Cardiovascular Events during World Cup Soccer ppt

Cardiovascular
Events during
World Cup
Soccer

T h e n e w e ngl a n d j o u r na l o f m e d icine
n engl j med 358;5 www.nejm.org january 31, 2008
475
original article
Cardiovascular Events during World Cup
Soccer
Ute Wilbert-Lampen, M.D., David Leistner, M.D., Sonja Greven, M.S.,
Tilmann Pohl, M.D., Sebastian Sper, Christoph Völker, Denise Güthlin,
Andrea Plasse, Andreas Knez, M.D., Helmut Küchenhoff, Ph.D.,
and Gerhard Steinbeck, M.D.
From Medizinische Klinik und Poliklinik I,
Campus Grosshadern (U.W L., D.L., T.P.,
S.S., C.V., A.P., A.K., G.S.), and Statis-
tisches Beratungslabor, Institut für Statis-
tik (S.G., D.G., H.K.), Ludwig-Maximilians-
Universität, Munich, Germany. Address
reprint requests to Dr. Wilbert-Lampen at
Med. Klinik und Poliklinik I, Campus Gross-
hadern, Marchioninistr. 15, D-81377 Mu-
nich, Germany, or at ute.wilbert-lampen@
med.uni-muenchen.de.
Drs. Wilbert-Lampen and Leistner con-
tributed equally to this article.
N Engl J Med 2008;358:475-83.

Copyright © 2008 Massachusetts Medical Society.
A b s t r ac t
Background
The Fédération Internationale de Football Association (FIFA) World Cup, held in
Germany from June 9 to July 9, 2006, provided an opportunity to examine the rela-
tion between emotional stress and the incidence of cardiovascular events.
Methods
Cardiovascular events occurring in patients in the greater Munich area were pro-
spectively assessed by emergency physicians during the World Cup. We compared
those events with events that occurred during the control period: May 1 to June 8
and July 10 to July 31, 2006, and May 1 to July 31 in 2003 and 2005.
Results
Acute cardiovascular events were assessed in 4279 patients. On days of matches
involving the German team, the incidence of cardiac emergencies was 2.66 times
that during the control period (95% confidence interval [CI], 2.33 to 3.04; P<0.001);
for men, the incidence was 3.26 times that during the control period (95% CI, 2.78
to 3.84; P<0.001), and for women, it was 1.82 times that during the control period
(95% CI, 1.44 to 2.31; P<0.001). Among patients with coronary events on days when
the German team played, the proportion with known coronary heart disease was
47.0%, as compared with 29.1% of patients with events during the control period.
On those days, the highest average incidence of events was observed during the first
2 hours after the beginning of each match. A subanalysis of serious events during
that period, as compared with the control period, showed an increase in the inci-
dence of myocardial infarction with ST-segment elevation by a factor of 2.49 (95%
CI, 1.47 to 4.23), of myocardial infarction without ST-segment elevation or unstable
angina by a factor of 2.61 (95% CI, 2.22 to 3.08), and of cardiac arrhythmia causing
major symptoms by a factor of 3.07 (95% CI, 2.32 to 4.06) (P<0.001 for all com-
parisons).
Conclusions
Viewing a stressful soccer match more than doubles the risk of an acute cardiovas-

cular event. In view of this excess risk, particularly in men with known coronary
heart disease, preventive measures are urgently needed.
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E
vents that induce environmental
stress in a large number of people in de-
fined areas — such as earthquakes, war,
and sporting events — may increase the risk of
cardiovascular events.
1-3
Reports of the associa-
tion between soccer matches and rates of illness
or death from cardiac causes have been contro-
versial.
4-9
The Fédération Internationale de Football As-
sociation (FIFA) World Cup was held in Germany
from June 9 to July 9, 2006. It provided the op-
portunity to investigate the relation of emotional
stress, experienced simultaneously in a predefined
population during the soccer matches, and car-
diovascular events, as prospectively assessed by
experienced emergency medicine physicians. We
hypothesized that in a country such as Germany
— where soccer is particularly popular — World
Cup matches involving the national team might
be a trigger strong enough to cause an increase

