… at a Run for your life ’Keefe,

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Editorial
Run for your life … at a
comfortable speed and not too far
James H O’Keefe,1,2 Carl J Lavie3,4
During the Greco-Persian War in 490
BCE, Phidippides, a 40-year-old herald
messenger ( professional running-courier)
ran the 26 miles from a battlefield near
Marathon, Greece, into Athens carrying
momentous news of Greek victory. Upon
arriving at the Acropolis, he proclaimed:
‘Joy, we have won!’ and then immediately collapsed and died.1 Fast-forward
about 2500 years to an era when the
baby-boomer’s came of age and longdistance running boomed. The prevailing
logic held that aerobic exercise is clearly
good for one’s health and that, if some
is good, more must be better. In 1975,
Dr Thomas Bassler, a physician/runner,
boldly proclaimed that, if you could run a
marathon, you were immune to death
from coronary heart disease (CHD).2 This
urban myth has long since been disproven; indeed an emerging body of evidence
suggests the opposite: extreme endurance
exercise may exact a toll on cardiovascular
(CV) health.
‘SHOW ME THE BODIES’
After our recent articles on this topic,1 3–5
Amby Burfoot, winner of the 1968 Boston
Marathon and Editor-at-Large for Runner’s
World Magazine, challenged our assertions
about the dangers of extreme endurance
efforts by demanding, ‘Show me the
bodies’. Amby has a good point: the risk of
dropping dead in a marathon is remote,
about 0.5 to 1 in 100,000 participants.6 But
the occasional marathoner or triathlete who
dies while strenuously exercising is the
‘canary in the coal mine’. Chronic extreme
exercise appears to cause excessive
‘wear-and-tear’ on the heart, inducing
adverse structural and electrical remodelling,
which offsets some of the CV benefits and
1
Saint Luke’s Mid America Heart Institute, Kansas City,
Missouri, USA; 2University Of Missouri-Kansas City
School of Medicine, Kansas City, Missouri, USA;
3
Department of Cardiology, John Ochsner Heart and
Vascular Institute, Ochsner Clinical School, The
University of Queensland School of Medicine, New
Orleans, Louisiana, USA; 4Pennington Biomedical
Research Center, Baton Rouge, Louisiana, USA
Correspondence to Dr James H O’Keefe, Saint Luke’s
Mid America Heart Institute,4330 Wornall Road, Suite
2000 Kansas City, MO 64111 phone: 816-751-8480
fax: 816-756-3645
[email protected]
longevity improvements conferred by moderate physical activity. Thus, even though
chronic extreme exercise may not kill you, it
may erase many of the health advantages of
regular moderate exercise.
Indeed, regular vigorous exercise is probably the single best step a person can take
to ensure robust CV health. In a study of
416 000 adults followed for a mean of
8 years, 40–50 min per day of vigorous
exercise reduced risk of death by about
40% (figure 1).7 In that study, at about
45 min, a point of diminishing returns is
reached whereby longer exercise efforts do
not appear to translate into lower death
risk. Light to moderate physical activity
reduced death rates too, albeit not as
strongly, but in this case more physical
activity appeared to be better, with no
plateau out to 110 min daily. Indeed, if we
had a pill that confers all the benefits of
exercise, many physicians might be
looking for work. Approximately 30–
45 min of daily vigorous exercise significantly reduces risks for many maladies
including early death, Alzheimer’s disease,
CHD, diabetes, osteoporosis and depression.4 5 Yet, as can be expected with any
potent drug, an insufficient dose will not
confer the optimal benefits, while an
excessive dose can cause harm, and even
death in extreme overdoses.
The ‘survival of the fittest’ concept
does not fully apply to the modern world,
where it appears that even the moderately
fit have an excellent CV prognosis and
superb longevity. Studies of CV fitness, as
measured by peak performance on a treadmill, show a curvilinear relationship
whereby improvements from unfit to
moderately fit confer dramatic reductions
in morbidity and mortality (figure 2).8
However, fitness levels above 12 metabolic
equivalents do not seem to translate into
additional gains in CV health and longevity. Thus, if one is training to be able to
run at speeds above 7.5 miles per hour,
this is being done for some reason other
than further improvements in life
expectancy.
CV DAMAGE FROM EXCESSIVE
EXERCISE
High-intensity exercise sessions lasting
beyond 1–2 h cause acute volume overload of the atria and right ventricle (RV),
which can bring about overstretching and
micro-tears in the myocardium, as evidenced by a transient rise in cardiac biomarkers,
including
troponin
and
B-natriuretic peptide and a fall in the RV
ejection fraction.9 Although within
1 week, these transitory abnormalities
usually return to baseline,9 after years to
decades of excessive exercise and repetitive injury, this pattern can lead to
patchy myocardial fibrosis, particularly in
the pliable walls of the heart such as the
atria and RV, creating a substrate for atrial
and potentially malignant ventricular
arrhythmias.1 3–5 In addition, long-term
excessive exercise may accelerate aging in
the heart, as evidenced by increased coronary artery calcification, diastolic ventricular dysfunction, and large-artery wall
stiffening.1 3–5
At rest, the heart pumps about 5 litres/
min; with strenuous aerobic exercise, the
cardiac output can rise 5–7-fold, pumping
up to 25–35 litres/min. This massive
increase in cardiac work is what the heart
is designed to do for short bursts, or even
for up to as long as 30 or 50 min
Figure 1 Duration of daily exercise and reduction in long-term all-cause mortality.7
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Editorial
predisposition to dangerous ventricular
dysrhythmias that have been documented
in some veteran extreme endurance athletes.14 Encouragingly, when the mice
were withdrawn from the ‘Iron-Mouse’
training regimen and allowed to resume
normal mouse physical activity levels,
their cardiac abnormalities showed
marked improvements, even showing
regression of myocardial fibrosis and resolution of the tendency toward serious
ventricular dysrhythmias.14
PHIDIPPIDES CARDIOMYOPATHY
Figure 2 Death rates as a function of cardiovascular fitness as measured by metabolic
equivalents achieved on maximal exercise treadmill testing.8 CVD, cardiovascular disease.
