Chronic Exercise: A Contributing Factor to Atrial Fibrillation?

Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in the clinical setting (1). In the general population, the prevalence of AF increases with age, ranging from 0.5% in patients below 40 years of age to 5% in patients older than 65 (2). Less is known about the prevalence in athletes, with several epidemiologic studies reporting different findings due to variations in age, years of training, and associated co-morbidities. What is known, however, is that athletes are prone to arrhythmias, and AF is the most common arrhythmia in the athletic population (2). A number of studies have described that vigorous endurance exercise, such as marathon running (3), cross-country skiing (4), and cycling (5) increases the risk of AF in man. Nevertheless, there is only a limited number of studies to date that investigated the epidemiology of AF in athletes. Moreover, mechanisms underlying AF development in athletes are not well defined.

A number of studies have shed light on possible causes of AF in athletes such as structural remodelling, autonomic nervous system alterations, hypovolemia, and illicit drug use, as reviewed previously (2). Because of their endurance training, athletes may experience a chronic increase in atrial pressure. Elevated atrial pressure by itself can lead to atrial dilation, AERP shortening, and increased AF inducibility in the isolated Langendorff-perfused rabbit hearts (6). On the other hand, one clinical study found that - while the left atrium was enlarged in a population of athletes - the incidence of AF and other supraventricular tachyarrhythmias was not increased (7). Besides enlargement, chronic inflammation leading to atrial fibrosis has also been proposed as a cause of AF in athletes (8, 9). This concept is supported by the observation of acute elevated inflammatory markers such as C-reactive protein in response to exercise (10). A recent study in exercised rats also revealed enhanced cardiac fibrosis and an increased arrhythmia inducibility (11).

Besides structural remodeling, alteration in the activity of the autonomic nervous system may also potentially contribute to AF in athletes. One study in dogs infused with catecholamines and/or acetylcholine suggests that cholinergic or vagal stimulation is mainly responsible for spontaneous AF initiation while adrenergic stimulation modulates the initiation as well as the maintenance of AF (12). This is supported by an older study also performed in dogs, in which vagal stimulation-induced AF by shortening the atrial refractory period created the necessary reentry circuits by shortening of the atrial refractory period (13). In humans, the GIRAFA study showed that vagal AF, or AF activated by the parasympathetic nervous system is the main form of lone AF, albeit the study was not conducted in athletes (14). Swanson (9) put forward the provocative hypothesis that esophageal acid reflux caused by exercise could stimulate the vagal nerves (due to the proximity to the esophagus) leading to AF in athletes. Finally, there are two other more extrinsic mechanisms that have been suggested to either induce or contribute to AF in athletes. One, if inappropriately hydrated, athletes may suffer from dehydration or hypovolemia, both of which have been suggested to cause AF in a case series (15). However, all patients in that particular patient cohort were critically ill, which questions the validity of these findings to all athlete subgroups. Several illicit drugs or substances banned by the World Anti-Doping Agency may cause cardiac arrhythmias including AF in athletes (16). These drugs include anabolic steroids, erythropoiesis-stimulating agents, growth hormone, and stimulants (2). However, more studies are needed to elucidate the molecular pathways responsible for AF induction and maintenance in these cases.

In this issue of JACC, Guasch and colleagues (17) have gone a step further to establish and characterize a novel animal model of endurance exercise. The authors focused on exploring the mechanisms underlying AF development related to chronic endurance training. Based on prior studies (11), the authors subjected rats to daily 1-hour treadmill training for 8 or 16 weeks, which mimicked chronic endurance-exercise in athletes. Based on maximum oxygen-uptake, the authors suggest that the 16-weeks treadmill-training regimen in rats corresponds roughly to about 10 years of exercise training in humans. Next, the authors demonstrated that the rats subjected to chronic exercise were more susceptible to pacing-induced AF. Furthermore, the increase in AF susceptibility was associated with an enhanced vagal tone, atrial dilation and increased fibrosis, similar to findings in humans with long-term endurance training (18). In addition, the authors showed that the cessation of exercise reversed AF inducibility in these animals, suggesting a cause-and-effect relationship between endurance exercise and AF promotion. However, this deconditioning protocol failed to attenuate atrial dilation and fibrosis, suggesting that molecular pathways other than structural remodeling also contribute to the AF arrhythmogenesis in athletes. Consistent with this notion, the authors demonstrated that an enhanced baroreflex and sensitivity to cholinergic stimulation of I_K,ACh, a G protein-gated K⁺ channel, play central roles in this exercise model. Furthermore, molecular studies suggested that altered mRNA expression levels of several regulators of G-protein signaling (RGS) proteins may contribute to the augmentation of I_K,Ach sensitivity to vagal tone. To further support this notion, the authors utilized a mouse model that lacks the RGS4 protein, mimicking the situation in the animal model, and demonstrated that RGS4 deficiency predisposes to pacing-induced AF.

This work by Guasch and colleagues (17) is the first study to date that provides mechanistic insights into the pathogenesis underlying AF caused by chronic vigorous exercise. Their findings suggest that enhanced vagal activity plays an important role, through an augmented baro-reflex responsiveness and increased sensitivity to cholinergic stimulation at the level of the atrial cardiomyocytes. Like every excellent innovative study, the present work raises several important questions. First, optical mapping experiments are needed in both animal models and in patients to determine the exact arrhythmic mechanism in response to endurance training. Second, it remains to be established whether other modes of high-intensity endurance training such as swimming and voluntary running wheels involved similar pathogenic mechanisms associated with AF promotion. Third, other studies have suggested that endurance training could also modify intracellular Ca²⁺ handling (19, 20). A number of studies from Dr. Wisloff’s group demonstrated that exercise training enhanced Ca²⁺ cycling, through increasing the activity of Ca²⁺/calmodulin-dependent kinase II (CaMKII) (19, 20). CaMKII activity was also found to be enhanced in AF patients (21) and associated with AF promotion through phosphorylation of its downstream targets, ryanodine receptor type-2 channels (RyR2) and phospholamban (PLN) (22). We recently demonstrated that the augmented CaMKII-mediated phosphorylation of RyR2 promotes AF initiation by amplifying Ca²⁺ release from sarcoplasmic reticulum, and ultimately increasing triggered activity by activation of Na⁺/Ca²⁺ exchanger (22). Therefore, it is intriguing to explore the possible mechanism of exercise-induced Ca²⁺ remodeling associated with AF pathogenesis. Finally, while detraining might be beneficial in athletes, it remains to be determined which aspects of detraining are most beneficial in terms of reducing the risk of cardiac arrhythmias.

It appears reasonable to propose I_K,ACh blockers as a promising approach to AF prevention in athletes prone to this condition, given that selective I_K,ACh blockers are currently being developed for the treatment of AF because of their atrial-specific channel inhibition (23). Since atrial myocytes from athletes have a higher I_K,ACh sensitivity, selective I_K,ACh blockers might be less likely to reduce the already lower heart rates in athletes as compared to similar drug classes such as muscarinic acetylcholine receptor antagonists. In summary, the paper by Guasch and colleagues (17) opens up new research avenues for both clinical and basic scientists to better understand the development and potential treatment of arrhythmias in athletes.