REVIEW URRENT C OPINION
Atrial fibrillation and the athletic heart Calum J. Redpath a and Peter H. Backx b
Purpose of review Endurance exercise, despite a plethora of proven health benefits, is increasingly recognized as a potential cause of lone atrial fibrillation. Moderate exercise reduces all-cause mortality and protects against developing atrial fibrillation. However, more intense exercise regimes confer modest incremental health benefits, induce cardiac remodelling and negate some of the cardiovascular benefits of exercise. The implications of endurance exercise and athletic heart are becoming increasingly relevant as the popularity of endurance exercise has increased 20-fold within a generation. Recent findings An apparent dose–response relationship exists between endurance exercise and left atrial dilatation. Repeated strenuous endurance exercise overloads atria, resulting in stretch-induced ‘microtears’, inflammation and endocardial scarring. Although these findings are observational in humans, similar mechanisms have recently been confirmed in animal models suggesting causation. Summary Currently, it is not known whether a ceiling for endurance exercise exists, and, if so, what factors determine the threshold of harm. Although preliminary research is promising, much work remains if we are to understand the mechanisms underpinning atrial fibrillation in athletes. Keywords athlete’s heart, atrial fibrillation, endurance exercise, inflammation
INTRODUCTION Atrial fibrillation is the most common sustained heart rhythm disorder, affecting millions of people worldwide [1,2]. The lifetime risk of developing atrial fibrillation in persons aged at least 40 years is now 25% and rising [1,3]. The vast majority of atrial fibrillation occurs secondary to other cardiovascular conditions such as structural heart disease [4]. However, in almost 10% of cases, atrial fibrillation occurs in the absence of accepted risk factors [5]. Historically considered a benign condition, ‘lone atrial fibrillation’ has recently been associated with adverse outcomes [5]. Ironically, endurance exercise, despite a plethora of proven health benefits, is increasingly recognized as a potential cause of lone atrial fibrillation [6,8 ].
system with an immediate activation of the sympathetic system and a sustained reduction in parasympathetic activity arising from direct neuronal inputs to the cardiac centre and possibly baroreceptor system from the motor cortex. Later, further alterations in autonomic nerve activity occur in response to changes in peripheral vascular resistance associated with metabolic demands associated with increased physical activity [9]. Heart rate acceleration accounts for most of the increase in cardiac output during exercise, but increases in stroke volume also occur during exercise and persist beyond recovery. Regular exercise results in persistent increases in cardiac modelling (i.e., mild chamber dilation and hypertrophy), stroke volume
&
a
ENDURANCE EXERCISE: TRANSFORMING AN ATHLETIC HEART INTO ‘PHEIDIPPIDES CARDIOMYOPATHY’? During exercise the cardiovascular system must rapidly distribute increased inspired oxygen to satisfy both the exercising skeletal muscle and the heart itself. The potential six-fold increase in cardiac output is coordinated by the autonomic nervous
Arrhythmia Service and the Cellular Electrophysiology Laboratory, University of Ottawa Heart Institute, Ottawa and bDivision of Cardiology, Departments of Physiology and Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada Correspondence to Dr Calum J. Redpath, Cellular Electrophysiology Laboratory, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada. Tel: +1 613 761 4070; e-mail: [email protected] Curr Opin Cardiol 2015, 30:17–23 DOI:10.1097/HCO.0000000000000130
0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-cardiology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Arrhythmias
KEY POINTS The optimal dose of exercise for cardiovascular health is significantly less than that which is necessary to develop peak cardiovascular performance. Recent data describing the intensity, duration and frequency of exercise all suggest a U-shaped relationship with lone atrial fibrillation and mortality. Persistent ‘cardiac overuse injury’ creates endocardial scarring, which is a common arrhythmogenic substrate. Data from animal models suggest increased vagal tone, sinus node remodelling and atrial inflammation predispose athletes to atrial fibrillation. Although detraining is effective, catheter ablation of atrial fibrillation in athletes, as in nonathletes, has been found to be highly effective and well tolerated, facilitating a return to endurance exercise.
and vagal tone. Moderate exercise, defined as 300 min per week of activity requiring three to six metabolic equivalents, for example, 45 min of brisk walking daily, has consistently been shown to have pleiotropic health benefits [10]. Moderate exercise reduces all-cause mortality in men and women and, more specifically, protects against developing atrial fibrillation [11–14]. However, more intense exercise regimes confer modest incremental benefits [15]. It is now apparent that the optimal dose of exercise for cardiovascular health is significantly less than that which is necessary to develop peak cardiovascular performance, as required for optimal performance in many competitive sports [16,17,18 ]. Exercise is classified according to the physiologic demands placed on the body during participation [19]. Classically, two opposing extremes are posited: first, isotonic (dynamic) exercise, for example, marathon running, and, second, isometric (static) exercise, for example, weightlifting, with various disciplines such as cycling and rowing combining aspects of both [19]. Endurance exercise has variously been defined as prolonged isotonic exercise at submaximal aerobic capacity and is classically associated with sustained elevation of cardiac output with normal or reduced peripheral vascular resistance [20]. Chronic endurance exercise-induced cardiac remodelling results in morphological adaptations collectively labelled ‘athlete’s heart’ [20–22]. The athlete’s heart consists primarily of eccentric left ventricular hypertrophy and left atrial dilatation [20–22]. The grey zone, beyond which an athletic heart begins to maladapt above the upper limit of normal, remains controversial [20,23,24]. Regardless, a constant observation is the altered structure &
18
www.co-cardiology.com
and function of the left atrium in endurance-trained athletes [23–27]. The implications of endurance exercise and athletic heart are becoming increasingly relevant as the popularity of disciplines such as marathon running has increased 20-fold within a generation [28]. However, the lustre of athleticism merits a degree of caution. Epidemiological data supporting endurance exercise as life prolonging are inconsistent [29,30]. Recent data describing the intensity, duration and frequency of exercise all suggest a U-shaped relationship with mortality (Fig. 1) [18 ,31,32]. Although controversial, a similar relationship between endurance exercise and risk of atrial fibrillation is emerging (Fig. 2 and Table 1) [7,13,14,33–37,38 ,39 ]. This has prompted some investigators to consider exercise as a drug with a dose–response relationship and a benefit threshold beyond which potential overdose and addiction occur [40]. Although the physical consequences of being either sedentary or overtrained have been recognized for years, the combination of biological factors which determine an individual’s exercise ceiling and the mechanism(s) by which endurance exercise may cause harm remain largely unknown [22,41]. &
&&
&&
MECHANISMS BY WHICH ENDURANCE EXERCISE MAY PROMOTE ATRIAL FIBRILLATION It is not uncommon for endurance athletes to perform exercise at levels of intensity, duration and frequency more than 10 times those recommended for prevention of cardiovascular disease [12–14]. An apparent dose–response relationship exists between endurance exercise and left atrial dilatation which arises primarily as a consequence of elevated venous filling pressures associated with increased venous return as well as venous constriction [42]. These elevations in venous pressure presumably occur as part of the physiological response to increase stroke volume during periods of increased cardiac demand. In athletes and nonathletes alike, left atrial dilatation is associated with an increased prevalence of atrial fibrillation [37,43]. Repeated strenuous endurance exercise overloads both atria and right ventricle and can disrupt fibre architecture, resulting in stretch-induced ‘microtears’ [44–46]. This cycle of ‘acute stress and chronic adaptation’ results in detectable levels of serologic markers of cardiac damage and in the long term is associated with inflammation and patchy fibrosis [22,45–47]. This persistent ‘cardiac overuse injury’ creates endocardial scarring, which is a common arrhythmogenic substrate [22,45–47,48 ]. A precedent for exercise &&
Volume 30 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Atrial fibrillation and the athletic heart Redpath and Backx
Likelihood of mortality
All-cause mortality
Cardiovascular mortality
1.2
1.2
1.0
1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0
Model 1 Model 2 Model 3
0.0 0
175
0
175
Leisure time running (mins/week)
FIGURE 1. U-shaped relationship between leisure time running and mortality in adults. Adults aged 18–100 years (mean age 44 years, 26% women) enrolled in the Aerobics Center Longitudinal Study were classified as nonrunners (0 min/week) or divided into quintiles according to total weekly leisure time running. Total follow-up was more than 500 000 person years in nonrunners and more than 200 000 person years in runners. Model 1 was adjusted for age (years), sex and examination year. Model 2 was adjusted as per model 1 plus smoking status (never, former or current), alcohol consumption (men >14 drinks per week, women >seven drinks per week), additional physical activities other than running and presence of parental cardiovascular disease. Model 3 was adjusted as per model 2 plus BMI (kg/m2) and presence of abnormal ECG, hypertension, diabetes mellitus and hypercholesterolaemia. Reproduced from [18 ]. &
Likelihood of incident AF
being arrhythmogenic exists and has stimulated researchers to investigate the potential mechanisms whereby endurance exercise could promote atrial fibrillation (Fig. 3) [49–52].
