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The Potential Cardiotoxic Effects of Exercise
Canadian Journal of Cardiology
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(2016) 1e8
Review
The Potential Cardiotoxic Effects of Exercise Andre La Gerche, MD, PhD Baker IDI Heart and Diabetes Institute, and Department of Cardiology, Alfred Hospital, Melbourne, Australia; and the Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
ABSTRACT
RESUM E
The emerging controversy related to the potential cardiotoxic effects of high doses of intense exercise need to be considered among the much stronger evidence that supports the pleomorphic benefits of exercise as a whole. However, there is fairly compelling evidence to support the association between long-term sport practice and an increased prevalence of atrial fibrillation and the fact that this relates to a chronic altered atrial substrate. This article was designed to challenge the reader with speculative science that suggests that exercise might promote permanent structural changes in the myocardium which can, in some individuals, predispose to arrhythmias. In terms of long-term health outcomes, it would seem that these small risks are outweighed by the many other benefits of exercise, including a likely decrease in atherosclerotic vascular events, although some recent results have brought into question whether the protective benefits of exercise on vascular events also extends to high-intensity exercise training. Above all else, in this article we sought to highlight current controversies to stimulate research on the many unanswered questions. In particular, there is a lack of adequately powered prospective studies from which we can measure health outcomes and their relationship to exercise-induced cardiac remodelling.
La nouvelle controverse relative aux possibles effets cardiotoxiques de riodes doit être revue à la l’exercice intensif pendant de longues pe lumière des preuves beaucoup plus probantes appuyant les nombreux ne ral. Il existe des bienfaits offerts par l’exercice physique en ge s à preuves assez concluantes à l’effet que les sports intenses pratique valence de la fibrillation auriculaire lie e à long terme augmentent la pre une modification du substrat auriculaire et cet article a pour but de fi en lui pre sentant l’hypothèse selon laquelle mettre le lecteur au de l’exercice serait susceptible d’entraîner des modifications structurelles disposer certaines perpermanentes du myocarde qui pourraient pre s, seraient sonnes à l’arythmie. Ces risques, somme toute limite s par les bienfaits ge ne raux de toutefois amplement compense duction des accidents vasculaires l’exercice physique, notamment la re s à l’athe roscle rose, et ce, même si les re sultats de certaines e tudes lie centes semblent remettre en question les bienfaits vasculaires de re à l’exercice intensif. Dans cet article, nous avons avant tout cherche faire ressortir la controverse actuelle afin de stimuler l’amorce de ponses aux nombreuses travaux de recherche visant à fournir des re questions qui demeurent toujours en suspens. Il y a notamment une nurie d’e tudes prospectives suffisamment importantes pour pouvoir pe et son association avec le mesurer les effets de l’exercice sur la sante remodelage cardiaque induit par l’exercice.
The science that underpins the pleomorphic benefits of exercise is concrete.1 As has been championed by strategies such as the “Exercise is Medicine” campaign, the benefits of exercise outperform any pharmacological therapy across a broad range of biological systems and if it were a patented pill it would be promoted as a miracle.2 Rather, this free and readily accessible therapy, which comes in a range of palatable formulations, is all too often overlooked during formulation of health plans for individuals. Against these overwhelming benefits, an article on the potential toxicities of exercise might be perceived as a barrier in the fight against
sedentary behaviour and the emerging epidemic in lifestyleassociated morbidity.3 However, this report was aimed to address an entirely different demographic, one at the other end of the spectrum from inactivity. As opposed to the unquestionable science behind the benefits of ‘getting off the couch,’ in this article we discuss the often questionable, incomplete, and controversial science behind the emerging concern that high levels of intense exercise might be associated with some adverse health effects. All available therapies, pharmacological or otherwise, have a dose-response relationship whereby benefits diminish at high doses and the risk of adverse events increases. An open mind would consider that this might even be possible for the very best available health therapydexercise. It is important to differentiate between exercise as a trigger of arrhythmias and sudden cardiac death (SCD) as opposed to exercise as a promoter of abnormalities of cardiac structure, which might itself contribute to clinical events. It has been observed that athletes might be at greater risk of
Received for publication October 13, 2015. Accepted November 5, 2015. Corresponding author: A/Prof Andre La Gerche, Sports Cardiology, Baker IDI Heart and Diabetes Institute, Level 4 Alfred Centre, 99 Commercial Rd, Melbourne 3004, Australia. Tel.: þ1-9288-4423; fax: þ61-39288-4422. E-mail: [email protected] See page 6 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2015.11.010 0828-282X/ 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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SCD compared with nonathletes, but most if not all of this excess is due to underlying abnormalities such as familial cardiomyopthies.4,5 Thus, the mainstream view is that adverse clinical events are explained by exercise acting as a trigger in individuals who are susceptible because of an independent underlying abnormality. In this review we address a largely separate and controversial premise, namely, that exercise might effect a change in the myocardial substrate, which might serve as a cause of arrhythmias in its own right. Nonlinear Dose-Response Relationship With Exercise The benefits of exercise are most clearly established for low- and moderate-intensities. As described by Blair et al.,6 all-cause mortality decreases progressively with fitness but there appears to be an “asymptote of benefit” at an intensity that represents only approximately 50% of a well trained athlete’s capacity.7 This is reinforced by recent large studies in male and female cohorts that have reported little or no additional benefit from performing daily strenuous exercise as opposed to less frequent or less intense exercise.8,9 Thus, there is a significant gap between the exercise intensity associated with clear health benefits and that routinely practiced by competitive athletes (Fig. 1). It is also notable that the exercise ranges associated with improved cardiovascular outcomes is less than that expected to result in significant exercise-induced cardiac remodelling (‘athlete’s heart’). Therefore, we should not assume that the benefit from lower intensities can be generalized to the high-level training that induces changes in cardiac morphology.
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Even the Highest Trained Athletes Live Longer There is compelling evidence that details better health outcomes and greater longevity among elite athletes compared with the general population. Landmark cohort studies from Finland reported fewer cardiovascular and cancer deaths in former elite athletes who had competed at an international level between the years 1920 and 1965 compared with referents selected from military enrollment records.11 However, the extent to which these improved outcomes can be attributed to exercise is difficult to ascertain because there were also important differences in smoking, alcohol consumption, obesity, and socioeconomic class. What reinforces the effect of these confounders is the fact that reductions in death were greatest in obstructive airway disease, a condition that is far more likely explained by differences in cigarette exposure than exercise.12 Similar findings were recently documented in Tour De France cyclists13 in whom the ‘healthy cohort effect’ was associated with being sufficiently healthy to ride a bike at the highest level of exertion, which translated into improved short-term mortality in which the relative reduction in deaths was greatest in diseases of the digestive and respiratory systems. Thus, we might confidently conclude that the pleomorphic benefits of an athletic lifestyle results in improved health outcomes, but that the risk reduction might not be directly attributable to exercise alone.
Improved Mortality in Athletes, but What About Morbidity? Is Endurance Exercise Associated With Arrhythmias? There is increasingly convincing evidence that longstanding endurance training might promote some cardiac
Figure 1. The benefits of moderate exercise and the issue of extrapolation. Epidemiological data, modified from Blair et al. with permission Copyright ª 1989 American Medical Association. All rights reserved.,6 shows reductions in mortality associated with increased fitness. The benefit appears to plateau at approximately 10 metabolic equivalents, which is approximately 50% of the fitness of an elite cyclist. Shown in the figure is a 23-year-old nonathlete (left) compared with a 23-year-old elite cyclist with a maximal oxygen consumption (VO2max) of 78 mL/min/kg (approximately 22 metabolic equivalents). Note that the echocardiographic images of the heart are presented to scale (15-cm marker in yellow circle). Thus, the increase in cardiac size in the cyclist is considerable and the clinical consequences of such profound remodelling remain uncertain (as signified by the dotted extrapolation of the efficacy curve). Reproduced from La Gerche et al.10 with permission from BMJ Publishing Group Ltd.
