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Optimal Running Dose and Cardiovascular Risk

McMullen, Christopher W., MD1; Harrast, Mark A., MD1; Baggish, Aaron L., MD2

Current Sports Medicine Reports: June 2018 - Volume 17 - Issue 6 - p 192–198
doi: 10.1249/JSR.0000000000000491
Training, Prevention, and Rehabilitation: Section Articles
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The cardiovascular benefits of regular exercise are well established. A mortality benefit has clearly been demonstrated for those that participate in light and moderate exercise. Less is known regarding the long-term effects of vigorous regular running over an extended period. In recent years, myocardial fibrosis, arrhythmias, and coronary artery calcium have been demonstrated in high-intensity exercisers. However, the prognostic implication of these findings remains unknown, and thus, there is insufficient evidence, and potentially not a need, to recommend a maximal running dose or limit for healthy individuals who already train intensively. For those otherwise healthy individuals who wish to run for cardiovascular health benefits, following the standard guidelines of 150 min of moderate-intensity exercise or 75 min of vigorous exercise weekly is recommended. Prevention and screening remain as key to lowering morbidity and mortality in all individuals.

1Department of Rehabilitation Medicine, University of Washington School of Medicine, Seattle, WA; and

2Cardiovascular Performance Program, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA

Address for correspondence: Christopher W. McMullen, MD, Sports Medicine Center at Husky Stadium, 3800 Montlake Blvd, NE Box 354060, Seattle, WA 98195; E-mail: chrism86@uw.edu.

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Introduction

The cardiovascular benefits and physiologic effects of regular exercise are well established (Fig.) (1–6). Additionally, mild-to-moderate regular exercise likely has a preventative effect on the development of cardiovascular disease (CVD), diabetes, and cancer as well as a mortality benefit (7). However, the long-term cardiovascular effects of vigorous exercise over an extended period are less known. This presents a challenge for the clinician counseling the endurance athlete at the higher end of the running dose spectrum on an optimal running dose that considers both cardiovascular risk and athletic performance. At least in elite athletes, there does not seem to be a mortality detriment associated with a career of very vigorous training (8,9). Paradoxically, evidence has been presented in the last decade to suggest that these endurance athletes may be more prone to myocardial fibrosis, arrhythmia, and atherosclerotic disease than their sedentary counterparts (10–12). Furthermore, this population is not immune to sudden cardiac death during sport, with latent coronary artery disease known to be the most common cause (13).

Figure 1

Figure 1

Mass-participation endurance events have become increasingly popular over the last few decades. In the period from 1990 to 2016, there has been a 3.5-fold increase in U.S. running event participants with 17,000,000 finishers in 2016 (14). In particular, during that same period, there also has been a notable increase in longer distance endurance events with a 6.3-fold increase in the number of half marathon finishers and 2.3-fold increase in marathon finishers. Additionally, marathon participants are getting older with 49% masters runners (age > 40 year) in 2015 compared with 26% in 1980 (14). The increasing number of runners and the fact that a significant cohort is older, with potentially age-related medical comorbidities, make it more likely that this population will seek advice from health care providers about the risks and benefits of regular endurance training and competition. Given the increasing recognition that no level of exercise confers complete immunity from CVD, it is important for health care providers to understand the clear benefits and potential risks of regular endurance exercise training to be able to appropriately counsel this athletic population. This review examines the best available evidence to date with a goal of outlining a practical approach to advising our patients on weighing the cardiovascular risks and benefits of competitive endurance training (Fig.).

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Mortality

Elite Competition

There is no apparent mortality consequence to an early career of intense training in elite athletes. For example, a study of Olympic athletes suggests that in general, a very competitive lifestyle involving years of high-intensity training confers a mortality benefit over a control population (8). Similarly, Tour de France participants were shown to have a substantial mortality benefit over the general French male population (9). In a study investigating athlete mortality in Finland with an average 50-year follow-up time, compared to men who were healthy as young adults, elite competitors had a 5- to 6-year increased life expectancy (15). Thus, there is no evidence that elite endurance competition earlier in an athlete’s life results in a mortality detriment; in fact, there may be a life expectancy increase within this group.

