Participation in recreational endurance exercise in the United States has significantly increased over the past several decades concomitant with parallel increases in estimates of masters level endurance athletes (generally considered >40 years old) (1,2). Although current guidelines for physical activity state that just 150 min of moderate exercise or 75 min of strenuous exercise per week lead to substantial health benefits (3), master endurance athletes routinely exceed this threshold. Recently, the debate over the potential negative effects of excess levels of exercise has garnered significant media and scientific attention (4,5). Specifically, long-term and high levels of endurance exercise have been associated with the development of earlier onset atrial fibrillation (AF) (6), reduced mortality benefits (7), increased coronary artery calcification (CAC) (8), and unexplained myocardial fibrosis (9).
In this review, we summarize current cardiovascular controversies as they relate to master endurance athletes (Fig.) and provide clinical perspectives to assist sports medicine practitioners who routinely care for this unique athletic population.
Regular exercise and physical activity decrease all-cause and cardiovascular mortality (3,10). However, for those who routinely exceed moderate exercise levels, recent data have challenged whether favorable outcomes resulting from exercise also apply to these highly active individuals. Several recent studies examining the relationship between exercise and mortality suggest a reduction or loss of benefit at the highest levels of physical activity, leading to what has been termed a “U-shaped” relationship between exercise and mortality (7,11,12). Lee et al. (13) separated active runners into quintiles based on running time, distance, frequency, amount, and speed and compared them with nonrunners. The authors found that runners had a 30% lower risk of all-cause death and 45% lower risk of cardiovascular death compared with sedentary individuals. Although mortality benefits were similar across all quintiles, there was a blunting of this benefit observed in the highest quintile of running (>176 min·wk−1). Similar observations were made by Arem et al. (11), in which the authors stratified a large cohort of individuals based on levels of physical activity. In this analysis, the most robust mortality benefit was observed in those exercising 3 to 5 times minimum physical activity levels (hazard ratio [HR], 0.63; 95% confidence interval [95% CI], 0.59–0.62). In those performing >10 times the recommended minimum physical activity levels, there was no additional mortality benefit. It is noteworthy that while these studies concluded that mortality benefits may plateau with the highest levels of exercise, there was no increase in mortality observed with extreme levels of physical activity.
Investigators who were a part of the Copenhagen City Heart Study analyzed all-cause mortality in the context of levels of jogging (7). The authors categorized joggers as light, moderate, or strenuous based on pace and hours per week of jogging and prospectively compared them to healthy sedentary controls with all-cause mortality as the primary end point. Compared with controls, the most robust mortality benefit was observed among light joggers (HR, 0.22; 95% CI, 0.10–0.47), whereas strenuous joggers had mortality rates similar to controls (HR, 1.97; 95% CI, 0.48–8.14). There are, however, important limitations present when examining this most strenuous group. Within this cohort, there were only 36 joggers (total healthy jogger N = 1,098) and just two mortalities (no cause of death reported) recorded. Given these limited event numbers and wide confidence intervals, conclusive judgments on the relationship between mortality and high levels of jogging in this study are limited (7).
It is important to acknowledge that prior studies also have reported enhanced longevity with high levels of physical activity as improved mortality has been documented in the highest-level endurance athletes. One retrospective cohort study analyzed 15,174 Olympic medalists and found improved mortality compared with age and sex-matched controls (relative conditional survival, 1.08; 95% CI, 1.07–1.10) (14). In another study of 786 professional male cyclists, 41% lower mortality was observed among elite cyclists compared with the general male population (15).
AF is the most common sustained cardiac arrhythmia and is characterized by chaotic atrial activity replacing normal sinus rhythm and disturbing the regular interaction between the atria and ventricles (16). The association of earlier onset AF with long-term endurance exercise training may represent the best interaction between exercise and acquired cardiac pathology (5). There is a sizeable body of evidence demonstrating increased incidence of AF in endurance athletes with increased training duration and intensity being most predictive of AF risk (6,17,18). High-intensity endurance athletes have an estimated 2 to 10 times higher frequency of AF compared with sedentary individuals, with one contemporary meta-analysis reporting a five times higher risk of AF in endurance athletes (odds ratio [OR], 5.29; 95% CI, 3.57–7.85) (18). In the largest study of AF in endurance athletes to date, Andersen et al. (19) retrospectively analyzed >52,000 participants of Vasaloppet, a long-distance cross-country skiing race. These athletes were tracked over a 10-year period to assess for the development of arrhythmias. Those who finished the most events and had the fastest relative finishing times had the highest risk of developing AF (HR, 1.29; 95% CI, 1.04–1.61 and HR, 1.20; 95% CI, 0.93–1.55, respectively).