La Gerche Andre Potential Cardiotoxic Effects of Exercise
arrhythmias. The range and risk of arrhythmias are discussed in an accompanying review in this issue of the Canadian Journal of Cardiology14 and is also summarized in Figure 2. Almost all studies have observed an association between atrial fibrillation (AF) in middle-aged men and previous endurance sport participation.18,20-26 This has not been observed in female athletes and the difference between sexes is not simply explained by the lesser proportional representation of women in endurance sport cohorts. In a systematic review that combined data from 6 contemporary studies, Abdulla and Nielsen calculated that athletes were 5.3 times more likely to develop AF than were matched nonathletic control subjects.15 Large population studies have shown an association between flecainide prescription and intense exercise training. Capitalizing on the reasonable assumption that lone AF is the primary indication for flecainide prescription the authors indirectly concluded an increased prevalence of AF among those who performed the most exercise.27 There are far fewer data that link athletic training with other cardiac arrhythmias. However, there are some intriguing mechanistic similarities between exercise-induced arrhythmogenic substrates in animal models and observations in humans. Ventricular ectopic beats are common among athletes but are benign and potentially reversible in the absence of structural heart disease.17,28 Some observations have suggested that more sustained ventricular arrhythmias might be more common among endurance athletes although it is important to remember that this represents a minority of the rare cases of SCD in athletes. A high incidence of life-threatening arrhythmias was observed by Heidbuchel et al. among athletes
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who presented with ventricular tachycardia and complex ventricular ectopy.19 These data suggest that endurance exercise is, at least in some predisposed individuals, associated with an increased propensity to arrhythmias but determination of the athletes who might be at risk of SCD can be extremely challenging and very specialized investigations might be required.19,29-31 It remains unclear as to whether the proarrhythmic remodelling in athletes is confined to an excess in AF or whether this is the loudest epidemiological signal owing to the fact that AF is the most prevalent arrhythmia. As is discussed in the following section, the structural remodelling associated with long-term endurance exercise training is not confined to the atria. An open mind to the issue would recognize that the rarity of life-threatening ventricular arrhythmias in the general population would mean that an extremely large population of athletes would need to be studied to identify an excess risk. What Predisposes Athletes to Arrhythmias? Potential Mechanisms If we accept the fairly consistent evidence that reports an increase in AF among athletes then we are left to consider the potential mechanisms. The concept of lone AF (AF in the absence of associated cardiopulmonary or other comorbid disease) is considered a historical concept by many investigators who note that there is an expanding list of pathological associations with AF such as obesity, sleep apnea, and subclinical cardiomyopathies, which are each associated with subtle abnormalities in inflammation, fibrosis, and myocyte
Figure 2. Increased incidence of arrhythmias in the athlete’s heart. There is a well demonstrated association between atrial fibrillation and/or flutter and endurance exercise training.15,16 There is also an increase in premature ventricular beats,17 although this tends to be benign in most athletes. Although there is some speculation that extreme exercise might cause serious arrhythmias in some cases,18-20 these events remain very uncommon. PPM, permanent pacemaker; RV, right ventricular.
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function in the atrium.32 It would seem that similar subclinical changes in atrial tissue might precede the onset of AF in athletes. Wilhelm et al. showed that there was an association between lifetime years of endurance exercise and left atrial volume. Furthermore, there was a progressively longer P wave duration, greater vagal activity, and more frequent atrial ectopics.33 This suggests an increase in the substrate, modulating factors, and triggers that together provide the ingredients necessary to increase AF risk. Luthi et al. observed that atrial size remained significantly increased in former professional cyclists despite having retired many years previously,34 and thereby provided some rationale by which to question the mainstream view that exercise-induced cardiac remodelling is a reversible physiological phenomenon. These hints suggest that adverse atrial remodelling in athletes are hard to validate. Atrial biopsies are seldom performed and noninvasive imaging techniques are insufficiently sensitive to detect abnormalities in atrial microstructure. However, murine studies support the concept of exerciseinduced proarrhythmogenic atrial remodelling. Guasch et al. compared rats that underwent an intensive 16-week exercise program (so-called “marathon rats”) with sedentary control rats and found that the former developed atrial dilation and fibrosis associated with a greater propensity to AF induction.35 In a similar manner, Aschar-Sobbi et al. showed that intense exercise increased susceptibility to AF, which was again associated with an increase in interstitial fibrosis. Intriguingly, they identified the proinflammatory cytokine (tumour necrosis factor [TNF]a) as a key modulator of fibrosis and that treatment with a specific TNFa inhibitor abolished AF risk.36 There was again some agreement between preclinical and human data with a recent report that suggested that proinflammatory cytokines such as TNFa, interleukin-12 and interleukin-1RA might be involved in exercise-induced myocardial injury in humans.37 The orthodox view regarding the effect of exercise on cardiac remodelling is that of a purely physiological process in which the hemodynamic load induces an increase in myocytes size and that this process occurs in reverse when the hemodynamic stimulus is removed.38 This theory would imply that cardiac size would return to normal in athletes who detrain. However, Pelliccia et al. prospectively followed 40 elite male athletes and found that although cardiac dimensions did decrease after decades of detraining, substantial cavity dilation persisted in one-fifth of the cohort and that the average cardiac dimensions remained well above what would be expected for the average population.39 This needs to be interpreted with caution because we do not know the athletes’ cardiac dimensions before exercise training and it is possible that people with larger hearts are more likely to excel in athletics as suggested by the reasonably strong association between heart size and maximal oxygen consumption at peak exercise (VO2max).40 In other words, heart size might be a cause, rather than a consequence of elite sports performance. However, it is perhaps more likely that this represents an extent of permanent structural change induced through many years of athletic training and the limited available prospective data support this premise.41 Then there is the question of how much remodelling can be considered appropriate and whether there is a point at which the increase in remodelling becomes maladaptive. This concept is akin to regurgitant valvular heart
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disease in which remodelling initially compensates for the greater volume load but a point is then reached whereby further increases in cardiac size reflect a reduction in contractile reserve. One of the clear limitations in using the analogy of valvular heart disease is the difference between a chronic hemodynamic load and the intermittent nature of exercise-induced remodelling. However, it is reasonable to at least question whether there is an upper limit for physiological changes in cardiac structure in response to intense endurance exercise. This is particularly pertinent for athletes who present with fatigue or altered performance for whom it can be extremely challenging to determine whether these symptoms relate to changes in cardiac structure and function. Perhaps the concept of “overtraining” can indeed be extended to the heart. Chronic Cardiac Remodelling as a Consequence of Repeated Bouts of Injury Transient increases in high-sensitivity troponin and B-type natriuretic peptide have been observed in almost all recent studies of athletes who perform intense endurance exercise.42 These biomarkers are relatively specific markers of myocyte damage and hemodynamic stretch, respectively, but their identification does not necessarily equate to permanent myocardial damage. Many of the body’s adaptive mechanisms are a result of transient tissue damage, which is subsequently repaired in a manner that renders that tissue more capable of tolerating subsequent stressors. This “supercompensation” causes skeletal muscle hypertrophy and functional improvements in response to load-bearing