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Low- to Moderate-level Exercise

Several large epidemiologic studies investigating mortality have consistently demonstrated benefit for those that participate in light and moderate physical activities over sedentary controls. In approximately 416,000 Taiwanese adults, Wen et al. (7) reported that moderate activity, defined as activity on par with brisk walking, reduced cardiovascular and all-cause mortality at 15 min daily. Similarly, in the Copenhagen City Heart Study, a study of approximately 5000 adults, including 1100 runners, Schnohr et al. (16) found an all-cause mortality benefit in those that jogged 1 to 2.4 h·wk−1 at a slow to average pace. In a larger study of approximately 55,000 adults including 12,000 runners, Lee et al. (17) investigated groups with even lower levels of exercise, showing an all-cause and cardiovascular mortality benefit at 5 to 10 min of jogging daily at speeds of <6 miles·h−1. Furthermore, in a massive study investigating physical activity in over a million women in the United Kingdom, Armstrong et al. (18) presented evidence to suggest that any exercise just once per week confers a reduced risk of CVD. Finally, another recent and large study by Arem et al. (19) pooled exercise dose data from six separate studies of the National Cancer Institute Cohort Consortium with >600,000 total subjects and similarly demonstrated a mortality benefit with low exercise levels. Specifically, they demonstrated a 20% risk reduction in those participants performing some, but less than guideline recommendations of 75 vigorous-intensity or 150 moderate-intensity minutes per week (20) over those individuals with no leisure time physical activity and a 31% risk reduction at one to two times this amount of activity. The mortality benefit of low- to moderate-level physical activity over inactivity is undoubtedly borne out in the epidemiologic studies above. Some exercise is clearly healthier than no exercise at all, and moderate levels of exercise on par with universal physical activity guidelines potentially leads to benefits beyond low levels of exercise.

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High-level Exercise

While the health benefits of low-to-moderate physical activity are clear, these studies demonstrate inconsistency in mortality as activity levels increase. Wen et al. showed increasing benefits with increasing duration and strenuousness without detriment at high levels of activity, topping out around 110 min daily for moderate exercise (brisk walking) and 50 min daily for vigorous exercise (running). Lee et al. similarly suggested mortality benefit maintained at high levels of running (>176 min weekly) though this was noted to be very slightly less than the benefit seen at 150 to 175 min of weekly running. Arem et al. demonstrated maximum benefit at three to five times above the minimum guideline recommendations with no detriment at the highest levels reported (10 times above the minimum guideline recommendation). In contrast to the above findings, the Copenhagen City Heart Study suggested a complete loss of mortality benefit in their strenuous runner group (defined as a pace of more than 7 miles·h−1 and either >4 h of running per week or 2.5 h of running per week with a frequency of more than three runs per week), demonstrating a U-shaped curve plotting activity level (jogging dose) versus mortality. Finally, Armstrong et al. suggested a decrease in cardiovascular benefit in the highest activity group (daily physical activity vs some physical activity), though there remained a benefit over no physical activity.

Methodological differences and weaknesses are likely largely to blame for the inconsistencies above. Most notably, in the Copenhagen City Heart Study, the strenuous runner group consisted of a much smaller cohort of runners (40 total, 3% of entire study population) compared with the sedentary group (413 total, 32%). The surprising result of the two deaths in this group (5% of 40 runners) lacks statistical power to draw substantial conclusions. Suggesting that more active runners suffer a mortality detriment based on these data alone would be highly misleading. Among the other studies, Lee et al. likely provided the most methodologically rigorous investigation. Its participants were divided into quintiles, thereby analyzing groups with equal numbers of subjects. Again, this study demonstrated that running dose escalation at the highest levels is likely neither incrementally better nor worse. Overall, the bulk of the data suggest that while pushing beyond guideline recommendations of 75 vigorous-intensity or 150 moderate-intensity minutes per week may not substantially increase cardiovascular health and, thus, mortality benefit, it is safe to do so.

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Exercise in Those With CVD

While the above studies worked to control for underlying risk factors of CVD in two studies specifically investigating those with coronary artery disease (21,22), there appeared to be a clear advantage for a middle ground of activity level with a mortality detriment seen most substantially in sedentary individuals and a slight loss of benefit seen in the highest activity level groups. Mons et al. (21) investigated approximately 1000 adults with stable coronary artery disease and found that inactive adults had a fourfold risk of cardiovascular and all-cause mortality in comparison to moderately frequent active adults (2 to 4 d of activity per week). Additionally, the most active group (daily activity) had an increased risk of cardiovascular and all-cause mortality, though this remained less of a risk than the inactive group (hazard ratio, 1.79 vs 6.40). Williams et al. (22) again demonstrated this reverse J-shaped curve with more substantial consequence in the highest activity group in a study of 2377 heart attack survivors. They showed running or walking decreased cardiovascular mortality risk progressively at most levels of exercise in patients after a cardiac event, but the benefit of exercise on cardiovascular mortality was substantially attenuated at the highest levels of exercise (twofold increased risk from the 3.6 to 7.2 MET-h·d−1 group to the >7.2 MET-h·d−1 group). Similar to the investigations discussed previously, there seems to be a clear benefit of some exercise over no exercise at all. However, special attention should be paid to assure that those with known coronary artery disease understand the potential risk involved in pushing past moderate levels of exercise.

