Endurance Exercise Induced Atrial Fibrillation (AF): Pathophysiology, Treatment and Prevention

AF also progressively increased. Consequently, all health-care professional and policy makers needed to understand why and how these paradoxical effects of exercise-induced AF clearly, and how they should be approached. In this review, we demonstrated the evidence that endurance exercise significantly increases the risk of developing AF. Moreover, low physical activity and poor cardiorespiratory fitness (CRF) contributes to increased AF incidence. While regularly and moderately intense exercise may provide therapeutic benefit for patients with AF as well as a reduction of AF incidence in general population. AbsTRACT Endurance Exercise Atrial (AF): Pathophysiology, The health benefits of regular moderate-intensity exercise are indisputable. Re-cently, concerns have been raised about atrial fibrillation (AF) risk of strenuous endurance exercise. On the other hand, most modest exercise intensity is associated with a decreased risk of AF. Many investigators indicated a J-shaped or U-shaped relationship between the broad range of physical activity and AF. The mechanism underlying the increased risk of AF with endurance exercise may be different from the pathophysiology of a reduced risk of moderate exercise. It was speculated that long-term endurance exercise may promote cardiac structural changes (dilatation and fibrosis), increase vagal tone, bradycardia, and inducing AF. It can cause serious symptoms that disturb the intensity of exercise activity and hence more attention should be considered to prevent AF during endurance exercise. Moreover, the reduction of exercise intensity will be the most effective prevention strategy to decrease AF risk.


Introduction
The benefit of physical activity and exercise for the reduction of cardiovascular disease incidence, morbidity and mortality is an undoubted procedure [1,2]. Although the benefits of exercise have been scientifically proven and are well-established, recent studies have reported an increase in sudden cardiac death during or shortly after intense physical activity led researchers to question whether vigorous exercise was harmful or not [3,4].
The accumulating evidence from studies performed in the past 2 decades supports the premise that strenuous physical activity is not only able to trigger cardiac events, but can also promote the development of cardiovascular diseases in individuals with no previous cardiovascular abnormalities [5][6][7][8]. These research have focused on the identification of arrhythmias originating in the atrium or the right ventricle. Specifically, the role of exercise in the development of atrial fibrillation (AF) has been acknowledged.
The significant of the endurance exercise induced AF as public health concerns was underscored for 2 reasons. Firstly, the lifestyles of young athletes are generally seen as a role model of a healthy way of life. Secondly, most exercise-induced heart conditions are diagnosed only in individuals engaged in vigorous exercise. Considering that the number of people undertaking intense forms of exercise has been steadily increasing for the past 20 years, without a doubt, the number of individuals affected by exercise-induced AF also progressively increased. Consequently, all health-care professional and policy makers needed to understand why and how these paradoxical effects of exercise-induced AF clearly, and how they should be approached. In this review, we demonstrated the evidence that endurance exercise significantly increases the risk of developing AF. Moreover, low physical activity and poor cardiorespiratory fitness (CRF) contributes to increased AF incidence. While regularly and moderately intense exercise may provide therapeutic benefit for patients with AF as well as a reduction of AF incidence in general population.

Atrial Fibrillation (AF)
Atrial fibrillation (AF) is the most common sustained arrhythmia worldwide and can increase the risk of stroke, heart failure, dementia, and mortality. Both its incidence and prevalence increase with age, especially over 65 years. Hospitalizations as a result of AF are rising annually and AF is associated with a two fold increase in premature mortality, placing an urgent demand for strategies to reverse these trends [9][10][11] [12]. These progressions correspond to the clinical AF which is often initially paroxysmal AF, after that progressing to persistent AF and finally permanent AF (Figure 1). Haïssaguerre and colleagues demonstrated that the muscular sleeves within the Pulmonary Veins (PVs) ostia served as the source of the ectopic beats which triggered AF in many patients with paroxysmal AF [13]. in multiple subsequent studies [14][15][16].
Atrial Electrical Remodeling: Electrical remodeling of the atria may be the result of AF and/or the result of hemodynamic derangements. The most significant pro-arrhythmic consequence of atrial electrical remodeling due to AF is the shortening of the refractory period due to down regulation of the Ca2+ current, accelerated repolarization and hyperpolarization of atrial cells due to increases in outward K+ currents, and conduction abnormalities due to altered expression and localization of connexins that connect atrial myocyte. All of these conditions promote re-entry and chaotic patterns of atrial activation [17]. parasympathetic innervation [19]. In addition, neural remodeling also occurs after myocardial infarction and cardiomyopathy and the modulation of the autonomic tone usually reduced the AF burden [20].