continuously. However, with protracted
efforts, these high volumes can overstretch the chambers, eventually disrupting cardiac muscle fibres and causing
micro-tears in the myocardium.10 The
presence of sustained exercise-induced elevations
in
catecholamines
and
pro-oxidant free radicals worsen the situation by adding inflammation to the
injury, leading eventually to scarring and
stiffening of the CV structures.10
A trial randomised 60 male patients
with CHD to vigorous exercise sessions
of either 30 or 60 min.11 The 30 min exercise workouts improved arterial elasticity
and produced minimal oxidant stress. In
contrast, the 60 min sessions increased
oxidant stress and worsened vascular
stiffness as measured by pulse wave velocity, particularly in those over the age
of 50. MRI scans of runners who have
been participating in marathons for
decades show a threefold increased incidence of scattered fibrosis and scarring in
the walls of the atria, interventricular
Figure 3
2
septum and RV (figure 3).12 Cardiologists
from Minnesota evaluated a group of
runners who had completed at least 25
marathons over 25 years and found a 60%
increase in coronary plaque burden compared with sedentary age-matched controls.1 These findings were replicated by a
group from Germany, who showed
increased coronary plaque in 108 chronic
marathoners compared with sedentary
controls.13 This scarring can set the stage
for dangerous heart rhythms, such as
atrial fibrillation, which is increased
approximately fivefold in veteran endurance athletes.10 Ventricular tachycardia
and sudden cardiac arrest can also be
seen in endurance athletes even in
the absence of CHD and hypertrophic
cardiomyopathy.1 5
An enlightening study by Benito et al
reinforced the concept of cardiac damage
from chronic excessive exercise. Mice
after being forced to run to exhaustion
every day for 4 months showed the
same cardiac enlargement, scarring and
Born to Run is a non-fiction bestseller
book published in 2009 that glamorises
ultra-endurance running. The story’s
hero is Micah True, an American who
dropped out of modern civilisation to
live and run with the Tarahumara
Indians in Mexico. Nicknamed Caballo
Blanco, or white horse, for his legendary
running endurance, he routinely ran
daily distances of 25–100 miles. This
March on a 12-mile training run in New
Mexico, Micah True dropped dead at age
58. On autopsy, his heart was enlarged
and thickened with ‘focal areas of interstitial chronic inflammatory infiltrate’ in
the myocardium; the coronary arteries
were ‘focally thickened with mild coronary arteriosclerosis’. Chief Medical
Investigator Ross Zumwalt, MD summarised the findings as, ‘Unclassified cardiomyopathy, which resulted in a cardiac
dysrhythmia during exertion’.15 When
considered in the context of True’s
decades-long lifestyle of daily ultramarathon running, we suspect that the
autopsy findings were an example of
‘Phidippides cardiomyopathy’—the constellation of cardiac pathology that has
been in observed in the hearts of some
veteran extreme endurance athletes.1
MRI scans showing scattered scarring (red arrows) in the heart, especially in the interventricular septum.14
Heart Month 0 Vol 0 No 0
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Editorial
MODERATE EXERCISE: THE
SWEET-SPOT FOR LONGEVITY
Two very recent studies presented in
abstract form at major national meetings
may revolutionise our thinking about
running and its health effects.16 17 One is
a prospective observational study that
followed 52 600 people for up to three
decades.17 The 14 000 runners in that
study had a 19% lower risk of death compared with the 42 000 non-runners. Yet,
when they sub-grouped the runners by
weekly mileage, those who ran over 20 or
25 miles per week seemed to lose their
survival advantage over the non-runners
(figure 4). On the other hand, those who
ran between 5 and 20 miles total per
week enjoyed a 25% decrease in risk of
death during follow-up. The same
pattern emerged for speed of running: the
fast runners, those running typically over
8 miles an hour, appeared to get no mortality benefit compared with the nonrunners, whereas those who fared best
usually ran about 6–7 miles per hour—a
comfortable jog for most people. In addition, the individuals who ran 6 or 7 days
per week appeared to lose the mortality
benefits, whereas the survival advantages
accrued best for those who ran 2–5 days
per week.16
The Copenhagen City Heart Study
showed remarkably similar results. After
following 20 000 Danes since 1976, they
found that the joggers lived about 6 years
longer than the non-runners, with a 44%
lower risk of death during the study.17
Intriguingly, those who did best were the
people who jogged at a slow to average
pace, for one to 2.5 h per week total,
accumulated during two or three sessions.