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Potential Cardiovascular Risks With High Levels of Physical Activity

The majority of the aforementioned epidemiologic studies demonstrate no detriment in the highest exercise dose groups over the sedentary population. However, as previously mentioned, some recent evidence has suggested increased rates of myocardial fibrosis, arrhythmia, and atherosclerotic disease in this group compared with their sedentary counterparts. Additionally, sudden death is a rare but known risk of exercise that is inherently increased with an increased number of episodes of exercise. The following represent several explanations for a possible loss of mortality benefit that may exist at higher doses of running.

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Sudden Death During Exercise

Sudden death is a known risk during physical activity and has long been reported (23). The Race Associated Cardiac Arrest Event Registry (RACER) study group of more than 10 million runners demonstrated a cardiac arrest incidence during long-distance races (marathons and half marathons) of 0.54 per 100,000 with 71% of arrests resulting in death (13). Higher incidence was suggested in longer races with arrests occurring more frequently in marathons versus half marathons (13). The proposed mechanism for this increased transient risk involves an increase in sympathetic nervous system activity during exercise, which notably, may occur more so near the end of races during the “finish line surge,” the area where most deaths occur (24). This results in an increase in heart rate and blood pressure while simultaneously decreasing vascular reactivity and endothelial function. Those physiologic changes can ultimately, through various possible mechanisms, lead to stroke, myocardial infarction, and/or sudden cardiac death (25). The RACER study helped partially clarify those underlying mechanisms via autopsy data. In younger individuals, genetic factors played a substantial role, with hypertrophic cardiomyopathy noted to be the most common cause of death. In older individuals (>40 years), it was not plaque rupture, but rather oxygen supply-and-demand mismatch from coronary artery disease, or demand ischemia, leading to arrhythmia that was thought to be the most common cause of death. Therefore, preexisting CVD is a substantial risk factor for arrest during prolonged physical activity.

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Exercise-induced Cardiovascular Adaptations

Cardiac adaptations resulting from years of endurance training have been previously reported and by some, deemed the “athlete’s heart” (1,26). Common pathophysiologic and anatomical changes that can be associated with an extended period of endurance training include ECG changes (sinus bradycardia, first-degree atrioventricular block, voltage criteria for left and right ventricular hypertrophy, T-wave inversion in V1 to V3, and incomplete right bundle branch block), structural changes (left ventricular wall thickness and right and left ventricular cavity size), and functional changes (increased diastolic filling and stroke volume) (26,27). These changes are generally regarded as healthy adaptations; however, other changes noted below that have been demonstrated in athletes with a prolonged history of endurance exercise garner more controversy.

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Heart Muscle Pathology

Wilson et al. (28) demonstrated late gadolinium enhancement, suggestive of myocardial fibrosis, in 6 of 12 veteran endurance athletes (compared with no enhancement in 20 controls and 17 young endurance athletes) with a clear association to years of training, number of prior marathons, and number of ultraendurance races (>50 miles) completed. Concordantly, in a study of 40 athletes by La Gerche et al. (11), focal gadolinium enhancement and increased right ventricular remodeling were more prevalent in those athletes with a longer history of competitive sport. Additionally, right ventricular function was found to be acutely reduced during intense endurance exercise, though left ventricular function remained normal. Thus, it was postulated that perhaps repeated bouts of ultraendurance exercise result in repeated episodes of right ventricular injury, and over a prolonged period, lead to right ventricular fibrosis. A very recent study by Tahir et al. (29) reported focal myocardial fibrosis in 9 of 54 male and 0 of 29 female triathletes and further identified peak exercise systolic blood pressure and competing in longer distance swimming (though not cycling and running) events to be independent predictors of fibrosis. Lastly, in contrast to the above studies, Abdullah et al. (30) investigated 92 seniors, 22 of which had a long history of near daily aerobic exercise and at least 20 years of competitive racing and found no relation between physical activity, regardless of dose, and the development of focal myocardial fibrosis. In fact, 0 of the 22 athletes in the most active group (six to seven sessions per week of > 30 min of aerobic activity and competitions including marathon racing) demonstrated any late gadolinium enhancement. Taken in whole, a relationship between high levels of endurance exercise over a career and the development of cardiac fibrosis remains unclear. Furthermore, the exact pathophysiology to why some athletes develop this condition is not well understood. Lastly, and most importantly, there is no clinical outcomes data to suggest that this fibrosis has any negative prognostic implications.

