According to the World Health Organization (WHO), physical activity is currently defined
as a bodily movement generated by skeletal muscles and needing energy expenditure,
while physical exercise is ranked as a subcategory of physical activity, being planned,
repetitive, structured, and focused on obtaining enhancement (or preservation) of
physical fitness.[1 ] Sports is instead typically defined as an activity based on physical exertion in
which individuals or teams compete against others. Sports is additionally divided
basically into “amateur” (also known as “recreational”), in which participants are
mostly or entirely engaged without remuneration, and “professional” in which athletes
are typically remunerated for the time spent in training and/or competing.[2 ] Unlike the widespread popular perception, these two definitions do not overlap with
those of “competitive” or “noncompetitive” physical exercise, because the aim of athletes
engaged in competitive sports involves—or is determined by—rivalry (therefore, entailing
the straightforward dichotomy between “winning” and “losing”), whereas subjects engaged
in noncompetitive (leisure) exercise are essentially undertaking physical activity
for the pleasure of it. The concept of competitive sports is also frequently associated
with that of “prize winning,” regardless of the real value of the “prize” (i.e., from
a simple medal to large amounts of money).
The clear-cut distinction between competitive and noncompetitive sports, as well as
that between recreational and professional sports, has relevant implications for human
health. Competitive and professional athletes often seek to enhance their athletic
performance by high volumes of training, use of dietary supplements, and sometimes
unfair practices (e.g., doping), thus pushing their bodies close to, and occasionally
over, their physiological limits.[3 ] On the contrary, the physiological boundaries of physical exercise, typically expressed
in “volume” as the sum of intensity and duration, are much lower for recreational
or noncompetitive individuals. However, recreational or noncompetitive individuals
may still be exposed to considerable health risks as their volume of physical exercise
increases, because their basic training is typically not adequate to sustain acute
escalations of exercise volume.[4 ]
[5 ] The paradigmatic example is that of a recreational runner, who used to run 5 to
10 km per week, but then decides to participate in a local marathon, covering a distance
that is by far in excess of the baseline training status.[6 ] Therefore, an appropriate balance between basic training and exercise volume is
what mostly defines the safe (or healthy) boundaries of physical activity. This evidence
has contributed to developing the concept of “tailored exercise,” which entails individually
customized activities and volumes of exercise.[6 ]
[7 ]
Recent statistics from the European Commission[8 ] identify that approximately 41% of European citizens are engaged in some forms of
physical exercise or sports at least once a week, 46% of whom practice vigorous physical
activity at least once per week, and 20% exercising ≥ 5 times per week. Interestingly,
nearly three quarters of those practicing vigorous physical exercise admitted to spending
≥ 60 minutes per week performing such exercise. Overall, the prevalence of physically
active men is slightly higher than that of physically active women (45 vs. 37%), while
the practice of regular exercise declines in parallel with aging (i.e., 64% in European
citizens aged 15–24 years compared with 30% in those aged 55 years or older). Those
with higher levels of education and belonging to higher socioprofessional categories
are more likely to exercise. This physical exercise mainly involves parks and other
outdoors settings (i.e., 40%), followed by in-house (i.e., 36%) or travel to work,
school, and shops (i.e., 25%). The vast majority (i.e., 74%) of those who regularly
practice physical exercise do not belong to clubs or teams, while the vast majority
also engage in physical activity or sports with the aim of improving health and fitness.
Interestingly, swimming is the most practiced form of physical activity in Europe
(22%), followed by cycling (19%), walking (14%), running (13%), and football (6%).