According to Dr Peter Schnohr, the
study’s director, ‘The relationship appears
much like alcohol intakes—mortality is
lower in people reporting moderate
jogging than in non-joggers or those
undertaking extreme levels of exercise’.17
THE U-CURVE
Hippocrates, the father of medicine and a
contemporary of Phidippides in ancient
Greece, taught, ‘The right amount of
nourishment and exercise, not too much,
not too little, is the safest way to
health’.1 If you listen to your body, this is
just common sense. Yet, nothing we have
published previously has stirred so much
controversy, especially among the general
public. Increasingly our culture is one of
extremes: during the past 30 years,
obesity has tripled in the USA and has
increased in much of the Western World,
while during the same time the number
of people completing a marathon has
risen 20-fold. On one side of the U-curve,
the couch loungers/channel surfers
embrace this message as justification for
continuing their sedentary lifestyle. And,
on the far end of the U-curve, the
extreme exercise aficionados want to
ignore the message and instead kill the
messenger. As with many things in
life, the safe and comfortable zone at
the bottom of the U curve—moderate
exercise—is the ‘sweet spot’ for which
most should try to aim.
Sitting is the new smoking; a sedentary
lifestyle will cause disability and disease,
and will shorten life expectancy. We are
not so much born to run as born to walk.
Ethnographic research indicates that, in
the environment of human evolution, our
ancient ancestors walked 4–10 miles a
day.4 Walking is superior to running for
mechanical efficiency and musculoskeletal
durability. Indeed, we advise our patients
that they can walk or garden hours a day
without concern about CV overuse injury.
So while it is true that exercise confers
powerful health benefits, the common
belief that more is better is clearly not
true. The unique and potent benefits of
exercise are best bestowed by moderate
exercise and physical activity. The exercise patterns for maximising CV fitness/
peak aerobic capacity are very different
from those that best confer CV health,
durability and overall longevity. So, if
one’s goal in life is to compete in the
marathon or triathlon of the Rio
Olympics in 2016, this will certainly
require high-intensity exercise for hours a
day. But, for those whose goal is to be
alive and well while watching the 2052
Olympics from the stands, then exercise
and physical activity at lower intensities
and durations would be more ideal.
CONCLUSION
The take home message for most is to
limit one’s vigorous exercise to 30–
50 min/day. If one really wants to do a
marathon or full-distance triathlon etc, it
may be best to do just one or a few and
then proceed to safer and healthier exercise patterns. On the other hand, light or
moderate intensity exercise does not
present the dose-dependent risks associated with excessive endurance exercise.
A routine of moderate physical activity
will add life to your years, as well as
years to your life. In contrast, running
too fast, too far, and for too many years
may speed one’s progress towards the
finish line of life.
Contributors JHO and CJL contributed.
Competing interests None.
Provenance and peer review Commissioned;
internally peer reviewed.
Author note A video presentation on this topic is
available on the internet: You Tube, TEDx Talk, James
O’Keefe, Run for your life… at a comfortable pace and
not too far.
Heart 0;0:1–4. doi:10.1136/heartjnl-2012-302886
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1977;301:579–92.
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O’Keefe JH, Vogel R, Lavie CJ, et al. Exercise like a
hunter-gatherer: a prescription for organic physical
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Patil HR, O’Keefe JH, Lavie CJ, et al. Cardiovascular
damage resulting from chronic excessive endurane
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Kim JH, Malhotra R, Chiampas G, et al. Cardiac
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Med 2012;366:130–40.
Wen CP, Wai JP, Tsai MK, et al. Minimum amount of
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Ector J, Ganame J, van der Merwe N, et al.
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Michaelides AP, Soulis D, Antoniades C, et al.
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Breuckmann F, Mohlenkamp S, Nassenstein K,
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Zumwalt R. Autopsy Report TRUE, MICAH RANDALL.
In: Investigator OotM, ed. Albuquerque: University of
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Heart Month 0 Vol 0 No 0
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Run for your life … at a comfortable speed
and not too far
James H O'Keefe and Carl J Lavie
Heart published online November 29, 2012
doi: 10.1136/heartjnl-2012-302886
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REVIEW
Potential Adverse Cardiovascular Effects From
Excessive Endurance Exercise
James H. O’Keefe, MD; Harshal R. Patil, MD; Carl J. Lavie, MD; Anthony Magalski, MD;
Robert A. Vogel, MD; and Peter A. McCullough, MD, MPH
Abstract
A routine of regular exercise is highly effective for prevention and treatment of many common chronic diseases and
improves cardiovascular (CV) health and longevity. However, long-term excessive endurance exercise may induce
pathologic structural remodeling of the heart and large arteries. Emerging data suggest that chronic training for and
competing in extreme endurance events such as marathons, ultramarathons, ironman distance triathlons, and very long
distance bicycle races, can cause transient acute volume overload of the atria and right ventricle, with transient
reductions in right ventricular ejection fraction and elevations of cardiac biomarkers, all of which return to normal
within 1 week. Over months to years of repetitive injury, this process, in some individuals, may lead to patchy
myocardial fibrosis, particularly in the atria, interventricular septum, and right ventricle, creating a substrate for atrial
and ventricular arrhythmias. Additionally, long-term excessive sustained exercise may be associated with coronary
artery calcification, diastolic dysfunction, and large-artery wall stiffening. However, this concept is still hypothetical
and there is some inconsistency in the reported findings. Furthermore, lifelong vigorous exercisers generally have low
mortality rates and excellent functional capacity. Notwithstanding, the hypothesis that long-term excessive endurance
exercise may induce adverse CV remodeling warrants further investigation to identify at-risk individuals and formulate
physical fitness regimens for conferring optimal CV health and longevity.