in the incidence of cardiac emergencies.
Me t hods
Acquisition of Data
The study sites were all in Bavaria: emergency
services in 15 locations, including the city of
Munich, the conurbation of Munich, and a rural
area, as well as 6 air rescue services and 3 inten-
sive care vehicles. The prospectively assessed study
period was June 9 to July 9, 2006. The periods of
May 1 to July 31 in 2005 and in 2003, as well as
May 1 to June 8 and July 10 to July 31, 2006, made
up the control period. The year 2004 was exclud-
ed on the basis of possible effects of the Euro-
pean Soccer Championship in Portugal that year.
We studied patients who had contacted emer-
gency services and had been treated by an emer-
gency medicine physician and given one of the
following final preclinical diagnoses: prolonged
acute chest pain due to myocardial infarction with
ST-segment elevation, myocardial infarction with-
out ST-segment elevation or unstable angina,
symptomatic cardiac arrhythmia, cardiac arrest
leading to cardiopulmonary resuscitation, or
therapeutic discharge of an implantable cardio-
verter–defibrillator. All patients included in the
study were admitted to a hospital for further
evaluation.
In order to rule out a possible increase in the
incidence of cardiovascular events caused by
shifts in population within the study area, we

included only those patients who had had an
event in their officially registered place of resi-
dence or within a 500-m radius of that residence.
Thus, cardiac events were analyzed for local Ger-
man residents only, not for visitors from inside
or outside Germany.
We analyzed the emergency medicine doctors’
records of the German Interdisciplinary Asso-
ciation for Intensive and Emergency Medicine
(DIVI).
10
From the records, the following data
were collected: date and location of the event,
time of the emergency call, time of the onset of
symptoms, details of the initial findings (i.e.,
blood pressure, heart rate, a brief medical his-
tory, and results on the electrocardiogram), the
final diagnosis, and the patient’s age and sex.
Weather data were obtained from Germany’s
national meteorologic service. Air-pollution data
were collected from the Environmental Authority
of the State of Bavaria.
The study protocol was approved by the ethics
committee of the Medical Faculty of the Ludwig-
Maximilians Universität and the Bavarian Medi-
cal Association. The requirement for informed
consent was waived.
Statistical Analysis
We used Poisson regression with a log link to
model the number of cardiovascular emergencies

per day.
11
A day was defined as a 24-hour period
beginning at noon. We compared events occur-
ring during three different periods: the 7 days of
World Cup matches played by the German team,
the 24 days of the World Cup without German
matches, and 242 control days (May 1 to June 8
and July 10 to July 31, 2006, and May 1 to July 31
in 2003 and 2005).
We calculated incidence ratios for the 7 days
of matches played by the German team and the
24 days of matches not involving the German
team as compared with the control period, using
indicator variables. We then calculated incidence
ratios for subgroups of patients, according to
their region of residence or their final diagnosis,
and compared them, assuming asymptotic nor-
mality of parameter estimates and independence
of events between subgroups.
In order to avoid confounding, we included in
our model the mean daily measurements for
temperature, barometric pressure, and levels of
particulate matter with a diameter smaller than
10 μm per cubic meter. All weather and air-pol-
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477
lution effects were checked for linearity with the

use of quadratic and smooth functions.
12
By us-
ing forward selection with Akaike’s information
criterion (AIC)
12
for the control-period data, we
included indicators for the year 2006 in our
model, as well as for the days Tuesday, Saturday,
and Sunday.
An autocorrelation plot of the Pearson residu-
als and a fitted quasi-Poisson regression analysis
involving an additional overdispersion parameter
clearly supported the assumptions of our model.
Analyses were performed with the use of the glm
and mgcv-gamm functions in the R software
package.
13,14
A P value of less than 0.05 was
considered to indicate statistical significance; all
tests were two-sided.
R e s ults
A total of 4279 patients with acute cardiovascular
events were included in the study. Figure 1 shows
the numbers of cardiovascular events per day.
The FIFA World Cup 2006 in Germany started on
June 9, 2006, and ended on July 9, 2006. Six of
the seven games in which the German team par-
ticipated were associated with an increase in the
number of cardiac emergencies over the number