Model 1 Model 2
1.2 1.0 0.8 0.6
The most common trigger for paroxysmal atrial fibrillation is ectopy originating in the pulmonary veins activating the left atrium [53]. However, the frequency and origin of ectopy occurring in athletes remain controversial [42,54,55]. Sinus bradycardia, common in the athletic population, has previously been associated with the genesis of atrial fibrillation [56]. The bradycardia observed in athletes has traditionally been attributed to increased parasympathetic tone, but recently it has been shown that sinus node remodelling may also occur [37,42,43,55,57 ]. This sinus node remodelling occurred, in part, due to reversible downregulation of the pacemaker current (If) [57 ]. In another laboratory study of endurance training, heart rate slowing was associated with enhanced vagal tone allied with increased cholinergic sensitivity due to downregulation of atrial regulator of G-proteinsignalling 4 proteins [58,59 ]. After 16 weeks of endurance training, mice displayed a phenotype very similar to that described in human endurance athletes; sinus slowing, enhanced vagal tone and enhanced atrial fibrillation vulnerability, all of which were reversible with detraining [59 ]. Although accepting initiation of atrial fibrillation is critical, if atrial fibrillation is to persist it must be triggered in a substrate capable of sustaining fibrillatory conduction [60]. Varying degrees of inflammation and fibrosis have been observed in atrial septal tissue from patients with lone atrial fibrillation, but no direct evidence in athletes’ atria is available yet [61]. Supporting a role for inflammation is the common observation that release of &
0.4
&
0.2 0.0 0
Low
Moderate
High
Leisure time exercise intensity
FIGURE 2. U-shaped relationship between intensity of leisure time exercise and risk of incident atrial fibrillation in older adults. Adults aged older than 65 years (mean age 73 years, 58% women) enrolled in the Cardiovascular Health Study were classified according to self-reported exercise intensity via the modified Minnesota Leisure Time Activities Questionnaire. Total follow-up was more than 47 000 person years. Model 1 was adjusted for age (years) and sex. Model 2 was adjusted as per model 1 plus race (white/nonwhite), enrolment site, education (< high school, high school, >high school), smoking status (never, former or current), pack-years of smoking, presence of cardiovascular disease, presence of chronic obstructive pulmonary disease, presence of diabetes mellitus, alcohol consumption and use of b-blocker medication. Reproduced from [13].
0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&
www.co-cardiology.com
19
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Arrhythmias Table 1. Summary of the epidemiological evidence indicating endurance exercise is associated with atrial fibrillation First author
Format
Athletes/Controls (n) 262/373
Odds ratio (confidence interval) for atrial fibrillation in athletes
Sport
Karjalainen [33]
Longitudinal
Orienteering
5.50 (1.3–24.4)
Elosua [34]
Retrospective
51/109
Various
2.87 (1.4–7.1)
Heidbuchel [35]
Retrospective
31/106
Various
1.81 (1.1–3.0)
Molina [36]
Longitudinal
252/305
Marathon running
8.80 (1.3–61.3)
Mont [37]
Prospective
107/107
Various
7.31 (2.3–22.9)
505/477
Various
0.87 (0.64–1.19)
2127/6321
Various
1.20 (1.02–1.41)
Mozaffarian [13]
Prospective
Aizer [7]
Retrospective
cardiac injury biomarkers and elevated cytokines, such as TNFa, occurs after prolonged exercise and correlates with ventricular fibrosis on noninvasive imaging [45,47,62,63]. In our own studies in rodents, we have found that TNFa is an essential component in the atrial remodelling, including fibrosis, inflammatory cell infiltration and atrial fibrillation vulnerability (manuscript submitted). Endurance training in rodents also induced structural remodelling; significant left atrial dilatation and fibrosis and left ventricular hypertrophy occurred and persisted despite a period of detraining [59 ]. In this and related studies, upregulation of atrial fibrotic markers and exercise-induced fibrosis was ameliorated by the renin–angiotensin receptor blocker losartan [58,59 ,64,65]. However, perhaps as should be expected, each of these factors individually appeared insufficient alone to maintain atrial &
&
fibrillation, suggesting that synergistic combinations are required for atrial fibrillation progression [59 ,60]. If atrial fibrillation progression occurs as a result of diverse yet synergistic processes, then individual athletes may possess specific, heterogeneic thresholds beyond which further endurance exercise becomes detrimental to health [60]. Although no genetic culprits have been identified to directly account for the role of the autonomic nervous system in atrial fibrillation pathogenesis, several interesting lines of investigation suggest a role in both trigger and substrate remodelling [66,67 ]. Circulating autoantibodies to both b-adrenoceptors and cholinergic M2 receptors, obtained from sera of atrial fibrillation patients, have been observed to induce both bradycardia and trigger ectopy-induced tachycardias in both pulmonary vein and atrial tissues [68–70]. &
&
Endurance exercise Atrial ectopy/pulmonary vein tachycardia
Substrate Trigger • Atrial dilatation •↑Vagal tone • Atrial fibrosis • SAN remodelling • Inflammation • Frequent ectopy
Athlete’s heart or Pheidippides cardiomyopathy?
Atrial fibrillation FIGURE 3. Possible synergistic mechanisms whereby endurance exercise promotes atrial fibrillation. SAN, sinoatrial node.
20
www.co-cardiology.com
Volume 30 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Atrial fibrillation and the athletic heart Redpath and Backx
Mutations in the gene SCN5A encoding the inward sodium current (INa), long recognized as culpable for the Brugada syndrome among others, are expressed in atrial ganglionic plexi, creating hyperexcitable atria prone to ectopy and atrial fibrillation [71–74]. The first genome-wide association study identified variants of the gene PITX2 on chromosome 4 as being present in 1 in 3 adults and variably associated with both atrial fibrillation and stroke [75]. Since then PITX2 variants have been correlated with left right cardiac embryogenesis, sinoatrial node development and pulmonary vein attachments [67 ,76]. Finally, perhaps atrial-specific inflammation or autocrine factors may have a role in fibrillogenesis. Mutations in the NPPA gene encoding for atrial natriuretic peptide are associated with the development of lone atrial fibrillation and theoretically link atrial inflammation, atrial stretch and atrial electrophysiology, all factors implicated in athletic atrial fibrillation [77–79]. Although such investigations are in their infancy, this ‘multihit hypothesis’ has potentially important implications for targeted upstream therapy and clinical response to antiarrhythmic drugs and stroke prevention [80–82]. &
IMPLICATIONS OF ATRIAL FIBRILLATION FOR ATHLETES Atrial fibrillation in athletes is less likely to be associated with the common risk factors for atrial fibrillation identified in the general population [4]. It is reasonable to consider atrial fibrillation in athletes as lone atrial fibrillation once endocrinopathy, cardiovascular comorbidities and other arrhythmia syndromes, such as Wolff–Parkinson–White syndrome, have been excluded [83]. Communication is central to managing an athlete with atrial fibrillation. It is likely that a cardiologist may comprise only one member of a team of attendants, with various treatment goals, involved in the circle of care [20]. Athletes tend to be highly symptomatic and are motivated to maintain endurance exercise [20,40,84]. Establishing whether atrial fibrillation is triggered during strenuous exercise, as in adrenergic atrial fibrillation, as opposed to the more common vagal atrial fibrillation is important for therapeutic planning [66]. Accepting individual variation, sympathetic atrial fibrillation may preferentially limit competition as opposed to vagal atrial fibrillation, which may predominantly limit training and subsequent performance. Consider consumption of sympathomimetics, legal or otherwise, alcohol and other supplements and/or banned substances such as steroids as possible culprits in fibrillogenesis [85,86]. A family history of arrhythmia syndromes or atrial
fibrillation may provide context or suggest cause [67 ]. If lone atrial fibrillation is asymptomatic, continuing to exercise is not considered harmful, although it should be noted that a period of detraining has been consistently demonstrated to reduce atrial fibrillation burden in athletes [87–89]. It is recommended to perform a supervised exercise stress test either to trigger a paroxysm of atrial fibrillation or to determine ventricular rate response for exercise prescription if atrial fibrillation is persistent [89]. An alternative is to review a loop recorder worn while training to correlate symptoms, establish atrial fibrillation burden and guide exercise recommendation. Exercise continuation, albeit at what is likely to represent a drastic reduction in intensity, has demonstrable benefits and is to be encouraged [10,40,90]. A rate control approach, although recommended and well tolerated in the majority of patients in the general population, is problematic in athletes because of negative effects on peak performance and because commonly used drugs to achieve rate control, such as b-adrenoceptor-blocking drugs, are considered performance enhancing in certain disciplines. If necessary, it is possible to obtain a therapeutic use exemption via national sporting bodies or refer to www.globaldro.com for further information. Although antiarrhythmic drugs make a valuable contribution to a rhythm control strategy, an alternative is to continue endurance exercise with ‘expectant’ staged management using prompt electrical cardioversion when necessary, then consider antiarrhythmic drugs in combination with atrioventricular nodal-blocking agents (see above) [83,91]. If used as a ‘pill in the pocket’, this approach can facilitate a return to continued endurance training without persistently impairing performance [83]. Thromboembolic risk is not known to be modified by endurance exercise and thus standard recommendations for oral anticoagulation prevail, notwithstanding any increased risk of bleeding due to exercise or sports participation itself [83]. Perhaps the most promising treatment modality for athletes suffering atrial fibrillation is catheter ablation [92]. Atrial fibrillation ablation in athletes has been found to be highly effective and well tolerated, with benefits comparable to those observed in nonathletic patients despite a return to endurance exercise [92–94]. Anecdotal experience is that athletes prefer to avoid pharmacological therapy, selecting an ablative strategy early, and this is endorsed by national guidelines under such circumstances [83,92].
