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Does exercise cause atrial fibrillation?
International Journal of Cardiology 181 (2015) 245–246
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Does exercise cause atrial fibrillation? Mohit K. Turagam ⁎, Poonam Velagapudi, Martin A. Alpert Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, USA
a r t i c l e
i n f o
Article history: Received 3 September 2014 Received in revised form 13 November 2014 Accepted 1 December 2014 Available online 3 December 2014 Keywords: Atrial fibrillation Exercise Physical activity Atrial remodeling Vagal tone
Atrial fibrillation (AF) is a common cardiac arrhythmia affecting 2.3 million individuals in the United States [1]. It is a frequent reason for hospital admissions and a major cause of morbidity and mortality with estimated annual costs of $6.6 billion dollars [2]. Several studies have suggested that physical activity decreases the risk of developing cardiovascular disease. The Center for Disease Control (CDC)/American College of Sports Medicine (ACSM) — Surgeon General's report recommended at least 30 min of moderate intensity aerobic activity 7 days a week. The effects of exercise/physical activity on the onset and progression of AF remain complex and variable depending on age, comorbidities, intensity and duration of exercise [3–5]. Several recent studies have demonstrated increased risk of AF with endurance exercise, especially in middle-aged athletes [3–5]. Other studies have also suggested that leisure time and vigorous exercise even at a non-competitive level increase AF risk in younger individuals [4,5]. In contrast the Cardiovascular Health Study, a prospective study in adults N65 years of age reported that light to moderate physical activities such as leisure-time activity and walking were associated to significantly lower risk of AF [6]. Several hypotheses have been proposed to explain the mechanism of AF with exercise. It is postulated that a complex interactions among sympathetic–parasympathetic tone, inflammation, oxidative stress, metabolic alterations and cardiac adaptations resulting in electrical and structural remodeling and fibrosis of the atrial myocardium contribute to the development of AF [7]. Endurance sports practices or ⁎ Corresponding author at: Room CE-306, University of Missouri, Health Science Center, 5, Hospital Dr, Columbia, MO 65212, USA. E-mail address: [email protected] (M.K. Turagam).
http://dx.doi.org/10.1016/j.ijcard.2014.12.024 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
long term exercise even at a non-competitive level is reported to be predominantly associated with increased parasympathetic tone which can trigger and facilitate macro-re-entry circuits in the atria by shortening the atrial refractory period promoting AF, even in structurally normal hearts [7–9]. Sympathetic activation with the release of adrenergic catecholamine during participation in intense competitive sports practices in highly trained athletes may also trigger AF by shortening the atrial action potential, refractory period and increased automaticity [7,9]. However, the duration, intensity and type of exercise that facilitates conversion from sympathetic to vagal tone, or vice-versa promoting AF are unknown. Atrial remodeling and adaptation are well known with endurance training. Guasch et al. [10] studied the effects of exercise on AF in rats. Rats were subjected to 1 h of treadmill training daily for 8 or 16 weeks followed by 4 or 8 weeks of exercise cessation. This study reported that at 16 weeks, there was increased vagal tone in exercising rats which normalized within 4 weeks of exercise cessation, possibly due to downregulation of RGS4 (regulators of G-protein signaling). The study also reported an increased atrial dilatation with fibrosis which failed to reverse after 8 weeks of exercise cessation. Arrhythmia inducibility with the development of atrial fibrosis from exercise was further supported by another study in a rat model [11]. Four week old male Wistar rats were subjected to an intensive training schedule for 4,8 or 16 weeks (10 minute run at 10 cm/s for 2 weeks followed by a 60 minute run at 60 cm/s for 5 days/week) compared to the control group. The study reported a higher incidence of eccentric hypertrophy and increased expression of fibrotic markers and messenger RNA in both atria and in the right ventricle after 16 weeks of exercise. In the exercise group there was regression of all the abnormal cardiac remodeling parameters to control levels within 8 weeks of detraining. Although, these studies provide valuable information on the effects of modifiable risk factors like exercise on the heart, it may be difficult to estimate how this translates into human physical activity and with other forms of exercise, intensity or duration even in animal models. It is also unclear if electrical remodeling or even microsomal structural remodeling may continue to persist at the molecular level even after exercise cessation which may subsequently develop a substrate for future AF. Inflammation (acute or chronic) generated by endurance training may be hypothesized to be the missing link between exercise, atrial remodeling and fibrosis; with some studies demonstrating increased inflammatory markers such as C-reactive protein, IL-6, IL-1β and TNF-α with exercise [7]. However, further studies are required to validate this hypothesis. The type of exercise involved is reported with risk of AF. Aizer et al. [4] reported that jogging was associated with an increased risk of AF, when compared to cycling, racquetball and swimming. Furthermore,