Exercise and Risk of AF
The cardiovascular benefits of regular exercise have been well demonstrated, including a significant reduction in cardiovascular morbidity and mortality for those meeting recommended guidelines.
However, the impact of physical activity on the incidence of AF has been less clear. Furthermore, we need to define the optimal dose and duration of exercise for the prevention and treatment of AF.
Several studies have shown that AF incidence is lowest amongst the most physically active participants. In the Cardiovascular Health Study, participants in the highest quartile of physical activity had a 46% lower incidence of AF, compared to those who were relatively sedentary [3]. In large cohorts of Swedish men and women, daily walking or cycling lowered the risk of AF by 12% and 19%, respectively [22,23]. Conversely, in the Women's Health Study, physical activity did not reduce AF incidence in adjusted analysis [24]. Moreover, in the Atherosclerosis Risk in Communities study, physically active status is associated with a small reduction in risk of AF [25].
Recently, Jin and colleagues reported the results of very large cohort (501,690 individuals without preexisting AF) "A Nationwide Cohort Study in General Population" and illustrated that meeting the recommended key target range of physical activity was associated with the maximum benefit for AF risk reduction in the general population. The dose-response relationship between physical activity level and AF risk revealed a U-shaped pattern [26].
The controversial findings regarding exercise and AF may be due to many factors, including the presence of other confounding risk factors. Additionally, the determining methods for AF incidence vary widely, including regular electrocardiography (EKG) through to self-report for AF which can result in subjective bias and timevarying changes in exercise measurement.  [29]. Many further studies reinforced the findings that heavy exercise was a significant predictor of AF incidence. All of the studies showed that people who participated in heavy exercise were at a 4-fold to 15-fold increased risk of AF compared with the general, sedentary population.

Endurance Exercise and AF
Furthermore, even the most active individuals aged <50 years in the general population (jogging for 5-7 days per week) had 1.7fold increased risk of AF [30][31][32][33][34]. In 2013, Thelle and colleagues reported the results of a study that included 309,540 Norwegian men and women that the risk of drug treated lone AF increases with declining resting heart rate in both sexes and with increasing level of self-reported exercise in men [6]. One year later, in a population of 509 elderly Norwegian men with a history of long-term endurance sport practice, Myrstad et al. demonstrated a higher incidence of AF compared with 1,768 elderly men in the general population, with an added risk of AF around 6.0%. Interestingly, light and moderate leisure-time physical activity during the previous years reduced the risk of AF [5]. They summarized that the association between exercise intensity and risk of AF assumed a U-shaped pattern ( Figure 2  Individuals categorized in the quintiles with the highest fitness had 1.3-fold higher risk of AF than the quintiles that were least fit [35]. Recently, Svedberg and colleagues reported that men with higher number of races and faster finishing times had the highest incidence of AF. This case-control study included 783,102 participants (Swedish skiers = 208,654 and matched sample of nonskiers = 527,448). Another large nationwide cohort study involved 501,690 individuals without pre-existing AF from Korea (mean age, 47.6 ± 14.3 years) demonstrated that meeting the recommended key target range of exercise was associated with maximal benefit for AF risk reduction in the general population. The dose-response relationship between intensity of exercise and AF risk showed a U-shaped pattern [36]. Another large population-based cohort of men and women from Norway (n = 20,484) reported that higher estimated cardiopulmonary fitness (eCRF) was inversely related to risk of AF. Men in the upper spectrum of eCRF did not have significant reduction in AF risk, suggesting a J-shaped pattern.
Moreover, improved eCRF status over 20 years was associated with less AF compared to decreased eCRF levels [37].

Mechanisms of AF in Endurance Exercise
Although the pathophysiology of AF is complex, its initiation and maintenance are commonly due to a rapidly firing ectopic focus or through multiple circuit re-entries. However, the mechanisms that contribute to the excess of AF amongst endurance sports participants remain unclear. Studies from many investigators revealed that the mechanisms included alterations of autonomic tone, left atrial enlargement and fibrosis, electrical remodeling, and increased inflammation of the atrium (Figure 3) [38][39][40][41][42][43]. Clinical studies reported that at rest and during low-intensity physical activity, endurance athletes had dominant vagal tone compared with non-athletes. Not only increased vagal tone but also low heart rates were demonstrated to be strong contributing factors in increasing incidence of AF. Enhanced vagal activity is known to be shorten the atrial refractory period and combined with slowed atrial conduction velocity could facilitate re-entry. These modifications, often expressed as athlete's heart, are assumed to be physiological, reversible modifications to the increased demands during exercise [44].