© 2012 Mayo Foundation for Medical Education and Research 䡲 Mayo Clin Proc. 2012;87(6):587-595
R
egular exercise is one of the cornerstones of
therapeutic lifestyle changes for producing
optimal cardiovascular (CV) and overall
health. Physical exercise, though not a drug, possesses many traits of a powerful pharmacological
agent. A routine of daily physical activity (PA) stimulates a number of beneficial physiologic changes in
the body and can be highly effective for prevention
and treatment of many of our most prevalent and
pernicious chronic diseases, including coronary
heart disease (CHD), hypertension, heart failure,
obesity, depression, and diabetes mellitus.1 People
who exercise regularly have markedly lower rates of
disability and a mean life expectancy that is 7 years
longer than that of their physically inactive contemporaries.2,3 Accordingly, physicians are increasingly
prescribing regular exercise training (ET) for their
patients. The potential benefits of regular ET are
listed in Table 1.4
However, as with any pharmacological agent, a
safe upper-dose limit potentially exists, beyond
which the adverse effects (musculoskeletal trauma,
metabolic derangements, CV stress, etc) of physical
ET may outweigh its benefits. A very large recent
study found that in sedentary individuals, even a
modest dose of PA, as little as 15 minutes per day,5
confers substantial health benefits and that these
benefits accrue in a dose-dependent fashion up to
about an hour per day of vigorous PA, beyond which
more ET does not yield further benefits (Figure 1).5,6
Similarly, a 15-year observational study of 52,000
adults found that runners had a 19% lower risk of
all-cause mortality compared with nonrunners, with
U-shaped mortality curves for distance, speed, and frequency. Running distances of about 1 to 20 miles per
week, speeds of 6 to 7 miles per hour, and frequencies
of 2 to 5 days per week were associated with lower
all-cause mortality, whereas higher mileage, faster
paces, and more frequent runs were not associated
with better survival.7 A randomized crossover trial assigned 60 male patients with CHD to ET sessions of
either 30 or 60 minutes. The 30-minute exercise sessions produced less oxidant stress and improved arterial elasticity, whereas 60-minute sessions worsened
oxidant stress and increased vascular stiffness as measured by pulse wave velocity, mainly in older patients.8
Thus, the benefits of ET are attainable with
comparatively modest levels of PA. Highly trained
endurance athletes often perform strenuous aerobic
exercise for several hours daily, often accumulating
workloads of 200 to 300 metabolic equivalent hours
(metabolic equivalents ⫻ hours) per week, which is
approximately 5- to 10-fold greater than the standard ET dose recommended for prevention of
CHD.1,9 The aim of this review is to explore the
hypothesis that long-term excessive endurance ET
in some individuals may induce adverse CV structural and electrical remodeling that might diminish
some of the benefits conferred by more moderate
intensities and durations of ET.
From Mid America Heart
Institute of Saint Luke’s Hospital of Kansas City, MO
(J.H.O., H.R.P., A.M.); John
Ochsner Heart and Vascular
Institute, Ochsner Clinical
School–The University of
Queensland School of Medicine, New Orleans, LA, and
Pennington Biomedical Research Center, Louisiana
State University System, Baton Rouge (C.J.L.); University
of Maryland, Baltimore
(R.A.V.); and St. John Providence Health System Providence Park Heart Institute,
Novi, MI (P.A.M.).
Mayo Clin Proc. 䡲 June 2012;87(6):587-595 䡲 http://dx.doi.org/10.1016/j.mayocp.2012.04.005 䡲 © 2012 Mayo Foundation for Medical Education and Research
www.mayoclinicproceedings.org
587
MAYO CLINIC PROCEEDINGS
ARTICLE HIGHLIGHTS
TABLE 1. Potential Benefits of Exercise Training
 People who exercise regularly have markedly lower rates of disability
and a mean life expectancy that is 7 years longer than that of their
physically inactive contemporaries. However, a safe upper-dose limit
potentially exists, beyond which the adverse effects of exercise may
outweigh its benefits.
 Chronic intense and sustained exercise can cause patchy myocardial
fibrosis, particularly in the atria, interventricular septum, and right ventricle, creating a substrate for atrial and ventricular arrhythmias.
 Chronic excessive sustained exercise may also be associated with
coronary artery calcification, diastolic dysfunction, and large-artery wall
stiffening.
 Veteran endurance athletes in sports such as marathon or ultramarathon running or professional cycling have been noted to have a 5-fold
increase in the prevalence of atrial fibrillation.
 Intense endurance exercise efforts often cause elevation in biomarkers
of myocardial injury (troponin and B-type natriuretic peptide), which
were correlated with transient reductions in right ventricular ejection
fraction.
Related to coronary heart disease risk factors
Increases serum high-density lipoprotein
cholesterol levels
Reduces serum triglyceride and possibly lowdensity lipoprotein cholesterol levels
Reduces indices of obesity
Reduces arterial blood pressure
Improves insulin sensitivity and glucose levels
Improves endothelial function
Helps with smoking cessation efforts
Reduces psychological stress
Hematologic
Decreases hematocrit and blood viscosity
Expands blood plasma volume
Increases red blood cell deformability and tissuelevel perfusion
Increases circulatory fibrinolytic activity
Other
Increases coronary flow reserve
Increases coronary collateral circulation
Increases tolerance of ischemia
Increases myocardial capillary density
SUDDEN CARDIAC DEATH AND ENDURANCE ET
Over the past 35 years, the number of Americans
participating in a marathon annually has risen 20fold; in 2010, an estimated half-million runners
completed a marathon in the United States.10 Sudden cardiac death (SCD) among marathoners is very
rare, with 1 event per 100,000 participants.6,7,11,12
Although that per-participant risk has not changed
over the decades, absolute mortality rates have increased as the number of participants has risen. The
final 1 mile of the marathon course represents less
than 5% of the total distance of 26.2 miles yet accounts for almost 50% of the SCDs during the
race.12,13
The fatality rate for triathlons is approximately
twice that of marathons, largely because of increased
CV events and drownings during the swim portion
of the races.14 The incidence of SCD among collegiate athletes during competition is about 1 per
40,000 participants per year for all athletes.15 It is
extremely important to keep in mind that the occurrence of SCD during marathons, triathlons, and collegiate athletic events is rare and should not deter
individuals from participating in vigorous ET; the
benefits of regular PA to the individual and to
society as a whole far outweigh potential risks. At
the same time, long-term training for and competing in extreme endurance events may predispose
to CV issues that are not seen in more moderate
forms of PA.