Despite the increase in prevalence, mechanisms underlying the development of AF in athletes remain speculative. Several proposed mechanisms include increased vagal tone, atrial enlargement, inflammation, and atrial fibrosis predisposing to triggered activity in the pulmonary veins (20). In a study by Wilhelm et al. (21), increased parasympathetic tone and atrial enlargement were observed among marathon runners with more lifetime training, suggesting that atrial remodeling and changes in parasympathetic tone may be important drivers of exercise-related AF. Recently, McNamara et al. (22) further explored the potential causal association between pathologic atrial remodeling and the development of AF. In this study, middle-aged subjects initiated an intense endurance exercise regimen and were followed for 24 months. The authors found that while subjects experienced disproportionate and longitudinal left atrial (LA) enlargement compared with left ventricular (LV) remodeling, they did not demonstrate electrophysiologic remodeling. Mechanistically, these data suggest that there may be different thresholds of maladaptive electrophysiologic alterations in response to endurance exercise that lead to the development of AF and that LA enlargement precedes the development of AF. It is important to emphasize that sedentary lifestyles contribute to AF development, and mild to moderate levels of physical activity reduce the risk of AF (23). The precise threshold at which exercise intensity and volume increases the risk of AF remains a topic of active investigation.
The treatment of AF in athletes presents challenges and lacks an evidence-based approach. Athletes are frequently intolerant of traditional first-line rate-control therapies with beta-blockers and calcium channel blockers due to limitations of exercise heart rate and corollary exercise intolerance. They also are prone to significant resting bradycardia, further limiting use of these medications. Restricting exercise training is an option that may reduce AF burden among athletes but there is little evidence supporting this approach, and many athletes may not be willing to reduce their exercise regimen (20). As there are no randomized trials assessing best AF management practices among athletes, recommendations are largely based on expert opinion (24). AF ablation is a reasonable option for athletes intolerant of antiarrhythmic drug therapy and detraining. Although there are no randomized controlled trials of AF ablation among athletes, small unblinded studies have reported that AF ablation can restore competitive activity in symptomatic athletes and that freedom from AF and safety outcomes are similar between athletes and controls (25,26). The recent Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial, a large randomized trial comparing AF ablation to drug therapy (not specifically inclusive of athletes), did not show ablation to be superior for cardiovascular outcomes but did demonstrate improved quality of life and greater symptom relief for those who had ablation (27). At present, treatment options require an individualized approach to each athlete.
Accelerated Coronary Artery Atherosclerosis
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality in the United States and the developed world (28). ASCVD progression is a complex process with calcification developing within atherosclerotic plaques in the coronary arteries. This CAC is an entity that has been recognized for more than a century and has been shown to correlate with the extent of coronary artery disease (29). CAC, quantified in Agatston units (AU), is used clinically to clarify cardiovascular risk and help guide medical treatment of intermediate and borderline risk patients (30).
Exercise lowers ASCVD risk and a sedentary lifestyle has been linked to CAC progression (10,31). Despite this well-established phenomenon, several studies have demonstrated a paradoxical relationship between extreme amounts of endurance exercise and increased CAC (Table). Mohlenkamp et al. (8) studied 108 healthy male marathon runners (>50 years old) and found CAC distribution to be higher in runners than in Framingham risk score (FRS) matched nonathlete controls (median, CAC 36 vs. 12 AU; P = 0.02). In a smaller observational study analyzing 50 male marathon runners versus 23 sedentary controls, higher CAC volumes in marathoners (84 mm3 vs. 44 mm3, P < 0.0001) also were observed. However, in both of these observational studies, contamination of baseline traditional cardiovascular risk was present with >50% prevalence of smoking in both study cohorts (8,32). Additionally, there was a lack of controlling for family history of early ASCVD (8,32).
More recent data have expanded on the association between intense endurance exercise and CAC. Aengevaeren et al. (33) evaluated 284 male endurance athletes in the context of lifelong exercise intensity and volume (defined as metabolic equivalent of task (MET)-min·wk−1) and CAC. The authors observed increased overall CAC (median score, 9.4; interquartile, 0–60.9 vs. 0 AU; interquartile, 0–43.5; P = 0.02), prevalence of CAC (68% vs. 43%, ORadjusted = 3.2 [95% CI, 1.6–6.6]), and prevalence of atherosclerotic plaque (77% vs. 56%, ORadjusted = 3.3 [95% CI, 1.6–7.1]) in the most active group (>2000 MET-min·wk−1) versus the least active group (<1000 MET-min·wk−1). Importantly, plaques were more often calcified versus mixed composition, indicating a more stable plaque composition. Similar to prior studies, a limitation of this study was the presence of baseline cardiovascular risk in the study cohort. A study published simultaneously by Merghani et al. was the first to control for baseline cardiovascular risk and included only low-risk master athletes (n = 152; mean FRS, 3.4%). Here, investigators found no significant difference in percentages of CAC scores of 0 in athletes (60%) compared with healthy sedentary controls (63%). Intriguingly, only male master endurance athletes had CAC >300 AU (11.3% vs. 0%, P = 0.009) and >50% luminal coronary stenoses (7.5% vs. 0%, P = 0.05) compared to controls. Similar to Aengevaeren et al. (33), plaques were predominantly calcific (72.7%) compared with sedentary men (61.5% mixed morphology plaques) (34).