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Arrhythmias

There is substantial evidence to link sustained aerobic exercise and atrial fibrillation; a fivefold increase in prevalence has been associated with activities, such as endurance running and professional cycling (12,31). Andersen et al. (32) assessed the risk of arrhythmias among male participants of a 90-km cross-country skiing event and found that faster finishing times and a higher number of completed races over a career were associated with a higher risk of atrial fibrillation and bradyarrhythmias. This association of atrial fibrillation with endurance sports is strongly related to intensity of endurance exercise, lifetime hours, and male sex. Flannery et al. (33) have recently detailed potential pathophysiologic mechanisms for this association, which include elevated left atrial pressures and remodeling of the left atrium, inflammation, myocardial fibrosis, elevated vagal tone, sinus bradycardia, and genetic predisposition.

While the association of atrial fibrillation in highly trained individuals is fairly certain, it is less clear in those with moderate exercise habits. In fact, in a study of nearly 6000 veterans by Faselis et al. (34), an increased exercise capacity was inversely related to atrial fibrillation incidence. While an increased morbidity and mortality associated with atrial fibrillation is well established (35), it is unlikely, but not definitively known, if the association between sustained high levels of endurance exercise and atrial fibrillation confers a substantial mortality detriment in this population.

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Coronary Atherosclerosis

Lastly, coronary atherosclerosis has been identified in marathon runners and is considered as a potential explanation for the possible loss of mortality benefit seen at high levels of aerobic activity. Mohlenkamp et al. (10) found higher than expected coronary artery calcium (CAC) scores in 108 healthy marathon runners ages 50 years and older who had completed five or more marathons in the past 3 years. Thirty-six percent of these runners were found to have CAC scores greater than 100 compared with just 22% in controls matched for age and cardiac risk factors. This prompted two recently published studies to further investigate the presence of coronary calcium morphology in the competitive and recreationally athletic population (36,37). Merghani et al. (36) investigated a group of 152 longtime competitive masters runners and cyclists (mean age, 55 years) without prior diagnosis of or risk factors for coronary artery disease and found that most athletes had normal CAC levels (60% of athletes vs 63% of controls). However, male athletes had a higher prevalence of atherosclerotic plaque (44% vs 22% of controls). Similarly, in a study by Aengevaeren et al. (37) investigating 284 healthy men (mean age, 55 years), participants with a reported higher lifelong exercise burden (>2000 MET-min·wk−1) were found to have a higher prevalence of atherosclerotic plaques and higher CAC scores than the less active groups. Importantly, both studies investigated plaque morphology. Merghani et al. found male athletes to have predominantly calcified plaques (73%), whereas sedentary males were found to have predominantly mixed morphology plaques (62%). Concordantly, Aengevaeren et al. found men with the highest exercise burden more often had calcified plaques (38% vs 16% in the least active group) and less often had mixed morphology plaques (48% vs 69% in the least active group). The exact etiology of these findings is uncertain. It is possible, though speculative, that the repetitive hemodynamic strain associated with running can, over years, lead to the development of protective calcification within the coronary arteries (38). Calcified plaques are less prone to rupture and thus are considered “stable” and less of a risk compared with mixed morphology plaques. A similar mechanism of repetitive strain and protective repair also may explain myocardial fibrosis found in this population as described above, though again, this remains speculative. Thus, while the increased presence of CAC in masters level athletes is certainly notable, without a better understanding of plaque composition and actual clinical outcomes data of athletes with elevated CAC, the prognostic significance of these findings remains unknown. It is unclear if lifelong endurance athletes with elevated CAC have the same negative prognostic implications as those who are sedentary.