588
Increases ventricular fibrillation thresholds
Reduces atherosclerosis
Possibly increases epicardial coronary artery size
Reduces major morbidity and mortality
From Mayo Clin Proc.4
The causes of SCD during or after extreme exertion in individuals younger than 30 years most
commonly include genetic causes such as hypertrophic cardiomyopathy, anomalous coronary arteries,
dilated cardiomyopathy, and congenital long QT
syndrome. In athletes older than 30 years, CHD and
acute myocardial infarction16 and ischemia are the
predominant causes of exercise-related SCD.17-23
ANIMAL STUDIES
In an elegant animal model of excessive endurance
ET, rats were trained (in part by prodding with electrical shocks to maintain high-intensity effort) to
run strenuously and continuously for 60 minutes
daily for 16 weeks, and then they were compared
with control sedentary rats.8,24 The running rats developed hypertrophy of the left ventricle (LV) and
the right ventricle (RV), diastolic dysfunction, and
dilation of the left atria and the right atria (RA); they
also showed increased collagen deposition and fibrosis in both the atria and ventricles (Figure 2).
Ventricular tachycardia was inducible in 42% of the
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running rats vs only 6% of the sedentary rats (P⫽.05).
Importantly, the fibrotic changes caused by 16 weeks
of intensive ET had largely regressed to normal by 8
weeks after the daily running regimen ceased.
This animal study found that daily excessive,
strenuous, uninterrupted running replicated the adverse cardiac structural remodeling and proarrhythmia substrate noted in observational studies of extreme endurance athletes. These findings support
the hypothesis that in some individuals, long-term
strenuous daily endurance ET, such as marathon
running or professional long-distance cycling, in
some individuals may cause cardiac fibrosis (especially in the atria and the RV and interventricular
septum), diastolic dysfunction, and increased susceptibility to atrial and ventricular arrhythmias. Many previous animal studies have also found acute, adverse
cardiac effects of prolonged (up to 6 hours) endurance
exercise, sometimes employing a rat model of coldwater swimming in which the animals were forced to
swim to avoid drowning.25 These studies are of uncertain clinical relevance because of the excessively stressful nature of the imposed exercise.
ATHLETE’S HEART
Chronic ET imposes increased hemodynamic demands that alter the loading conditions of the heart,
particularly among athletes participating in sports requiring sustained elevations in cardiac work, such as
long-distance running, rowing, swimming, and cycling.26 Highly trained individuals develop cardiac adaptations including enlarged LV and RV volumes, increased LV wall thickness and cardiac mass, and
increased left atrial size.21-23 In the general population,
these structural changes are associated with poor cardiac prognosis.27 However, these structural alterations, together with a preserved LV ejection fraction
(EF), have been considered typical findings of the “athlete’s heart.”18-20,28 Of concern, accumulating information suggests that some of the remodeling that
occurs in endurance athletes may not be entirely
benign.17,29-32 For example, in elite athletes, cardiac
dimensions do not completely regress to normal levels
even several years after the athlete has retired from
competition and heavy ET.33
BIOMARKER EVIDENCE FOR CARDIAC DAMAGE
WITH EXTREME ENDURANCE ET
Running is a prototypical natural PA and often plays
an integral and important role in an active, healthy
lifestyle.9,34-36 However, uninterrupted very long
distance running as is generally done while training
for and participating in marathons and other extreme endurance events may produce adverse CV
effects in susceptible individuals. Serologic markers
of cardiac damage, including cardiac troponin, cre-
All-cause mortality reduction (%)
CARDIOVASCULAR EFFECTS OF ENDURANCE EXERCISE
50
40
35%
29%
30
20%
20
14%
Vigorous
Moderate
Total
10
0
0
10
20
30
40
50
60
70
80
90
100
110
Daily physical activity duration (min)
FIGURE 1. Relationship between dose of physical activity and reduction
in all-cause mortality. The mortality benefits of exercise appear with even
small amounts of daily exercise and peak at 50 to 60 minutes of vigorous
exercise per day. From Lancet,5 with permission.
