World Journal of Cardiovascular Diseases, 2013, 3, 17-20 WJCD
http://dx.doi.org/10.4236/wjcd.2013.35A003 Published Online August 2013 (http://www.scirp.org/journal/wjcd/)
The rationale for pre-race aspirin to protect susceptible
runners from sudden cardiac death during marathons:
Deconstructing the Pheidippides conundrum
Arthur J. Siegel
Internal Medicine, McLean Hospital, Belmont, USA
Received 22 May 2013; revised 27 June 2013; accepted 13 July 2013
Copyright © 2013 Arthur J. Siegel. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Objectives: While endurance exercise such as train-
ing for marathons is cardioprotective, cardiac arrests
and sudden death occur in previously healthy runners
during races predominantly in middle-aged males
due to atherosclerotic heart disease. Recent evidence
related to this problem is reviewed herein including
epidemiologic studies and findings related to acute
cardiac risk in asymptomatic middle-aged male run-
ners during races. Method: Literature review related
to the above. Findings: The risks of cardiac arrest and
sudden death were 1 in 57,002 and 1 in 171,005 respec-
tively in runners with a mean age of 49.7 years among
1,710,052 participants in marathons in the United
States since 1980. Atherosclerotic heart disease was
the cause of death in over 90% of cases in two retro-
spective studies and a greater than two-fold increase
in cardiac arrests was observed in middle-aged men
in the latter half of a 10-year prospective registry be-
ginning in the year 2000. Asymptomatic middle-aged
male runners sho wed elevated bioma rkers of inflamma-
tion such as interleukin-6, C-reactive protein together
with procoagulant effects including in vivo platelet ac-
tivation, indicating susceptibility to atherothrombosis.
Conclusions: Antithrombotic prophylaxis is evidence-
based by validated clinical paradigms to prevent car-
diac arrest and sudden death in susceptibile mara-
thon runners at high risk for atherothrombosis dur-
ing races.
Keywords: Marathon Running; Cardiac Arrest; Acute
Myocardial In f a rct i on; At herothrombosis; Aspiri n
Prophylaxis
1. INTRODUCTION
While endurance exercise such as marathon training is
cardioprotective, an increased risk for sudden cardiac
death during races has been demonstrated predominantly
in middle-aged male participants. The conundrum of how
runners at low resting cardiovascular risk become vul-
nerable to cardiac arrest during races is explored herein
together with consideration of strategies for prevention.
2. MATERIAL AND METHODS
Review of medical literature related to the epidemiology
and pathogenesis of sudden cardiac death in marathon
runners during marathon races. Rates of cardiac arrest
and sudden death were 1 in 57,002 and 171,005, respec-
tively, in runners with a mean age of 49.7 years among
1,710,052 participants in United States marathons since
1980. Atherosclerotic heart disease was the cause of death
in over 90% of cases in those over age 40 in two retro-
spective studies. A greater than two-fold increase in car-
diac arrests events was observed in middle-aged males in
the latter half of a 10-year prospective registry ending in
the year 2010. Regarding pathogenesis, neutrophilia and
elevated biomarkers of inflammation including interleu-
kin-6 and C-reactive protein occurred in asymptomatic
middle-aged males during races as a likely consequence
of exertional rhabdomyolysis. Inflammation was accom-
panied by a hemostatic imbalance with procoagulant ef-
fects including elevated fibrinogen, D-dimer and in vivo
activation of platelets, conferring a transient risk for
atherothrombosis.
3. DISCUSSION
Because of concerns generated by the legacy of Pheidi-
ppides’ sudden cardiac death in 490 B.C. (Figure 1), the
first of many studies on Boston marathon runners in
1899 postulated an adverse effect of skeletal muscle
injury on the heart [1]. Epidemiological evidence regar-
ding such events during races in the modern era has re-

A. J. Siegel / World Journal of Cardiovascular Diseases 3 (2013) 17-20 18
Figure 1. Pheidippides’ sudden cardiac death in the Atheneum
in 490 B.C. after declaring victory over the invading Persian
army on the Plains of Marathon (by anonymous).
cently been published together with findings related to
the underlying pathogenesis. Rates of cardiac arrest and
sudden death were 1 in 57 ,002 an d 171 ,0 05 , resp ectively,
in runners with a mean age of 49.7 years among 1,710,052
participants in United States marathons since 1980 [2].
Atherosclerotic heart disease was the cause of death in
over 90% of runners over age 40 in two retrospective
studies [2,3]. A greater than two-fold increase in cardiac
arrests was observed in middle-aged males in the latter
half of a 10-yea r pr ospective registry en di n g in 20 1 0 [4] .