exercises and this same concept might well explain the changes in cardiac structure and function that enable athletes to tolerate the high hemodynamic stressors of intense exercise. However, it is also possible that after a more profound or more frequent exercise stimulus, the recovery processes might be insufficient to compensate for the extent of injury and thereby result in permanent alterations in cardiac structure and function. The effect of exercise stress on the heart might not equally affect the 2 ventricles. Most studies that assessed left ventricular (LV) function in the postrace setting observed little or no change in LV function,43 whereas a number of recent studies have reported far more substantive decrements in right ventricular (RV) function.44-49 Also, 2 recent studies documented moderately strong correlations between measures of RV dysfunction and levels of troponin and B-type natriuretic peptide,45,47 whereas a similar association between biomarkers and postrace changes in LV function were not observed.42 Exercise-Induced or Gene-Elusive Arrhythmogenic RV Cardiomyopathy Two questions arise from the observation of disproportionate RV injury after an acute bout of intense exercise: (1) why the right ventricle?; and (2) are there any long-term consequences? The potential mechanisms that might explain the susceptibility of the right ventricle to exercise-induced strain and injury have been reviewed extensively elsewhere.50 In brief, studies that have compared LV and RV hemodynamics during exercise have measured greater proportional increases in work and wall stress on the thin-walled
La Gerche Andre Potential Cardiotoxic Effects of Exercise
right ventricle.51,52 This is largely because pulmonary artery pressures increase proportionally according to the level of exercise performed, and thereby represents a substantial increase in RV work, which might constrain exercise performance if maintained for prolonged periods. The long-term consequence of disproportionate hemodynamic stress and greater RV injury is chronic structural RV remodelling. The relationship between physical activity levels and disproportionate increases in RV volumes has been shown in athletes51 and also in the general population.53 Of concern is that in some predisposed individuals this RV remodelling might represent an arrhythmogenic substrate. Heidbuchel et al. coined the term “exercise-induced arrhythmogenic RV cardiomyopathy” to describe the observation that ventricular arrhythmias in endurance athletes most frequently originate from the right ventricle and are often associated with mild abnormalities in RV structure and function, whereas the left ventricle is rarely involved.19 In a cohort of 47 athletes with exercise-induced RV remodelling, there was a high incidence of serious arrhythmias in 5 years of follow-up, which suggests that the syndrome is potentially as malignant as familial arrhythmogenic RV cardiomyopathy. However, the exerciseinduced syndrome seemed different in that there was little or no evidence of familial disease. Even after intensive familial screening and genotyping, the yield of familial cases was far fewer than expected.54 As was subsequently validated by the John Hopkins group of Calkins, the phenotype of arrhythmogenic right ventricular cardiomyopathy (ARVC) could be caused by a desmosomal gene mutation combined with modest exercise but could also be seen in athletes without a mutation but with a history of extensive exercise training. Reflecting the possibility of another milder genetic predisposition, the Calkins group referred to this exercise-induced phenotype as “gene-elusive ARVC.”55 Similar to the agreement between human and murine data that described the relationship between exercise and AF, the “marathon rat” studies from the Barcelona and Montreal groups of Mont and Nattel show striking resemblance to the human experience regarding ventricular arrhythmias.56 Compared with sedentary rats, intensely trained rats developed a propensity for ventricular arrhythmias (inducible in 6% vs 42%; P ¼ 0.05) and this was associated with an increase in RV inflammation and fibrosis. Just as in humans, LV structural and histological changes were absent. Histological confirmation of the hypothesis that exercise can cause low-grade fibrosis in human athletes is understandably elusive. A noninvasive marker would provide a more practical means to determine whether fibrosis is indeed more common in athletes. Delayed gadolinium enhancement (DGE) refers to a technique in which magnetic resonance imaging is performed after administration of gadolinium contrast, which leaks into inflamed or scarred tissue. DGE tends to be absent in young athletic cohorts with fairly modest volumes of lifetime training.48,49,57 In contrast, DGE has been observed in 12%50% of extensively trained veteran athletes and tended to be more common in athletes who had greater cardiac volumes.45,58-60 In each of these studies the patches of DGE were very small, localized to the interventricular septum at the points of right ventricle insertion and were not directly associated with arrhythmias or clinical events. In contrast, in a recent report an association between ventricular arrhythmias and larger
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patches of mid and epicardial fibrosis in the left ventricle of athletes was observed.20 It might be that these more substantive regions of scar reflect a previous bout of subclinical myocarditis rather than having been caused by exercise in its own rite. The relationship between DGE and clinical outcomes is a source of considerable speculation. It is yet to be determined whether DGE is of any significance in athletes and whether risk is dependent on the quantity and location of the lesions and its distribution across the myocardial layers. Is the Risk of Ischemic Heart Disease Increased With Intense Exercise? There is no topic in which the paradox between the benefits of low- and moderate-intensity exercise and the potential risk of high-intensity exercise would seem more diametrically opposed. Exercise represents a powerful therapy in coronary artery disease prevention, SCD, and is a positive modulator of coronary risk factors including hypertension, hyperglycemia, and dyslipidemia.61 Against this wealth of evidence there is a small body of literature that asserts that long-term endurance training might promote atherosclerosis and coronary events in predisposed individuals. Mohlenkamp et al. studied 108 middle-aged marathon runners and observed a burden of atherosclerotic disease on computed tomography coronary angiogram that was similar to that of age-matched subjects and greater than that expected if subjects were matched according to Framingham risk score.59 Among these subjects there was an increased prevalence of DGE on magnetic resonance imaging (12% of subjects compared with 3% in nonathletes), although the pattern was consistent with ischemic injury in only a minority.58 A number of athletes with abnormalities found on computed tomography coronary angiogram proceeded to revascularization but the extent to which these procedures were driven by the investigation results is difficult to establish. There was no increase in longterm risk of myocardial infarction or total mortality relative to a matched population.62 What these data remind us is that exercise does not offer complete protection from atherosclerosis and nor does it reverse years of exposure to adverse risk factor exposure. More than half of the studied subjects were former smokers and 5% continued to smoke while engaged in training and racing marathons. Although not precisely detailed, it would seem that many of the subjects studied had only fairly recently taken up marathon running, which introduces the potential for a selection bias in which subjects concerned about their previous or current health status might be more likely to volunteer for a “screening” study. Importantly, these studies did not address the extent to which exercise modifies risk but rather, perhaps unsurprisingly, showed that atherosclerosis does not disappear when running shoes are put on for the first time. Studies of persons who have been lifelong exercise enthusiasts would seem a more appropriate cohort to address the effect of high-level exercise on coronary risk factors, burden of atherosclerosis, and long-term events. Recently, data from the Copenhagen City Heart study received significant popular press exposure on the basis of the study’s conclusion that the health benefits of jogging might follow a U-shaped curve with the greatest benefit derived by those who perform light and moderate exercise.63 The authors concluded from a hopelessly underpowered sample of 36
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Canadian Journal of Cardiology Volume - 2016
Figure 3. Controversies and the level of supporting evidence. This figure attempts to provide some context for the current controversies regarding exercise-induced cardiotoxicity by comparing the compelling evidence for cardiovascular benefits of exercise and the less well evidenced emerging concerns regarding cardiac damage. AF, atrial fibrillation; VT, ventricular tachycardia.
