Mechanisms of atrial fibrillation in athletes: what we know and what we do not know
Neth Heart J
Mechanisms of atrial fibrillation in athletes: what we know and what we do not know
E. Guasch 0
L. Mont 0
M. Sitges 0
0 Institut Clinic Cardiovascular, Hospital Clínic de Barcelona; IDIBAPS; Universitat de Barcelona; CIBERCV. , 08036 Barcelona, Catalonia , Spain
Exercise is an emerging cause of atrial fibrillation (AF) in young individuals without coexisting cardiovascular risk factors. The causes of exercise-induced atrial fibrillation remain largely unknown, and conclusions are jeopardised by apparently conflicting data. Some components of the athlete's heart are known to be arrhythmogenic in other settings. Bradycardia, atrial dilatation and, possibly, atrial premature beats are therefore biologically plausible contributors to exercise-induced AF. Challenging findings in an animal model suggest that exercise might also prompt the development of atrial fibrosis, possibly due to cumulative minor structural damage after each exercise bout. However, there is very limited, indirect data supporting this hypothesis in athletes. Age, sex, the presence of comorbidities and cardiovascular risk factors, and genetic individual variability might serve to flag those athletes who are at the higher risk of exercise-induced AF. In this review, we will critically address current knowledge on the mechanisms of exercise-induced AF.
Atrial fibrillation; Endurance; Exercise; Atrial fibrosis; Vagal tone
Atrial fibrillation (AF) is the most frequent sustained
arrhythmia in the developed world, bearing a poor quality of
life and increasing the risk of stroke and mortality.
Prevalence of AF has been steadily increasing in recent years, and
the number of individuals with AF is expected to double by
]. The main factors promoting AF are ageing,
structural heart disease, hypertension and diabetes, but these are
absent in up to 15% of AF patients. The cause of AF in
these young patients with no cardiovascular conditions has
been the focus of extensive research in recent years, and
obstructive sleep apnoea, obesity, tall stature and genetic
predisposition have all been associated with increased risk
of AF [
Reports published at the end of the 1990’s suggested that
veteran athletes are also at a higher-than-expected risk of
]. Subsequent small  and large
epidemiological studies including >1 million individuals [
this association. Endurance training is now a well-accepted
cause of AF [
]. Heavily trained athletes are, on average,
at a 3–8-fold increased risk of AF [
] and its prevalence
is as high as 15% in veteran elite athletes [
physical activity history is reported by up to 60% of young
patients with AF in the absence of any cardiopulmonary
]. In the daily practice, exercise-induced AF is
usually diagnosed in middle-aged males who have been
practicing very intense endurance sports (e. g., marathon
], cycling [
], cross-country skiing [
]) in the
long-term (>10 years) [
]. Not uncommonly, AF is
diagnosed some years after regular training has been
]. Overall, these data challenge the notion that the
benefits of physical activity have no appreciable limits [
The emergence of exercise as a potential cause of AF is
relatively novel, and its pathology and underlying
mechanisms remain largely unknown. Few works have shed some
light on the causes of exercise-induced AF, and
uncertainties are still prevailing in this field. Is AF only a marker of
extreme physical adaptation or is it associated with a
pathological substrate? If so, do we have any evidence in humans
of a deleterious effect of physical activity on cardiac
structures? Why does the healthy exercise become harmful? Do
illicit performance-enhancing substances play a role? While
clinical and epidemiological evidence for exercise-induced
AF is compelling, there is little evidence for a deleterious
effect in the left ventricle: why do these cardiac
chambers behave so differently? And, finally, why do only a few
Middle-aged males who have been engaged in strenuous endurance training for more than
10 years and who are otherwise healthy, are at the highest risk of developing AF caused
Vagal enhancement, atrial dilation and, possibly, atrial myocardial fibrosis are likely
contributors to exercise-induced AF, but definitive evidence in athletes is still warranted.
Atrial fibrosis in athletes might be the consequence of increased atrial stretch, inflammation
and oxidative stress during strenuous exercise, that incompletely recover between bouts.
Large knowledge gaps in the mechanisms of exercise-induced AF impedes providing
evidence-based directives aiming at improving primary prevention or treatment of AF
specifically in athletes.
athletes develop AF? In this review, these issues will be
critically reviewed on the basis of current evidence.
Is exercise-induced AF an extreme form of physiological adaptation?
Our knowledge of the substrate that sustains AF in athletes
is poor, largely speculative, based on general notions of AF
pathology and, in few cases, derived from clinically
relevant animal models. In the classic and simple, but useful,
Coumel’s triangle, an appropriate substrate, a predisposing
modulator and a timely trigger are needed in variable
proportions to initiate and maintain AF (Fig. 1). The currently
available evidence for the potential contribution of each of
these mechanisms in exercise-induced AF is summarised in
Tab. 1. Interestingly, some of the classical components of
the physiologic cardiac adaptation to regular physical
activity (so-called athlete’s heart) have also been associated
to AF pathology.