Epidemiology and Causes of Sudden Death in Athletes
Sudden death in athletes is conventionally defined as an unexpected and instantaneous
death occurring during or immediately after (i.e., within 1–3 hours) exercise, due
to any cause except violence.[9 ]
[10 ] Although no definitive classification criteria have been defined so far, it is conventionally
accepted that the possible causes of sudden death in sports can be divided into cardiac,
that is, sudden cardiac death (SCD), and noncardiac (see [Table 1 ]). Sudden cardiac arrest (SCA) is instead defined as abrupt loss of heart function
in subjects with or without heart disease, mainly due to a sudden and unexpected cessation
in heartbeat, potentially leading to SCD.[11 ]
Table 1
Leading causes of sudden death in athletes
Noncardiac
• Hyperthermia, including heat stroke
• Use of illicit drugs
• Acute pulmonary diseases, including pulmonary embolism
• Acute cerebral diseases, including stroke and hyponatremic encephalopathy
• Sickle cell disease
• Rhabdomyolysis
Cardiac
• Hypertrophic or dilated cardiomyopathies
• Coronary artery abnormalities
• Myocarditis
• Arrhythmogenic cardiomyopathies, including channelopathies
• Valvulopathies
• Coronary artery disease
• Aortic stenosis or rupture
Overall, the percentage of sudden deaths occurring during, or immediately after, exercising
is ∼5% of all sudden deaths.[12 ] The frequency of sudden death in athletes seems to vary widely in the current scientific
literature, depending on sample size, targeted population, geographical area, and
definition of sudden death.[13 ] Even in endurance sports, such as marathon running, the frequency is highly heterogeneous
among published studies.[14 ] The number of studies which have so far investigated sudden death in athletes is
enormous. A PubMed search using the keywords “sudden death” AND “sport” OR “athletes”
with no date or language restrictions produces more than 1,300 documents. Since it
is largely infeasible to thoroughly evaluate each single study from such a long list,
and given the known heterogeneity of available studies, we will instead report here
the findings of some of the most interesting or informative studies based on our knowledge
and viewpoint.
In 1980, Maron et al investigated the possible causes of sudden death in 29 competitive
young athletes (i.e., aged 13–30 years) by necroscopy,[15 ] and found that the vast majority of deaths (28/29; 97%) were caused by probable
(6 out of 29; 21%) or unequivocal (22 out of 29; 76%) cardiovascular causes. Hypertrophic
cardiomyopathy (HCM) was found to be by far the most common abnormality (14 out of
29; 48%), followed by idiopathic left ventricular hypertrophy (5 out of 29; 17%) and
coronary artery disease (CAD) (3 out of 29; 10%). In an ensuing investigation published
nearly 20 years after this earlier report, Maron et al reported the findings of a
large U.S. registry including 1,866 athletes who suddenly died or survived of a SCA
while practicing sports over a 27-year period.[16 ] The overall incidence of sudden death was estimated at 0.61/100,000 person-years.
Cardiovascular causes could be identified in more than 56% of cases (1,049 out of
1,866), the most frequent of which were possible or certain HCM (370 out of 1,866;
19.8%), myocarditis (57 out of 1,866; 3.1%), and arrhythmogenic right ventricular
cardiomyopathy (ARVC) (41 out of 1,866; 2.2%). CAD was identified in 23 out of 1,866
(1.2%) cases, while the most frequent noncardiac causes (excluding injuries) were
heat stroke, abuse of illicit drugs, and acute pulmonary diseases. Most cases were
recorded in American football athletes, followed by basketball, soccer, and baseball
players. A third study was then published by the same team of authors in 2016, based
on data of 2,046 athletes contained in the U.S. National Registry of Sudden Death
in Athletes accumulated between the years 1980 and 2011.[17 ] Autopsy-confirmed cardiovascular diseases could be identified in 802 out 2,046 (40%)
cases, mainly represented by HCM (302 out of 2,046; 14.8%), coronary arteries abnormalities
(158 out 2,046; 7.7%), myocarditis (57 out of 2,046; 2.8%), ARVC (43 out of 2,046;
2.1%), and CAD (38 out of 2,046; 1.9%). The most frequently involved sports disciplines
were football, basketball, baseball, and cross-country running. Interestingly, the
most frequent noncardiovascular- and noninjury-related causes of sudden death were
illicit drug abuse (81 out of 2,046; 4.0%) and sickle cell disease (31 out of 2,046;
1.5%). The vast majority of subjects with confirmed SCD were noncompetitive athletes
(746 out of 842; 88.6%).
A remarkably high frequency of cardiovascular disorders (163 out of 200; 81.5%), followed
by cerebral (15 out of 200; 7.5%) and pulmonary (10 out of 200; 5%) diseases was found
in 200 cases of sudden death in young Italian athletes aged 35 years or younger.[18 ] The most common cardiovascular causes of SCD were CAD (23%), followed by arrhythmogenic
cardiomyopathies (22%), valvulopathies (10%), and HCM (5.5%).