246
M.K. Turagam et al. / International Journal of Cardiology 181 (2015) 245–246
the relative risk of AF increased significantly (1.53 times) in those subjects who indulged in jogging 5–7 times/week when compared to those who jogged b 1 day/week. This association was further supported by another study [12] which reported that athletes in the high training group (N4500 lifetime training hours) when compared to low (b 1500 lifetime training hours) were associated with a higher vagal tone (47 ± 16 ms vs 34 ± 13, p = 0.002) and increased signal-averaged Pwave duration on electrocardiogram which may have contributed to AF. These results can be partly explained by fundamental differences in cardiovascular adaptation to static versus dynamic training at the cellular, metabolic and autonomic nervous system levels that can increase AF risk. There are few studies demonstrating the natural course of paroxysmal AF in endurance athletes or even in individuals engaged in leisure exercise. A small observational study of 30 male endurance athletes (mean age 48 years) with paroxysmal AF reported that AF remained stable in 50% and progressed to permanent AF in 17% of the subjects after a 9 year follow-up [13]. These results should be interpreted with caution due to the small sample size and data collection via a questionnaire. The incidence of AF in this study may be an under-representation as it is now well known that AF remains asymptomatic in a substantial number of individuals. There is enough evidence to suggest that cardiac adaptation and autonomic activation play a substantial role in increasing the risk of AF with endurance exercise. Based on the evidence so far, several important questions remain unanswered (1) what is the natural history of AF in individuals exercising at a non-competitive level; (2) what are the duration, intensity and type of exercise or physical activity that increase AF risk; and (3) how much physical activity promotes progression of AF? One possible explanation is that exercise may have a “threshold” effect beyond a certain limit may have adverse cardiovascular implications including increased risk of AF. Recent studies have suggested the presence of a reverse J-shaped phenomenon where individuals who are at either ends of the exercise spectrum (minimally-active and over-indulgent in exercise) are at an increased risk of AF and have different mechanisms [5]. Increased systemic hypertension, proinflammatory cytokines, pericardial fat deposition, cardiomyopathy, predominant sympathetic tone and sleep apnea can be attributed to AF risk in sedentary or minimally active individuals with higher body mass index while increased vagal tone, atrial dilatation, remodeling, fibrosis and inflammation are typically associated with the risk with overindulge in exercise [7,14]. Some studies have also demonstrated the role of genetics in AF. It is possible that certain genetic polymorphism may play a role in identifying individuals at risk and progression of AF with exercise. In patients in who there is a suspicion that exercise is the cause or progression of AF, exercise cessation or detraining may reduce or even overcome the arrhythmic event [7]. However, there is a need for further investigation on what aspects of exercise cessation reduces arrhythmic risk or even may prevent further progression. Physicians should be aware of the possible risk of AF with over- indulgence in exercise as
well as sedentary individuals. Physical inactivity can lead to a far greater problem with regard to cardiovascular health than over activity. Individuals with AF may be recommended to continue to be physically active but be aware about the warning signs like palpitations, lightheadedness, chest pain and shortness of breath when the exercise must be terminated. Further prospective studies are necessary to help understand the underlying mechanism of exercise, and the effects of different types of exercise on AF. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] A.S. Go, E.M. Hylek, K.A. Phillips, Y. Chang, L.E. Henault, J.V. Selby, D.E. Singer, Prevalence of diagnosed atrial fibrillation in adults national implications for rhythm management and stroke prevention: the and Risk Factors in Atrial Fibrillation (ATRIA) Study, JAMA 285 (2001) 2370–2375. [2] K.S. Coyne, C. Paramore, S. Grandy, M. Mercader, M. Reynolds, P. Zimetbaum, Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States, Value Health 9 (5) (2006) 348–356. [3] J. Abdulla, J.R. Nielsen, Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis, Europace 11 (2009) 1156–1159. [4] A. Aizer, J.M. Gaziano, N.R. Cook, J.E. Manson, J.E. Buring, C.M. Albert, Relation of vigorous exercise to risk of atrial fibrillation, Am. J. Cardiol. 103 (2009) 1572–1577. [5] N. Drca, A. Wolk, M. Jensen-Urstad, S.C. Larsson, Atrial fibrillation is associated with different levels of physical activity levels at different ages in men, Heart 100 (13) (2014) 1037–1042. [6] D. Mozaffarian, C.D. Furberg, B.M. Psaty, D. Siscovick, Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study, Circulation 118 (8) (2008) 800–807. [7] M.K. Turagam, P. Velagapudi, A.G. Kocheril, Atrial fibrillation in athletes, Am. J. Cardiol. 109 (2) (2012) 296–302. [8] L. Mont, D. Tamborero, R. Elosua, I. Molina, B. Coll-Vinent, B. Sitges, M. Vidal, A. Scalise, A. Tejeira, A. Berruez, J. Brugada, GIRAFA (Grup Integrat de Recerca en Fibril·lació Auricular) Investigators, Physical activity, height, and left size are independent risk factors for lone atrial fibrillation in middle-aged healthy individuals, Europace 10 (2008) 15–20. [9] P. Coumel, Paroxysmal atrial fibrillation: a disorder of autonomic tone? Eur. Heart J. 15 (1994) 9–16. [10] E. Guasch, B. Benito, X. Qi, C. Cifelli, P. Naud, Y. Shi, A. Mighiu, J.C. Tardif, A. Tadevosyan, Y. Chen, M.A. Gillis, Y.K. Iwasaki, D. Dobrev, L. Mont, S. Heximer, S. Nattel, Atrial fibrillation promotion by endurance exercise: demonstration and mechanistic exploration in an animal model, J. Am. Coll. Cardiol. 62 (1) (2013) 68–77. [11] B. Benito, G. Gay-Jordi, A. Serrano-Mollar, E. Guasch, Y. Shi, J.C. Tardif, J. Brugada, S. Nattel, L. Mont, Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training, Circulation 123 (1) (2011) 13–22. [12] M. Wilhelm, L. Roten, H. Tanner, I. Wilhelm, J.P. Schmid, H. Saner, Atrial remodeling, autonomic tone, and lifetime training hours in nonelite athletes, Am. J. Cardiol. 108 (2011) 580–585. [13] J. Hoogsteen, G. Schep, N.M. Van Hemel, E.E. Van Der Wall, Paroxysmal atrial fibrillation in male endurance athletes. A 9-year follow-up, Europace 6 (3) (2004) 222–228. [14] A.R. Menezes, C.J. Lavie, J.J. Dinicolantonio, J. O'Keefe, D.P. Morin, S. Khatib, F.M. AbiSamra, F.H. Messerli, R.V. Milani, Cardiometabolic risk factors and atrial fibrillation, Rev. Cardiovasc. Med. 14 (2–4) (2013) e73–e81.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Does exercise cause atrial fibrillation? Mohit K. Turagam ⁎, Poonam Velagapudi, Martin A. Alpert Division of Cardiovascular Medicine, University of Missouri School of Medicine, Columbia, MO, USA
a r t i c l e
i n f o
Article history: Received 3 September 2014 Received in revised form 13 November 2014 Accepted 1 December 2014 Available online 3 December 2014 Keywords: Atrial fibrillation Exercise Physical activity Atrial remodeling Vagal tone
Atrial fibrillation (AF) is a common cardiac arrhythmia affecting 2.3 million individuals in the United States [1]. It is a frequent reason for hospital admissions and a major cause of morbidity and mortality with estimated annual costs of $6.6 billion dollars [2]. Several studies have suggested that physical activity decreases the risk of developing cardiovascular disease. The Center for Disease Control (CDC)/American College of Sports Medicine (ACSM) — Surgeon General's report recommended at least 30 min of moderate intensity aerobic activity 7 days a week. The effects of exercise/physical activity on the onset and progression of AF remain complex and variable depending on age, comorbidities, intensity and duration of exercise [3–5]. Several recent studies have demonstrated increased risk of AF with endurance exercise, especially in middle-aged athletes [3–5]. Other studies have also suggested that leisure time and vigorous exercise even at a non-competitive level increase AF risk in younger individuals [4,5]. In contrast the Cardiovascular Health Study, a prospective study in adults N65 years of age reported that light to moderate physical activities such as leisure-time activity and walking were associated to significantly lower risk of AF [6]. Several hypotheses have been proposed to explain the mechanism of AF with exercise. It is postulated that a complex interactions among sympathetic–parasympathetic tone, inflammation, oxidative stress, metabolic alterations and cardiac adaptations resulting in electrical and structural remodeling and fibrosis of the atrial myocardium contribute to the development of AF [7]. Endurance sports practices or ⁎ Corresponding author at: Room CE-306, University of Missouri, Health Science Center, 5, Hospital Dr, Columbia, MO 65212, USA. E-mail address: [email protected] (M.K. Turagam).