0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-cardiology.com
21
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Arrhythmias
CONCLUSION Moderate exercise is beneficial for health and protects against atrial fibrillation. However, an increasing number of people are either overtraining by performing endurance exercise or unmasking previously latent genetic predispositions to atrial fibrillation, or both. It is not known whether a ceiling for endurance exercise exists, and, if so, what factors determine the threshold of harm. Although preliminary research is promising, much work remains if we are to understand the mechanisms underpinning atrial fibrillation in athletes. Currently, there is little data to inform evidence-based recommendations to athletes with atrial fibrillation. However, by cooperating with the athletic community, we have an exciting opportunity to further unravel the diverse pathogenesis of the most common sustained arrhythmia in humans. Acknowledgements Clipart in Fig. 3 from 123RF.com. Financial support and sponsorship No funding was received to perform this work. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014; 129:837–847. 2. Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation 2014; 129:399–410. 3. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004; 110:1042–1046. 4. Schnabel RB, Sullivan LM, Levy D, et al. Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study. Lancet 2009; 373:739–745. 5. Kozlowski D, Budrejko S, Lip GY, et al. Lone atrial fibrillation: what do we know? Heart 2010; 96:498–503. 6. Abdulla J, Nielsen JR. Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis. Europace 2009; 11:1156–1159. 7. Aizer A, Gaziano JM, Cook NR, et al. Relation of vigorous exercise to risk of atrial fibrillation. Am J Cardiol 2009; 103:1572–1577. 8. O’Keefe JH, Lavie CJ. Run for your life .... at a comfortable speed and not too & far. Heart 2013; 99:516–519. This editorial succinctly reviews the controversy surrounding the potential deleterious effects of endurance exercise. 9. Guyton AC, Hall JE. Textbook of medical physiology. 12th ed. Philadelphia: Saunders Elsevier; 2011. 10. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63 (25 Pt B):2960–2984. 11. Blair SN, Kampert JB, Kohl HW III, et al. Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women. JAMA 1996; 276:205–210.
22
www.co-cardiology.com
12. Thompson PD, Buchner D, Pina IL, et al. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation 2003; 107:3109–3116. 13. Mozaffarian D, Furberg CD, Psaty BM, Siscovick D. Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study. Circulation 2008; 118:800–807. 14. Ofman P, Khawaja O, Rahilly-Tierney CR, et al. Regular physical activity and risk of atrial fibrillation: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol 2013; 6:252–256. 15. Sattelmair J, Pertman J, Ding EL, et al. Dose response between physical activity and risk of coronary heart disease: a meta-analysis. Circulation 2011; 124:789–795. 16. Wen CP, Wai JP, Tsai MK, et al. Minimum amount of physical activity for reduced mortality and extended life expectancy: a prospective cohort study. Lancet 2011; 378:1244–1253. 17. O’Keefe JH, Schnohr P, Lavie CJ. The dose of running that best confers longevity. Heart 2013; 99:588–590. 18. Lee DC, Pate RR, Lavie CJ, et al. Leisure-time running reduces all-cause and & cardiovascular mortality risk. J Am Coll Cardiol 2014; 64:472–481. Recent data directly describing the U-shaped relationship between exercise and mortality. 19. Mitchell JH, Haskell W, Snell P, Van Camp SP. Task Force 8: classification of sports. J Am Coll Cardiol 2005; 45:1364–1367. 20. Baggish AL, Wood MJ. Athlete’s heart and cardiovascular care of the athlete: scientific and clinical update. Circulation 2011; 123:2723–2735. 21. Ellison GM, Waring CD, Vicinanza C, Torella D. Physiological cardiac remodelling in response to endurance exercise training: cellular and molecular mechanisms. Heart 2012; 98:5–10. 22. George K, Whyte GP, Green DJ, et al. The endurance athletes heart: acute stress and chronic adaptation. Br J Sports Med 2012; 46 (Suppl 1): i29–i36. 23. Nagashima J, Musha H, Takada H, Murayama M. New upper limit of physiologic cardiac hypertrophy in Japanese participants in the 100-km ultramarathon. J Am Coll Cardiol 2003; 42:1617–1623. 24. George KP, Warburton DE, Oxborough D, et al. Upper limits of physiological cardiac adaptation in ultramarathon runners. J Am Coll Cardiol 2011; 57:754–755. 25. Pluim BM, Zwinderman AH, van der Laarse A, van der Wall EE. The athlete’s heart. A meta-analysis of cardiac structure and function. Circulation 2000; 101:336–344. 26. Pelliccia A, Maron BJ, Di Paolo FM, et al. Prevalence and clinical significance of left atrial remodeling in competitive athletes. J Am Coll Cardiol 2005; 46:690–696. 27. D’Andrea A, Riegler L, Cocchia R, et al. Left atrial volume index in highly trained athletes. Am Heart J 2010; 159:1155–1161. 28. Lamppa R. 2014 Annual Marathon Report. Running USA; 2014. 29. Teramoto M, Bungum TJ. Mortality and longevity of elite athletes. J Sci Med Sport 2010; 13:410–416. 30. Ruiz JR, Moran M, Arenas J, Lucia A. Strenuous endurance exercise improves life expectancy: it’s in our genes. Br J Sports Med 2011; 45:159–161. 31. Church TS, LaMonte MJ, Barlow CE, Blair SN. Cardiorespiratory fitness and body mass index as predictors of cardiovascular disease mortality among men with diabetes. Arch Intern Med 2005; 165:2114–2120. 32. Schnohr P, Marott JL, Lange P, Jensen GB. Longevity in male and female joggers: the Copenhagen City Heart Study. Am J Epidemiol 2013; 177:683– 689. 33. Karjalainen J, Kujala UM, Kaprio J, et al. Lone atrial fibrillation in vigorously exercising middle aged men: case-control study. BMJ 1998; 316:1784– 1785. 34. Elosua R, Arquer A, Mont L, et al. Sport practice and the risk of lone atrial fibrillation: a case-control study. Int J Cardiol 2006; 108:332–337. 35. Heidbuchel H, Anne W, Willems R, et al. Endurance sports is a risk factor for atrial fibrillation after ablation for atrial flutter. Int J Cardiol 2006; 107:67–72. 36. 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; 10:618–623. 37. Mont L, Tamborero D, Elosua R, et al. Physical activity, height, and left atrial size are independent risk factors for lone atrial fibrillation in middle-aged healthy individuals. Europace 2008; 10:15–20. 38. Guasch E, Nattel S. Cross Talk proposal: prolonged intense exercise training && does lead to myocardial damage. J Physiol 2013; 591 (Pt 20):4939–4941. First of two manuscripts to debate the merits of the data describing the adverse cardiovascular effects of endurance exercise. 39. Ruiz JR, Joyner M, Lucia A. CrossTalk opposing view: prolonged intense && exercise does not lead to cardiac damage. J Physiol 2013; 591 (Pt 20): 4943–4945. Second of two manuscripts to debate the controversy surrounding the possible adverse effects of endurance exercise. 40. Vina J, Sanchis-Gomar F, Martinez-Bello V, Gomez-Cabrera MC. Exercise acts as a drug; the pharmacological benefits of exercise. Br J Pharmacol 2012; 167:1–12.
