CrossTalk proposal: Prolonged intense exercise training does lead to myocardial damage

Physical activity is an efficient way to fight cardiovascular disease and prolong life expectancy. For many years the concept ‘the more, the better’ has prevailed in relation to physical activity. However, recent studies suggest that high-intensity, long-lasting exercise can have harmful effects. To approach exercise as a ‘drug’ with upper-limit safety thresholds for some individuals, we address three puzzling questions: (1) Why did these deleterious effects remain concealed until recently? (2) What precisely are the potentially deleterious consequences of excessive training? (3) Which mechanisms mediate these negative consequences? Recent American Heart Association (AHA) Guidelines propose thrice-weekly 20 min vigorous exercise sessions (Haskell et al. 2007). This recommendation stems from epidemiological studies showing graded benefit when exercise load is categorized into quantiles. However, categorization does not reveal outcomes for small groups that remain obscured within larger populations. Thus, exercise benefits might not apply to extreme forms, which are poorly represented in most epidemiological studies. AHA guidelines recognize that ‘[…] the shape of the dose–response curves, the possible points of maximal benefit, […] remain unclear.’ Accordingly, deleterious effects of exercise should be specifically sought beyond a threshold where exercise becomes potentially excessive. In the absence of such knowledge, extreme exercise is gaining adherents. In the USA, more than 500,000 runners finished a marathon in 2012 (Fig. 1), this number having steadily increased for the last 20 years (Lamppa, 2013). Typically, preparing for a marathon requires 20–40 running-miles per week, along with cross-training. This exercise regime is several-fold greater than that recommended by the AHA (Haskell et al. 2007). Moreover, the prevalence of extreme training adherents will probably continue to rise, increasing the potential impact of negative cardiac effects of excess exercise. Temporal evolution of numbers of individuals participating in marathon runs in the USA An increasing body of evidence points to increased arrhythmia incidence and a risk of accelerated atherosclerosis in highly trained athletes. Isolated ventricular premature beats and ventricular runs are frequent in athletes and reversible after detraining (Biffi et al. 2004). Complex arrhythmias usually arise from a dysfunctional and enlarged right ventricle (RV) (Ector et al. 2007). Symptomatic ventricular arrhythmias in predisposed individuals subjected to high-intensity training are associated with increased sudden death risk when accompanied by arrhythmia inducibility at electrophysiological study (Heidbuchel et al. 2003) or in the presence of overt cardiac disease (Biffi et al. 2002). Studies in Finnish orienteering runners first suggested an increased incidence of atrial fibrillation (AF) in athletes (Karjalainen et al. 1998). These results were later confirmed in elite endurance sport practitioners such as marathon runners (Molina et al. 2008), cyclists (Baldesberger et al. 2008) and Nordic skiers (Grimsmo et al. 2010). Overall, AF risk is increased 5- to 10-fold in elite athletes. Furthermore, AF risk correlates with the number of finished marathons, indicating a dose–response relationship (Wilhelm et al. 2012). Most epidemiological studies failing to show increased AF risk with exercise training in general populations probably had an underrepresentation of highly trained athletes (Ofman et al. 2013). These results underline the fact that high-intensity training is needed to promote AF. Recent analyses suggest reversal of the beneficial effects of exercise on coronary artery disease at high exercise levels in elite athletes. Increased coronary artery calcium score in veteran marathon runners indicates a higher atherosclerotic burden (Mohlenkamp et al. 2008). Moderate exercise-induced survival benefit is lost in individuals jogging at a fast pace more than 4 h week−1 (Schnohr et al. 2013). Further studies focusing on the atherosclerotic burden in high-intensity athletes are warranted. Myocardial fibrosis is a hallmark of maladaptive cardiac remodelling associated with long-term endurance training. Recent experimental reports show myocardial fibrosis in the atria (Guasch et al. 2013) and RV (Benito et al. 2011) of high-intensity trained rats, providing