http://dx.doi.org/10.1016/j.ijcard.2014.12.024 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
long term exercise even at a non-competitive level is reported to be predominantly associated with increased parasympathetic tone which can trigger and facilitate macro-re-entry circuits in the atria by shortening the atrial refractory period promoting AF, even in structurally normal hearts [7–9]. Sympathetic activation with the release of adrenergic catecholamine during participation in intense competitive sports practices in highly trained athletes may also trigger AF by shortening the atrial action potential, refractory period and increased automaticity [7,9]. However, the duration, intensity and type of exercise that facilitates conversion from sympathetic to vagal tone, or vice-versa promoting AF are unknown. Atrial remodeling and adaptation are well known with endurance training. Guasch et al. [10] studied the effects of exercise on AF in rats. Rats were subjected to 1 h of treadmill training daily for 8 or 16 weeks followed by 4 or 8 weeks of exercise cessation. This study reported that at 16 weeks, there was increased vagal tone in exercising rats which normalized within 4 weeks of exercise cessation, possibly due to downregulation of RGS4 (regulators of G-protein signaling). The study also reported an increased atrial dilatation with fibrosis which failed to reverse after 8 weeks of exercise cessation. Arrhythmia inducibility with the development of atrial fibrosis from exercise was further supported by another study in a rat model [11]. Four week old male Wistar rats were subjected to an intensive training schedule for 4,8 or 16 weeks (10 minute run at 10 cm/s for 2 weeks followed by a 60 minute run at 60 cm/s for 5 days/week) compared to the control group. The study reported a higher incidence of eccentric hypertrophy and increased expression of fibrotic markers and messenger RNA in both atria and in the right ventricle after 16 weeks of exercise. In the exercise group there was regression of all the abnormal cardiac remodeling parameters to control levels within 8 weeks of detraining. Although, these studies provide valuable information on the effects of modifiable risk factors like exercise on the heart, it may be difficult to estimate how this translates into human physical activity and with other forms of exercise, intensity or duration even in animal models. It is also unclear if electrical remodeling or even microsomal structural remodeling may continue to persist at the molecular level even after exercise cessation which may subsequently develop a substrate for future AF. Inflammation (acute or chronic) generated by endurance training may be hypothesized to be the missing link between exercise, atrial remodeling and fibrosis; with some studies demonstrating increased inflammatory markers such as C-reactive protein, IL-6, IL-1β and TNF-α with exercise [7]. However, further studies are required to validate this hypothesis. The type of exercise involved is reported with risk of AF. Aizer et al. [4] reported that jogging was associated with an increased risk of AF, when compared to cycling, racquetball and swimming. Furthermore,
246
M.K. Turagam et al. / International Journal of Cardiology 181 (2015) 245–246
the relative risk of AF increased significantly (1.53 times) in those subjects who indulged in jogging 5–7 times/week when compared to those who jogged b 1 day/week. This association was further supported by another study [12] which reported that athletes in the high training group (N4500 lifetime training hours) when compared to low (b 1500 lifetime training hours) were associated with a higher vagal tone (47 ± 16 ms vs 34 ± 13, p = 0.002) and increased signal-averaged Pwave duration on electrocardiogram which may have contributed to AF. These results can be partly explained by fundamental differences in cardiovascular adaptation to static versus dynamic training at the cellular, metabolic and autonomic nervous system levels that can increase AF risk. There are few studies demonstrating the natural course of paroxysmal AF in endurance athletes or even in individuals engaged in leisure exercise. A small observational study of 30 male endurance athletes (mean age 48 years) with paroxysmal AF reported that AF remained stable in 50% and progressed to permanent AF in 17% of the subjects after a 9 year follow-up [13]. These results should be interpreted with caution due to the small sample size and data collection via a questionnaire. The incidence of AF in this study may be an under-representation as it is now well known that AF remains asymptomatic in a substantial number of individuals. There is enough evidence to suggest that cardiac adaptation and autonomic activation play a substantial role in increasing the risk of AF with endurance exercise. Based on the evidence so far, several important questions remain unanswered (1) what is the natural history of AF in individuals exercising at a non-competitive level; (2) what are the