runners aged 37 14 years who performing more than 4 hours of “vigorous jogging” per week that the adjusted hazard ratio of 1.97 for all-cause mortality reflected an increased risk. They seemed to neglect the massive confidence intervals mandated of such a tiny sample size and that, in fact, the confidence intervals suggested anything from a 50% reduction in mortality to an 8-fold increase. It is very difficult to interpret anything from these data with regard to higher doses of regular exercise and it would seem that the authors’ very prescriptive conclusion, that the most favourable dose of running was “no more than 3 running days per week, at a slow or average pace” is unfounded. Conclusions Against a backdrop of overwhelming and pleomorphic benefits of exercise, in this report we aimed to challenge the reader with some emerging controversies regarding potential cardiotoxic effects of exercise. In Figure 3, we attempt to provide some context for the controversies discussed to this point and the relative strength of evidence to support them. Many of these emerging controversies are on the basis of small cross-sectional cohort studies and small mechanistic studies, which are dwarfed by the large population studies that support the benefits of exercise, albeit in doses of exercise less than that commonly practiced by elite sportspersons. What Is Needed? Much of the discussion regarding the relative risks and benefits of long-term endurance sports training is hijacked by definitive media-grabbing statements, which have fueled an environment in which one might be criticized for even questioning the benefits of exercise. The answers regarding the healthfulness of ‘extreme’ exercise is not complete and there are valid questions being raised. Because this is a question that
affects such a large proportion of society it is something that deserves investment. The lack of large prospective studies of persons engaged in high-volume and high-intensity exercise represents the biggest deficiency in the literature to date, and, although this represents a logistical and financial challenge, many questions will remain controversial until such data emerge. Funding Sources Dr La Gerche is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia and a Future Leader Fellowship from the National Heart Foundation of Australia. Disclosures The author has no conflicts of interest to disclose. References 1. Khan KM, Thompson AM, Blair SN, et al. Sport and exercise as contributors to the health of nations. Lancet 2012;380:59-64. 2. Sallis R, Franklin B, Joy L, et al. Strategies for promoting physical activity in clinical practice. Prog Cardiovasc Dis 2015;57:375-86. 3. Bauman AE, Reis RS, Sallis JF, et al. Correlates of physical activity: why are some people physically active and others not? Lancet 2012;380: 258-71. 4. Corrado D, Basso C, Rizzoli G, Schiavon M, Thiene G. Does sports activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol 2003;42:1959-63. 5. Marijon E, Tafflet M, Celermajer DS, et al. Sports-related sudden death in the general population. Circulation 2011;124:672-81.
La Gerche Andre Potential Cardiotoxic Effects of Exercise 6. Blair SN, Kohl HW 3rd, Paffenbarger RS Jr, et al. Physical fitness and allcause mortality. A prospective study of healthy men and women. JAMA 1989;262:2395-401. 7. La Gerche A, Prior DL, Heidbuchel H. Strenuous endurance exercise: is more better for everyone? Our genes won’t tell us. Br J Sports Med 2011;45:162-4. 8. Armstrong ME, Green J, Reeves GK, Beral V, Cairns BJ. Frequent physical activity may not reduce vascular disease risk as much as moderate activity: large prospective study of women in the United Kingdom. Circulation 2015;131:721-9. 9. Shiroma EJ, Sesso HD, Moorthy MV, Buring JE, Lee IM. Do moderateintensity and vigorous-intensity physical activities reduce mortality rates to the same extent? J Am Heart Assoc 2014;3:e000802. 10. La Gerche A, McMullen JR. Let’s keep running... exercise, basic science and the knowledge gaps. Heart 2015;101:742-4. 11. Sarna S, Sahi T, Koskenvuo M, Kaprio J. Increased life expectancy of world class male athletes. Med Sci Sports Exerc 1993;25:237-44. 12. Kujala UM, Tikkanen HO, Sarna S, et al. Disease-specific mortality among elite athletes. JAMA 2001;285:44-5. 13. Marijon E, Tafflet M, Antero-Jacquemin J, et al. Mortality of French participants in the Tour de France (1947-2012). Eur Heart J 2013;34: 3145-50. 14. Chahal HS, Elizabeth Mostofsky E, Mittleman MA, et al. Aerobic fitness and risk of ventricular arrhythmia following physical exertion. Can J Cardiol 2016 [in press]. 15. 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;11:1156-9. 16. Claessen G, Colyn E, La Gerche A, et al. Long-term endurance sport is a risk factor for development of lone atrial flutter. Heart 2011;97:918-22. 17. Biffi A, Maron BJ, Verdile L, et al. Impact of physical deconditioning on ventricular tachyarrhythmias in trained athletes. J Am Coll Cardiol 2004;44:1053-8. 18. Baldesberger S, Bauersfeld U, Candinas R, et al. Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists. Eur Heart J 2008;29:71-8. 19. Heidbuchel H, Hoogsteen J, Fagard R, et al. High prevalence of right ventricular involvement in endurance athletes with ventricular arrhythmias. Role of an electrophysiologic study in risk stratification. Eur Heart J 2003;24:1473-80. 20. Schnell F, Claessen G, La Gerche A, et al. Subepicardial delayed gadolinium enhancement in asymptomatic athletes: let sleeping dogs lie? Br J Sports Med 2016;50:111-7. 21. Karjalainen J, Kujala UM, Kaprio J, Sarna S, Viitasalo M. Lone atrial fibrillation in vigorously exercising middle aged men: case-control study. BMJ 1998;316:1784-5. 22. Grimsmo J, Grundvold I, Maehlum S, Arnesen H. High prevalence of atrial fibrillation in long-term endurance cross-country skiers: echocardiographic findings and possible predictorsea 28-30 years follow-up study. Eur J Cardiovasc Prev Rehabil 2010;17:100-5. 23. Molina L, Mont L, Marrugat J, et al. Long-term endurance sport practice increases the incidence of lone atrial fibrillation in men: a follow-up study. Europace 2008;10:618-23. 24. Mont L, Sambola A, Brugada J, et al. Long-lasting sport practice and lone atrial fibrillation. Eur Heart J 2002;23:477-82.