Volume 30 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Atrial fibrillation and the athletic heart Redpath and Backx 41. Crespo CJ, Keteyian SJ, Heath GW, Sempos CT. Leisure-time physical activity among US adults. Results from the Third National Health and Nutrition Examination Survey. Arch Intern Med 1996; 156:93–98. 42. Wilhelm M, Roten L, Tanner H, et al. Atrial remodeling, autonomic tone, and lifetime training hours in nonelite athletes. Am J Cardiol 2011; 108:580–585. 43. 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; 17:100–105. 44. Trivax JE, Franklin BA, Goldstein JA, et al. Acute cardiac effects of marathon running. J Appl Physiol (1985) 2010; 108:1148–1153. 45. Wilson M, O’Hanlon R, Prasad S, et al. Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes. J Appl Physiol (1985) 2011; 110:1622–1626. 46. 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. 47. Shave R, George KP, Atkinson G, et al. Exercise-induced cardiac troponin T release: a meta-analysis. Med Sci Sports Exerc 2007; 39:2099–2106. 48. Andrade J, Khairy P, Dobrev D, Nattel S. The clinical profile and pathophy&& siology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res 2014; 114:1453–1468. An excellent contemporary review of the pathophysiology of atrial fibrillation. 49. Kirchhof P, Fabritz L, Zwiener M, et al. Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice. Circulation 2006; 114:1799–1806. 50. Fabritz L, Hoogendijk MG, Scicluna BP, et al. Load-reducing therapy prevents development of arrhythmogenic right ventricular cardiomyopathy in plakoglobin-deficient mice. J Am Coll Cardiol 2011; 57:740–750. 51. James CA, Bhonsale A, Tichnell C, et al. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/ cardiomyopathy-associated desmosomal mutation carriers. J Am Coll Cardiol 2013; 62:1290–1297. 52. Syeda F, Kemper M, Vloumidi E, et al. 205 Atrial arrhythmia susceptibility in arrhythmogenic right ventricular cardiomyopathy. Heart 2014; 100 (Suppl 3):A112–A113. 53. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998; 339:659–666. 54. Bjornstad H, Storstein L, Meen HD, Hals O. Ambulatory electrocardiographic findings in top athletes, athletic students and control subjects. Cardiology 1994; 84:42–50. 55. 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; 29:71–78. 56. Grundvold I, Skretteberg PT, Liestol K, et al. Low heart rates predict incident atrial fibrillation in healthy middle-aged men. Circ Arrhythm Electrophysiol 2013; 6:726–731. 57. 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. The first manuscript to demonstrate sinus node remodelling due to exercise. 58. Cifelli C, Rose RA, Zhang H, et al. RGS4 regulates parasympathetic signaling and heart rate control in the sinoatrial node. Circ Res 2008; 103:527–535. 59. 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. The first manuscript to directly investigate the atrial effects of endurance exercise. 60. Heijman J, Voigt N, Nattel S, Dobrev D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res 2014; 114:1483–1499. 61. Frustaci A, Chimenti C, Bellocci F, et al. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997; 96:1180–1184. 62. Jee H, Jin Y. Effects of prolonged endurance exercise on vascular endothelial and inflammation markers. J Sports Sci Med 2012; 11:719–726. 63. Bernecker C, Scherr J, Schinner S, et al. Evidence for an exercise induced increase of TNF-alpha and IL-6 in marathon runners. Scand J Med Sci Sports 2013; 23:207–214. 64. Benito B, Gay-Jordi G, Serrano-Mollar A, et al. Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation 2011; 123:13–22. 65. Gay-Jordi G, Guash E, Benito B, et al. Losartan prevents heart fibrosis induced by long-term intensive exercise in an animal model. PLoS One 2013; 8:e55427. 66. Chen PS, Chen LS, Fishbein MC, et al. Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. Circ Res 2014; 114:1500– 1515. 67. Tucker NR, Ellinor PT. Emerging directions in the genetics of atrial fibrillation. & Circ Res 2014; 114:1469–1482. A recent update on the contribution of genetic studies to our understanding of atrial fibrillation mechanisms. 68. Baba A, Yoshikawa T, Fukuda Y, et al. Autoantibodies against M2-muscarinic acetylcholine receptors: new upstream targets in atrial fibrillation in patients with dilated cardiomyopathy. Eur Heart J 2004; 25:1108–1115.
69. Stavrakis S, Yu X, Patterson E, et al. Activating autoantibodies to the beta-1 adrenergic and m2 muscarinic receptors facilitate atrial fibrillation in patients with Graves’ hyperthyroidism. J Am Coll Cardiol 2009; 54:1309–1316. 70. Li H, Scherlag BJ, Kem DC, et al. Atrial tachycardia provoked in the presence of activating autoantibodies to beta2-adrenergic receptor in the rabbit. Heart Rhythm 2013; 10:436–441. 71. Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998; 392:293– 296. 72. Scornik FS, Desai M, Brugada R, et al. Functional expression of ‘cardiac-type’ Nav1.5 sodium channel in canine intracardiac ganglia. Heart Rhythm 2006; 3:842–850. 73. Li Q, Huang H, Liu G, et al. Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing. Biochem Biophys Res Commun 2009; 380:132–137. 74. Ilkhanoff L, Arking DE, Lemaitre RN, et al. A Common SCN5A Variant is Associated with PR Interval and Atrial Fibrillation among African Americans. J Cardiovasc Electrophysiol 2014. [Epub ahead of print] 75. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007; 448:353–357. 76. Wang J, Bai Y, Li N, et al. Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation. Proc Natl Acad Sci U S A 2014; 111:9181–9186. 77. Hodgson-Zingman DM, Karst ML, Zingman LV, et al. Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. N Engl J Med 2008; 359:158– 165. 78. Kong X, Wang X, Xu W, et al. Natriuretic peptide receptor a as a novel anticancer target. Cancer Res 2008; 68:249–256. 79. Perrin MJ, Gollob MH. The role of atrial natriuretic peptide in modulating cardiac electrophysiology. Heart Rhythm 2012; 9:610–615. 80. Darbar D, Roden DM. Genetic mechanisms of atrial fibrillation: impact on response to treatment. Nat Rev Cardiol 2013; 10:317–329. 81. Tada H, Shiffman D, Smith JG, et al. Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke. Stroke 2014; 45:2856–2862. 82. Woods CE, Olgin J. Atrial fibrillation therapy now and in the future: drugs, biologicals, and ablation. Circ Res 2014; 114:1532–1546. 83. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014. [Epub ahead of print] 84. McAllister DR, Motamedi AR, Hame SL, et al. Quality of life assessment in elite collegiate athletes. Am J Sports Med 2001; 29:806–810. 85. Furlanello F, Serdoz LV, Cappato R, De AL. Illicit drugs and cardiac arrhythmias in athletes. Eur J Cardiovasc Prev Rehabil 2007; 14:487–494. 86. Turagam MK, Velagapudi P, Kocheril AG. Atrial fibrillation in athletes. Am J Cardiol 2012; 109:296–302. 87. Furlanello F, Bertoldi A, Dallago M, et al. Atrial fibrillation in elite athletes. J Cardiovasc Electrophysiol 1998; 9 (Suppl 8):S63–S68. 88. Hoogsteen J, Schep G, van Hemel NM, van der Wall EE. Paroxysmal atrial fibrillation in male endurance athletes. A 9-year follow up. Europace 2004; 6:222–228. 89. Zipes DP, Ackerman MJ, Estes NA III, et al. Task Force 7: arrhythmias. J Am Coll Cardiol 2005; 45:1354–1363. 90. Reed JL, Mark AE, Reid RD, Pipe AL. The effects of chronic exercise training in individuals with permanent atrial fibrillation: a systematic review. Can J Cardiol 2013; 29:1721–1728. 91. Dobrev D, Carlsson L, Nattel S. Novel molecular targets for atrial fibrillation therapy. Nat Rev Drug Discov 2012; 11:275–291. 92. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm 2012; 9:632–696. 93. Furlanello F, Lupo P, Pittalis M, et al. Radiofrequency catheter ablation of atrial fibrillation in athletes referred for disabling symptoms preventing usual training schedule and sport competition. J Cardiovasc Electrophysiol 2008; 19:457– 462. 94. Calvo N, Mont L, Tamborero D, et al. Efficacy of circumferential pulmonary vein ablation of atrial fibrillation in endurance athletes. Europace 2010; 12:30–36.