Recently, Harmon et al published the results of a large survey based on the U.S. National
Collegiate Athletic Association database, in which all cases of sudden death involving
collegial athletes were identified during a 5-year period (years 2004–2008).[19 ] Overall, 273 deaths could be recorded during 1,969,663 athlete participant-years
(i.e., 13.9/100,000 person-years), with 80 medical deaths (i.e., excluding injuries
and suicides; 4.1/100,000 person-years). Cardiac causes were identified in more than
half of the cases (45 out of 80; 56%), while other important causes were heat stroke
and sickle cell disease. The most involved sports was basketball, followed by football
and swimming.
In a large epidemiological study aimed to define incidence and outcome of SCA in athletes
engaged in marathon and half-marathon running in the United States over a 10-year
period, the overall frequency of SCA was 0.54/100,000 person-years, nearly fourfold
higher in athletes engaged in marathons than in half-marathon running (i.e., 1.01
vs. 0.27/100,000 person-years).[20 ] The leading causes of SCA were HCM (49%) and CAD (16%), followed by arrhythmias
(14%), hyponatremia and hyperthermia (both 7%), and other cardiomyopathies (3%). In
another large prospective study on middle-aged (i.e., 35–65 years) residents of a
large U.S. community, an overall of 1,247 cases of SCD could be identified, 63 (5%)
of which occurring during sports activities (incidence, 2.2/100,000 person-years).[21 ] Interestingly, the leading underlying cause of SCD was CAD (36 out of 63; 57.1%),
while a positive history of heart disease could also be recorded in 20 out of 63 (31.7%)
cases.
Chappex et al published an interesting retrospective study based on autopsy records
and aimed to compare the possible triggers of SCD related and nonrelated to physical
exercise.[22 ] Overall, exercise-related sudden deaths were substantially lower than those that
were nonexercise-related (i.e., 12 vs. 88%). In both populations, CAD was the most
commonly encountered abnormality. However, in 357 cases of sudden death collected
over a 10-year period in United Kingdom athletes,[23 ] arrhythmogenic cardiomyopathies were the most frequent causes of SCD (55%), followed
by left ventricular hypertrophy (22%), coronary arteries abnormalities (5%), and CAD
(2%). The sports disciplines most involved were running (92 out of 357; 25.8%) and
football (91 out of 357; 25.5%), followed by cycling and gymnastics (both 30 out of
357; 8.4%) and swimming (22 out of 357; 6.2%). The vast majority of subjects were
competitive athletes (245 out of 357; 68.6%).
In 2016, Risgaard collected data from death certificates, autopsy reports, discharge
summaries, and registries in Denmark, to identify all possible cases of sudden death
that occurred between 2007 and 2009.[24 ] Overall, 881 cases could be identified, 44 (5.0%) of which were attributable to
exercise (11 in competitive athletes and 33 in noncompetitive athletes). In subjects
aged less than 50 years, the overall frequency of SCD was 8.6/100,000 person-years,
increasing to 38.5/100,000 person-years in subjects aged 48 to 49 years. The most
common causes of sudden death were CAD (158 out of 881; 17.9%), followed by sudden
unexplained mortality (136 out of 881; 15.4%). Notably, no significant difference
in the frequency of sudden death could be observed between noncompetitive and competitive
athletes. Most exercise-related events occurred in runners, followed by cyclists and
soccer players. Similarly, among nine cases of sudden death or SCA registered over
a 25-year period (i.e., from 1990 to 2014) in a 14-km running event annually held
in Sydney (Australia),[25 ] yielding a frequency of 3/100,000 person-years, a heart attack was identified as
the cause of SCD in the majority of cases (five out of nine; 56%), followed by SCA
(four out of nine; 34%). On those who had an autopsy performed, CAD was present in
the majority of cases (27 out of 61; 44%).[25 ] Likewise, among triathlon participants from the U.S. National Registry of Sudden
Death in Athletes followed up for 30 years,[26 ] 135 cases of sudden death or SCA were identified (1.74/100,000 person-years), mostly
occurring during the swimming trial (90 out of 135; 67%), while only 8 cases (6%)
could be recorded during postrace recovery.