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25. 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;108:332-7. 26. 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. 27. Thelle DS, Selmer R, Gjesdal K, et al. Resting heart rate and physical activity as risk factors for lone atrial fibrillation: a prospective study of 309 540 men and women. Heart 2013;99:1755-60. 28. Biffi A, Pelliccia A, Verdile L, et al. Long-term clinical significance of frequent and complex ventricular tachyarrhythmias in trained athletes. J Am Coll Cardiol 2002;40:446-52. 29. Corrado D, Basso C, Leoni L, et al. Three-dimensional electroanatomical voltage mapping and histologic evaluation of myocardial substrate in right ventricular outflow tract tachycardia. J Am Coll Cardiol 2008;51: 731-9. 30. Dello Russo A, Pieroni M, Santangeli P, et al. Concealed cardiomyopathies in competitive athletes with ventricular arrhythmias and an apparently normal heart: role of cardiac electroanatomical mapping and biopsy. Heart Rhythm 2011;8:1915-22. 31. La Gerche A, Claessen G, Dymarkowski S, et al. Exercise-induced right ventricular dysfunction is associated with ventricular arrhythmias in endurance athletes. Eur Heart J 2015;36:1998-2010. 32. Wyse DG, Van Gelder IC, Ellinor PT, et al. Lone atrial fibrillation: does it exist? J Am Coll Cardiol 2014;63:1715-23. 33. Wilhelm M, Roten L, Tanner H, et al. Atrial remodeling, autonomic tone, and lifetime training hours in nonelite athletes. Am J Cardiol 2011;108:580-5. 34. Luthi P, Zuber M, Ritter M, et al. Echocardiographic findings in former professional cyclists after long-term deconditioning of more than 30 years. Eur J Echocardiogr 2008;9:261-7. 35. 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. 36. Aschar-Sobbi R, Izaddoustdar F, Korogyi AS, et al. Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFalpha. Nat Commun 2015;6:6018. 37. La Gerche A, Inder WJ, Roberts TJ, et al. Relationship between Inflammatory cytokines and indices of cardiac dysfunction following intense endurance exercise. PLoS One 2015;10:e0130031. 38. Hill JA, Olson EN. Cardiac plasticity. N Engl J Med 2008;358:1370-80. 39. Pelliccia A, Maron BJ, De Luca R, et al. Remodeling of left ventricular hypertrophy in elite athletes after long-term deconditioning. Circulation 2002;105:944-9. 40. La Gerche A, Burns AT, Taylor AJ, et al. Maximal oxygen consumption is best predicted by measures of cardiac size rather than function in healthy adults. Eur J Appl Physiol 2012;112:2139-47. 41. Spence AL, Carter HH, Naylor LH, Green DJ. A prospective randomized longitudinal study involving 6 months of endurance or resistance exercise. Conduit artery adaptation in humans. J Physiol 2013;591: 1265-75. 42. Shave R, Baggish A, George K, et al. Exercise-induced cardiac troponin elevation: evidence, mechanisms, and implications. J Am Coll Cardiol 2010;56:169-76. 43. Middleton N, Shave R, George K, et al. Left ventricular function immediately following prolonged exercise: a meta-analysis. Med Sci Sports Exerc 2006;38:681-7.
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44. Elliott AD, La Gerche A. The right ventricle following prolonged endurance exercise: are we overlooking the more important side of the heart? A meta-analysis. Br J Sports Med 2015;49:724-9.
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45. 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.
55. Sawant AC, Bhonsale A, Te Riele AS, et al. Exercise has a disproportionate role in the pathogenesis of arrhythmogenic right ventricular dysplasia/cardiomyopathy in patients without desmosomal mutations. J Am Heart Assoc 2014;3:e001471.
46. Oxborough D, Shave R, Warburton D, et al. Dilatation and dysfunction of the right ventricle immediately after ultraendurance exercise: exploratory insights from conventional two-dimensional and speckle tracking echocardiography. Circ Cardiovasc Imaging 2011;4:253-63.
56. 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.
47. Neilan TG, Januzzi JL, Lee-Lewandrowski E, et al. Myocardial injury and ventricular dysfunction related to training levels among nonelite participants in the Boston marathon. Circulation 2006;114:2325-33.
57. O’Hanlon R, Wilson M, Wage R, et al. Troponin release following endurance exercise: is inflammation the cause? A cardiovascular magnetic resonance study. J Cardiovasc Magn Reson 2010;12:38.
48. Mousavi N, Czarnecki A, Kumar K, et al. Relation of biomarkers and cardiac magnetic resonance imaging after marathon running. Am J Cardiol 2009;103:1467-72.
58. Breuckmann F, Mohlenkamp S, Nassenstein K, et al. Myocardial late gadolinium enhancement: prevalence, pattern, and prognostic relevance in marathon runners. Radiology 2009;251:50-7.
49. Trivax JE, Franklin BA, Goldstein JA, et al. Acute cardiac effects of marathon running. J Appl Physiol 2010;108:1148-53. 50. Heidbuchel H, Prior DL, La Gerche A. Ventricular arrhythmias associated with long-term endurance sports: what is the evidence? Br J Sports Med 2012;46(suppl 1):i44-50. 51. La Gerche A, Heidbuchel H, Burns AT, et al. Disproportionate exercise load and remodeling of the athlete’s right ventricle. Med Sci Sports Exerc 2011;43:974-81. 52. Lewis GD, Bossone E, Naeije R, et al. Pulmonary vascular hemodynamic response to exercise in cardiopulmonary diseases. Circulation 2013;128: 1470-9. 53. Aaron CP, Tandri H, Barr RG, et al. Physical activity and right ventricular structure and function. The MESA-Right Ventricle Study. Am J Respir Crit Care Med 2011;183:396-404. 54. La Gerche A, Robberecht C, Kuiperi C, et al. Lower than expected desmosomal gene mutation prevalence in endurance athletes with
59. Mohlenkamp S, Lehmann N, Breuckmann F, et al. Running: the risk of coronary events: prevalence and prognostic relevance of coronary atherosclerosis in marathon runners. Eur Heart J 2008;29:1903-10. 60. Wilson M, O’Hanlon R, Prasad S, et al. Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes. J Appl Physiol 2011;110: 1622-6. 61. Kokkinos P, Myers J. Exercise and physical activity: clinical outcomes and applications. Circulation 2010;122:1637-48. 62. Mohlenkamp S, Leineweber K, Lehmann N, et al. Coronary atherosclerosis burden, but not transient troponin elevation, predicts long-term outcome in recreational marathon runners. Basic Res Cardiol 2014;109: 391. 63. Schnohr P, O’Keefe JH, Marott JL, Lange P, Jensen GB. Dose of jogging and long-term mortality: the Copenhagen City Heart Study. J Am Coll Cardiol 2015;65:411-9.
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(2016) 1e8
Review
The Potential Cardiotoxic Effects of Exercise Andre La Gerche, MD, PhD Baker IDI Heart and Diabetes Institute, and Department of Cardiology, Alfred Hospital, Melbourne, Australia; and the Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
ABSTRACT
RESUM E
The emerging controversy related to the potential cardiotoxic effects of high doses of intense exercise need to be considered among the much stronger evidence that supports the pleomorphic benefits of exercise as a whole. However, there is fairly compelling evidence to support the association between long-term sport practice and an increased prevalence of atrial fibrillation and the fact that this relates to a chronic altered atrial substrate. This article was designed to challenge the reader with speculative science that suggests that exercise might promote permanent structural changes in the myocardium which can, in some individuals, predispose to arrhythmias. In terms of long-term health outcomes, it would seem that these small risks are outweighed by the many other benefits of exercise, including a likely decrease in atherosclerotic vascular events, although some recent results have brought into question whether the protective benefits of exercise on vascular events also extends to high-intensity exercise training. Above all else, in this article we sought to highlight current controversies to stimulate research on the many unanswered questions. In particular, there is a lack of adequately powered prospective studies from which we can measure health outcomes and their relationship to exercise-induced cardiac remodelling.
La nouvelle controverse relative aux possibles effets cardiotoxiques de riodes doit être revue à la l’exercice intensif pendant de longues pe lumière des preuves beaucoup plus probantes appuyant les nombreux ne ral. Il existe des bienfaits offerts par l’exercice physique en ge s à preuves assez concluantes à l’effet que les sports intenses pratique valence de la fibrillation auriculaire lie e à long terme augmentent la pre une modification du substrat auriculaire et cet article a pour but de fi en lui pre sentant l’hypothèse selon laquelle mettre le lecteur au de l’exercice serait susceptible d’entraîner des modifications structurelles disposer certaines perpermanentes du myocarde qui pourraient pre s, seraient sonnes à l’arythmie. Ces risques, somme toute limite s par les bienfaits ge ne raux de toutefois amplement compense duction des accidents vasculaires l’exercice physique, notamment la re s à l’athe roscle rose, et ce, même si les re sultats de certaines e tudes lie centes semblent remettre en question les bienfaits vasculaires de re à l’exercice intensif. Dans cet article, nous avons avant tout cherche faire ressortir la controverse actuelle afin de stimuler l’amorce de ponses aux nombreuses travaux de recherche visant à fournir des re questions qui demeurent toujours en suspens. Il y a notamment une nurie d’e tudes prospectives suffisamment importantes pour pouvoir pe et son association avec le mesurer les effets de l’exercice sur la sante remodelage cardiaque induit par l’exercice.