On the one hand, atrial size is a well-recognised
independent predictor of incident AF [
]. In experimental models,
dilatation of the left atrium facilitates the instauration and
perpetuation of AF even in the absence of myocardial
]. We still do not fully understand the mechanisms
behind AF promotion in dilated atria, but disparities on
conduction velocity throughout the left atrium probably
]. Conduction heterogeneity in dilated atria might
be originated by cellular electrophysiological changes
occurring at cellular level in hypertrophied cardiomyocytes
]. Moreover, atrial dilatation increases the atrial critical
mass and facilitates the establishment of re-entrant
electrical activity and AF [
]. On the other hand, atrial dilatation
is a hallmark of the athlete’s heart [
]. Atrial dilatation
results from the adaptation of the atria to regular training:
both atria enlarge to accommodate the increased cardiac
output requirements during exercise. However, the
characteristics of atrial dilatation are not exhaustively known. It is
currently unknown whether atrial dilation geometry differs
in athletes and in patients with a heart disease. Notably, at
a similar degree of atrial dilatation, atrial function seems to
be preserved in athletes, but not in patients with a structural
heart disease [
A slow heart rate is a common finding in well-trained
individuals. For decades, bradycardia in athletes has been
attributed to an imbalance in autonomic tone characterised
by parasympathetic tone enhancement and sympathetic
tone withdrawal. Parasympathetic tone shortens the atrial
refractory period and thereby facilitates re-entry and AF.
Results in an animal model suggest that exercise enhances
parasympathetic tone partially through an increased
cardiac sensitivity to acetylcholine, an effect mediated by
downregulation of regulators of G protein signalling (RGS)
]. In this model, parasympathetic enhancement was
central in the early stages of exercise-induced AF
]. Notably, most AF relapses in athletes occur in
vagally-dominant situations such as during sleep or after
]. Remarkable clinical implications may derive
if parasympathetic tone is confirmed as a main driver of
exercise-induced AF. For example, antiarrhythmic drugs
with vagolytic properties (e. g., dysopiramide [
be favoured over other options, and intracardiac autonomic
ganglia could become a primary target in ablation
procedures . Conversely, adrenergic-mediated AF is less
frequent in athletes [
]. Although the parasympathetic and
sympathetic tone shorten atrial refractoriness to a
similar extent, the more heterogeneous atrial parasympathetic
innervation yields a larger arrhythmic susceptibility [
The notion that parasympathetic tone enhancement is
the sole cause of bradycardia in athletes has recently been
disputed. D’Souza et al. elegantly demonstrated in mice
that a reduction in intrinsic heart rate (i. e., changes in
the sinus node function independent of autonomic
regulation) through HCN4 downregulation governs bradycardia
in trained individuals [
], thereby supporting conclusions
from previous studies in athletes [
]. Moreover, the
modification of the intrinsic properties of the sinus node is
consistent with reports pointing to a high prevalence of sinus
node disease and pacemaker requirement in athletes [
The increased atrial refractoriness dispersion during
bradycardia might indeed link intrinsic heart rate reduction to
exercise-induced AF pathology [
It is likely that both autonomic tone-mediated
remodelling and intrinsic heart rate-mediated remodelling
contribute to bradycardia in athletes, and that the balance
between both factors change with training intensity and/or
sport discipline [
]. In the general population, either
parasympathetic tone-driven bradycardia or intrinsic heart
rate-driven, bradycardia is associated with a higher risk of
In the general population, atrial premature beats may
trigger AF events in the presence of other predisposing
factors or, when very frequent, may be the main etiological
factor. It has been postulated that endurance athletes present
with a higher burden of atrial premature beats than
sedentary individuals [
]. Nevertheless, it remains unknown
whether such a mild increase is enough to significantly
contribute to the AF burden in athletes.
Both atrial enlargement and bradycardia are more
evident in endurance sports athletes than in strength sports
(e. g., weight-lifting) practitioners. In parallel,
exercise-induced AF is far more frequent in endurance athletes. On
this basis, some authors hypothesised that AF might be an
extreme manifestation of the physiological athlete’s heart.
However, recent results from our and other groups disputed
this notion. Works in animal models suggested that atrial
fibrosis, a clearly pathological hallmark, could contribute to
exercise-induced AF pathology. Atrial fibrosis disrupts
normal electrical conduction in the atrium and, possibly,
interferes with myocyte-fibroblast electrical coupling, thereby
facilitating the establishment of re-entries and, eventually,
]. In a rat model, we first found that a 16-week
intense training protocol increased AF inducibility in an
electrophysiological test. In addition to atrial dilatation and
an enhanced parasympathetic tone, we observed increased
atrial interstitial fibrosis [
], a finding that has been
subsequently confirmed by others [
]. Of note, both
studies found a modest ( 60%) increase in atrial fibrosis [
], contrasting to much larger atrial fibrosis deposits in
other pathologic settings known to be associated with AF,
such as left ventricular dysfunction or valve disease. In
these conditions, atrial fibrosis increases up to 500% .
Although some experimental work suggests that
exerciseinduced atrial fibrosis drives AF inducibility [
], it is
also plausible that additional contributing factors should
be present, at least in the early stages of exercise-induced
Do we have data on pathological remodelling in humans?