Studies in asymptomatic middle-aged runners during
races provide evidence that inflammation likely due to
skeletal muscle injury activated atherothrombosis to ac-
count for the triggering of acute cardiac events during
marathons in runners at low resting cardiovascular risk
[5]. Elevated serum creatine kinase as an index of exer-
tional rhabdomyolysis in runners after “hitting the wall”
was accompanied by neutrophilia, increased interleukin-
6, C-reactive protein and matrix metallo-protein ase-9 [6-
9]. Inflammation by this paradigm may render previous-
ly silent low-profile coronary atherosclerotic plaques vul-
nerable to rupture leading to acute myocardial infarction
[10].
Additionally, asymptomatic runners demonstrated a
hemostatic imbalance with procoagulant effects during
races, including increased fibrinogen, elevated D-dimer
and in vivo activation of platelets [11,12]. Biomarkers in
runners at low resting cardiovascular risk morph into a
profile creating a “perfect storm” for an acute coronary
syndrome.
A report of 3 runners with acute myocardial infarc-
tions due to plaque rupture after the 2011 Boston mara-
thon validates these findings in asymptomatic runners as
relevant to the pathogenesis of cardiac arrest and sudden
death in the epidemiological studies [13].
Evidence for the triggering of sudden cardiac death
during marathons by atherothrombosis in runners with
previously silent coronary atherosclerosis invites consi-
deration of strategies for prevention and treatment. Aspi-
rin prophylaxis has been shown to prevent first myo-
cardial infarctions in previously healthy individuals in
the final report on aspirin prophylaxis in the Physicians’
Healthy Study (PHS) in 1989, which finding has been
confirmed in subsequent meta-analyses of randomized
clinical trials [14,15].
Marathon runners are prime candidates for such trea-
tment, which is currently endorsed by the American
Heart Association for individuals at high, if transient,
cardiovascular risk. A low-dose non-enteric coated aspi-
rin taken even at the starting line can confer antithrom-
botic protection for the vulnerable period during and up
to 24 hours after the race [16]. This strategy is evidence-
based to prevent acute myocardial infarctions in asymp-
tomatic runners whose Achilles’ heel is the soft-coated
low-profile atherosclerotic plaque which may morph into
a culprit lesion.
What advice should we give susceptible runners re-
ceive regarding the cardiac risk of marathon races ana-
logous to the Food and Drug Administration’s advisory
on the excess of sudden cardiac deaths with azithromycin
in patients with cardiovascular disease [17]? We can en-
dorse pre-race aspirin to reduce the number of tragic car-
diac events during marathons according to the rationale
shown in Figure 2 [18]. Id ea lly wi th consultation and ap-
proval by their physicians, runners should be advised to
take pre-race low-dose aspirin to confer optimal protec-
tion during a vulnerable period of inflammation-induced
atherothrombotic risk while also minimizing complica-
tions associated with continuous usage such as gastro-
intestinal bleeding. Once embraced by the marathon run-
ning community, the efficacy of prerace aspirin might be
assessed prospectively among marathon runners at all
levels of ability including those who may be at risk for ac-
celerated coronary atherosclerosis from repetitive partici-
pation in races over many years [19].
While the jury may still be out on the question of di-
rect adverse myocardial effects of intense endurance ex-
ercise, [20,21] evidence for the triggering of cardiac ar-
rest and sudden death effect during marathon running is
Figure 2. The rationale for pre-race low-dose aspirin by ma-
rathon runners.

A. J. Siegel / World Journal of Cardiovascular Diseases 3 (2013) 17-20 19
compelling. “To aspirin or not to aspirin” should no lon-
ger be a question for susceptible marathon runners for
whom pre-race low-dose aspirin is already evidence-ba-
sed as cardioprotective. This strategy deserves conside-
ration to protect individuals from acute cardiac events du-
ring less intense recreational sports and perhaps espe-
cially for those previously seden tary who may initiate an
exercise program as promoted by the “million hearts”
initiative [22,23]. Pre-exercise low-dose aspirin looks
like a “win-win” situation for all these scenarios. Hippo-
crates, who is said to have prescribed aspirin-like reme-
dies in the time of Pheidippides, would likely concur with
this strategy as a case in point of “First, do no harm”.
4. CONCLUSION
The increased risk for cardiac arrest and sudden death
during marathon running occurs predominantly in mid-
dle-aged males with previously silent coronary heart di-
sease. The use of pre-race low-dose aspirin is evidence-
based by validated clinical paradigms to protect such run-
ners from acute cardiac events during races triggered by
high, even if transient, atherothrombotic risk.
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