0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-cardiology.com
23
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Atrial fibrillation and the athletic heart Calum J. Redpath a and Peter H. Backx b
Purpose of review Endurance exercise, despite a plethora of proven health benefits, is increasingly recognized as a potential cause of lone atrial fibrillation. Moderate exercise reduces all-cause mortality and protects against developing atrial fibrillation. However, more intense exercise regimes confer modest incremental health benefits, induce cardiac remodelling and negate some of the cardiovascular benefits of exercise. The implications of endurance exercise and athletic heart are becoming increasingly relevant as the popularity of endurance exercise has increased 20-fold within a generation. Recent findings An apparent dose–response relationship exists between endurance exercise and left atrial dilatation. Repeated strenuous endurance exercise overloads atria, resulting in stretch-induced ‘microtears’, inflammation and endocardial scarring. Although these findings are observational in humans, similar mechanisms have recently been confirmed in animal models suggesting causation. Summary Currently, it is not known whether a ceiling for endurance exercise exists, and, if so, what factors determine the threshold of harm. Although preliminary research is promising, much work remains if we are to understand the mechanisms underpinning atrial fibrillation in athletes. Keywords athlete’s heart, atrial fibrillation, endurance exercise, inflammation
INTRODUCTION Atrial fibrillation is the most common sustained heart rhythm disorder, affecting millions of people worldwide [1,2]. The lifetime risk of developing atrial fibrillation in persons aged at least 40 years is now 25% and rising [1,3]. The vast majority of atrial fibrillation occurs secondary to other cardiovascular conditions such as structural heart disease [4]. However, in almost 10% of cases, atrial fibrillation occurs in the absence of accepted risk factors [5]. Historically considered a benign condition, ‘lone atrial fibrillation’ has recently been associated with adverse outcomes [5]. Ironically, endurance exercise, despite a plethora of proven health benefits, is increasingly recognized as a potential cause of lone atrial fibrillation [6,8 ].
system with an immediate activation of the sympathetic system and a sustained reduction in parasympathetic activity arising from direct neuronal inputs to the cardiac centre and possibly baroreceptor system from the motor cortex. Later, further alterations in autonomic nerve activity occur in response to changes in peripheral vascular resistance associated with metabolic demands associated with increased physical activity [9]. Heart rate acceleration accounts for most of the increase in cardiac output during exercise, but increases in stroke volume also occur during exercise and persist beyond recovery. Regular exercise results in persistent increases in cardiac modelling (i.e., mild chamber dilation and hypertrophy), stroke volume
&
a
ENDURANCE EXERCISE: TRANSFORMING AN ATHLETIC HEART INTO ‘PHEIDIPPIDES CARDIOMYOPATHY’? During exercise the cardiovascular system must rapidly distribute increased inspired oxygen to satisfy both the exercising skeletal muscle and the heart itself. The potential six-fold increase in cardiac output is coordinated by the autonomic nervous
Arrhythmia Service and the Cellular Electrophysiology Laboratory, University of Ottawa Heart Institute, Ottawa and bDivision of Cardiology, Departments of Physiology and Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada Correspondence to Dr Calum J. Redpath, Cellular Electrophysiology Laboratory, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada. Tel: +1 613 761 4070; e-mail: [email protected] Curr Opin Cardiol 2015, 30:17–23 DOI:10.1097/HCO.0000000000000130
0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-cardiology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Arrhythmias
KEY POINTS The optimal dose of exercise for cardiovascular health is significantly less than that which is necessary to develop peak cardiovascular performance. Recent data describing the intensity, duration and frequency of exercise all suggest a U-shaped relationship with lone atrial fibrillation and mortality. Persistent ‘cardiac overuse injury’ creates endocardial scarring, which is a common arrhythmogenic substrate. Data from animal models suggest increased vagal tone, sinus node remodelling and atrial inflammation predispose athletes to atrial fibrillation. Although detraining is effective, catheter ablation of atrial fibrillation in athletes, as in nonathletes, has been found to be highly effective and well tolerated, facilitating a return to endurance exercise.
and vagal tone. Moderate exercise, defined as 300 min per week of activity requiring three to six metabolic equivalents, for example, 45 min of brisk walking daily, has consistently been shown to have pleiotropic health benefits [10]. Moderate exercise reduces all-cause mortality in men and women and, more specifically, protects against developing atrial fibrillation [11–14]. However, more intense exercise regimes confer modest incremental benefits [15]. It is now apparent that the optimal dose of exercise for cardiovascular health is significantly less than that which is necessary to develop peak cardiovascular performance, as required for optimal performance in many competitive sports [16,17,18 ]. Exercise is classified according to the physiologic demands placed on the body during participation [19]. Classically, two opposing extremes are posited: first, isotonic (dynamic) exercise, for example, marathon running, and, second, isometric (static) exercise, for example, weightlifting, with various disciplines such as cycling and rowing combining aspects of both [19]. Endurance exercise has variously been defined as prolonged isotonic exercise at submaximal aerobic capacity and is classically associated with sustained elevation of cardiac output with normal or reduced peripheral vascular resistance [20]. Chronic endurance exercise-induced cardiac remodelling results in morphological adaptations collectively labelled ‘athlete’s heart’ [20–22]. The athlete’s heart consists primarily of eccentric left ventricular hypertrophy and left atrial dilatation [20–22]. The grey zone, beyond which an athletic heart begins to maladapt above the upper limit of normal, remains controversial [20,23,24]. Regardless, a constant observation is the altered structure &
18
www.co-cardiology.com
and function of the left atrium in endurance-trained athletes [23–27]. The implications of endurance exercise and athletic heart are becoming increasingly relevant as the popularity of disciplines such as marathon running has increased 20-fold within a generation [28]. However, the lustre of athleticism merits a degree of caution. Epidemiological data supporting endurance exercise as life prolonging are inconsistent [29,30]. Recent data describing the intensity, duration and frequency of exercise all suggest a U-shaped relationship with mortality (Fig. 1) [18 ,31,32]. Although controversial, a similar relationship between endurance exercise and risk of atrial fibrillation is emerging (Fig. 2 and Table 1) [7,13,14,33–37,38 ,39 ]. This has prompted some investigators to consider exercise as a drug with a dose–response relationship and a benefit threshold beyond which potential overdose and addiction occur [40]. Although the physical consequences of being either sedentary or overtrained have been recognized for years, the combination of biological factors which determine an individual’s exercise ceiling and the mechanism(s) by which endurance exercise may cause harm remain largely unknown [22,41]. &
&&
&&
MECHANISMS BY WHICH ENDURANCE EXERCISE MAY PROMOTE ATRIAL FIBRILLATION It is not uncommon for endurance athletes to perform exercise at levels of intensity, duration and frequency more than 10 times those recommended for prevention of cardiovascular disease [12–14]. An apparent dose–response relationship exists between endurance exercise and left atrial dilatation which arises primarily as a consequence of elevated venous filling pressures associated with increased venous return as well as venous constriction [42]. These elevations in venous pressure presumably occur as part of the physiological response to increase stroke volume during periods of increased cardiac demand. In athletes and nonathletes alike, left atrial dilatation is associated with an increased prevalence of atrial fibrillation [37,43]. Repeated strenuous endurance exercise overloads both atria and right ventricle and can disrupt fibre architecture, resulting in stretch-induced ‘microtears’ [44–46]. This cycle of ‘acute stress and chronic adaptation’ results in detectable levels of serologic markers of cardiac damage and in the long term is associated with inflammation and patchy fibrosis [22,45–47]. This persistent ‘cardiac overuse injury’ creates endocardial scarring, which is a common arrhythmogenic substrate [22,45–47,48 ]. A precedent for exercise &&
Volume 30 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Atrial fibrillation and the athletic heart Redpath and Backx
Likelihood of mortality
All-cause mortality
Cardiovascular mortality
1.2
1.2
1.0
1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0
Model 1 Model 2 Model 3
0.0 0
175
0
175
Leisure time running (mins/week)
FIGURE 1. U-shaped relationship between leisure time running and mortality in adults. Adults aged 18–100 years (mean age 44 years, 26% women) enrolled in the Aerobics Center Longitudinal Study were classified as nonrunners (0 min/week) or divided into quintiles according to total weekly leisure time running. Total follow-up was more than 500 000 person years in nonrunners and more than 200 000 person years in runners. Model 1 was adjusted for age (years), sex and examination year. Model 2 was adjusted as per model 1 plus smoking status (never, former or current), alcohol consumption (men >14 drinks per week, women >seven drinks per week), additional physical activities other than running and presence of parental cardiovascular disease. Model 3 was adjusted as per model 2 plus BMI (kg/m2) and presence of abnormal ECG, hypertension, diabetes mellitus and hypercholesterolaemia. Reproduced from [18 ]. &
Likelihood of incident AF
being arrhythmogenic exists and has stimulated researchers to investigate the potential mechanisms whereby endurance exercise could promote atrial fibrillation (Fig. 3) [49–52].
