample size affected also
statistical power and it prevented to analyze if there were any
differences in outcome depending on type of sport and time distance
between AF diagnosis and CA time. Furthermore, assessment of
recrudescence was performed mainly with 24-hour Holter monitoring and
asymptomatic AF episodes may have been lost. However, athletes tended to
be more often symptomatic than NA and asymptomatic AF should not have
significantly affected success rate in athletes. CTI concomitant
ablation was left to operator choice and it may have affected final
results. Further prospective studies with a larger number of patients
are required.

\textbf{Conclusions}

AF catheter ablation is a safe and efficient therapeutic option in
athletes and it should be considered instead of drugs to early resume
competitive sport activity. Concomitant CTI ablation may have a
favorable role in this subset of patients.

\textbf{Acknowledgments:} none.



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\textsuperscript{2} Claessen G, Colyn E, La Gerche A, Koopman P, Alzand
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