The confirmation in humans of a pathologic substrate in
intensively trained individuals is still pending. In particular,
the need of invasive tests to assess atrial fibrosis hampers
its confirmation in athletes. Atrial biopsies are an
unrealistic approach to quantify myocardial fibrosis in apparently
healthy individuals, and magnetic resonance techniques are
still underdeveloped. Therefore, only indirect estimates are
Results on plasmatic biomarkers are consistent with the
presence of a profibrotic state in some trained individuals.
Active or veteran athletes present with higher levels of
profibrotic markers, such as galectin-3 [
], ST2 [
circulating pro-fibrotic microRNAs such as mir-21 [
collagen turnover peptides PICP, CITP and TIMP-1 [
These plasmatic biomarkers have been associated with
incident or recurrent AF in clinical works in the general
population and in patients with structural heart disease [
It should be noted, though, that the interpretation of these
results is complex and, at best, suggest the existence of
a pro-fibrotic systemic environment that could favour atrial
Echocardiographic parameters such as atrial strain have
been used as surrogate markers for the degree of atrial
fibrosis in patients undergoing mitral valve surgery [
However, results in well-trained endurance athletes are
The ECG is an easy, widely available tool that may be
useful to provide a rough approach to atrial structures. In
patients with mitral valve disease, p-wave duration
associates with atrial fibrosis and size [
], and flags those
individuals at an increased risk of AF. Endurance athletes
present with an accumulated physical activity-dependent
pwave prolongation [
]. In football players, such a
prolongation is independent of atrial size, and thereby fibrosis
evolves as a plausible underlying substrate [
What triggers pathological remodelling?
Secondary prevention trials [
] and observational studies
assessing incident AF in older individuals or in individuals
with a high burden of cardiovascular risk factors [
demonstrate that low to moderate load of physical
activity is safe and may even be antiarrhythmic. Conversely,
a high exercise load may promote AF in some individuals.
Overall, these findings depict a U-shaped relationship
between exercise load and AF incidence [
]. It is unclear
which are the determinants promoting the transition from
safe exercise to the appearance of exercise-induced atrial
fibrillation. Chances are that atrial dilatation or
bradycardia beyond a certain level in well-trained athletes facilitate
AF. It is also possible, though speculative, that an increase
in AF incidence associates with the establishment of atrial
In this regard, the mechanisms behind the potential
instauration of atrial fibrosis remain unknown. Fig. 2
summarises the factors that have been postulated to contribute
to exercise-induced atrial fibrosis. It is possible that
systemic or mechanic insults during strenuous exercise bouts
inflict cumulative microstructural myocardial damage. As
for the right ventricle, it has been postulated that such
damage develops after incomplete recovery between exercise
bouts, thereby leading to permanent damage to the atria.
Pro-inflammatory insults and low-level inflammation
have been associated with AF incidence in the general
]. Although regular physical activity has been
demonstrated to yield a systemic chronic
anti-inflammatory effect, each exercise bout disturbs the inflammatory
balance and prompts a pro-inflammatory status. Intense
exercise transiently increases neutrophil count and induces
the release of pro-inflammatory cytokines such as
interleukin-6, interleukin-8, C-reactive protein and ST2 [
]. Systemic inflammation may locally extend to the
myocardium. In a swimming-based animal model,
extenuating exercise bouts were associated with myocardial
leukocyte infiltration . Interestingly, local inflammation
mediated by stretch-activated tumour necrosis-alpha
(TNFα) seems to be critical in exercise-induced atrial fibrosis
]. In humans, a transient p-wave prolongation
after ultra-distance races was observed independently of
atrial size, leading the authors to postulate that transient
inflammatory infiltration or oedema could cause such
conduction disturbances [
]. Changes in plasma of
TNFα and interleukin-12p70 concentrations correlate to right
ventricular dysfunction after ultra-distance races in
welltrained athletes [
]. Oxidative stress, which has also been
linked to an increased AF incidence [
], increases in
a load-dependent way after exercise [
]. Several attempts
have been undertaken to blunt the pro-inflammatory and
oxidative status after strenuous exercise with nutritional
supplements and drugs, yielding conflicting results on the
systemic inflammatory status [
], and showing no
benefits on cardiac haemodynamic overload markers .
A transient increase of cardiac necrosis markers (e. g.,
troponin I and troponin T) after long distance races was
reported some years ago and claimed to be a marker of
cardiac necrosis during exercise. Plasmatic troponin levels
were associated with right, but not left, ventricular transient
dysfunction after strenuous exercise [
], but a worse
outcome in those athletes with repetitive troponin elevation has
not been demonstrated. However, our current
understanding of troponin release during long races involves a process
of cardiomyocyte membrane permeabilisation rather than
pathological ischaemia [
]. To date, repetitive myocardial
ischaemia and necrosis cannot be established as a source of
Each exercise bout involves a volume overload that
superimposes a mechanical stress to which the thin atrial
wall is particularly sensitive. Wall stress positively
correlates with intracavitary pressure and size, and inversely
with wall thickness. Atrial enlargement implies that wall
stress is higher, according to Laplace’s law (Fig. 2).