Model 1 Model 2
1.2 1.0 0.8 0.6
The most common trigger for paroxysmal atrial fibrillation is ectopy originating in the pulmonary veins activating the left atrium [53]. However, the frequency and origin of ectopy occurring in athletes remain controversial [42,54,55]. Sinus bradycardia, common in the athletic population, has previously been associated with the genesis of atrial fibrillation [56]. The bradycardia observed in athletes has traditionally been attributed to increased parasympathetic tone, but recently it has been shown that sinus node remodelling may also occur [37,42,43,55,57 ]. This sinus node remodelling occurred, in part, due to reversible downregulation of the pacemaker current (If) [57 ]. In another laboratory study of endurance training, heart rate slowing was associated with enhanced vagal tone allied with increased cholinergic sensitivity due to downregulation of atrial regulator of G-proteinsignalling 4 proteins [58,59 ]. After 16 weeks of endurance training, mice displayed a phenotype very similar to that described in human endurance athletes; sinus slowing, enhanced vagal tone and enhanced atrial fibrillation vulnerability, all of which were reversible with detraining [59 ]. Although accepting initiation of atrial fibrillation is critical, if atrial fibrillation is to persist it must be triggered in a substrate capable of sustaining fibrillatory conduction [60]. Varying degrees of inflammation and fibrosis have been observed in atrial septal tissue from patients with lone atrial fibrillation, but no direct evidence in athletes’ atria is available yet [61]. Supporting a role for inflammation is the common observation that release of &
0.4
&
0.2 0.0 0
Low
Moderate
High
Leisure time exercise intensity
FIGURE 2. U-shaped relationship between intensity of leisure time exercise and risk of incident atrial fibrillation in older adults. Adults aged older than 65 years (mean age 73 years, 58% women) enrolled in the Cardiovascular Health Study were classified according to self-reported exercise intensity via the modified Minnesota Leisure Time Activities Questionnaire. Total follow-up was more than 47 000 person years. Model 1 was adjusted for age (years) and sex. Model 2 was adjusted as per model 1 plus race (white/nonwhite), enrolment site, education (< high school, high school, >high school), smoking status (never, former or current), pack-years of smoking, presence of cardiovascular disease, presence of chronic obstructive pulmonary disease, presence of diabetes mellitus, alcohol consumption and use of b-blocker medication. Reproduced from [13].
0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&
www.co-cardiology.com
19
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Arrhythmias Table 1. Summary of the epidemiological evidence indicating endurance exercise is associated with atrial fibrillation First author
Format
Athletes/Controls (n) 262/373
Odds ratio (confidence interval) for atrial fibrillation in athletes
Sport
Karjalainen [33]
Longitudinal
Orienteering
5.50 (1.3–24.4)
Elosua [34]
Retrospective
51/109
Various
2.87 (1.4–7.1)
Heidbuchel [35]
Retrospective
31/106
Various
1.81 (1.1–3.0)
Molina [36]
Longitudinal
252/305
Marathon running
8.80 (1.3–61.3)
Mont [37]
Prospective
107/107
Various
7.31 (2.3–22.9)
505/477
Various
0.87 (0.64–1.19)
2127/6321
Various
1.20 (1.02–1.41)
Mozaffarian [13]
Prospective
Aizer [7]
Retrospective
cardiac injury biomarkers and elevated cytokines, such as TNFa, occurs after prolonged exercise and correlates with ventricular fibrosis on noninvasive imaging [45,47,62,63]. In our own studies in rodents, we have found that TNFa is an essential component in the atrial remodelling, including fibrosis, inflammatory cell infiltration and atrial fibrillation vulnerability (manuscript submitted). Endurance training in rodents also induced structural remodelling; significant left atrial dilatation and fibrosis and left ventricular hypertrophy occurred and persisted despite a period of detraining [59 ]. In this and related studies, upregulation of atrial fibrotic markers and exercise-induced fibrosis was ameliorated by the renin–angiotensin receptor blocker losartan [58,59 ,64,65]. However, perhaps as should be expected, each of these factors individually appeared insufficient alone to maintain atrial &
&
fibrillation, suggesting that synergistic combinations are required for atrial fibrillation progression [59 ,60]. If atrial fibrillation progression occurs as a result of diverse yet synergistic processes, then individual athletes may possess specific, heterogeneic thresholds beyond which further endurance exercise becomes detrimental to health [60]. Although no genetic culprits have been identified to directly account for the role of the autonomic nervous system in atrial fibrillation pathogenesis, several interesting lines of investigation suggest a role in both trigger and substrate remodelling [66,67 ]. Circulating autoantibodies to both b-adrenoceptors and cholinergic M2 receptors, obtained from sera of atrial fibrillation patients, have been observed to induce both bradycardia and trigger ectopy-induced tachycardias in both pulmonary vein and atrial tissues [68–70]. &
&
Endurance exercise Atrial ectopy/pulmonary vein tachycardia
Substrate Trigger • Atrial dilatation •↑Vagal tone • Atrial fibrosis • SAN remodelling • Inflammation • Frequent ectopy
Athlete’s heart or Pheidippides cardiomyopathy?
Atrial fibrillation FIGURE 3. Possible synergistic mechanisms whereby endurance exercise promotes atrial fibrillation. SAN, sinoatrial node.
20
www.co-cardiology.com
Volume 30 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Atrial fibrillation and the athletic heart Redpath and Backx
Mutations in the gene SCN5A encoding the inward sodium current (INa), long recognized as culpable for the Brugada syndrome among others, are expressed in atrial ganglionic plexi, creating hyperexcitable atria prone to ectopy and atrial fibrillation [71–74]. The first genome-wide association study identified variants of the gene PITX2 on chromosome 4 as being present in 1 in 3 adults and variably associated with both atrial fibrillation and stroke [75]. Since then PITX2 variants have been correlated with left right cardiac embryogenesis, sinoatrial node development and pulmonary vein attachments [67 ,76]. Finally, perhaps atrial-specific inflammation or autocrine factors may have a role in fibrillogenesis. Mutations in the NPPA gene encoding for atrial natriuretic peptide are associated with the development of lone atrial fibrillation and theoretically link atrial inflammation, atrial stretch and atrial electrophysiology, all factors implicated in athletic atrial fibrillation [77–79]. Although such investigations are in their infancy, this ‘multihit hypothesis’ has potentially important implications for targeted upstream therapy and clinical response to antiarrhythmic drugs and stroke prevention [80–82]. &
IMPLICATIONS OF ATRIAL FIBRILLATION FOR ATHLETES Atrial fibrillation in athletes is less likely to be associated with the common risk factors for atrial fibrillation identified in the general population [4]. It is reasonable to consider atrial fibrillation in athletes as lone atrial fibrillation once endocrinopathy, cardiovascular comorbidities and other arrhythmia syndromes, such as Wolff–Parkinson–White syndrome, have been excluded [83]. Communication is central to managing an athlete with atrial fibrillation. It is likely that a cardiologist may comprise only one member of a team of attendants, with various treatment goals, involved in the circle of care [20]. Athletes tend to be highly symptomatic and are motivated to maintain endurance exercise [20,40,84]. Establishing whether atrial fibrillation is triggered during strenuous exercise, as in adrenergic atrial fibrillation, as opposed to the more common vagal atrial fibrillation is important for therapeutic planning [66]. Accepting individual variation, sympathetic atrial fibrillation may preferentially limit competition as opposed to vagal atrial fibrillation, which may predominantly limit training and subsequent performance. Consider consumption of sympathomimetics, legal or otherwise, alcohol and other supplements and/or banned substances such as steroids as possible culprits in fibrillogenesis [85,86]. A family history of arrhythmia syndromes or atrial
fibrillation may provide context or suggest cause [67 ]. If lone atrial fibrillation is asymptomatic, continuing to exercise is not considered harmful, although it should be noted that a period of detraining has been consistently demonstrated to reduce atrial fibrillation burden in athletes [87–89]. It is recommended to perform a supervised exercise stress test either to trigger a paroxysm of atrial fibrillation or to determine ventricular rate response for exercise prescription if atrial fibrillation is persistent [89]. An alternative is to review a loop recorder worn while training to correlate symptoms, establish atrial fibrillation burden and guide exercise recommendation. Exercise continuation, albeit at what is likely to represent a drastic reduction in intensity, has demonstrable benefits and is to be encouraged [10,40,90]. A rate control approach, although recommended and well tolerated in the majority of patients in the general population, is problematic in athletes because of negative effects on peak performance and because commonly used drugs to achieve rate control, such as b-adrenoceptor-blocking drugs, are considered performance enhancing in certain disciplines. If necessary, it is possible to obtain a therapeutic use exemption via national sporting bodies or refer to www.globaldro.com for further information. Although antiarrhythmic drugs make a valuable contribution to a rhythm control strategy, an alternative is to continue endurance exercise with ‘expectant’ staged management using prompt electrical cardioversion when necessary, then consider antiarrhythmic drugs in combination with atrioventricular nodal-blocking agents (see above) [83,91]. If used as a ‘pill in the pocket’, this approach can facilitate a return to continued endurance training without persistently impairing performance [83]. Thromboembolic risk is not known to be modified by endurance exercise and thus standard recommendations for oral anticoagulation prevail, notwithstanding any increased risk of bleeding due to exercise or sports participation itself [83]. Perhaps the most promising treatment modality for athletes suffering atrial fibrillation is catheter ablation [92]. Atrial fibrillation ablation in athletes has been found to be highly effective and well tolerated, with benefits comparable to those observed in nonathletic patients despite a return to endurance exercise [92–94]. Anecdotal experience is that athletes prefer to avoid pharmacological therapy, selecting an ablative strategy early, and this is endorsed by national guidelines under such circumstances [83,92].