during the control period.
In a match on June 9, Germany beat Costa
Rica (match 1 in Fig. 1); there was an increase in
the number of cardiovascular events on this day
as compared with the mean number during the
control period. This effect was even more pro-
nounced in the second preliminary match, when
Germany beat Poland in a dramatic game, with
the winning goal scored in the last minute
(match 2). The increase in the number of events
was less pronounced on the day of the match in
which Germany beat Ecuador (match 3); Germany
had already qualified for the next round.
The following matches were assumed to have
provoked a very high level of emotional stress,
because they were knockout games. On June 24,
Germany beat Sweden (match 4 in Fig. 1); the
increase in the number of cardiovascular events
over that in the control period was pronounced.
The quarterfinal on June 30 (match 5), in which
Germany beat Argentina after a dramatic penalty
shoot-out, was associated with a major increase
in the number of events. On the day of the semi-
final, in which Germany lost to Italy and failed
to reach the final (match 6), the number of events
increased roughly to the same extent as on the
day of the match against Argentina. On the day
of the match that determined third place, in
which Germany beat Portugal (match 7), the num-
ber of events was not increased. The final match

(match 8), Italy versus France, was again associat-
ed with a moderate increase in cardiac events.
Barometric pressure was positively associated
with an increase in the number of cardiovascu-
lar events (incidence ratio, 1.12 per 10 hPa), as
were the year 2006 (1.15), Tuesday (1.13), and
Sunday (1.07); Saturday showed a negative as-
sociation (0.78). Temperature (incidence ratio,
0.97 per 10°C) and particulate matter with a di-
ameter smaller than 10 μm (1.01 per 10 μg per
cubic meter) were forced a priori into the model,
although no effect could be demonstrated dur-
ing the study period. Consequently, the incidence
ratios listed in
Tables 1 and 2
were adjusted for
all these covariables.
Table 1
shows the incidence ratios for cardio-
vascular events. After adjustment for covariates,
the incidence during the matches involving the
German team was 2.66 times that during the
control period. No decrease in the number of
22p3
1
2
3
4
5
6

7
8
2003
2005
2006
70
Cardiovascular Events (no./day)
60
40
30
10
50
20
0
May 1 May 15 June 1 June 15 July 1 July 15 July 30
AUTHOR:
FIGURE:
JOB:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail
Line
H/T
Combo
Revised
AUTHOR, PLEASE NOTE:

Figure has been redrawn and type has been reset.
Please check carefully.
REG F
Enon
1st
2nd
3rd
Wilbert-Lampen
1 of 2
01-31-08
ARTIST: ts
35805 ISSUE:
Figure 1. Daily Cardiovascular Events in the Study Population from May 1
to July 31 in 2003, 2005, and 2006.
The FIFA World Cup 2006 in Germany started on June 9, 2006, and ended
on July 9, 2006. The 2006 World Cup matches with German participation
are indicated by numbers 1 through 7: match 1, Germany versus Costa
Rica; match 2, Germany versus Poland; match 3, Germany versus Ecuador;
match 4, Germany versus Sweden; match 5, Germany versus Argentina;
match 6, Germany versus Italy; and match 7, Germany versus Portugal (for
third-place standing). Match 8 was the final match, Italy versus France.
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cardiovascular events was observed during the
hours or days after the games with German par-
ticipation.
Analysis of the regional subgroups indicated a
significant increase in the number of events dur-