Additionally, if the curvature of the atria changes (i. e.,
becoming more elliptic), wall stress might also increase (the
flatter the wall, the higher the wall stress) [
natriuretic peptide (ANP) levels, a marker of atrial stretch,
is increased at rest in athletes in comparison with healthy
]. Atrial pressure increases during
], further increasing wall stretch and prompting
a subsequent deleterious remodelling. Such deleterious
effects might be particularly notorious in a subset of athletes
with dilated and dysfunctional atria [
]. Increasing loads
of physical activity are associated with an acute,
dose-dependent transient atrial dysfunction, which becomes severe
after very intense and prolonged bouts [
aforementioned, increased atrial wall stress has been shown to trigger
TNF-mediated activation of local inflammation, eventually
leading to atrial fibrosis in an animal model [
Blocking TNF-α did prevent exercise-induced atrial fibrosis and
inducibility. Speculatively, hidden hypertension or
hypertension during exercise bouts may further exacerbate this
increase in atrial wall stress and accelerate it [
increased atrial wall stretch appears as an attractive trigger
for pathological remodelling after strenuous exercise, but
definitive proof remains elusive.
What makes the atrium different, why is it selectively affected?
For a long time, research in sports cardiology focussed on
the study of left ventricle adaptation to variable amounts of
physical activity. It was convincingly demonstrated that left
ventricle adaptation to high loads of physical activity does
not usually convey pathological stigmas. Proteomic studies
emphasised the physiological remodelling of the left
ventricle in intensively-trained animals [
], and some studies
suggest that physical activity may even protect against
ventricular arrhythmias [
]. However, the atria and right
ventricle were scarcely studied.
The recent demonstration of potentially deleterious
effects of very high doses of physical activity has moved
the focus towards the atria and the right ventricle [
The physiological remodelling of the left ventricle contrasts
with the identification of atrial and right ventricular
arrhythmias in athletes. Morphological, functional and molecular
differences between left ventricle, right ventricle and both
atria underlie a distinct response to high levels of physical
As described in the previous section, the morphology
of the atrium makes it particularly vulnerable to
haemodynamic disturbances. Haemodynamic overload promotes
atrial dilatation and, subsequently, increases wall stretch.
Conversely, the ability of the left ventricle to respond to
repetitive mechanical overload by thickening its
myocardial walls enables the left ventricle to maintain wall stretch
within a non-deleterious range [
]. This adds to
differences in the cellular and molecular characterisation of
atria and ventricles. Indeed, atrial fibroblasts show an
enhanced reactivity to pathological stimuli in comparison with
ventricular fibroblasts , resulting in a remarkably larger
atrial than ventricular fibrosis burden upon the instauration
of non-ischaemic heart failure in animal models [
Altogether, clinical outcomes, morphological
characteristics and fibroblast reactivity data suggest that the atria
have a greater sensitivity to the haemodynamic overload
than the left ventricle, potentially justifying that the atria
are primarily affected by the deleterious consequences of
strenuous physical activity [
Are performance-enhancing drugs a plausible explanation for exercise-induced AF?
Performance-enhancing drugs have been postulated to
contribute to AF burden in athletes. Nevertheless, the obscure
nature of doping hinders any robust conclusion and thereby
this issue remains, at best, speculative. Available data from
athletes who have been banned from competition suggest
that the most commonly used substances in high-level
endurance-trained athletes who aim to improve their
performance are erythropoietin (EPO), anabolic-androgenic
steroids (AAS), and stimulant and sympathomimetic drugs.
Erythropoietin and its derivatives increase erythrocyte
synthesis and oxygen supply to peripheral muscle, evolving
as a tempting drug for endurance athletes. To date, however,
there is no data reporting AF as a significant side effect of
The use of AAS has been associated with AF in
isolated case reports [
]. A study with body-builders recently
demonstrated that chronic anabolic steroid administration
associates with a prolonged atrial electromechanical delay
]. Atrial electromechanical delay predicts new-onset AF,
likely reflecting underlying substrate abnormalities [
Sympathomimetic drugs, such as ephedrine and
amphetamine derivates, are used as stimulants and might
trigger AF; a specific form of apoptosis in myocardial
biopsies termed eosinophilic bands has been associated
with ephedrine intake [
Nevertheless, we should note that the use of
performance-enhancing substances is not exclusive for
long-distance endurance sports. Rather, their use is also relatively
common in bodybuilders and weight-lifters, although no
reports demonstrating an increased risk of AF in these cohorts
Fig. 3 Representation of the factors contributing to the balance
between the antiarrhythmic and the pro-arrhythmic effect of exercise
has been published. It should be acknowledged, though, that
it is biologically plausible that the effect of
performanceenhancing substances is boosted in those endurance
athletes in whom both a larger chamber dilatation/fibrosis and
parasympathetic tone enhancement occur.
Why do only few athletes develop AF?