atine kinase MB, and B-type natriuretic peptide,
have been documented to increase in up to 50% of
participants during and after marathon running7,10-14 (Figure 3).9,12,37-40 Additionally, transient renal dysfunction has been observed with extreme endurance ET efforts causing volume
depletion and diminished renal filtration, with elevations in serum urea nitrogen, serum creatinine,
and cystatin C.41 Increased levels of cardiac biomarkers including troponin after extreme ET endurance events, such as marathons, may reflect myocardial cell damage at the sites of myocyte slippage of
one cell along another due to loss of integrity of desmosomal connections.15,42 However, the significance
of the elevated cardiac biomarkers after endurance efforts remains uncertain, and it has been argued that
these may be entirely benign transient increases resulting from CV adaptations to long-term ET.12,16,38,43
ADVERSE STRUCTURAL REMODELING
Accumulating evidence suggests that the adverse effects of both short-term intense PA and cumulative
endurance exercise are most apparent in the rightsided cardiac chambers. Cardiac output at rest is
approximately 5 L/min but typically increases 5-fold
to about 25 L/min during vigorous ET.21 Long-term
daily sessions of hours of continuous strenuous PA
cause dilation of the RA and RV. During the postexercise period, the cardiac geometric dimensions are
restored, but with this recurrent stretch of the chambers and reestablishment of the chamber geometry,
some individuals may be prone to the development
of chronic structural changes including chronic dilatation of the RV and RA with patchy myocardial
scarring in response to the recurrent volume over-
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589
MAYO CLINIC PROCEEDINGS
4 wk
8 wk
16 wk
Sedentary
RV FW sections
200 µm
Exercise
B
RV FW
IVS
LV FW
8 wk
6
5
4
3
2
1
0
Fibrosis (%)
4 wk
6
5
4
3
2
1
0
Fibrosis (%)
Fibrosis (%)
A
RV FW
IVS
LV FW
6
5
4
3
2
1
0
16 wk
*
Sedentary
Exercise
RV FW
IVS
LV FW
FIGURE 2. A, Picrosirius-stained photomicrographs of RV sections. By 16 weeks, the RVs of exercising
rats show widespread interstitial collagen deposition with disarray of myocardial architecture (arrows).
B, Mean ⫾ standard error of the mean collagen content in RV FW, IVS, and LV FW. *P⬍.05 (exercising
vs sedentary rats). FW ⫽ free wall; IVS ⫽ interventricular septum; LV ⫽ left ventricle; RV ⫽ right
ventricle. From Circulation,24 with permission.
load and excessive cardiac strain.17-19,29,44 These
abnormalities are often asymptomatic and probably
accrue over many years; they might predispose to
serious arrhythmias such as atrial fibrillation and/or
ventricular arrhythmias (VAs).
A prospective study of 25 runners (13 women
and 12 men) found that running a marathon caused
acute dilation of the RA and RV, with a sudden decrease in the RVEF.32 La Gerche et al45 studied a
cohort of 40 highly trained aerobic athletes after
competing in endurance events including marathon
(mean time to completion, 3 hours), half-ironman
triathlon (5.5 hours), full-ironman triathlon (11
hours), and alpine bicycle race (8 hours). They
found that these intense endurance exercise efforts
caused elevations in biomarkers of myocardial injury (troponin and B-type natriuretic peptide),
which were correlated with reductions in RVEF
(Figure 4), but not LVEF, on immediate (mean, 45
minutes) post-race echocardiography. The reductions in RVEF and the increases in RV volumes,
which returned entirely to baseline within 1 week,
590
were seen most often in races of longer durations
(Figure 5). Of this cohort of endurance athletes, 5
(12.5%) had myocardial scarring as detected by focal gadolinium enhancement on cardiac magnetic
resonance imaging (MRI) (Figure 6). The myocardial scarring and chronic RV remodeling were more
common in athletes with the largest cumulative experience in competitive endurance events.45 In
summary, this study suggests that intense endurance exercise induces acute RV dysfunction while
largely sparing the LV. Even when short-term RV
recovery appears complete, long-term training for
and competing in extreme endurance exercise may
lead to myocardial fibrosis and remodeling in a
small subgroup.9,20,21,45
Ector et al29 reported that the decrease in RVEF
is less significant in athletes with no symptoms of
arrhythmia than in endurance athletes who have
symptoms of arrhythmias, in whom the RV size increases and the RVEF is significantly lower. Another
study of endurance athletes who have symptoms of
VAs found that 50% of them had RV structural ab-
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CARDIOVASCULAR EFFECTS OF ENDURANCE EXERCISE
CORONARY ARTERY CHANGES
Veteran endurance marathon runners in one study
had coronary arteries that, at resting baseline, were
similar in size to those of sedentary controls, but the
marathoners had greater coronary artery dilating capacity.52 Mohlenkamp et al30 studied 108 middleaged German long-term marathon runners and
compared them with matched nonrunner controls.
They observed a greater atherosclerotic burden in
the marathoners as documented by higher coronary
artery calcium (CAC) scores. Additionally, during
100
hs-cTnT concentration (ng/L)
75
50
25
Upper
reference
limit (14 ng/L)
0
1 wk
before race
Immediately
after race
24 h
after race
72 h
after race
FIGURE 3. High-sensitivity cardiac troponin T (hs-cTnT) concentrations
before, immediately after, and 24 and 72 hours after marathon race. From
Med Sci Sports Exerc,40 with permission.