Novel insights into outcomes associated with CAC in the context of exercise dose have been recently published from the Cooper Center Longitudinal Study (35,36). Radford et al. (35) studied 8425 men without clinical ASCVD and demonstrated that after adjusting for CAC, increased cardiorespiratory fitness (CRF) was independently associated with lower risk of cardiovascular events. For every additional MET of fitness, there was an 11% decrease in cardiovascular events (HR, 0.89; 95% CI, 0.84–0.94). It was noteworthy that there were still more cardiovascular events in the subjects with high CAC stratified by level of CRF. DeFina et al. (36) analyzed 21,758 men and found that extremely active men with >3000 MET-min·wk−1 of activity had an 11% increased risk of CAC >100 AU compared with less physically active groups. Subjects were followed up for a decade, and investigators found that among men with CAC >100 AU, those with >3000 MET-min·wk−1 of activity did not demonstrate increased all-cause or cardiovascular mortality compared with those with physical activity of less than 1500 MET-min·wk−1, suggesting that high levels of physical activity did not increase mortality in the presence of increased CAC. Importantly, an increased incidence ratio for all-cause mortality was observed among all subjects with CAC, highlighting the importance of CAC as it relates to risk and mortality. One limitation of this study was the absence of women due to the extremely low event rate among women in this registry. Differentiating sex-specific risk of exercise and CAC progression remains an important future research direction.
Mechanisms underlying the accelerated progression of CAC among male master athletes are uncertain. Prior studies have demonstrated increased parathyroid hormone and serum calcium levels after endurance exercise (37). It also is plausible that CAC may develop as a consequence of increased shear stress on the coronary arteries during repetitive bouts of extreme endurance exercise (5). Calcified plaques are more stable and inversely related to cardiovascular events, suggesting that even though athletes may have more calcified coronary plaques, this may be an adaptive phenomenon, making them less prone to acute rupture (38).
Arrythmogenic Cardiac Remodeling and Fibrosis
Arrythmogenic right ventricular cardiomyopathy (ARVC) is a predominantly genetic disorder characterized by pathologic fibrofatty replacement of normal myocardium, primarily in the right ventricle (RV). Individuals with ARVC typically have mutations in genes that code for desmosomes, proteins that connect neighboring myocytes (39). The natural history of ARVC is variable, but predisposes risk for heart failure, pathologic ventricular arrhythmias, and sudden cardiac death. In more advanced forms, the pathology can involve the LV (40). As it relates to exercise, there are data to suggest that in ARVC mutation carriers, endurance exercise accelerates the development of heart failure and ventricular arrhythmias (41).
Among endurance athletes, prior observational data sets suggest that there may be an association between chronic exposure to high doses of endurance exercise and potential RV maladaptation. Mechanistically, it has been proposed that endurance training leads to repetitive increases in pulmonary pressures without a compensatory decrease in pulmonary vascular resistance, translating into increased RV afterload that then leads to maladaptive RV remodeling, scarring, and substrate for ventricular arrhythmias (42). Benito et al. produced RV hypertrophy and fibrosis in a rat model. After 16 wk of strenuous exercise training induced by tail shocks, 42% of the rats studied had inducible ventricular tachycardia compared with just 6% of the control rats. These inducible arrhythmias and accompanying fibrosis regressed with detraining, suggesting that in this animal model, exposure to high amounts of endurance exercise may lead to cardiac fibrosis and a proarrhythmic substrate (43). In an observational study of humans from Ector et al. (44), RV angiography was performed in endurance athletes with and without ventricular arrhythmias. RV dysfunction was present in those with arrhythmias and lacking in those without ventricular arrhythmias. Notably, only a minority of the subjects with arrhythmia, 6 (27%) of 22, met diagnostic criteria for ARVC.