While exercise is performed by a large part of the
population, only some athletes will develop AF. Moreover, some
individuals may get protected by exercise from AF, as
]. Fig. 3 summarises the potential factors
involved in this complex relationship. In terms of AF
incidence, the arrhythmogenicity of exercise likely results from
the net balance between its beneficial (e. g., improvement of
risk factors burden) and its potentially pro-arrhythmic (e. g.,
atrial fibrosis) effects; age and the presence of
cardiovascular risk factors modulate this relationship . Elderly
individuals accruing several cardiovascular risk factors may
benefit from exercise [
]. Conversely, middle-aged
individuals without cardiovascular risk factors may be more
prone to exercise-induced AF [
On top of these factors, it is evident that some degree
of genetically-derived interindividual variability facilitates
the development of a pathological remodelling or enhance
athlete’s heart features [
]. Men are apparently at a higher
risk, likely because of bigger atria and a more extensive
remodelling as compared with women [
longer follow-up in contemporaneous cohorts of women
is warranted [
]. The presence of certain genetic
mutations or polymorphisms may put some athletes at a higher
risk. A mutation in a subunit of the IKs potassium channel
has been shown to confer an increased sensitivity to atrial
stretch and could therefore facilitate AF during
hypertension or in athletes [
]. Unfortunately, to date, there are
insufficient data that reliably identify those athletes who
are at risk of exercise-induced AF.
The higher incidence of AF in athletes is now
well-accepted, but its causes remain elusive. Atrial dilatation and
parasympathetic enhancement are likely contributors. Some
data in animals suggest that extreme physical activity
associates with a pathological remodelling involving atrial
fibrosis. Transient inflammation and an increase in atrial
wall stress, associated with uncomplete recovery between
exercise bouts, could trigger the development of atrial
fibrosis. Nevertheless, confirmation in humans is still
waiting, largely due to limitations in registries and
histological confirmation. On the other hand, the contribution of
performance-enhancing substances does not appear to be
remarkable. Overall, data are still insufficient to adopt
specific prevention and diagnostic or prognostic strategies in
the clinical setting. With our current knowledge, the
potential risk of AF should not be used to limit the amount of
Funding This manuscript was partially supported by grants from the
Instituto de Salud Carlos III (PI13/01580, PI16/00703); Ministerio
de Economia y Competitividad (SAF2015–64136R); CERCA
programme/Generalitat de Catalunya; European Union’s Horizon2020
research and innovation programme under grant agreement nº 633196
(CATCH-ME); and Centro de Investigación Biomédica en RED
Conflict of interest E. Guasch, L. Mont and M. Sitges declare that they
have no competing interests.
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1. Krijthe BP , Kunst A , Benjamin EJ , et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060 . Eur Heart J. 2013 ; 34 : 2746 - 51 .
2. Calvo N , Ramos P , Montserrat S , et al. Emerging risk factors and the dose-response relationship between physical activity and lone atrial fibrillation: a prospective case-control study . Europace . 2016 ; 18 : 57 - 63 .
3. Gudbjartsson DF , Arnar DO , Helgadottir A , et al. Variants conferring risk of atrial fibrillation on chromosome 4q25 . Nature . 2007 ; 448 : 353 - 7 .
4. Mont L , Sambola A , Brugada J , et al. Long-lasting sport practice and lone atrial fibrillation . Eur Heart J . 2002 ; 23 : 477 - 82 .
5. Karjalainen J , Kujala UM , Kaprio J , Sarna S , Viitasalo M. Lone atrial fibrillation in vigorously exercising middle aged men: casecontrol study . BMJ . 1998 ; 316 : 1784 - 5 .
6. Molina L , Mont L , Marrugat J , et al. Long-term endurance sport practice increases the incidence of lone atrial fibrillation in men: a follow-up study . Europace . 2008 ; 10 : 618 - 23 .
7. Andersen K , Rasmussen F , Held C , Neovius M , Tynelius P , Sundström J . Exercise capacity and muscle strength and risk of vascular disease and arrhythmia in 1.1 million young Swedish men: cohort study . BMJ . 2015 ; 351 : h4543 .
8. Kirchhof P , Benussi S , Kotecha D , et al. ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS . Eur Heart J . 2016 ; 37 : 2893 - 962 .
9. Grimsmo J , Grundvold I , Maehlum S , Arnesen H . High prevalence of atrial fibrillation in long-term endurance cross-country skiers: echocardiographic findings and possible predictors-a 28-30 years follow-up study . Eur J Cardiovasc Prev Rehabil . 2010 ; 17 : 100 - 5 .
10. Baldesberger S , Bauersfeld U , Candinas R , et al. Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists . Eur Heart J . 2008 ; 29 : 71 - 8 .
11. Andersen K , Farahmand B , Ahlbom A , et al. Risk of arrhythmias in 52 755 long-distance cross-country skiers: a cohort study . Eur Heart J . 2013 ; 34 : 3624 - 31 .
12. Guasch E , Mont L . Diagnosis, pathophysiology, and management of exercise-induced arrhythmias . Nat Rev Cardiol . 2017 ; 14 : 88 - 101 .
13. Eckel RH , Jakicic JM , Ard JD , et al. AHA/ACC guideline on lifestyle management to reduce cardiovascular rsk: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines . J Am Coll Cardiol . 2013 ; 63 : 2960 - 84 .
14. Vaziri SM , Larson MG , Benjamin EJ , Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation . The Framingham Heart Study. Circulation . 1994 ; 89 : 724 - 30 .