In 2017, Landry et al published the results of a large retrospective investigation
based on data of the Rescu Epistry cardiac arrest database (subjects aged between
12 and 45 years), and averaging 18.5 million person-years of observation.[27 ] Overall, 74 SCA were recorded during sports participation, 58 occurring in competitive
sports and 16 in noncompetitive sports, thus leading to a global incidence of 0.76
SCA per 100,000 athlete-years. The leading cause of SCA in athletes aged 35 years
or younger was a structural and primary arrhythmia, while CAD was the leading cause
in those aged 35 to 45 years. The authors concluded that the risk of SCA was relatively
low in athletes participating in sports activities compared with the incidence in
the general population of the same age group (i.e., 4.84 cases per 100,000 person-years).
Accordingly, some interesting conclusions can therefore be made based on published
information on sudden death or SCA in athletes. First, the overall risk of sudden
death in athletes, albeit relatively low (usually comprised between 0.1 and 38/100,000
person-years) and globally comparable to that of the general population,[9 ] remains significant since up to 20% of all sudden deaths occur while exercising.
The most frequent underlying disorders encountered in SCD are HCM and CAD representing
altogether over three quarters of all conditions. Interestingly, the risk related
to CAD increases with aging (> 35 years old), while that attributable to cardiomyopathies
and/or fatal arrhythmias is especially frequent among younger individuals (< 35 years
old).
Pathogenesis of Ischemic Myocardial Injury in Physical Exercise
Many of the previously described studies showed that obstructive CAD is one of the
leading underlying conditions encountered in athletes who died or experienced of a
SCA while exercising, becoming the main cause of SCD in subjects aged 35 years or
older.[28 ]
[29 ] Obstructive CAD is the result of a progressively worsening coronary atherosclerosis,
which leads to a partial or total occlusion of the blood vessel. A superimposed arterial
thrombosis and a disruption in oxygen supply to myocardial tissue occur when the degree
of vessel stenosis is high (i.e., > 75%). This phenomenon may be accompanied, or not,
by ulceration or complete rupture of atherosclerotic plaque.[30 ]
[31 ] According to the most recent classification, this is now defined as the “typical”
(“type 1”) myocardial infarction, while the so-called type 2 myocardial infarction
recognizes distinctive mechanisms leading to irreversible ischemic myocardial injury,
mainly attributable to imbalance between oxygen demand from the contracting myocardium
and oxygen supply.[32 ] Recent studies have shown that a transitory myocardial injury is almost physiological
in endurance athletes and is directly related to exercise volume.[33 ] Nevertheless, when oxygen supply is no longer sufficient to withstand the enhanced
cardiac demand characterizing physical exercise (coronary blood flow may increase
up to fivefold during heavy exercise),[34 ] oxygen availability dramatically drops and the ischemic damage becomes gradually
irreversible (i.e., myocardial infarction with necrosis of myocardial tissue). This
can actually be attributable to at least three biological mechanisms, as shown in
[Fig. 1 ].[35 ]
Fig. 1 Possible mechanisms leading to myocardial ischemia during physical exercise.
The first mechanism is a likely consequence of vasoconstriction caused by an intense
release of catecholamines, up to the so-called adrenaline rush, occurring during stress
and strenuous efforts.[36 ] This condition, also known as “Takotsubo syndrome”, is likely attributable to catecholamine-induced
coronary vasoconstriction and/or spasm combined with enhanced cardiac workload, ultimately
leading to ischemic myocardial injury in a setting of a coronary tree with no, or
only modest presence of, atherosclerotic lesions on angiography ([Fig. 1 ]).[37 ]
[38 ]
The second mechanism is principally attributable to the presence of modest CAD (i.e.,
even < 25–50%), which would not be sufficient to trigger an irreversible ischemic
injury in resting conditions, but which may instead become clinically significant
as the oxygen demand by the contracting myocardium substantially increases during
heavy physical exercise ([Fig. 1 ]).[34 ] This is probably the most typical mechanism underlying SCD cases recorded among
“weekend warriors” or in occasional endurance runners.[29 ] It is also interesting to note here that physical exercise acutely triggers many
prothrombotic changes, including enhanced thrombin generation and platelet hyperreactivity,
which may ultimately amplify the severity of coronary thrombosis.[39 ]
The third mechanism is substantially independent of the structure and function of
the coronary tree, but is attributable to insufficient oxygen availability in blood,
which becomes much more clinically significant during heavy exercise. The most typical
condition is acute or chronic anemia, in which the concentration of hemoglobin transported
within the erythrocytes is no longer sufficient to meet the enhanced oxygen demand
of contracting myocardium, thus leading to irreversible ischemic injury even in the
lack of significant CAD or superimposed thrombosis ([Fig. 1 ]).[40 ]
Notably, this classification of type 2 myocardial infarction is not always straightforward
because an overlap among the three mechanisms may occur in certain individuals (i.e.,
catecholamines-induced vasoconstriction may also occur in patients with modest coronary
atherosclerosis), nor can it be excluded that some athletes may actually suffer from
a typical type 1 myocardial infarction. Two recent studies published by Merghani et
al[41 ] and by Aengevaeren et al[42 ] showed that though the prevalence of coronary atherosclerosis seems to be higher
in athletes than in sedentary subjects with comparable risk profile, coronary plaques
in physically active people appear more stable in nature, so attenuating the risk
of rupture and subsequent myocardial ischemia. These findings, along with evidence
of a considerable increase of peak coronary blood flow during exercise, make it very
likely that type 2 myocardial infarction may be the most frequent cause of myocardial
ischemia in athletes with SCA and/or SCD ([Fig. 1 ]).