Substrate: Atrial Remodeling
The endurance training leads to a harmonic enlargement of all four cardiac chambers as an adaptation to exercise conditioning.
Since the atrial walls are much thinner than the ventricular walls, Additionally, endurance training influences the growing heart of preadolescent athletes with an additive increase in bi-atrial size, suggesting that morphological adaptations can also occur in the early phases of the sports career. Training-induced remodeling was associated with a preserved bi-atrial function, supporting the hypothesis of a physiological remodeling [46]. D' Andrea and colleagues reported that among a large population of highly trained athletes, a mild enlargement of LA volume index was relatively common and may be regarded as a physiologic adaptation to exercise conditioning [47]. These results support the notion that autonomic neuro-modulation may emerge as an alternative non-pharmacological, non-ablative modality to treat paroxysmal AF [51]. A conversion from vagal to adrenergic predominance has been demonstrated in highly trained athletes prior to competitions. Adrenergic predominance favors automaticity and micro re-entries in structurally remodeled atrium.

Triggers: Atrial Ectopic Beats
Atrial ectopic beats or premature atrial contractions can be generated from irritable foci anywhere in the atria. In particular, those originating from pulmonary veins have been shown to be the triggers in most episodes of paroxysmal AF. Atrial ectopic beats increased with age and also as a consequence of physical activity. It was proposed that increased atrial ectopic beats could explain the increased risk of AF associated with sport practice. However, these findings were not confirmed by Baldesberger and colleagues whose results did not find an increase in incidence of atrial ectopic beats in former professional cyclists [52]. Moreover, Elliott et al. could not demonstrate the increased vagal parameters or atrial ectopic beats in 99 recreational endurance athletes [53]. Hence, the hypothesis of increased atrial ectopic beats to explain the association between sports and AF cannot be adequately confirmed with the currently available data.

Diagnosis
AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial electrical activation and consequently ineffective atrial contractions. EKG demonstrates irregular RR intervals, absence of distinct repeating P waves, and presence of the fibrillatory waves (f waves). During AF, the atria contract at a rate of 350-900 beats/min, conducting to the ventricles at a rate of 90-170 beats/min [54]. Patients with AF may present with mild or no symptoms, heart failure, myocardial infarction, stroke, or hemodynamic collapse. Symptoms such as syncope, palpitations, and dyspnea on exertion reported by patients should be rigorously evaluated. A systematic review concluded that pulse rate is 94% sensitive and 72% specific for diagnosis [55]. A detailed history and a complete physical examination are an affirmative. Onset of symptoms with relation to exercise needs to be demonstrated. A history of the use of alcohol, sports supplements and energy drinks is an important data. All patients should undergo a standard testing which includes a basic metabolic panel to assess for any underlying electrolyte abnormalities, a thyroid panel and a transthoracic echocardiography. Holter monitor may be used to determine whether symptoms correlate with paroxysmal AF.

Management
In patients who are hemodynamically unstable, immediate evaluation and treatment are needed, including emergency cardioversion. In stable AF patients, treatment depends on the duration of AF and the presence of underlying cardiac diseases or other comorbidities. AF treatment poses three main therapeutic dilemmas including control ventricular rate, convert the rhythm back to normal sinus rhythm and start anticoagulant to prevent stroke and myocardial infarction in the future [56].

Control Ventricular Rate
The essential part of AF treatment is ventricular rate control.
Reducing ventricular contraction will improve hemodynamic function and diastolic ventricular filling. It can also reduce myocardial oxygen demand and increase coronary perfusion and improve mechanical function. Ventricular rate control is the definitive treatment for AF which is considered to be permanent in nature. Most patients should be treated with either a cardiospecific beta-blocker or a rate-limiting calcium channel blocker. Beta-blockers are preferred in patients with left ventricular dysfunction and calcium channel blockers are advantageous in patients with Chronic Obstructive Pulmonary Disease (COPD) or asthma (Table 1) [57]. Amiodarone is suitable for patients with heart failure because of its powerful rate-limiting effect, but it has multiple toxicities. Lenient rate control to achieve a resting ventricular rate less than 110 bpm is reasonable in the majority of patients. Strictly ventricular rate control less than 80 bpm during rest may be appropriate if needed to resolve symptoms. However, beta-blockers and calcium channel blockers are contraindicated in patients with pre-excitation (e.g. Wolff-Parkinson-White syndrome) [58]. Moreover, in patients with acute heart failure, severe COPD and asthma, non-cardio selective beta-blockers are also contraindicated. In rare cases where ventricular rate control cannot be achieved by medication due to either drug intolerance or inefficiency, catheter-based treatment may be an alternative choice. Ablation of the atrio-ventricular junction, achieved by either radiofrequency current or deep freezing, leads to destruction of the functional connection between the atria and the ventricles [59].