RV ejection fraction (%)
normalities by MRI.46 This RV dysfunction is likely
induced by recurrent extreme and sustained highlevel PA, with marked elevations in pulmonary
artery pressures of up to 80 mm Hg in some athletes,9 which eventually may cause scattered areas of
myocardial injury (as evidenced by the increases in
troponin) with subsequent fibrotic scarring, typically in the RV and atria.17,22,23,29,31,32 These
observations have led to speculation about the existence of a syndrome of exercise-induced arrhythmogenic RV cardiomyopathy that shares some features
with the familial RV disease but is caused by chronic
high-level endurance ET rather than a genetic
predisposition.9
Another study using MRI to assess the effects of
long-term very long distance running on myocardial
structure31 comprised 102 ostensibly healthy male
runners ranging in age from 50 to 72 years who had
completed at least 5 marathons during the previous
3 years, compared with 102 age-matched controls.31 Approximately 12% of these apparently
healthy marathon runners have evidence of
patchy myocardial scarring, manifested as late gadolinium enhancement; this was 3-fold more common
than in age-matched controls. Of additional concern,
the CHD event rate during 2-year follow-up was significantly higher in the marathon runners than in controls (P⬍.0001).31 A similar smaller study found
pathologic myocardial fibrosis by cardiac MRI in 6 of
12 asymptomatic men (50%) who were lifelong veteran endurance athletes, but no cases in younger endurance athletes and age-matched controls.24
Aortic stiffness and arterial pulse wave velocity,
which are markers for adverse CV prognosis,47,48
may be increased in veteran ultraendurance athletes.
A study of 47 individuals who trained extensively
for and competed in marathons found that pulse
wave velocity and aortic stiffness were significantly
higher in the group of marathoners compared with
controls.49 It is possible that the sustained shear
stress caused by protracted endurance efforts eventually may induce fibrotic changes and decreases in
arterial wall elasticity. Diastolic dysfunction of both
the RV and LV has also been observed in individuals
doing long-term extreme ET and racing.50,51
55
50
P=.050
45,47
40
35
Baseline
Post-race
Marathon (3 h)
Endurance triathlon (5.5 h)
Delayed
Alpine cycling (8 h)
Ultratriathlon (11 h)
FIGURE 4. Duration-dependent effect of endurance events on right ventricular (RV) ejection fraction. From Eur Heart J,45 with permission.
follow-up the adverse CV event rates in the marathoners were equivalent to those in a population
with established CHD.30 In a similar study,
Schwartz et al53 reported on a US cohort of longterm marathon runners, defined as individuals who
completed at least 25 marathons over the previous
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591
MAYO CLINIC PROCEEDINGS
Baseline
End-diastolic
volume
170
±30 mL
End-systolic
volume
66
83
±14 mL
±17 mL
150
±23 mL
Post-race
+9 mL
P=.015
+13 mL
P<.001
–7 mL
P=.003
–5 mL
P=.011
FIGURE 5. Differential effect of prolonged intense exercise on right and
left ventricular volumes. Baseline volumes are shown on the left, and the
changes in volume post-race are shown on the right. Right ventricular
volumes increased in the post-race setting, whereas left ventricular volumes decreased, resulting in a decrease in right ventricular ejection
fraction but not left ventricular ejection fraction. From Eur Heart J,45 with
permission.
25 years, and found higher than expected levels of
CAC and calcified coronary plaque volume. That
study, utilizing computed tomographic coronary
angiography, found that the long-term marathoners
had significantly more calcified plaque volume than
sedentary controls (mean, 274 mm3 vs 169 mm3).
In a case report, Goel et al54 observed a 49-year-old
marathoner who had significant obstructions in all 3
major epicardial coronary arteries without associated risk factors and who generated protracted oxidative stress with prolonged running.
In another study of veteran endurance athletes,
mean LV mass, as determined by MRI, was significantly greater in a group of marathon runners than
in controls, and the increased LV mass correlated
with higher CAC scores. Specifically, those marathoners with an LV mass greater than 150 g had a
significantly higher CAC score than those with an
LV mass less than 150 g.30 The investigators also
found a mismatch between the risk factor profile
and the amount CAC, particularly in the marathoners with an LV mass greater than 150 g.
592
PATHOPHYSIOLOGY OF LONG-TERM EXTREME ET
Figure 7 shows the pathophysiology and possible
adverse CV consequences (fibrosis, atrial arrhythmias, VAs, and SCD) associated with endurance
ET and competition, such as marathon running.