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Optimal Running Dose

Epidemiologic studies suggest the greatest mortality benefit is with moderate levels of weekly aerobic activity (7,16,18). For running specifically, there is an increasing benefit from no exercise through a dose of 1 to 2.5 h of running per week at a slow to moderate pace, with less clear evidence at higher levels of running (7,16). Moderate activity in these studies is on par with guideline recommendations of 150 min of moderate-intensity exercise or 75 min of vigorous exercise weekly (20). Notably, even levels of physical activity well below these recommendations seem to confer a mortality benefit over no aerobic activity at all (17). The literature is less conclusive regarding very high levels of physical activity over a prolonged period. Epidemiologic studies suffer from a lack of uniformity in defining amount, type, and duration of aerobic activity. Additionally, individuals with a history of high levels of physical activity are often the least represented group. Regarding studies that have specifically investigated high-intensity athletes, while observational data have been presented, linking a history of high levels of activity to the development of myocardial fibrosis, arrhythmias, and CAC, the prognostic significance of these findings remain unclear. Thus, to date, there is insufficient evidence to state a clear maximum dose of running at which benefit becomes lost or outweighed by potential harms. Currently the published data suggest that “more” is not necessarily better than a moderate level of running, but “more” may not be worse either. Clinicians should therefore not dissuade healthy people who already participate at the higher end of the running dose spectrum from their chosen activity level.

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Prevention and Recommendations

Primary Prevention for CVD

Standard primary prevention strategies for CVD, including monitoring activity, diet, alcohol consumption, and weight, as well as promoting smoking cessation, are recommended for all our athletes (39). In addition, athletes at all ages should be counseled about the importance of CVD risk factor assessment. Ascertainment of family cardiovascular history coupled with assessment of blood pressure and a fasting serum lipid panel represent primary preventative standards of care. Furthermore, we recommend a preparticipation screen, which on an individualized basis may include maximum effort-limited exercise testing, in those new to running or those athletes wishing to increase their level of activity according to the American College of Sports Medicine’s guidelines (40). Our full recommendations are presented in the Table.

Table

Table

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Secondary Prevention for CVD-related Events

It is important to differentiate the general population from those individuals with established CVD because some evidence suggests that daily vigorous activity, compared with more moderate amounts of exercise, may increase mortality in the latter group (21,22). Thus, secondary prevention via aggressive risk factor reduction coupled with a thoughtful individualized discussion about the risks and benefits of vigorous exercise is critical in the management of this patient population. In asymptomatic high-level athletes with established CVD, maximum effort-limited exercise stress testing with consideration of adjunct imaging or metabolic gas exchange measurement should be considered on a case-by-case basis. At present, the use of cardiac imaging to evaluate for CAC score and/or myocardial fibrosis is not a component of our routine assessment of asymptomatic athletes in either the primary or secondary CVD settings. CAC score data, in limited situations, may provide additional information for those patients who resist medical therapy for established risk factors (38), but it must be emphasized that the prognostic value of CAC data have yet to be established in athlete populations. Consequently, we do not recommend reducing exercise exposure based solely on the CAC score in otherwise healthy individuals. A well-informed discussion and shared decision making process between athlete and physician regarding training recommendations based on the available evidence and the athlete’s competitive goals is our suggested approach. Acknowledging some of the uncertainty in this shared decision making process given the published evidence to date is crucial as well.

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Tertiary Prevention for Sudden Cardiac Death

On-site medical care should be provided for all organized competitive endurance events. The scope of this care will necessarily vary as a function of athlete field size, event duration and environmental conditions, and local resources. We encourage race organizers to assess their needs and to work with local emergency medical providers and volunteer medical professionals to establish an infrastructure that is commensurate with their individual event. Lastly and critically, automated external defibrillator (AED) use has been shown to improve survival in race-related sudden cardiac arrest (24), and we therefore highly recommend incorporating AED access at or near the race start, throughout the race course with strategic positioning and the ability to move the AED in emergency situations, and in the final miles including the finish line. AED access and utilization should be coupled with a comprehensive EMS response plan.

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Conclusions

There are well-established mortality and health benefits associated with light and moderate exercise. Less is known regarding the effect of prolonged high-intensity exercise on cardiac health and mortality. While myocardial fibrosis, arrhythmias, and CAC have been demonstrated in high-intensity exercisers, the prognostic implication of these findings remains unknown, and thus, there is insufficient evidence to recommend a maximal running dose or limit for healthy individuals. There is likely some risk of training intensively at the high end of the running dose spectrum for some individuals; however, clinicians should not discourage those healthy individuals who wish to undertake competitive endurance training for fear of accelerating coronary artery disease or another cardiovascular process. For those otherwise healthy individuals who wish to run for cardiovascular health benefits, following the standard guidelines of 150 min of moderate-intensity exercise or 75 min of vigorous exercise weekly is certainly consistent with the health benefits demonstrated in the aforementioned running dose studies. Finally, prevention and screening remain key to lowering morbidity and mortality in all individuals.

The authors declare no conflict of interest and do not have any financial disclosures.

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