ing days on which Germany played in a match,
as compared with the control period, for patients
who lived in the city (incidence ratio, 2.63), those
who lived in the suburbs (3.11), and those who
lived in the countryside (1.99). The incidence of
events that led to interhospital transfer for fur-
ther evaluation increased as well (incidence ratio,
3.39). All effects were significant (P<0.001), al-
though there were no significant differences
among the incidence ratios between the regional
subgroups (P = 0.13). In contrast, we could not
demonstrate a significant increase in the num-
ber of events on the 24 days of the World Cup
without German participation.
Table 2
shows descriptive characteristics of pa-
tients who had a cardiovascular event, based on
the history taken by the emergency medicine phy-
sician. During the 7 days of matches played by
the German team, the proportion of patients who
were men was much higher (71.5%) than during
the control period (56.7%). For men, the inci-
dence of cardiovascular events during the days
of matches involving the German team was 3.26
times that in the control period; for women, the
incidence was 1.82 times that in the control
period; both effects were significant (P<0.001).
During the 7 days of matches played by the
German team, as compared with the control pe-
riod, patients tended to be younger (mean age,

65.4 vs. 68.5 years), the average heart rate and
systolic blood pressure were slightly lower, and
more patients had known coronary artery disease
(47.0% vs. 29.1%). In order to assess the effect of
stress in relation to the presence or absence of
known coronary artery disease, we calculated the
incidence ratios for patients with a history of
coronary artery disease, and for those without,
during the 7 days of matches played by the Ger-
man team. The number of events in patients with
known coronary artery disease increased by a
factor of 4.03, and in those without known coro-
Table 1. Incidence Ratios for Cardiovascular Events on Days during the World Cup, as Compared with Days during
the Control Period, in the Overall Group and in Subgroups.*
Group
Total No.
of Patients
Event during
7 Days of Matches
Involving Germany
(N = 302)
Event during 24 Days
of the World Cup
without German Matches
(N = 436)
Event during
242 Days of the
Control Period
(N = 3541)
Overall 4279

No. of events per day 43.1 18.2 14.6
Incidence ratio (95% CI) 2.66 (2.33–3.04) 1.11 (0.99–1.25) 1.00
P value <0.001 0.08
City 2474
Incidence ratio (95% CI) 2.63 (2.19–3.15) 1.17 (1.00–1.37) 1.00
P value <0.001 0.04
Suburb 503
Incidence ratio (95% CI) 3.11 (2.15–4.48) 1.20 (0.86–1.66) 1.00
P value <0.001 0.29
Countryside 726
Incidence ratio (95% CI) 1.99 (1.42–2.79) 0.93 (0.70–1.24) 1.00
P value <0.001 0.63
Interhospital transfer 576
Incidence ratio (95% CI) 3.39 (2.45–4.69) 1.06 (0.77–1.45) 1.00
P value <0.001 0.74
* Incidence ratios were calculated as the mean number of cardiovascular events per day for days during the World Cup
divided by the mean number per day for days during the control period. Data were adjusted for environmental and tem-
poral variables.
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479
nary artery disease by a factor of 2.05, as com-
pared with the number of events during the
control period. Both increases were significant
(P<0.001). The difference between the incidence
ratios of the two groups was also significant
(P<0.001).
For prespecified subgroup analyses, we grouped
the emergency medicine doctor’s final diagnosis

into four categories (
Table 3
). During the 7 days
of games with German participation, there were
6.1 myocardial infarctions with ST-segment eleva-
tion per day, as compared with 2.6 per day dur-
ing the control period, corresponding to an adjust-
ed incidence ratio of 2.49. During the 7 days, the
incidence ratio for chest pain, classified as myo-
cardial infarction without ST-segment elevation
or unstable angina, was 2.61; for the composite
of cardiac arrhythmias causing major symptoms,
the incidence ratio was 3.07, and for cardiac ar-
rhythmias causing minor symptoms, it was 2.13.
All increases were significant, but the effects
were similar among the four diagnostic catego-
ries (P = 0.62).
Figure 2 shows the numbers of events on days
of German matches relative to the start of the
game. There was a clear association between the
start of the match and the onset of cardiac symp-
toms. The highest number of events was observed
within the 2 hours after the start of the match,
with numbers that were higher than the average
(12.6 events) for several hours before and after
the match.
Dis cussion
Our results show a strong and significant in-
crease in the incidence of cardiovascular events
(including the acute coronary syndrome and