a substrate for arrhythmias. Plasma fibrosis markers are increased in veteran endurance athletes (Lindsay & Dunn, 2007). In the atria, the electrocardiographic P-wave duration (reflecting atrial conduction time) is increased in marathon runners, a finding not explained by changes in atrial size and thus suggesting substrate modification (Wilhelm et al. 2011). RV tissue samples obtained from selected athletes with a high burden of ventricular arrhythmias show inflammatory infiltrates and fibrosis (Dello et al. 2011). Magnetic resonance imaging has proven valuable for non-invasive assessment of left ventricular (LV) structural remodelling. Late gadolinium enhancement, an indicator of myocardial fibrosis, is detectable in the LV of roughly 10% of marathon runners (Mohlenkamp et al. 2008; Breuckmann et al. 2009; La Gerche et al. 2012). Among very extreme athletes (averaging four ironman triathlons, 65 ultra-marathons and 178 marathons), up to 50% presented with ischaemic or myocarditis-like LV myocardial fibrosis patterns (Wilson et al. 2011). Case reports showing diffuse LV fibrosis in autopsy specimens from highly trained athletes support these studies. Mechanisms leading to myocardial fibrosis in endurance athletes remain elusive. Haemodynamic changes probably play an important role. Intense physical activity induces a 6-fold increase in cardiac output and doubles systemic and pulmonary systolic blood pressure, to which the RV is particularly sensitive because of its thin wall and particular geometry (La Gerche et al. 2011). Repetitive insults eventually lead to RV dilatation and dysfunction (La Gerche et al. 2012), particularly in genetically prone individuals (Kirchhof et al. 2006). The renin–angiotensin–aldosterone system probably contributes. Ultramarathon running transiently increases plasma concentrations of the profibrotic neurohormone aldosterone 5-fold (Burge et al. 2011), and the angiotensin-receptor blocker losartan prevents experimental exercise-induced myocardial fibrosis (Gay-Jordi et al. 2013). Marathon running induces transient immune deficiency after a race (Gleeson et al. 2011), which may facilitate subclinical myocarditis and ventricular scarring. The cardiac chamber dilatation occurring in athletes might contribute to arrhythmogenesis (Guasch et al. 2013) by increasing vulnerability to re-entry. The incomplete reversal of left atrial and LV dilatation several years after the suspension of exercise training further supports a ‘non-physiological’ enlargement in highly trained athletes (Pelliccia et al. 2002). Endurance training initiates a complex cascade of proinflammatory followed by anti-inflammatory cytokines. Exercise-induced inflammation develops earlier and more intensely (Kim et al. 2009), while persisting for longer periods (Scherr et al. 2011), as the exercise duration increases. Other factors could play a dual role. Parasympathetic enhancement in athletes drives beneficial anti-inflammatory effects and those preventing sudden death, but is also a potentially central contributor to the AF substrate associated with repetitive high-intensity endurance exercise (Guasch et al. 2013). The health benefits of moderate exercise are well established, but there is growing evidence of the potentially deleterious cardiovascular effect of sustained, very high-intensity training. This evidence raises several important and unanswered questions: Does a deleterious-effect threshold exist? Is such a threshold present in all individuals, or only in those who are predisposed to high-level exercise risks? How can we identify the threshold for individual athletes? Are all sorts of exercise equivalent? The answers to these questions are important if we are to ensure that the beneficial cardiac effects of exercise are not compromised by overdosing the medicine. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief comment. Comments may be posted up to 6 weeks after publication of the article, at which point the discussion will close and authors will be invited to submit a ‘final word’. To submit a comment, go to http://jp.physoc.org/letters/submit/jphysiol;591/20/4939 The authors declare no conflict of interest. Supported by the Canadian Institutes of Health Research (MOP68929 and MGP6957), the Heart and Stroke Foundation of Canada and the Fondation Leducq. Disclaimer: Supplementary materials have been peer-reviewed but not copyedited. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.