Converting the Rhythm Back
Rhythm-control strategy included all therapeutic interventions aimed at prevention of AF recurrences and restoration of sinus rhythm using a combination of approaches including cardioversion, antiarrhythmic drugs and catheter ablation. Restoration of sinus rhythm may be achieved by means of either antiarrhythmic drugs or delivery of electrical shock. Electrical cardioversion terminates AF immediately in more than 90% of all patients. However, it requires sedation, which itself is not a risk-free intervention and does not prevent immediate recurrence of AF. Pharmacological cardioversion, on the other hand, does not require sedation, but its success rate ranges only about 30 -60%. Moreover, it is more timeconsuming due to the time required for an antiarrhythmic drug to reach therapeutic concentration. Since rhythm-control strategy is the approach which aimed improving the quality of life rather than reducing the mortality, the choice of drug needs to be the safest one [60]. Electro-physiologic radiofrequency ablation is a non-operative, catheter-based procedure used to isolate and destroy abnormal foci responsible for AF. Specific foci that cause AF have been found to be at or near the pulmonary vein ostia in the left atrium and used as the target for radiofrequency ablation procedure. However, AF may recur after ablation, and a repeat procedure may be required in around 20% of AF patients. This procedure is contraindicated in patients who cannot be anti-coagulated one month before and at least several months after the procedure. Atrio-ventricular nodal ablation with pacemaker implantation may be beneficial for older patients with tachycardia induced cardiomyopathy and persons with refractory ventricular rate control despite maximal medical treatment [61].

Start Anticoagulant
Prevention of thromboembolic complications of AF can be achieved by administration of medications attenuating bloodclotting capacity to individuals at high risk of ischemic stroke. The significant aspect of anticoagulation therapy is maintaining the fine balance between the benefit of reducing propensity to clotting, the potential harm of the drugs related to the prolonging of bleeding time, and the risk of bleeding complications. The CHA2DS2-VA (Congestive heart failure, Hypertension, Age > 75 years [

Prevention of AF in Vigorous Exercise
The World Health Organization (WHO) recommends that adults aged 18 -64 years should engage in at least 150 min/ week of moderate intensity exercise or 75 min/week of vigorous intensity exercise or an equivalent combination [65]. However, the dose-response association between exercise volumes and health outcomes is characterized by a U-shaped or reverse J-shaped curve [26,37,43,66,67]. So, it is of outmost importance to recognize if AF episodes are attributed to excessive exercise or not. In such cases, the initial approach is the reduction of the excessive exercise.
The explanation of this improvement of the patients from AF is a reduction of exercise volume can shift the autonomic balance from elevated vagal tone towards a higher adrenergic tone and decrease the burden of vagally mediated AF. Furlanello et al. described a good response to sport abstinence in top-level athletes with AF [68]. Hoogsteen et al. also showed that up to 30% of athletes experienced fewer episodes of AF by reducing sport activity. They also demonstrated about the extrinsic factors which will affect AF occurrence in the endurance sport activities. These included long and intense periods of training could generate substantial shifts in body fluids due to changes in volume regulation, changes in potassium and sodium levels, high body temperature, hourly loss of 1 or 2 liters of body fluids, inappropriate fluid intake, and a significant loss in magnesium which can induce AF. All of these factors could be the confounders in the relationship between endurance exercise and AF [69]. It is mean that the prevention of AF in endurance exercise need to also aware about the risks from extrinsic factors.

Conclusion
The relationship between physical activity volume and AF risks reveals to be U-shaped or J-shaped pattern. The exercise at volumes of 5 -18 MET-h/weeks may result in AF risks reduction.
In contrast, volumes of exercise exceeding 18 MET-h/weeks may increase in AF risks. Moreover, endurance exercises are associated with several cardiac maladaptation which increased AF risks. The combination of endurance exercise in the presence of known or occult cardiac abnormality is the major cause of exercise induced fatalities. AF in endurance exercise causes serious symptoms that disturb sporting activity and reduce exercise tolerance and hence more attention should be paid to prevent it. The most effective prevention strategy is the reduction of the volume and the strength of endurance exercise.

Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.