symptomatic cardiac arrhythmia), in a defined
sample of the German population, in association
Table 2. Characteristics of the Patients Who Had an Acute Cardiovascular Event on Days during the World Cup
as Compared with Days during the Control Period.*
Characteristic
Total No.
of Patients
Event during
7 Days of Matches
Involving Germany
(N = 302)
Event during 24 Days
of the World Cup
without German Matches
(N = 436)
Event during
242 Days of the
Control Period
(N = 3541)
Male sex 2490
Percent of patients 71.5 61.0 56.7
Incidence ratio (95% CI) 3.26 (2.78–3.84) 1.16 (1.00–1.35) 1.00
P value <0.001 0.05
Female sex 1789
Percent of patients 28.5 39.0 43.3
Incidence ratio (95% CI) 1.82 (1.44–2.31) 1.04 (0.87–1.44) 1.00
P value <0.001 0.67
Age — yr 4275 65.4±14.8 69.2±14.3 68.5±14.5
Heart rate — bpm 3537 87.0±32.5 92.0±35.2 92.9±36.9
Systolic blood pressure — mm Hg 4279 138.5±35.8 142.2±35.5 142.6±35.3

Known coronary artery disease 1319
Percent of patients 47.0 33.9 29.1
Incidence ratio (95% CI) 4.03 (3.28–4.95) 1.17 (0.95–1.43) 1.00
P value <0.001 0.13
No known coronary artery disease 2960
Incidence ratio (95% CI) 2.05 (1.72–2.44) 1.08 (0.94–1.25) 1.00
P value <0.001 0.29
* Plus–minus values are means ±SD. Incidence ratios were calculated as the mean number of cardiovascular events per
day for days during the World Cup divided by the mean number per day for days during the control period. Data were
adjusted for environmental and temporal variables.
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with matches involving the German team during
the FIFA World Cup held in Germany in 2006. In
contrast, the average daily number of cardiac
emergencies during soccer matches involving
foreign teams was well within the range of val-
ues obtained during the control period. Since the
incidence ratios were close to 1 for the days around
the German matches, it is clear that watching an
important soccer match, which can be associated
with intense emotional stress, triggers the acute
coronary syndrome and symptomatic cardiac ar-
rhythmia.
An association between soccer matches and
rates of illness or death from cardiovascular
causes has been previously investigated in six
retrospective epidemiologic studies.

4-9
Four as-
sessed mortality due to myocardial infarction and
stroke,
4,5,7,8
one assessed hospital admission due
to myocardial infarction and stroke,
6
and the last
involved a combined end point of cardiac and
extracardiac diseases.
9
Data were collected by
central bureaus for statistics. The results are
inconsistent: two studies showed an increase in
the relative risk of an event on the day of a
Table 3. Incidence Ratios for Cardiovascular Events on Days during the World Cup, as Compared with Days during
the Control Period, According to the Final Diagnosis.*
Diagnostic Category
Event during
7 Days of Matches
Involving Germany
(N = 302)
Event during 24 Days
of the World Cup
without German Matches
(N = 436)
Event during
242 Days of the
Control Period

(N = 3541)
STEMI
No. of patients 43 73 634
No. of events per day 6.1 3.0 2.6
Incidence ratio (95% CI) 2.49 (1.47–4.23) 1.09 (0.69–1.75) 1.00
P value <0.001 0.71
NSTEMI or unstable angina
No. of patients 171 243 1873
No. of events per day 24.4 10.1 7.7
Incidence ratio (95% CI) 2.61 (2.22–3.08) 1.11 (0.96–1.28) 1.00
P value <0.001 0.17
Cardiac arrhythmia causing major symptoms
No. of patients 71 89 767
No. of events per day 10.1 3.7 3.2
Incidence ratio (95% CI) 3.07 (2.32–4.06) 1.13 (0.87–1.47) 1.00
P value <0.001 0.35
Cardiac arrhythmia causing minor symptoms
No. of patients 17 31 267
No. of events per day 2.4 1.3 1.1
Incidence ratio (95% CI) 2.13 (1.24–3.66) 1.10 (0.71–1.71) 1.00
P value 0.006 0.66
Any category
No. of patients 302 436 3541
No. of events per day 43.1 18.2 14.6
* Cardiac arrhythmias causing major symptoms were defined as those characterized by atrial fibrillation with rapid conduc
-
tion (>100 beats per minute), ventricular tachycardia, cardiac arrest, or discharge of an implantable cardioverter–defibril-
lator. The composite of cardiac arrhythmias causing minor symptoms were defined as those characterized by sinus
tachycardia, sinus bradycardia, atrial fibrillation with normal conduction, or premature beats. Incidence ratios were calcu-
lated as the mean number of cardiovascular events per day for days during the World Cup divided by the mean number