0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-cardiology.com
21
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Arrhythmias
CONCLUSION Moderate exercise is beneficial for health and protects against atrial fibrillation. However, an increasing number of people are either overtraining by performing endurance exercise or unmasking previously latent genetic predispositions to atrial fibrillation, or both. It is not known whether a ceiling for endurance exercise exists, and, if so, what factors determine the threshold of harm. Although preliminary research is promising, much work remains if we are to understand the mechanisms underpinning atrial fibrillation in athletes. Currently, there is little data to inform evidence-based recommendations to athletes with atrial fibrillation. However, by cooperating with the athletic community, we have an exciting opportunity to further unravel the diverse pathogenesis of the most common sustained arrhythmia in humans. Acknowledgements Clipart in Fig. 3 from 123RF.com. Financial support and sponsorship No funding was received to perform this work. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014; 129:837–847. 2. Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation 2014; 129:399–410. 3. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004; 110:1042–1046. 4. Schnabel RB, Sullivan LM, Levy D, et al. Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study. Lancet 2009; 373:739–745. 5. Kozlowski D, Budrejko S, Lip GY, et al. Lone atrial fibrillation: what do we know? Heart 2010; 96:498–503. 6. Abdulla J, Nielsen JR. Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis. Europace 2009; 11:1156–1159. 7. Aizer A, Gaziano JM, Cook NR, et al. Relation of vigorous exercise to risk of atrial fibrillation. Am J Cardiol 2009; 103:1572–1577. 8. O’Keefe JH, Lavie CJ. Run for your life .... at a comfortable speed and not too & far. Heart 2013; 99:516–519. This editorial succinctly reviews the controversy surrounding the potential deleterious effects of endurance exercise. 9. Guyton AC, Hall JE. Textbook of medical physiology. 12th ed. Philadelphia: Saunders Elsevier; 2011. 10. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63 (25 Pt B):2960–2984. 11. Blair SN, Kampert JB, Kohl HW III, et al. Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women. JAMA 1996; 276:205–210.
22
www.co-cardiology.com
12. Thompson PD, Buchner D, Pina IL, et al. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation 2003; 107:3109–3116. 13. Mozaffarian D, Furberg CD, Psaty BM, Siscovick D. Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study. Circulation 2008; 118:800–807. 14. Ofman P, Khawaja O, Rahilly-Tierney CR, et al. Regular physical activity and risk of atrial fibrillation: a systematic review and meta-analysis. Circ Arrhythm Electrophysiol 2013; 6:252–256. 15. Sattelmair J, Pertman J, Ding EL, et al. Dose response between physical activity and risk of coronary heart disease: a meta-analysis. Circulation 2011; 124:789–795. 16. Wen CP, Wai JP, Tsai MK, et al. Minimum amount of physical activity for reduced mortality and extended life expectancy: a prospective cohort study. Lancet 2011; 378:1244–1253. 17. O’Keefe JH, Schnohr P, Lavie CJ. The dose of running that best confers longevity. Heart 2013; 99:588–590. 18. Lee DC, Pate RR, Lavie CJ, et al. Leisure-time running reduces all-cause and & cardiovascular mortality risk. J Am Coll Cardiol 2014; 64:472–481. Recent data directly describing the U-shaped relationship between exercise and mortality. 19. Mitchell JH, Haskell W, Snell P, Van Camp SP. Task Force 8: classification of sports. J Am Coll Cardiol 2005; 45:1364–1367. 20. Baggish AL, Wood MJ. Athlete’s heart and cardiovascular care of the athlete: scientific and clinical update. Circulation 2011; 123:2723–2735. 21. Ellison GM, Waring CD, Vicinanza C, Torella D. Physiological cardiac remodelling in response to endurance exercise training: cellular and molecular mechanisms. Heart 2012; 98:5–10. 22. George K, Whyte GP, Green DJ, et al. The endurance athletes heart: acute stress and chronic adaptation. Br J Sports Med 2012; 46 (Suppl 1): i29–i36. 23. Nagashima J, Musha H, Takada H, Murayama M. New upper limit of physiologic cardiac hypertrophy in Japanese participants in the 100-km ultramarathon. J Am Coll Cardiol 2003; 42:1617–1623. 24. George KP, Warburton DE, Oxborough D, et al. Upper limits of physiological cardiac adaptation in ultramarathon runners. J Am Coll Cardiol 2011; 57:754–755. 25. Pluim BM, Zwinderman AH, van der Laarse A, van der Wall EE. The athlete’s heart. A meta-analysis of cardiac structure and function. Circulation 2000; 101:336–344. 26. Pelliccia A, Maron BJ, Di Paolo FM, et al. Prevalence and clinical significance of left atrial remodeling in competitive athletes. J Am Coll Cardiol 2005; 46:690–696. 27. D’Andrea A, Riegler L, Cocchia R, et al. Left atrial volume index in highly trained athletes. Am Heart J 2010; 159:1155–1161. 28. Lamppa R. 2014 Annual Marathon Report. Running USA; 2014. 29. Teramoto M, Bungum TJ. Mortality and longevity of elite athletes. J Sci Med Sport 2010; 13:410–416. 30. Ruiz JR, Moran M, Arenas J, Lucia A. Strenuous endurance exercise improves life expectancy: it’s in our genes. Br J Sports Med 2011; 45:159–161. 31. Church TS, LaMonte MJ, Barlow CE, Blair SN. Cardiorespiratory fitness and body mass index as predictors of cardiovascular disease mortality among men with diabetes. Arch Intern Med 2005; 165:2114–2120. 32. Schnohr P, Marott JL, Lange P, Jensen GB. Longevity in male and female joggers: the Copenhagen City Heart Study. Am J Epidemiol 2013; 177:683– 689. 33. Karjalainen J, Kujala UM, Kaprio J, et al. Lone atrial fibrillation in vigorously exercising middle aged men: case-control study. BMJ 1998; 316:1784– 1785. 34. Elosua R, Arquer A, Mont L, et al. Sport practice and the risk of lone atrial fibrillation: a case-control study. Int J Cardiol 2006; 108:332–337. 35. Heidbuchel H, Anne W, Willems R, et al. Endurance sports is a risk factor for atrial fibrillation after ablation for atrial flutter. Int J Cardiol 2006; 107:67–72. 36. 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; 10:618–623. 37. Mont L, Tamborero D, Elosua R, et al. Physical activity, height, and left atrial size are independent risk factors for lone atrial fibrillation in middle-aged healthy individuals. Europace 2008; 10:15–20. 38. Guasch E, Nattel S. Cross Talk proposal: prolonged intense exercise training && does lead to myocardial damage. J Physiol 2013; 591 (Pt 20):4939–4941. First of two manuscripts to debate the merits of the data describing the adverse cardiovascular effects of endurance exercise. 39. Ruiz JR, Joyner M, Lucia A. CrossTalk opposing view: prolonged intense && exercise does not lead to cardiac damage. J Physiol 2013; 591 (Pt 20): 4943–4945. Second of two manuscripts to debate the controversy surrounding the possible adverse effects of endurance exercise. 40. Vina J, Sanchis-Gomar F, Martinez-Bello V, Gomez-Cabrera MC. Exercise acts as a drug; the pharmacological benefits of exercise. Br J Pharmacol 2012; 167:1–12.