Individuals who do long-term ET and race over
very long distances induce sustained (often for 1
to several hours daily) elevations in heart rate,
blood pressure, cardiac output, and cardiac
chamber volumes.9 Heavy and sustained ET generates large quantities of free radicals55 that likely
outstrip the buffering capacity of the system, leaving these individuals susceptible to oxidative
stress and transient cardiomyocyte dysfunction.45
This repetitive cycle may stimulate immune cells,
including lymphocytes, macrophages, and mast
cells, to secrete cytokines that signal the myofibroblasts to proliferate and secrete procollagen,
which is then cross-linked to form mature collagen,41 eventually resulting in fibrosis deposited in
patches in the myocardium and more diffusely in
the large arteries.9,46
PROARRHYTHMIC EFFECTS OF EXCESSIVE
ENDURANCE ET
Although it has been recognized that elite-level
endurance athletes commonly have electrocardiographic abnormalities and atrial and ventricular
ectopy,28,44,54 these functional adaptations traditionally have not been thought to predispose to serious arrhythmias or SCD. However, it appears that
adverse cardiac remodeling induced by excessive ET
can create an arrhythmogenic substrate, and rhythm
abnormalities may be the most common CV
problems encountered by veteran endurance athletes.29,31,54 Indeed, long-term sustained vigorous
aerobic ET such as marathon or ultramarathon running or professional cycling has been associated
with as much as a 5-fold increase in the prevalence
of atrial fibrillation.19,30,31,37,55-63
Potential mechanisms underlying the association
of long-term excessive exercise and atrial fibrillation
are speculative but may include increased vagal and
sympathetic tone, bradycardia, inflammatory changes,
atrial wall fibrosis, and increased atrial size.59 Some
data indicate that atrial size may be larger in veteran
endurance athletes than in age-matched sedentary
controls.64 Indeed, the left atrium may be enlarged in
as many as 20% of competitive athletes, and this may
be a predictor for atrial fibrillation.59,64
In addition, complex ventricular ectopy, including ventricular tachycardia and rarely SCD,11
occurs even in very fit individuals.12,29 Despite the
fact that these studies generally excluded athletes
with findings suggestive of familial arrhythmogenic
RV dysplasia, the VAs typically originate from a
mildly dysfunctional RV and/or the interventricular
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CARDIOVASCULAR EFFECTS OF ENDURANCE EXERCISE
Extreme exercise efforts
(eg, marathon)
Catecholamine
O2 Demand
↑↑↑Preload
and ↑afterload
↑↑↑
↑Troponin, ↑CK-MB, ↑BNP
Immediate effects
Chronic training
LV dilatation
LV hypertrophy
↑LV mass
Long-term effects
↑Cardiac chamber sizes
Patchy areas of fibrosis
↑ Atrial arrhythmias
↑ Ventricular arrhythmias
↑ Incidence of SCD
Right heart strain
RA/RV dilatation
RV hypokinesis
Diastolic dysfunction
Subacute effects
↑
CONCLUSION
In some individuals, long-term excessive endurance ET
may cause adverse structural and electrical cardiac remodeling, including fibrosis and stiffening of the atria,
RV, and large arteries. This theoretically might provide a
substrate for atrial and ventricular arrhythmias and increase CV risk. Further investigation is warranted to identify the exercise threshold for potential toxicity, screening
for at-risk individuals, and ideal ET regimens for optimizing CV health. For now, on the basis of animal and human data, CV benefits of vigorous aerobic ET appear to
accrue in a dose-dependent fashion up to about 1 hour
daily, beyond which further exertion produces diminishing returns and may even cause adverse CV effects in
some individuals.
Consensus Guidelines for Physical Activity and
Public Health from the American Heart Association
FIGURE 6. Delayed gadolinium enhancement in 5 athletes. Images of 5
athletes in whom focal delayed gadolinium enhancement was identified in
the interventricular septum (arrows), compared with a normal study in an
athlete (top left). From Eur Heart J,45 with permission.
↑
RISK STRATIFICATION FOR ENDURANCE
ATHLETES
Currently, we have no proven screening methods
for detecting potential CV pathologic changes associated with extreme endurance ET. A logical strategy
for now might be to deploy postcompetition cardiac
biomarkers, echocardiography, and/or advanced imaging such as cardiac MRI to identify individuals at risk
for and/or with subclinical adverse structural remodeling and substrate for arrhythmias, but the cost would
likely be prohibitive.65 Computed tomography for
CAC scoring may be useful, particularly for those older
than 50 years who have been training extensively for
and competing in extreme endurance events. Exercise
testing generally has not been found to be helpful in
screening extreme endurance athletes, nor has costeffectiveness or clinical yield been found with the other
testing described earlier.
An obligatory pattern of compulsive and excessive daily exercise has been described that may have
adverse long-term mental and physical health consequences.67 A questionnaire developed to identify
obligatory exercisers may be useful for screening
veteran endurance athletes.68
Normal
↑
septum.20,29,46,65,66 The patchy myocardial fibrosis
(fibrillary collagen deposition) that may develop as a
reparative response to damaged myocardium can
favor reentry, which is well established as a substrate
for arrhythmia.29,51
Long-term extreme endurance ET and competition also stimulate multiple other disruptions, including episodic release of excessive catecholamines with
resultant coronary vasoconstriction, chronic elevations
of heart rate, changes in free fatty acid metabolism,
lactic acidosis, and metabolic derangements.41
Cardiac fibrosis
FIGURE 7. Proposed pathogenesis of cardiomyopathy in endurance athletes. BNP ⫽ B-type natriuretic peptide; CK-MB ⫽ creatine kinase MB;
LV ⫽ left ventricle; RA ⫽ right atrium; RV ⫽ right ventricle; SCD ⫽
sudden cardiac death.
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MAYO CLINIC PROCEEDINGS
and American College of Sports Medicine call for at
least 150 minutes per week of moderate ET or 75
minutes per week of vigorous ET in the general adult
population.1 Those guidelines also suggest that
larger doses of ET may be necessary in some groups,
such as those with or at risk for CHD (30 to 60
minutes daily), adults trying to prevent the transition to overweight or obesity (45 to 60 minutes per
day), and formerly obese individuals trying to prevent weight regain (60 to 90 minutes per day). The
guidelines also caution that high-intensity ET increases risk of musculoskeletal injuries and adverse
CV events.1
Abbreviations and Acronyms: CAC ⴝ coronary artery
calcium; CHD ⴝ coronary heart disease; CV ⴝ cardiovascular; EF ⴝ ejection fraction; ET ⴝ exercise training; LV ⴝ left
ventricular; MRI ⴝ magnetic resonance imaging; PA ⴝ physical activity; RA ⴝ right atrium; RV ⴝ right ventricular;
SCD ⴝ sudden cardiac death; VA ⴝ ventricular arrhythmia
Correspondence: Address to James H. O’Keefe, MD, 4330
Wornall Rd, Ste 2000, Kansas City, MO 64111 ([email protected]
saint-lukes.org).
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