per day for days during the control period. Data were adjusted for environmental and temporal variables. NSTEMI de-
notes myocardial infarction without ST-segment elevation, and STEMI myocardial infarction with ST-segment elevation.
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match,
4,5
another showed an increase but did
not evaluate it statistically,
6
two did not show an
increase,
7,8
and one showed a decrease.
9
In con-
trast, the conceptual design of the present study
was to prospectively evaluate clinical end points
(myocardial infarction with ST-segment elevation,
myocardial infarction without ST-segment eleva-
tion or unstable angina, and symptomatic cardiac
arrhythmia) in a predefined population before,
during, and after an entire soccer tournament,
with assessments by a team of experienced emer-
gency physicians. Using this study design, we
found that the risk of an acute cardiovascular
event on days on which matches were played by
the German team was considerably increased
overall, by a factor of 2.7; similar results were

also found for all diagnostic subgroups.
Carroll et al.
6
found a significant increase in
the incidence of acute myocardial infarction after
the national team lost a penalty shoot-out, and
we have documented an increase in the incidence
of cardiac events after the German team won a
penalty shoot-out. Apparently, of prime impor-
tance for triggering a stress-induced event is not
the outcome of a game — a win or a loss — but
rather the intense strain and excitement experi-
enced during the viewing of a dramatic match,
such as one with a penalty shoot-out.
Several studies have indicated that triggering
is more common in patients with known coro-
nary artery disease than in those without it.
1,15,16

Our results are consistent with these findings:
cardiovascular events on days of soccer matches
with German participation were associated with
an increased rate of known coronary heart dis-
ease. More specifically, events occurred in all pa-
tients more frequently during the 7 days of match-
es played by the German team than during the
control period, and the increase was greater
among those with a history of coronary artery
disease than among those without such a history
(incidence ratio, 4.03 vs. 2.05). We assume that

patients with preexisting coronary artery disease
had, on average, more extensive underlying dis-
ease (more vulnerable plaques), leading to more
frequent acute coronary syndromes, than did pa-
tients who were considered to be healthy before
the event.
The emergency records enabled us to analyze
the exact temporal relationship between the emo-
tional trigger (the soccer match) and the onset
of symptoms prompting the emergency call.
Averaged over all seven games involving Germa-
ny, the incidence of events increased during the
several hours before the match, the highest inci-
dence was observed during the 2 hours after the
start of the match, and the incidence remained
increased for several hours after the end of the
match. Trigger studies typically assess activities
that are regarded as acute trigger mechanisms
during the period of 1 or 2 hours before cardiac
symptoms occur.
15,16
Thus, our findings with re-
spect to the relationship between the timing of
the trigger and the cardiovascular event fully con-
cur with those in other trigger studies.
In accordance with other studies,
3-6
we found
that most of the additional cardiac emergencies
occurred in men. This phenomenon may be ex-

plained by sex-specific pathophysiological differ-
ences
17
or by differences in the degree of interest
in soccer matches or vulnerability to emotional
triggers.
18
A trigger can be defined as a stimulus that
produces pathophysiological changes leading
directly to disease — in this case, cardiovascu-
lar diseases.
18
Although various mechanisms of
stress-induced cardiac arrhythmias have been
described,
19-21
those underlying the induction of
acute coronary syndromes are less clear. As pre-
viously reported, stress hormones may directly
influence endothelial and monocytic function.
22-24