The science that underpins the pleomorphic benefits of exercise is concrete.1 As has been championed by strategies such as the “Exercise is Medicine” campaign, the benefits of exercise outperform any pharmacological therapy across a broad range of biological systems and if it were a patented pill it would be promoted as a miracle.2 Rather, this free and readily accessible therapy, which comes in a range of palatable formulations, is all too often overlooked during formulation of health plans for individuals. Against these overwhelming benefits, an article on the potential toxicities of exercise might be perceived as a barrier in the fight against
sedentary behaviour and the emerging epidemic in lifestyleassociated morbidity.3 However, this report was aimed to address an entirely different demographic, one at the other end of the spectrum from inactivity. As opposed to the unquestionable science behind the benefits of ‘getting off the couch,’ in this article we discuss the often questionable, incomplete, and controversial science behind the emerging concern that high levels of intense exercise might be associated with some adverse health effects. All available therapies, pharmacological or otherwise, have a dose-response relationship whereby benefits diminish at high doses and the risk of adverse events increases. An open mind would consider that this might even be possible for the very best available health therapydexercise. It is important to differentiate between exercise as a trigger of arrhythmias and sudden cardiac death (SCD) as opposed to exercise as a promoter of abnormalities of cardiac structure, which might itself contribute to clinical events. It has been observed that athletes might be at greater risk of
Received for publication October 13, 2015. Accepted November 5, 2015. Corresponding author: A/Prof Andre La Gerche, Sports Cardiology, Baker IDI Heart and Diabetes Institute, Level 4 Alfred Centre, 99 Commercial Rd, Melbourne 3004, Australia. Tel.: þ1-9288-4423; fax: þ61-39288-4422. E-mail: [email protected] See page 6 for disclosure information.
http://dx.doi.org/10.1016/j.cjca.2015.11.010 0828-282X/ 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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SCD compared with nonathletes, but most if not all of this excess is due to underlying abnormalities such as familial cardiomyopthies.4,5 Thus, the mainstream view is that adverse clinical events are explained by exercise acting as a trigger in individuals who are susceptible because of an independent underlying abnormality. In this review we address a largely separate and controversial premise, namely, that exercise might effect a change in the myocardial substrate, which might serve as a cause of arrhythmias in its own right. Nonlinear Dose-Response Relationship With Exercise The benefits of exercise are most clearly established for low- and moderate-intensities. As described by Blair et al.,6 all-cause mortality decreases progressively with fitness but there appears to be an “asymptote of benefit” at an intensity that represents only approximately 50% of a well trained athlete’s capacity.7 This is reinforced by recent large studies in male and female cohorts that have reported little or no additional benefit from performing daily strenuous exercise as opposed to less frequent or less intense exercise.8,9 Thus, there is a significant gap between the exercise intensity associated with clear health benefits and that routinely practiced by competitive athletes (Fig. 1). It is also notable that the exercise ranges associated with improved cardiovascular outcomes is less than that expected to result in significant exercise-induced cardiac remodelling (‘athlete’s heart’). Therefore, we should not assume that the benefit from lower intensities can be generalized to the high-level training that induces changes in cardiac morphology.
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Even the Highest Trained Athletes Live Longer There is compelling evidence that details better health outcomes and greater longevity among elite athletes compared with the general population. Landmark cohort studies from Finland reported fewer cardiovascular and cancer deaths in former elite athletes who had competed at an international level between the years 1920 and 1965 compared with referents selected from military enrollment records.11 However, the extent to which these improved outcomes can be attributed to exercise is difficult to ascertain because there were also important differences in smoking, alcohol consumption, obesity, and socioeconomic class. What reinforces the effect of these confounders is the fact that reductions in death were greatest in obstructive airway disease, a condition that is far more likely explained by differences in cigarette exposure than exercise.12 Similar findings were recently documented in Tour De France cyclists13 in whom the ‘healthy cohort effect’ was associated with being sufficiently healthy to ride a bike at the highest level of exertion, which translated into improved short-term mortality in which the relative reduction in deaths was greatest in diseases of the digestive and respiratory systems. Thus, we might confidently conclude that the pleomorphic benefits of an athletic lifestyle results in improved health outcomes, but that the risk reduction might not be directly attributable to exercise alone.
Improved Mortality in Athletes, but What About Morbidity? Is Endurance Exercise Associated With Arrhythmias? There is increasingly convincing evidence that longstanding endurance training might promote some cardiac
Figure 1. The benefits of moderate exercise and the issue of extrapolation. Epidemiological data, modified from Blair et al. with permission Copyright ª 1989 American Medical Association. All rights reserved.,6 shows reductions in mortality associated with increased fitness. The benefit appears to plateau at approximately 10 metabolic equivalents, which is approximately 50% of the fitness of an elite cyclist. Shown in the figure is a 23-year-old nonathlete (left) compared with a 23-year-old elite cyclist with a maximal oxygen consumption (VO2max) of 78 mL/min/kg (approximately 22 metabolic equivalents). Note that the echocardiographic images of the heart are presented to scale (15-cm marker in yellow circle). Thus, the increase in cardiac size in the cyclist is considerable and the clinical consequences of such profound remodelling remain uncertain (as signified by the dotted extrapolation of the efficacy curve). Reproduced from La Gerche et al.10 with permission from BMJ Publishing Group Ltd.
La Gerche Andre Potential Cardiotoxic Effects of Exercise
arrhythmias. The range and risk of arrhythmias are discussed in an accompanying review in this issue of the Canadian Journal of Cardiology14 and is also summarized in Figure 2. Almost all studies have observed an association between atrial fibrillation (AF) in middle-aged men and previous endurance sport participation.18,20-26 This has not been observed in female athletes and the difference between sexes is not simply explained by the lesser proportional representation of women in endurance sport cohorts. In a systematic review that combined data from 6 contemporary studies, Abdulla and Nielsen calculated that athletes were 5.3 times more likely to develop AF than were matched nonathletic control subjects.15 Large population studies have shown an association between flecainide prescription and intense exercise training. Capitalizing on the reasonable assumption that lone AF is the primary indication for flecainide prescription the authors indirectly concluded an increased prevalence of AF among those who performed the most exercise.27 There are far fewer data that link athletic training with other cardiac arrhythmias. However, there are some intriguing mechanistic similarities between exercise-induced arrhythmogenic substrates in animal models and observations in humans. Ventricular ectopic beats are common among athletes but are benign and potentially reversible in the absence of structural heart disease.17,28 Some observations have suggested that more sustained ventricular arrhythmias might be more common among endurance athletes although it is important to remember that this represents a minority of the rare cases of SCD in athletes. A high incidence of life-threatening arrhythmias was observed by Heidbuchel et al. among athletes
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who presented with ventricular tachycardia and complex ventricular ectopy.19 These data suggest that endurance exercise is, at least in some predisposed individuals, associated with an increased propensity to arrhythmias but determination of the athletes who might be at risk of SCD can be extremely challenging and very specialized investigations might be required.19,29-31 It remains unclear as to whether the proarrhythmic remodelling in athletes is confined to an excess in AF or whether this is the loudest epidemiological signal owing to the fact that AF is the most prevalent arrhythmia. As is discussed in the following section, the structural remodelling associated with long-term endurance exercise training is not confined to the atria. An open mind to the issue would recognize that the rarity of life-threatening ventricular arrhythmias in the general population would mean that an extremely large population of athletes would need to be studied to identify an excess risk. What Predisposes Athletes to Arrhythmias? Potential Mechanisms If we accept the fairly consistent evidence that reports an increase in AF among athletes then we are left to consider the potential mechanisms. The concept of lone AF (AF in the absence of associated cardiopulmonary or other comorbid disease) is considered a historical concept by many investigators who note that there is an expanding list of pathological associations with AF such as obesity, sleep apnea, and subclinical cardiomyopathies, which are each associated with subtle abnormalities in inflammation, fibrosis, and myocyte
Figure 2. Increased incidence of arrhythmias in the athlete’s heart. There is a well demonstrated association between atrial fibrillation and/or flutter and endurance exercise training.15,16 There is also an increase in premature ventricular beats,17 although this tends to be benign in most athletes. Although there is some speculation that extreme exercise might cause serious arrhythmias in some cases,18-20 these events remain very uncommon. PPM, permanent pacemaker; RV, right ventricular.