Volume 30 Number 1 January 2015
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Atrial fibrillation and the athletic heart Redpath and Backx 41. Crespo CJ, Keteyian SJ, Heath GW, Sempos CT. Leisure-time physical activity among US adults. Results from the Third National Health and Nutrition Examination Survey. Arch Intern Med 1996; 156:93–98. 42. Wilhelm M, Roten L, Tanner H, et al. Atrial remodeling, autonomic tone, and lifetime training hours in nonelite athletes. Am J Cardiol 2011; 108:580–585. 43. 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; 17:100–105. 44. Trivax JE, Franklin BA, Goldstein JA, et al. Acute cardiac effects of marathon running. J Appl Physiol (1985) 2010; 108:1148–1153. 45. Wilson M, O’Hanlon R, Prasad S, et al. Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes. J Appl Physiol (1985) 2011; 110:1622–1626. 46. 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. 47. Shave R, George KP, Atkinson G, et al. Exercise-induced cardiac troponin T release: a meta-analysis. Med Sci Sports Exerc 2007; 39:2099–2106. 48. Andrade J, Khairy P, Dobrev D, Nattel S. The clinical profile and pathophy&& siology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res 2014; 114:1453–1468. An excellent contemporary review of the pathophysiology of atrial fibrillation. 49. Kirchhof P, Fabritz L, Zwiener M, et al. Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice. Circulation 2006; 114:1799–1806. 50. Fabritz L, Hoogendijk MG, Scicluna BP, et al. Load-reducing therapy prevents development of arrhythmogenic right ventricular cardiomyopathy in plakoglobin-deficient mice. J Am Coll Cardiol 2011; 57:740–750. 51. James CA, Bhonsale A, Tichnell C, et al. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/ cardiomyopathy-associated desmosomal mutation carriers. J Am Coll Cardiol 2013; 62:1290–1297. 52. Syeda F, Kemper M, Vloumidi E, et al. 205 Atrial arrhythmia susceptibility in arrhythmogenic right ventricular cardiomyopathy. Heart 2014; 100 (Suppl 3):A112–A113. 53. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998; 339:659–666. 54. Bjornstad H, Storstein L, Meen HD, Hals O. Ambulatory electrocardiographic findings in top athletes, athletic students and control subjects. Cardiology 1994; 84:42–50. 55. 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; 29:71–78. 56. Grundvold I, Skretteberg PT, Liestol K, et al. Low heart rates predict incident atrial fibrillation in healthy middle-aged men. Circ Arrhythm Electrophysiol 2013; 6:726–731. 57. 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. The first manuscript to demonstrate sinus node remodelling due to exercise. 58. Cifelli C, Rose RA, Zhang H, et al. RGS4 regulates parasympathetic signaling and heart rate control in the sinoatrial node. Circ Res 2008; 103:527–535. 59. 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. The first manuscript to directly investigate the atrial effects of endurance exercise. 60. Heijman J, Voigt N, Nattel S, Dobrev D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res 2014; 114:1483–1499. 61. Frustaci A, Chimenti C, Bellocci F, et al. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997; 96:1180–1184. 62. Jee H, Jin Y. Effects of prolonged endurance exercise on vascular endothelial and inflammation markers. J Sports Sci Med 2012; 11:719–726. 63. Bernecker C, Scherr J, Schinner S, et al. Evidence for an exercise induced increase of TNF-alpha and IL-6 in marathon runners. Scand J Med Sci Sports 2013; 23:207–214. 64. Benito B, Gay-Jordi G, Serrano-Mollar A, et al. Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation 2011; 123:13–22. 65. Gay-Jordi G, Guash E, Benito B, et al. Losartan prevents heart fibrosis induced by long-term intensive exercise in an animal model. PLoS One 2013; 8:e55427. 66. Chen PS, Chen LS, Fishbein MC, et al. Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. Circ Res 2014; 114:1500– 1515. 67. Tucker NR, Ellinor PT. Emerging directions in the genetics of atrial fibrillation. & Circ Res 2014; 114:1469–1482. A recent update on the contribution of genetic studies to our understanding of atrial fibrillation mechanisms. 68. Baba A, Yoshikawa T, Fukuda Y, et al. Autoantibodies against M2-muscarinic acetylcholine receptors: new upstream targets in atrial fibrillation in patients with dilated cardiomyopathy. Eur Heart J 2004; 25:1108–1115.
69. Stavrakis S, Yu X, Patterson E, et al. Activating autoantibodies to the beta-1 adrenergic and m2 muscarinic receptors facilitate atrial fibrillation in patients with Graves’ hyperthyroidism. J Am Coll Cardiol 2009; 54:1309–1316. 70. Li H, Scherlag BJ, Kem DC, et al. Atrial tachycardia provoked in the presence of activating autoantibodies to beta2-adrenergic receptor in the rabbit. Heart Rhythm 2013; 10:436–441. 71. Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998; 392:293– 296. 72. Scornik FS, Desai M, Brugada R, et al. Functional expression of ‘cardiac-type’ Nav1.5 sodium channel in canine intracardiac ganglia. Heart Rhythm 2006; 3:842–850. 73. Li Q, Huang H, Liu G, et al. Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing. Biochem Biophys Res Commun 2009; 380:132–137. 74. Ilkhanoff L, Arking DE, Lemaitre RN, et al. A Common SCN5A Variant is Associated with PR Interval and Atrial Fibrillation among African Americans. J Cardiovasc Electrophysiol 2014. [Epub ahead of print] 75. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007; 448:353–357. 76. Wang J, Bai Y, Li N, et al. Pitx2-microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation. Proc Natl Acad Sci U S A 2014; 111:9181–9186. 77. Hodgson-Zingman DM, Karst ML, Zingman LV, et al. Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. N Engl J Med 2008; 359:158– 165. 78. Kong X, Wang X, Xu W, et al. Natriuretic peptide receptor a as a novel anticancer target. Cancer Res 2008; 68:249–256. 79. Perrin MJ, Gollob MH. The role of atrial natriuretic peptide in modulating cardiac electrophysiology. Heart Rhythm 2012; 9:610–615. 80. Darbar D, Roden DM. Genetic mechanisms of atrial fibrillation: impact on response to treatment. Nat Rev Cardiol 2013; 10:317–329. 81. Tada H, Shiffman D, Smith JG, et al. Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke. Stroke 2014; 45:2856–2862. 82. Woods CE, Olgin J. Atrial fibrillation therapy now and in the future: drugs, biologicals, and ablation. Circ Res 2014; 114:1532–1546. 83. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014. [Epub ahead of print] 84. McAllister DR, Motamedi AR, Hame SL, et al. Quality of life assessment in elite collegiate athletes. Am J Sports Med 2001; 29:806–810. 85. Furlanello F, Serdoz LV, Cappato R, De AL. Illicit drugs and cardiac arrhythmias in athletes. Eur J Cardiovasc Prev Rehabil 2007; 14:487–494. 86. Turagam MK, Velagapudi P, Kocheril AG. Atrial fibrillation in athletes. Am J Cardiol 2012; 109:296–302. 87. Furlanello F, Bertoldi A, Dallago M, et al. Atrial fibrillation in elite athletes. J Cardiovasc Electrophysiol 1998; 9 (Suppl 8):S63–S68. 88. Hoogsteen J, Schep G, van Hemel NM, van der Wall EE. Paroxysmal atrial fibrillation in male endurance athletes. A 9-year follow up. Europace 2004; 6:222–228. 89. Zipes DP, Ackerman MJ, Estes NA III, et al. Task Force 7: arrhythmias. J Am Coll Cardiol 2005; 45:1354–1363. 90. Reed JL, Mark AE, Reid RD, Pipe AL. The effects of chronic exercise training in individuals with permanent atrial fibrillation: a systematic review. Can J Cardiol 2013; 29:1721–1728. 91. Dobrev D, Carlsson L, Nattel S. Novel molecular targets for atrial fibrillation therapy. Nat Rev Drug Discov 2012; 11:275–291. 92. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm 2012; 9:632–696. 93. Furlanello F, Lupo P, Pittalis M, et al. Radiofrequency catheter ablation of atrial fibrillation in athletes referred for disabling symptoms preventing usual training schedule and sport competition. J Cardiovasc Electrophysiol 2008; 19:457– 462. 94. Calvo N, Mont L, Tamborero D, et al. Efficacy of circumferential pulmonary vein ablation of atrial fibrillation in endurance athletes. Europace 2010; 12:30–36.
0268-4705 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-cardiology.com
23
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