Preventing Sudden Cardiac Death during and After Physical Exercise
According to the WHO,[43 ] physical exercise remains one of the leading measures for preventing the onset and
the complications of a large number of the most frequent human disorders (i.e., coronary
heart disease, stroke, diabetes, cancer, depression, fractures), but is also essential
for weight maintenance, increasing fitness, and for decreasing the risk of all-cause
mortality. The WHO currently recommends that adults (i.e., between 18 and 64 years)
should be engaged in not less than 150 minutes of moderate-intensity aerobic physical
exercise or in not less than 75 minutes of vigorous-intensity aerobic physical activity
per week, performed in bouts of not less than 10 minutes duration. Additional health
benefits may be achieved with engagement in moderate-intensity aerobic physical activity
up to 300 minutes or in 150 minutes of vigorous-intensity aerobic physical activity
throughout the week. Nearly identical recommendations have been provided by the American
Heart Association.[44 ]
Although little doubts exist that these straightforward recommendations should be
widely promoted for maintenance of health and fitness, the risk of adverse events
(especially SCD and/or cardiac arrest) during exercise remains tangible, as highlighted
by the current scientific literature. Therefore, the gap between the putative benefits
and the possible risks of physical exercise should be closed by developing additional
recommendations, especially aimed to identify subjects at enhanced risk of adverse
events while exercising.[45 ] Interestingly, more than 50% of middle-aged individuals who suffer SCA have warning
symptoms up to 4 weeks before the fatal event.[46 ] In this regard, preparticipation screening (PPS), an approach aimed to identify
athletes at risk of SCA and/or SCD, is highly recommended by the American Heart Association,
the European Society of Cardiology, and the International Olympic Committee[6 ] because it is the most effective strategy to prevent these events.[47 ] Likewise, education during screening procedure by health professionals also seems
recommended, instructing subjects to reach realistic goals in terms of performance
and exercise safely by planning the optimal individually tailored training program,
as well as to be aware of warning signs or symptoms of cardiovascular disease (angina
pectoris, ischemic equivalents, palpitations, impaired consciousness), or sudden appearance
of a cardiovascular event associated with exercise. Therefore, from our point of view,
implementing and/or reinforcing the recommendation of undergoing PPS, both in competitive
and noncompetitive athletes, and providing appropriate education during or immediately
after screening, may reflect a good practice standard to adopt. Briefly, PPS in young
population includes family history, physical examination, and a 12-lead electrocardiogram.[47 ] In adults, however, the risk calculation using scoring methods (based on age, sex,
blood pressure, blood cholesterol, and smoking history) is also recommended.[47 ]
[48 ] Last but not least, undergoing an annual follow-up with maximal exercise testing
(and even other cardiologic evaluations such as an echocardiogram) is also advised
in elderly and middle-aged individuals with an increased risk for coronary events
who wish to practice moderate/intense exercise.[6 ]
[47 ]
[49 ] Finally, no definitive evidence currently exists about the clinical efficiency of
performing additional investigations such as blood and genetic testing, with the exception
of urinalysis and iron stores assessment in female athletes.[49 ]