Thus, future evaluations of endothelial and mono-
cytic mediators in patients with stress-induced
cardiovascular events might clarify the mecha-
nisms of emotional triggering.
The excess risk of cardiovascular events associ-
ated with viewing stressful soccer matches (and
probably other sporting events) is considerable,
and evaluation of preventive measures is needed,

particularly in patients with preexisting coronary
artery disease. Interventions that might be con-
sidered include the administration or the increase
in dose of beta-adrenergic-blocking drugs, anti-
inflammatory agents such as statins, or anti-
platelet drugs such as aspirin, as well as the
blockade of stress-mediating receptors. In addi-
tion, nonmedical strategies, such as behavioral
therapy for coping with stress, should be con-
sidered.
Our study has several limitations. The differ-
entiation of myocardial infarction without ST-seg-
ment elevation from unstable angina was impos-
sible because of the limited prehospital diagnosis.
However, all patients with these diagnoses were
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found to require hospital admission for further
evaluation. In addition, the rate of interhospital
transport to specialized medical centers increased
equally in all diagnostic subgroups, showing a
high rate of serious cardiac events. We therefore
believe that the increase in the incidence of myo-
cardial infarction without ST-segment elevation
or unstable angina reflected the induction of
both conditions by stress, rather than emotion-
ally induced, temporary episodes of angina. To
confirm this, we would have to know the tropo-

nin levels.
Although the patients’ conditions were evalu-
ated by experienced emergency medicine physi-
cians, some misclassifications might have oc-
curred. However, this limitation is unlikely to
have affected differently the 7 days of matches
played by the German team, the 24 days of
matches not involving the German team, and the
control period.
Our results do not permit the identification
of the exact triggers that provoked the additional
cardiovascular events observed. Lack of sleep,
overeating, consumption of junk food, heavy alco-
hol ingestion, smoking, and failure to comply with
the medical regimen should all be considered.
In conclusion, we found a significant increase
in the incidence of cardiovascular events (consist-
ing of both the acute coronary syndrome and
symptomatic cardiac arrhythmia), in a defined
sample of the German population, in association
with matches involving the German team during
the FIFA World Cup, held in Germany in 2006.
We hypothesize that these additional emergencies
were triggered by emotional stress in relation to
soccer matches involving the national team. Fu-
ture studies are needed to assess stress trigger-
ing in association with other sporting events and
to analyze the efficacy of medical treatment, non-
medical treatment, or both in reducing this stress-
related excess risk of cardiovascular events.

Supported by the Else Kröner-Fresenius Foundation (grant
P34/05//A28/05//F01, to Dr. Wilbert-Lampen).
No potential conflict of interest relevant to this article was
reported.
We thank the FIFA Committee of Sports Medicine (W. Kinder-
mann and T. Graf-Baumann), the working committee of the
emergency physicians in Bavaria (P. Sefrin), the General German
Automobile Association (ADAC) air rescue service (E. Stolpe, G.
Bradschetl, and T. Schlechtriemen), the Fire Department of Mu-
nich (W. Schäuble and A. Stadler), and the Institute for Emer-
gency Medicine and Medical Management, Ludwig-Maximilians
University of Munich (C. Lackner, K. Peter, W.E. Mutschler, G.
Steinbeck, and J C. Tonn) for logistic support; staff of the Fac-
ulty of Anesthesia, Ludwig-Maximilians University of Munich
(S. Prückner, G. Kuhnle, and E. Weninger); Krankenhaus
Schwabing (E. Höcherl and A. Dauber); Rinecker Klinik (S. Grie-
bat); Krankenhaus Bogenhausen (R. Königer); Krankenhaus
Dritter Orden (G. Schwarzfischer); Kreisklinik Pasing (W. Gutsch);
Kreisklinik Perlach (R. Spies); Klinikum Traunstein (J. Kersting);
Klinikum Freising (C. Metz and C. Kurpiers); Krankenhaus Erd-
ing (D. Dworzak); Krankenhaus Wolfratshausen (M. Trautnitz);
Klinikum Straubing (Vogel and R. Mrugalla); Klinikum Kemp-
ten (G. Zipperlen); BG-Klinik Murnau (the hospital of an occu-
pational cooperative society) (M. Dotzer); Zentralklinikum
Augsburg (P. Wengert and W. Behr); Stadtklinik Bad Tölz (K.
Kiehling and M. Lang); Arbeiter–Samariter Bund Munich (K.
Kollenberger); and the air rescue services Christoph-1, Chris-
toph-14, Christoph-15, Christoph-17, Christoph-Munich, and
Christoph-Murnau (E. Stolpe, P. Meyer-Bender, J. Kersting, R.
Mrugalla, H. Vogel, G. Zipperlen, E. Weninger, and T. van

