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Editorial
Marathoner’s Heart?
Paul D. Thompson, MD; Fred S. Apple, PhD; Alan Wu, PhD
E
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during extreme exertion6 (especially in susceptible individuals7), and lead to such conditions as dilutional hyponatremia8
has remained an important medical interest in the risks of
prolonged exercise.
In this issue of Circulation, Neilan and colleagues9 provide
evidence for cardiac damage during marathon running. These
authors measured the serum biomarkers troponin T (cTnT)
and N-terminal probrain naturetic peptide (NT-proBNP) and
performed echocardiographic measurements of cardiac function in 60 recreational runners before and 20 minutes after the
2004 and 2005 Boston Marathon, a 42-km (26.2-mile) foot
race. None of the runners had increased cTnT concentrations
before the race, but 60% had cTnT concentrations greater
than the 99th percentile of normal (ⱖ0.01 ng/mL) after the
run, and 40% had cTnT values concentrations at or above the
concentration used by Neilan and colleagues to diagnose
myocardial necrosis (⬎0.03 ng/mL). NT-proBNP concentrations roughly doubled from a median of 106 before to 182
pg/mL after the race. Left ventricular (LV) size and ejection
fraction did not change, but estimated pulmonary artery (PA)
systolic pressure increased, and right ventricular (RV) enddiastolic volume and the percent change in RV area, an
estimate of RV systolic function, decreased. There was also a
decrease in LV early diastolic filling and an increase in late
diastolic filling, which was consistent with reduced LV
compliance. Furthermore, changes in both cTnT and NTproBNP correlated with changes in cardiac function, and
reductions in RV systolic function correlated with the increase in cTnT. Changes in serum cTnT and NT-proBNP
levels and cardiac performance were most marked in runners
with the least prerace training (P⫽0.03 for difference in
median change between groups). Specifically, runners who
averaged fewer than 35 miles of running per week had the
largest increases in cTnT and NT-proBNP and the biggest
decreases in RV contractility. There were no changes in
ischemia-modified albumin (IMA) immediately after the
race. IMA is a marker used to exclude myocardial ischemia,
but only if cTnT is also not increased. Moreover, it is well
known that increased lactate concentrations and decreases in
albumin, both of which occur during and after a marathon
race, can cause false-negative IMA results. Therefore, these
latter findings should be viewed with caution.
The authors duly note that this is not the first article to
document increases in serological markers of myocardial
damage or changes in echocardiographic indices of myocardial function with prolonged exertion. Indeed, according to a
literature search for articles published from 2004 to 2006
alone, there were at least 10 articles documenting increases in
cTnT with prolonged exercise, at least 5 documenting increases in serum NT-proBNP concentrations, and at least 6
suggesting decreases in left ventricular systolic or diastolic
function after prolonged exercise (P.D. Thompson, unpub-
fforts to evaluate the risks and benefits of exercise,
especially prolonged endurance exercise, are almost
as old as scientific medicine itself. Hippocrates, the
father of scientific medicine, included a chapter on athletic
training in his book Regimens in Health and suggested that
exercise should be moderate and only part of a healthy
lifestyle.1 Hippocrates was a near contemporary of Pheideppides, an Athenian who, in 490 BC, reportedly died after
running 40 km (24 miles) from Marathon to Athens to
announce the Athenians’ victory. Unfortunately, this oftenquoted story is probably only partly true. The runner was
unlikely to have been named Pheidippides. The distance was
likely much greater and probably extended from Athens to
Sparta to recruit more soldiers, back to Athens to announce
that the Spartans were not coming, and, finally, from Athens
to Marathon and back—a total distance of approximately 500
km.1 Furthermore, the exhausted runner probably did not die,
because his death is not noted by Herodotus, the major
historian of the event. There is an element of truth to the
legend, however, because 50 years later, Eucles did die after
running to Athens,1 providing at least some support for the
dangers of prolonged exertion.