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function in the atrium.32 It would seem that similar subclinical changes in atrial tissue might precede the onset of AF in athletes. Wilhelm et al. showed that there was an association between lifetime years of endurance exercise and left atrial volume. Furthermore, there was a progressively longer P wave duration, greater vagal activity, and more frequent atrial ectopics.33 This suggests an increase in the substrate, modulating factors, and triggers that together provide the ingredients necessary to increase AF risk. Luthi et al. observed that atrial size remained significantly increased in former professional cyclists despite having retired many years previously,34 and thereby provided some rationale by which to question the mainstream view that exercise-induced cardiac remodelling is a reversible physiological phenomenon. These hints suggest that adverse atrial remodelling in athletes are hard to validate. Atrial biopsies are seldom performed and noninvasive imaging techniques are insufficiently sensitive to detect abnormalities in atrial microstructure. However, murine studies support the concept of exerciseinduced proarrhythmogenic atrial remodelling. Guasch et al. compared rats that underwent an intensive 16-week exercise program (so-called “marathon rats”) with sedentary control rats and found that the former developed atrial dilation and fibrosis associated with a greater propensity to AF induction.35 In a similar manner, Aschar-Sobbi et al. showed that intense exercise increased susceptibility to AF, which was again associated with an increase in interstitial fibrosis. Intriguingly, they identified the proinflammatory cytokine (tumour necrosis factor [TNF]a) as a key modulator of fibrosis and that treatment with a specific TNFa inhibitor abolished AF risk.36 There was again some agreement between preclinical and human data with a recent report that suggested that proinflammatory cytokines such as TNFa, interleukin-12 and interleukin-1RA might be involved in exercise-induced myocardial injury in humans.37 The orthodox view regarding the effect of exercise on cardiac remodelling is that of a purely physiological process in which the hemodynamic load induces an increase in myocytes size and that this process occurs in reverse when the hemodynamic stimulus is removed.38 This theory would imply that cardiac size would return to normal in athletes who detrain. However, Pelliccia et al. prospectively followed 40 elite male athletes and found that although cardiac dimensions did decrease after decades of detraining, substantial cavity dilation persisted in one-fifth of the cohort and that the average cardiac dimensions remained well above what would be expected for the average population.39 This needs to be interpreted with caution because we do not know the athletes’ cardiac dimensions before exercise training and it is possible that people with larger hearts are more likely to excel in athletics as suggested by the reasonably strong association between heart size and maximal oxygen consumption at peak exercise (VO2max).40 In other words, heart size might be a cause, rather than a consequence of elite sports performance. However, it is perhaps more likely that this represents an extent of permanent structural change induced through many years of athletic training and the limited available prospective data support this premise.41 Then there is the question of how much remodelling can be considered appropriate and whether there is a point at which the increase in remodelling becomes maladaptive. This concept is akin to regurgitant valvular heart
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disease in which remodelling initially compensates for the greater volume load but a point is then reached whereby further increases in cardiac size reflect a reduction in contractile reserve. One of the clear limitations in using the analogy of valvular heart disease is the difference between a chronic hemodynamic load and the intermittent nature of exercise-induced remodelling. However, it is reasonable to at least question whether there is an upper limit for physiological changes in cardiac structure in response to intense endurance exercise. This is particularly pertinent for athletes who present with fatigue or altered performance for whom it can be extremely challenging to determine whether these symptoms relate to changes in cardiac structure and function. Perhaps the concept of “overtraining” can indeed be extended to the heart. Chronic Cardiac Remodelling as a Consequence of Repeated Bouts of Injury Transient increases in high-sensitivity troponin and B-type natriuretic peptide have been observed in almost all recent studies of athletes who perform intense endurance exercise.42 These biomarkers are relatively specific markers of myocyte damage and hemodynamic stretch, respectively, but their identification does not necessarily equate to permanent myocardial damage. Many of the body’s adaptive mechanisms are a result of transient tissue damage, which is subsequently repaired in a manner that renders that tissue more capable of tolerating subsequent stressors. This “supercompensation” causes skeletal muscle hypertrophy and functional improvements in response to load-bearing exercises and this same concept might well explain the changes in cardiac structure and function that enable athletes to tolerate the high hemodynamic stressors of intense exercise. However, it is also possible that after a more profound or more frequent exercise stimulus, the recovery processes might be insufficient to compensate for the extent of injury and thereby result in permanent alterations in cardiac structure and function. The effect of exercise stress on the heart might not equally affect the 2 ventricles. Most studies that assessed left ventricular (LV) function in the postrace setting observed little or no change in LV function,43 whereas a number of recent studies have reported far more substantive decrements in right ventricular (RV) function.44-49 Also, 2 recent studies documented moderately strong correlations between measures of RV dysfunction and levels of troponin and B-type natriuretic peptide,45,47 whereas a similar association between biomarkers and postrace changes in LV function were not observed.42 Exercise-Induced or Gene-Elusive Arrhythmogenic RV Cardiomyopathy Two questions arise from the observation of disproportionate RV injury after an acute bout of intense exercise: (1) why the right ventricle?; and (2) are there any long-term consequences? The potential mechanisms that might explain the susceptibility of the right ventricle to exercise-induced strain and injury have been reviewed extensively elsewhere.50 In brief, studies that have compared LV and RV hemodynamics during exercise have measured greater proportional increases in work and wall stress on the thin-walled
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right ventricle.51,52 This is largely because pulmonary artery pressures increase proportionally according to the level of exercise performed, and thereby represents a substantial increase in RV work, which might constrain exercise performance if maintained for prolonged periods. The long-term consequence of disproportionate hemodynamic stress and greater RV injury is chronic structural RV remodelling. The relationship between physical activity levels and disproportionate increases in RV volumes has been shown in athletes51 and also in the general population.53 Of concern is that in some predisposed individuals this RV remodelling might represent an arrhythmogenic substrate. Heidbuchel et al. coined the term “exercise-induced arrhythmogenic RV cardiomyopathy” to describe the observation that ventricular arrhythmias in endurance athletes most frequently originate from the right ventricle and are often associated with mild abnormalities in RV structure and function, whereas the left ventricle is rarely involved.19 In a cohort of 47 athletes with exercise-induced RV remodelling, there was a high incidence of serious arrhythmias in 5 years of follow-up, which suggests that the syndrome is potentially as malignant as familial arrhythmogenic RV cardiomyopathy. However, the exerciseinduced syndrome seemed different in that there was little or no evidence of familial disease. Even after intensive familial screening and genotyping, the yield of familial cases was far fewer than expected.54 As was subsequently validated by the John Hopkins group of Calkins, the phenotype of arrhythmogenic right ventricular cardiomyopathy (ARVC) could be caused by a desmosomal gene mutation combined with modest exercise but could also be seen in athletes without a mutation but with a history of extensive exercise training. Reflecting the possibility