15. Neuberger H-R , Schotten U , Blaauw Y , et al. Chronic atrial dilatation, electrical remodeling, and atrial fibrillation in the goat . J Am Coll Cardiol . 2006 ; 47 : 644 - 53 .
16. Spach MS , Heidlage JF , Dolber PC , Barr RC . Electrophysiological effects of remodeling cardiac gap junctions and cell size: experimental and model studies of normal cardiac growth . Circ Res . 2000 ; 86 : 302 - 11 .
17. Zou R , Kneller J , Leon LJ , Nattel S. Substrate size as a determinant of fibrillatory activity maintenance in a mathematical model of canine atrium . Am J Physiol Heart Circ Physiol . 2005 ; 289 : H1002 - H12 .
18. Wilhelm M , Roten L , Tanner H , Wilhelm I , Schmid J-P , Saner H. Atrial remodeling, autonomic tone, and lifetime training hours in nonelite athletes . Am J Cardiol . 2011 ; 108 : 580 - 5 .
19. Gabrielli L , Enríquez A , Córdova S , Yáñez F , Godoy I , Corbalán R . Assessment of left atrial function in hypertrophic cardiomyopathy and athlete's heart: a left atrial myocardial deformation study . Echocardiography . 2012 ; 29 : 943 - 9 .
20. Guasch E , Benito B , Qi X , et al. Atrial fibrillation promotion by endurance exercise: demonstration and mechanistic exploration in an animal model . J Am Coll Cardiol . 2013 ; 62 : 68 - 77 .
21. Boucher M , Chassaing C , Herbet A , Duchêne-Marullaz P . Interactions with the cardiac cholinergic system: effects of disopyramide and its mono-N-dealkylated metabolite . Life Sci . 1992 ; 50 : PL161 - PL6 .
22. Verma A , Saliba WI , Lakkireddy D , et al. Vagal responses induced by endocardial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation . Heart Rhythm . 2007 ; 4 : 1177 - 82 .
23. Liu L , Nattel S. Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity . Am J Physiol Heart Circ Physiol . 1997 ; 273 ( 2 Pt 2 ): H805 - H16 .
24. D'Souza A , Bucchi A , Johnsen AB , et al. Exercise training reduces resting heart rate via downregulation of the funny channel HCN4 . Nat Commun . 2014 ; 5 : 3775 .
25. Katona PG , McLean M , Dighton DH , Guz A . Sympathetic and parasympathetic cardiac control in athletes and nonathletes at rest . J Appl Physiol . 1982 ; 52 : 1652 - 7 .
26. Luck JC , Engel TR . Dispersion of atrial refractoriness in patients with sinus node dysfunction . Circulation . 1979 ; 60 : 404 - 12 .
27. Azevedo LF , Perlingeiro PS , Hachul DT , et al. Sport modality affects bradycardia level and its mechanisms of control in professional athletes . Int J Sports Med . 2014 ; 35 : 954 - 9 .
28. Skov MW , Bachmann TN , Rasmussen PV , et al. Association between heart rate at rest and incident atrial fibrillation (from the Copenhagen Electrocardiographic Study) . Am J Cardiol . 2016 ; 118 : 708 - 13 .
29. Talan DA , Bauernfeind RA , Ashley WW , Kanakis C , Rosen KM . Twenty-four hour continuous ECG recordings in long-distance runners . Chest . 1982 ; 82 : 19 - 24 .
30. Burstein B , Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation . J Am Coll Cardiol . 2008 ; 51 : 802 - 9 .
31. Aschar-Sobbi R , Izaddoustdar F , Korogyi AS , et al. Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFα . Nat Commun . 2015 ; 6 : 6018 .
32. Cardin S , Guasch E , Luo X , et al. Role for microRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure . Circ Arrhythm Electrophysiol . 2012 ; 5 : 1027 - 35 .
33. Hättasch R , Spethmann S , de Boer RA , et al. Galectin-3 increase in endurance athletes . Eur J Prev Cardiol . 2014 ; 21 : 1192 - 9 .
34. Roca E , Nescolarde L , Lupón J , et al. The dynamics of cardiovascular biomarkers in non-elite marathon runners . J Cardiovasc Transl Res . 2017 ; 10 : 206 - 8 .
35. Baggish AL , Hale A , Weiner RB , et al. Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training . J Physiol . 2011 ; 589 : 3983 - 94 .
36. Lindsay MM , Dunn FG . Biochemical evidence of myocardial fibrosis in veteran endurance athletes . Br J Sports Med . 2007 ; 41 : 447 - 52 .
37. Nortamo S , Ukkola O , Lepojärvi S , et al. Association of sST2 and hs-CRP levels with new-onset atrial fibrillation in coronary artery disease . Int J Cardiol . 2017 ; 248 : 173 - 8 .
38. Fashanu OE , Norby FL , Aguilar D , et al. Galectin-3 and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study . Am Heart J . 2017 ; 192 : 19 - 25 .
39. Swartz MF , Fink GW , Sarwar MF , et al. Elevated pre-operative serum peptides for collagen I and III synthesis result in post-surgical atrial fibrillation . J Am Coll Cardiol . 2012 ; 60 : 1799 - 806 .