Cardiac fatigue is defined as transient myocardial dysfunction associated with cardiac biomarker release after ultraendurance exercise and is considered a normal physiologic response to intense endurance exercise (45). La Gerche et al. (9) observed this physiology in a cohort of endurance athletes and elegantly demonstrated the critical role played by the RV. Among 40 highly trained endurance athletes studied before and after completion of an ultraendurance event, there was strong correlation between increases in postrace cardiac biomarkers (cardiac troponin-I [cTnI] and B-type natriuretic peptide [BNP]) and reductions in RV ejection fraction (cTnI r = 0.49, P = 0.002; BNP r = 0.52, P = 0.001). RV function recovered within 1 wk. Intriguingly, 13% of athletes (n = 5) had focal delayed gadolinium enhancement by cardiac magnetic resonance imaging (precompetition) in the interventricular septum at RV insertion points, indicative of underlying myocardial fibrosis. The clinical significance and underlying mechanisms responsible for these observations remain uncertain. A recent study of 33 endurance athletes from Bohm et al. (46) contrasts the findings from LaGerche et al. as no subjects demonstrated unexplained myocardial fibrosis.
Clinical Implications, Uncertainties, and Future Directions
As the population of aging recreational endurance athletes increases worldwide, responding to appropriate concerns voiced by master endurance athletes in the clinical setting can be challenging. At present, there is a clear need for long-term and carefully collected prospective data to clarify ongoing uncertainties with each of the specific controversies reviewed. It also is imperative to understand the limitations of the current data available to appropriately counsel patients.
Although prior epidemiologic data suggest a U-shaped curve may be present for all-cause mortality in the context of increasing exercise dose, epidemiologic outcomes data specific to master endurance athletes are lacking (7). As such, unique characteristics of master endurance athletes, including diet, training patterns, and lifestyle habits, have not been included in prior data sets. Future prospective epidemiologic studies focused on this population should include the careful evaluation of both traditional and nontraditional risk factors that are present among endurance athletes that could impact long-term outcomes data. Based on the summation of current evidence, there are no data that demonstrate extreme exercise habits increase mortality.
AF has a relatively strong association with extreme endurance exercise although there is no established causal relationship. Future studies of master endurance athletes should focus on identifying specific phenotypes that increase the risk of developing AF, characterizing long-term outcomes among athletes with AF, and clarifying underlying mechanisms of disease. Prospectively obtained data are necessary as well as consideration of including novel imaging modalities (47). Best management practices for AF remain uncertain and represent another critical arena of future investigation.
Recent data suggest that male master endurance athletes are at increased risk for the development of CAC compared with sedentary low-risk controls (33,34,36). Currently, defining specific phenotypes among male master athletes that could increase the risk of CAC progression are lacking. Similarly, underlying mechanisms remain speculative and best management practices for low-risk master athletes with CAC are uncertain. Recent outcomes data demonstrate no increase in mortality in subjects with CAC engaging in high intensity and volume endurance exercise (35,36). While calcified coronary plaques are more stable and less prone to rupture, the presence of increased CAC is still associated with a higher burden of cardiovascular morbidity (38). This highlights the importance of adequately risk stratifying athletes based on standard cardiac prevention guidelines (30).
Whether acquired myocardial fibrosis is associated with long-term endurance exercise remains uncertain. Similar to all of these controversies, careful phenotyping of master endurance athletes in combination with long-term outcomes data for those found to have asymptomatic myocardial fibrosis are required to understand the significance of this finding.
Ultimately, the development of large, prospective registries of highly active individuals, including master endurance athletes, will be necessary to advance our understanding of cardiovascular risk in this unique population. In addition to sports medicine clinics, recreational athletic groups and clubs could assist the capture of appropriate subjects. Registry data should include detailed and careful phenotyping with imaging, clinical characteristics, capture of unique risk profiles present among highly trained athletes, and sampling of novel biochemical markers (48,49).
In clinical practice, practitioners are faced with the challenge of counseling the safety of long-term endurance exercise to concerned master athletes both with and without prior established cardiovascular disease. At present, contemporary medicine has moved away from a paternalistic model and clinicians must instead explore individual patient values in combination with understanding current medical guidelines and evidence-based practices. This paradigm, referred to as shared-decision making, has become the cornerstone of patient-centered care and is a significant part of the decision making process within sports cardiology (50). Counseling master endurance athletes in clinical sports cardiology practice requires both an understanding of emerging evidence and the limitations of current data.
While the cardiovascular benefits of regular and moderate levels of exercise are well established, controversy exists as to whether extreme levels of physical activity and exercise may lead to potential adverse cardiovascular outcomes. Though many uncertainties are present, there continues to be no definitive data to support practitioners advice against high-level exercise for healthy individuals who choose to engage in high levels of physical activity. Guideline-based cardiovascular risk stratification remains appropriate for this population along with a shared decision making approach for those master athletes presenting with established cardiovascular risk and/or disease.
J.H.K. is supported by the National Institutes of Health (K23 HL128795).
The authors declare no conflict of interest.
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