of another milder genetic predisposition, the Calkins group referred to this exercise-induced phenotype as “gene-elusive ARVC.”55 Similar to the agreement between human and murine data that described the relationship between exercise and AF, the “marathon rat” studies from the Barcelona and Montreal groups of Mont and Nattel show striking resemblance to the human experience regarding ventricular arrhythmias.56 Compared with sedentary rats, intensely trained rats developed a propensity for ventricular arrhythmias (inducible in 6% vs 42%; P ¼ 0.05) and this was associated with an increase in RV inflammation and fibrosis. Just as in humans, LV structural and histological changes were absent. Histological confirmation of the hypothesis that exercise can cause low-grade fibrosis in human athletes is understandably elusive. A noninvasive marker would provide a more practical means to determine whether fibrosis is indeed more common in athletes. Delayed gadolinium enhancement (DGE) refers to a technique in which magnetic resonance imaging is performed after administration of gadolinium contrast, which leaks into inflamed or scarred tissue. DGE tends to be absent in young athletic cohorts with fairly modest volumes of lifetime training.48,49,57 In contrast, DGE has been observed in 12%50% of extensively trained veteran athletes and tended to be more common in athletes who had greater cardiac volumes.45,58-60 In each of these studies the patches of DGE were very small, localized to the interventricular septum at the points of right ventricle insertion and were not directly associated with arrhythmias or clinical events. In contrast, in a recent report an association between ventricular arrhythmias and larger
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patches of mid and epicardial fibrosis in the left ventricle of athletes was observed.20 It might be that these more substantive regions of scar reflect a previous bout of subclinical myocarditis rather than having been caused by exercise in its own rite. The relationship between DGE and clinical outcomes is a source of considerable speculation. It is yet to be determined whether DGE is of any significance in athletes and whether risk is dependent on the quantity and location of the lesions and its distribution across the myocardial layers. Is the Risk of Ischemic Heart Disease Increased With Intense Exercise? There is no topic in which the paradox between the benefits of low- and moderate-intensity exercise and the potential risk of high-intensity exercise would seem more diametrically opposed. Exercise represents a powerful therapy in coronary artery disease prevention, SCD, and is a positive modulator of coronary risk factors including hypertension, hyperglycemia, and dyslipidemia.61 Against this wealth of evidence there is a small body of literature that asserts that long-term endurance training might promote atherosclerosis and coronary events in predisposed individuals. Mohlenkamp et al. studied 108 middle-aged marathon runners and observed a burden of atherosclerotic disease on computed tomography coronary angiogram that was similar to that of age-matched subjects and greater than that expected if subjects were matched according to Framingham risk score.59 Among these subjects there was an increased prevalence of DGE on magnetic resonance imaging (12% of subjects compared with 3% in nonathletes), although the pattern was consistent with ischemic injury in only a minority.58 A number of athletes with abnormalities found on computed tomography coronary angiogram proceeded to revascularization but the extent to which these procedures were driven by the investigation results is difficult to establish. There was no increase in longterm risk of myocardial infarction or total mortality relative to a matched population.62 What these data remind us is that exercise does not offer complete protection from atherosclerosis and nor does it reverse years of exposure to adverse risk factor exposure. More than half of the studied subjects were former smokers and 5% continued to smoke while engaged in training and racing marathons. Although not precisely detailed, it would seem that many of the subjects studied had only fairly recently taken up marathon running, which introduces the potential for a selection bias in which subjects concerned about their previous or current health status might be more likely to volunteer for a “screening” study. Importantly, these studies did not address the extent to which exercise modifies risk but rather, perhaps unsurprisingly, showed that atherosclerosis does not disappear when running shoes are put on for the first time. Studies of persons who have been lifelong exercise enthusiasts would seem a more appropriate cohort to address the effect of high-level exercise on coronary risk factors, burden of atherosclerosis, and long-term events. Recently, data from the Copenhagen City Heart study received significant popular press exposure on the basis of the study’s conclusion that the health benefits of jogging might follow a U-shaped curve with the greatest benefit derived by those who perform light and moderate exercise.63 The authors concluded from a hopelessly underpowered sample of 36
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Figure 3. Controversies and the level of supporting evidence. This figure attempts to provide some context for the current controversies regarding exercise-induced cardiotoxicity by comparing the compelling evidence for cardiovascular benefits of exercise and the less well evidenced emerging concerns regarding cardiac damage. AF, atrial fibrillation; VT, ventricular tachycardia.
runners aged 37 14 years who performing more than 4 hours of “vigorous jogging” per week that the adjusted hazard ratio of 1.97 for all-cause mortality reflected an increased risk. They seemed to neglect the massive confidence intervals mandated of such a tiny sample size and that, in fact, the confidence intervals suggested anything from a 50% reduction in mortality to an 8-fold increase. It is very difficult to interpret anything from these data with regard to higher doses of regular exercise and it would seem that the authors’ very prescriptive conclusion, that the most favourable dose of running was “no more than 3 running days per week, at a slow or average pace” is unfounded. Conclusions Against a backdrop of overwhelming and pleomorphic benefits of exercise, in this report we aimed to challenge the reader with some emerging controversies regarding potential cardiotoxic effects of exercise. In Figure 3, we attempt to provide some context for the controversies discussed to this point and the relative strength of evidence to support them. Many of these emerging controversies are on the basis of small cross-sectional cohort studies and small mechanistic studies, which are dwarfed by the large population studies that support the benefits of exercise, albeit in doses of exercise less than that commonly practiced by elite sportspersons. What Is Needed? Much of the discussion regarding the relative risks and benefits of long-term endurance sports training is hijacked by definitive media-grabbing statements, which have fueled an environment in which one might be criticized for even questioning the benefits of exercise. The answers regarding the healthfulness of ‘extreme’ exercise is not complete and there are valid questions being raised. Because this is a question that
affects such a large proportion of society it is something that deserves investment. The lack of large prospective studies of persons engaged in high-volume and high-intensity exercise represents the biggest deficiency in the literature to date, and, although this represents a logistical and financial challenge, many questions will remain controversial until such data emerge. Funding Sources Dr La Gerche is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia and a Future Leader Fellowship from the National Heart Foundation of Australia. Disclosures The author has no conflicts of interest to disclose. References 1. Khan KM, Thompson AM, Blair SN, et al. Sport and exercise as contributors to the health of nations. Lancet 2012;380:59-64. 2. Sallis R, Franklin B, Joy L, et al. Strategies for promoting physical activity in clinical practice. Prog Cardiovasc Dis 2015;57:375-86. 3. Bauman AE, Reis RS, Sallis JF, et al. Correlates of physical activity: why are some people physically active and others not? Lancet 2012;380: 258-71. 4. Corrado D, Basso C, Rizzoli G, Schiavon M, Thiene G. Does sports activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol 2003;42:1959-63. 5. Marijon E, Tafflet M, Celermajer DS, et al. Sports-related sudden death in the general population. Circulation 2011;124:672-81.
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