40. McManus DD , Tanriverdi K , Lin H , et al. Plasma microRNAs are associated with atrial fibrillation and change after catheter ablation (the miRhythm study) . Heart Rhythm . 2015 ; 12 : 3 - 10 .
41. Cameli M , Lisi M , Righini FM , et al. Usefulness of atrial deformation analysis to predict left atrial fibrosis and endocardial thickness in patients undergoing mitral valve operations for severe mitral regurgitation secondary to mitral valve prolapse . Am J Cardiol . 2013 ; 111 : 595 - 601 .
42. Sanchis L , Sanz-De La Garza M , Bijnens B , et al. Gender influence on the adaptation of atrial performance to training . Eur J Sport Sci . 2017 ; 1391 : 1 - 7 .
43. Brugger N , Krause R , Carlen F , et al. Effect of lifetime endurance training on left atrial mechanical function and on the risk of atrial fibrillation . Int J Cardiol . 2014 ; 170 : 419 - 25 .
44. Scott CC , Leier CV , Kilman JW , Vasko JS , Unverferth DV . The effect of left atrial histology and dimension on P wave morphology . J Electrocardiol . 1983 ; 16 : 363 - 6 .
45. Win TT , Venkatesh BA , Volpe GJ , et al. Associations of electrocardiographic P-wave characteristics with left atrial function, and diffuse left ventricular fibrosis defined by cardiac magnetic resonance: the PRIMERI study . Heart Rhythm . 2015 ; 12 : 155 - 62 .
46. Wilhelm M , Roten L , Tanner H , Schmid J-P , Wilhelm I , Saner H . Long-term cardiac remodeling and arrhythmias in nonelite marathon runners . Am J Cardiol . 2012 ; 110 : 129 - 35 .
47. Petersson R , Berge HM , Gjerdalen GF , et al. P-wave morphology is unaffected by atrial size: a study in healthy athletes . Ann Noninvasive Electrocardiol . 2014 ; 19 : 366 - 73 .
48. Malmo V , Nes BM , Amundsen BH , et al. Aerobic interval training reduces the burden of atrial fibrillation in the short term: a randomized trial . Circulation . 2016 ; 133 : 466 - 73 .
49. Qureshi WT , Alirhayim Z , Blaha MJ , et al. Cardiorespiratory fitness and risk of incident atrial fibrillation: results from the Henry ford exercise testing (FIT) project . Circulation . 2015 ; 131 : 1827 - 34 .
50. Bapat A , Zhang Y , Post WS , et al. Relation of physical activity and incident atrial fibrillation (from the Multi-Ethnic Study of Atherosclerosis) . Am J Cardiol . 2015 ; 116 : 883 - 8 .
51. Mozaffarian D , Furberg CD , Psaty BM , Siscovick D. Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study . Circulation . 2008 ; 118 : 800 - 7 .
52. Guo Y , Lip GYH , Apostolakis S. Inflammation in atrial fibrillation . J Am Coll Cardiol . 2012 ; 60 : 2263 - 70 .
53. Kasapis C , Thompson PD . The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review . J Am Coll Cardiol . 2005 ; 45 : 1563 - 9 .
54. La Gerche A , Inder WJ , Roberts TJ , Brosnan MJ , Heidbuchel H , Prior DL . Relationship between inflammatory cytokines and indices of cardiac dysfunction following intense endurance exercise . PLoS ONE . 2015 ; 10 : 1 - 15 .
55. Bekos C , Zimmermann M , Unger L , et al. Non-professional marathon running: RAGE axis and ST2 family changes in relation to open-window effect, inflammation and renal function . Sci Rep . 2016 ; 6 : 32315 .
56. Oláh A , Németh BT , Mátyás C , et al. Cardiac effects of acute exhaustive exercise in a rat model . Int J Cardiol . 2015 ; 182 : 258 - 66 .
57. Wilhelm M , Zueger T , De Marchi S , et al. Inflammation and atrial remodeling after a mountain marathon . Scand J Med Sci Sports . 2014 ; 24 : 519 - 25 .
58. Tahhan AS , Sandesara PB , Hayek SS , et al. Association between oxidative stress and atrial fibrillation . Heart Rhythm . 2017 ; 98 : 1615 - 6 .
59. Hattori N , Hayashi T , Nakachi K , et al. Changes of ROS during a two-day ultra-marathon race . Int J Sports Med . 2009 ; 30 : 426 - 9 .
60. Grabs V , Kersten A , Haller B , et al. Rutoside and hydrolytic enzymes do not attenuate marathon-induced inflammation . Med Sci Sports Exerc . 2017 ; 49 : 387 - 95 .
61. McAnulty SR , Owens JT , McAnulty LS , et al. Ibuprofen use during extreme exercise: effects on oxidative stress and PGE2 . Med Sci Sports Exerc . 2007 ; 39 : 1075 - 9 .
62. Clauss S , Scherr J , Hanley A , et al. Impact of polyphenols on physiological stress and cardiac burden in marathon runners-results from a substudy of the BeMaGIC study . Appl Physiol Nutr Metab . 2017 ; 42 : 523 - 8 .
63. La Gerche A , Burns AT , Mooney DJ , et al. Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes . Eur Heart J . 2012 ; 33 : 998 - 1006 .