duration, intensity and type of exercise or physical activity that increase AF risk; and (3) how much physical activity promotes progression of AF? One possible explanation is that exercise may have a “threshold” effect beyond a certain limit may have adverse cardiovascular implications including increased risk of AF. Recent studies have suggested the presence of a reverse J-shaped phenomenon where individuals who are at either ends of the exercise spectrum (minimally-active and over-indulgent in exercise) are at an increased risk of AF and have different mechanisms [5]. Increased systemic hypertension, proinflammatory cytokines, pericardial fat deposition, cardiomyopathy, predominant sympathetic tone and sleep apnea can be attributed to AF risk in sedentary or minimally active individuals with higher body mass index while increased vagal tone, atrial dilatation, remodeling, fibrosis and inflammation are typically associated with the risk with overindulge in exercise [7,14]. Some studies have also demonstrated the role of genetics in AF. It is possible that certain genetic polymorphism may play a role in identifying individuals at risk and progression of AF with exercise. In patients in who there is a suspicion that exercise is the cause or progression of AF, exercise cessation or detraining may reduce or even overcome the arrhythmic event [7]. However, there is a need for further investigation on what aspects of exercise cessation reduces arrhythmic risk or even may prevent further progression. Physicians should be aware of the possible risk of AF with over- indulgence in exercise as
well as sedentary individuals. Physical inactivity can lead to a far greater problem with regard to cardiovascular health than over activity. Individuals with AF may be recommended to continue to be physically active but be aware about the warning signs like palpitations, lightheadedness, chest pain and shortness of breath when the exercise must be terminated. Further prospective studies are necessary to help understand the underlying mechanism of exercise, and the effects of different types of exercise on AF. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] A.S. Go, E.M. Hylek, K.A. Phillips, Y. Chang, L.E. Henault, J.V. Selby, D.E. Singer, Prevalence of diagnosed atrial fibrillation in adults national implications for rhythm management and stroke prevention: the and Risk Factors in Atrial Fibrillation (ATRIA) Study, JAMA 285 (2001) 2370–2375. [2] K.S. Coyne, C. Paramore, S. Grandy, M. Mercader, M. Reynolds, P. Zimetbaum, Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States, Value Health 9 (5) (2006) 348–356. [3] J. Abdulla, J.R. Nielsen, Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis, Europace 11 (2009) 1156–1159. [4] A. Aizer, J.M. Gaziano, N.R. Cook, J.E. Manson, J.E. Buring, C.M. Albert, Relation of vigorous exercise to risk of atrial fibrillation, Am. J. Cardiol. 103 (2009) 1572–1577. [5] N. Drca, A. Wolk, M. Jensen-Urstad, S.C. Larsson, Atrial fibrillation is associated with different levels of physical activity levels at different ages in men, Heart 100 (13) (2014) 1037–1042. [6] D. Mozaffarian, C.D. Furberg, B.M. Psaty, D. Siscovick, Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study, Circulation 118 (8) (2008) 800–807. [7] M.K. Turagam, P. Velagapudi, A.G. Kocheril, Atrial fibrillation in athletes, Am. J. Cardiol. 109 (2) (2012) 296–302. [8] L. Mont, D. Tamborero, R. Elosua, I. Molina, B. Coll-Vinent, B. Sitges, M. Vidal, A. Scalise, A. Tejeira, A. Berruez, J. Brugada, GIRAFA (Grup Integrat de Recerca en Fibril·lació Auricular) Investigators, Physical activity, height, and left size are independent risk factors for lone atrial fibrillation in middle-aged healthy individuals, Europace 10 (2008) 15–20. [9] P. Coumel, Paroxysmal atrial fibrillation: a disorder of autonomic tone? Eur. Heart J. 15 (1994) 9–16. [10] E. Guasch, B. Benito, X. Qi, C. Cifelli, P. Naud, Y. Shi, A. Mighiu, J.C. Tardif, A. Tadevosyan, Y. Chen, M.A. Gillis, Y.K. Iwasaki, D. Dobrev, L. Mont, S. Heximer, S. Nattel, Atrial fibrillation promotion by endurance exercise: demonstration and mechanistic exploration in an animal model, J. Am. Coll. Cardiol. 62 (1) (2013) 68–77. [11] B. Benito, G. Gay-Jordi, A. Serrano-Mollar, E. Guasch, Y. Shi, J.C. Tardif, J. Brugada, S. Nattel, L. Mont, Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training, Circulation 123 (1) (2011) 13–22. [12] M. Wilhelm, L. Roten, H. Tanner, I. Wilhelm, J.P. Schmid, H. Saner, Atrial remodeling, autonomic tone, and lifetime training hours in nonelite athletes, Am. J. Cardiol. 108 (2011) 580–585. [13] J. Hoogsteen, G. Schep, N.M. Van Hemel, E.E. Van Der Wall, Paroxysmal atrial fibrillation in male endurance athletes. A 9-year follow-up, Europace 6 (3) (2004) 222–228. [14] A.R. Menezes, C.J. Lavie, J.J. Dinicolantonio, J. O'Keefe, D.P. Morin, S. Khatib, F.M. AbiSamra, F.H. Messerli, R.V. Milani, Cardiometabolic risk factors and atrial fibrillation, Rev. Cardiovasc. Med. 14 (2–4) (2013) e73–e81.