Article p 2325
Competitive athletics thrived in Victorian England because
they were thought to build moral and ethical fitness, and the
concept of an “athlete’s heart” was more a moral than a
physiological concept.1 The emergence of such sports as the
Oxford–Cambridge boat race, endurance cycling, and running was accompanied by concern for the cardiac dangers of
prolonged exercise. F.C. Skey, a London physician, suggested that “the hard exercise in rowing” was one of the most
common causes of heart disease.2 These concerns about
rowers’, bicyclists’, and runners’ hearts persisted into the
20th century and were only dispelled by studies demonstrating the benefits of regular physical activity.2 Nevertheless,
recognition that vigorous or prolonged exercise can transiently increase the risk of sudden cardiac death in those with
occult heart disease,3–5 produce exertional rhabdomyolysis
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Henry Low Heart Center and Division of Cardiology,
Hartford Hospital, Hartford, Conn (P.D.T.); Department of Laboratory
Medicine and Pathology, Hennepin County Medical Center and University of Minnesota School of Medicine, Minneapolis (F.S.A.); and
Department of Laboratory Medicine, University of California Medical
School, San Francisco (A.W.).
Correspondence to Alan Wu, PhD, San Francisco General Hospital,
1001 Potrero Ave, San Francisco, CA 94110. E-mail
[email protected]
(Circulation. 2006;114:2306-2308.)
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.663245
2306
Thompson et al
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lished data, 2006). Given such overwhelming evidence of
myocardial harm from prolonged exertion and the observation that physical fitness and training do not fully protect fully
against increases in cardiac biomarkers in the present9 or
prior10 reports, should not prudent clinicians prohibit such
activities, even among their healthiest and most fit patients?
Perhaps F.C. Skey has been proven right after 139 years!
These results should provoke concern, but it may too early
to conclude that clinically important myocardial damage
occurs with prolonged endurance exercise. First, to our
knowledge, there is no evidence that former endurance
athletes suffer more heart failure or cardiac dysfunction from
accumulated myocardial damage, although we are unaware of
long-term studies evaluating the clinical status of recreational
marathon runners similar to those who comprise the present
report. Indeed, marathon participation by large numbers of
modestly trained runners is a relatively recent phenomenon.
We do not know the long-term effects of such participation,
although nearly all epidemiological studies support a cardiovascular benefit from habitual physical activity.11,12
Second, although these increased serum markers must be
assumed to be of cardiac origin, reports of cTnT increases
with prolonged exercise are reminiscent of earlier reports by
some of these same authors13 using increased creatine
kinase-MB (CK-MB) concentrations to document myocardial
damage after similar exercise. These concerns were alleviated
when increased concentrations of CK-MB concentrations in
skeletal muscle were demonstrated in biopsies from distance
runners14 and the percentage of CK-MB in the gastrocenemius muscle was shown to increase during marathon training.15 CK-MB is the developmental form of CK and is
expressed in embryonal muscle.16 Consequently, because
exercise training can injure skeletal muscle, the repair process
may recruit primitive regenerating muscle fibers containing
increased muscle CK-MB, which is then released with the
muscle injury produced by the exercise event. cTnT is also
the predominant early developmental TnT isoform17 and is
present in regenerating skeletal muscle. Among patients with
polymyositis or Duchenne dystrophy, cTnT was present in
skeletal muscle samples in 8 of 13 and 6 of 6 patients,
respectively.11 However, the currently available clinical cTnT
assay used by Neilan et al9 does not detect the regenerating
isoform of cTnT or cTnT in muscle from marathon runners
(Apple, unpublished data, 1999). Consequently, it is most
likely that the cTnT is of cardiac origin. The long-term
significance of this possible cardiac injury is unknown.
Animal models support the concept that cTnT is released
from cardiac muscle with strenuous exercise. Rats forced to
swim for 5 hours had increases in serum cTnT concentrations
as well as histologic evidence of myocyte damage 24 and 48
hours after exertion.18 Interestingly, exercise training for only
8 days before the swim reduced the histologic evidence of
cardiac injury.