64. Eijsvogels TMH , Fernandez AB , Thompson PD . Are there deleterious cardiac effects of acute and chronic endurance exercise? Physiol Rev . 2016 ; 96 : 99 - 125 .
65. Gabrielli L , Bijnens BH , Butakoff C , et al. Atrial functional and geometrical remodeling in highly trained male athletes: for better or worse? Eur J Appl Physiol . 2014 ; 114 : 1143 - 52 .
66. Rogers PJ , Tyce GM , Bailey KR , Bove AA . Exercise-induced increases in atrial natriuretic factor are attenuated by endurance training . J Am Coll Cardiol . 1991 ; 18 : 1236 - 41 .
67. Date H , Imamura T , Onitsuka H , et al. Differential increase in natriuretic peptides in elite dynamic and static athletes . Circ J . 2003 ; 67 : 691 - 6 .
68. Reeves JT , Groves BM , Cymerman A , et al. Operation everest II: cardiac filling pressures during cycle exercise at sea level . Respir Physiol . 1990 ; 80 : 147 - 54 .
69. Gabrielli L , Bijnens BH , Brambila C , et al. Differential atrial performance at rest and exercise in athletes: potential trigger for developing atrial dysfunction? Scand J Med Sci Sports . 2016 ; 26 : 1444 - 54 .
70. Sanz-de__PARTICLESPACE_ _la Garza M , Grazioli G , Bijnens BH , et al. Acute, exercise dose-dependent impairment in atrial performance during an endurance race: 2D ultrasound speckletracking strain analysis . Jacc Cardiovasc Imaging . 2016 ; 9 : 1380 - 8 .
71. Leischik R , Spelsberg N , Niggemann H , Dworrak B , Tiroch K. Exercise-induced arterial hypertension-an independent factor for hypertrophy and a ticking clock for cardiac fatigue or atrial fibrillation in athletes? F1000Res . 2014 ; 3 : 105 .
72. Dantas PS , Sakata MM , Perez JD , et al. Unraveling the role of high-intensity resistance training on left ventricle proteome: is there a shift towards maladaptation? Life Sci . 2016 ; 152 : 156 - 64 .
73. Ejlersen H , Andersen ZJ , von Euler-Chelpin MC , Johansen PP , Schnohr P , Prescott E . Prognostic impact of physical activity prior to myocardial infarction: case fatality and subsequent risk of heart failure and death . Eur J Prev Cardiol . 2017 ; 24 ( 10 ): 1112 - 9 .
74. Dor-Haim H , Lotan C , Horowitz M , Swissa M. Intensive exercise training improves cardiac electrical stability in myocardialinfarcted rats . J Am Heart Assoc . 2017 ; 6 : e5989 .
75. Sanz-de la Garza M , Rubies C , Batlle M , et al. Severity of structural and functional right ventricular remodeling depends on training load in an experimental model of endurance exercise . Am J Physiol Heart Circ Physiol . 2017 ; 3 : H459 - H68 .
76. La Gerche A , Heidbüchel H , Burns AT , et al. Disproportionate exercise load and remodeling of the athlete's right ventricle . Med Sci Sports Exerc . 2011 ; 43 : 974 - 81 .
77. Burstein B , Libby E , Calderone A , Nattel S. Differential behaviors of atrial versus ventricular fibroblasts: a potential role for plateletderived growth factor in atrial-ventricular remodeling differences . Circulation . 2008 ; 117 : 1630 - 41 .
78. Hanna N , Cardin S , Leung T-K , Nattel S. Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacinginduced congestive heart failure . Cardiovasc Res . 2004 ; 63 : 236 - 44 .
79. Lau DH , Stiles MK , John B , Shashidhar YGD , Sanders P . Atrial fibrillation and anabolic steroid abuse . Int J Cardiol . 2007 ; 117 : e86 - e7 .
80. Akçakoyun M , Alizade E , Gündogˇ du R , et al. Long-term anabolic androgenic steroid use is associated with increased atrial electromechanical delay in male bodybuilders . Biomed Res Int . 2014 ; 2014 : 45152
81. De Vos CB , Weijs B , Crijns HJGM , et al. Atrial tissue Doppler imaging for prediction of new-onset atrial fibrillation . Heart . 2009 ; 95 : 835 - 40 .
82. Casella M , Dello Russo A , Izzo G , et al. Ventricular arrhythmias induced by long-term use of ephedrine in two competitive athletes . Heart Vessels . 2015 ; 30 : 280 - 3 .
83. Guasch E , Mont L . Exercise, sex and atrial fibrillation: arrhythmogenesis beyond Y-chromosome? Heart . 2015 ; 101 : 1607 - 9 .
84. Otway R , Vandenberg JI , Guo G , et al. Stretch-sensitive KCNQ1 mutation. A link between genetic and environmental factors in the pathogenesis of atrial fibrillation ? J Am Coll Cardiol . 2007 ; 49 : 578 - 86 .
85. Chang S-L , Chen Y-C , Chen Y-J , et al. Mechanoelectrical feedback regulates the arrhythmogenic activity of pulmonary veins . Heart . 2007 ; 93 : 82 - 8 .