Third, echocardiography and, indeed, all noninvasive measures of myocardial function are only estimates of cardiac
performance. Echocardiogram results have been validated by
other methods, but, to our knowledge, they have not been
validated in the population in this study. For example, PA
pressure measurements with echocardiography often assume
Marathoner’s Heart
2307
a right atrial (RA) pressure of 10 mm Hg, although this is not
specified in the present report.9 Reductions in intravascular
volume could decrease RA pressure and overestimate PA
pressure. Runners in the present study lost an average of only
3 lb, but changes in body weight underestimate fluid shifts
into the muscle with exercise.19 Body builders use this
phenomenon to produce the pumped muscle appearance
before competition. Indices of LV diastolic function are also
affected by changes in intravascular volume20 and are not
totally independent of heart rate. Heart rate was 40 beats per
minute faster after the marathon and could have decreased
early, and increased late, diastolic filling. Changes in cardiac
performance did correlate directly with changes in serum
markers of injury and inversely with training mileage, adding
support to the concept of real myocardial damage; however,
statistical associations should not be used to indicate
causation.
The study by Neilan et al9 also adds to the debate over
whether cardiac troponin can be released in patients with
reversible myocardial injury. In the editorial accompanying
the redefinition of acute myocardial infarction, Jaffe et al21
suggested that although increases in myocardial biomarkers
probably reflected irreversible myocardial injury, there might
be a continuum of reversible to irreversible release, and it
might be impossible to determine the degree of injury from
biomarkers. Guidelines authored by the Cardiac Society of
Australia and New Zealand22 were also noncommittal, noting
the controversy over whether cytosolic troponin could be
released with reversible myocardial ischemia. More recently,
Lakkireddy et al23 reported transient cardiac troponin and
BNP increases as well as echocardiographic changes in a
patient with myocardial injury caused by Gram-positive
aerobic diphtheria. This report indicated that troponin can be
released in what appears to be reversible cardiac injury. In
contrast to the controversy on troponin release in reversible
injury, it has not been as rigorously examined whether B-type
natriuretic peptide and NT-proBNP can be released in reversible injury or synthesized after the stress of long-distance
running. In patients undergoing radionuclide exercise stress
testing, those with myocardial ischemia had 4-fold higher
NT-proBNP concentrations than those without ischemia.24
The novelty of this article is the demonstration of an inverse
relationship between cardiac biomarker release with V̇O2max,
miles of training in the 8 weeks before the race, finishing time
in the race, and muscle soreness.25 A study on the mechanism
of cardiac injury, as suggested by echocardiography or
imaging, is warranted.
These comments are not intended to detract from the
present report,9 but we urge caution in the interpretation of
this report, both by physicians and the lay press, and we urge
examination of the issues raised. It is critically important that
future investigators use other measures to examine myocardial function after exercise and to validate the many echocardiographic reports of myocardial dysfunction. Changes in
cTnT should be confirmed by other markers of myocardial
injury such as cTnI. If concerns about myocardial damage
cannot be dismissed, it is important to determine the longterm sequelae of prolonged exercise among minimally trained
marathoners. It is also important to determine with certainty
2308
Circulation
November 28, 2006
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whether skeletal muscle is a possible source of some of the
biomarkers reported. This seems unlikely, but it should not be
dismissed without additional consideration, given the historical experience with CK-MB in similar athletes. On the other
hand, given the present results, it is possible in retrospect that
even the earlier reports of CK-MB increases with endurance
exercise were indicative of myocardial injury. Clinically,
physicians should be aware that myocardial markers can
increase after prolonged exercise and that such increases
require confirmation and other symptoms before assuming
that athletes have suffered classical ischemic myocardial
injury. Finally, participants in such events should adequately
prepare for such events because all markers of possible
myocardial dysfunction were more pronounced in the leasttrained runners. Even the Victorians would agree with the
latter suggestion.
The present report is disturbing, considering the present
widespread interest and participation in recreational endurance events. There is, however, compelling evidence for the
cardiovascular benefits of regular physical activity, and we
should be circumspect in once again evaluating the possibility
that there are indeed deleterious consequences of the “marathoner’s heart.”
Disclosures
None.
10.
11.
12.
13.
14.
15.
16.
17.
18.
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KEY WORDS: Editorials
䡲
exercise
䡲
muscles
Marathoner's Heart?
Paul D. Thompson, Fred S. Apple and Alan Wu
Circulation. 2006;114:2306-2308
doi: 10.1161/CIRCULATIONAHA.106.663245
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