Bömmel) for the recruitment of patients and assistance; and
Andrea Ossig for her help with quality assurance and analyses
of the data.
22p3
30
No. of Cardiovascular Events
Onset of Cardiac Symptoms Relative to Start of Match (hr)
25
15
10
20
5
0
−12 −8 −4 0 4 8 12
AUTHOR:
FIGURE:
JOB:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail
Line
H/T
Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.

Please check carefully.
REG F
Enon
1st
2nd
3rd
Wilbert-Lampen
2 of 2
01-31-08
ARTIST: ts
35805 ISSUE:
Figure 2. Daily Cardiovascular Events According to the Time of Onset
of Symptoms before or after the Start of the Match.
The number of events was summed for all seven matches with German
participation. The start of the match is represented by the black triangle.
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registration
The Journal requires investigators to register their clinical trials
in a public trials registry. The members of the International Committee
of Medical Journal Editors (ICMJE) will consider most clinical trials for publication
only if they have been registered (see N Engl J Med 2004;351:1250-1).
Current information on requirements and appropriate registries
is available at www.icmje.org/faq.pdf.
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editorials
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1773
No potential conflict of interest relevant to this article was re-
ported.
This article (10.1056NEJMe078042) was published at www.
nejm.org on March 28, 2007.

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Cardiovascular Risks of Antiretroviral Therapy
James H. Stein, M.D.
Treatment with potent antiretroviral therapy has
transformed human immunodeficiency virus (HIV)
infection from a rapidly fatal disease into a chron-
ic illness that some patients can live with for more
than two decades. However, shortly after antiretro-
viral therapy was introduced, there were several
reports of acute myocardial infarction and pre-
mature atherosclerotic vascular disease among
young patients receiving such treatment.
1
Atten-
tion quickly focused on the protease inhibitors,
with speculation that lipodystrophy and its asso-
ciated metabolic disorders, including hyperlipi-
demia and insulin resistance, were increasing the
cardiovascular risk.
These findings were alarming, and a flurry of

research reports and editorials created a sense
of an impending “epidemic” of cardiovascular
disease, described by one writer as a “clockwork
bomb” that might explode.
2
Adding to the fire
were reports from observational studies suggest-
ing that the risk of myocardial infarction was
higher among patients receiving antiretroviral
therapy and particularly that the use of protease
inhibitors might increase cardiovascular risk.
3

However, the data were not consistent, and the
largest study, the Veterans Affairs Quality En-
hancement Research Initiative for HIV, reported
that rates of hospital admission for cardiovascu-
lar disease declined after the introduction of anti-
retroviral therapy, that the number of deaths
from cardiovascular causes did not increase, and
that specific classes of antiretroviral drugs were
not related to cardiovascular risk during a mean
follow-up of 15 months.
4
Unfortunately, the asso-
ciation between antiretroviral therapy and cardio-
vascular disease remained uncertain because sev-
eral of these studies had methodologic limitations,
including incomplete case ascertainment, incom-
plete data regarding exposure to antiretroviral

therapy, and a low number of cardiovascular
events.
3,4
Recently, several well-designed prospective
studies have shed some light on the complex in-
teractions among the use of antiretroviral ther-
Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
T h e n e w e ngl a n d j o u r na l o f m e dicine
n engl j med 356;17 www.nejm.org april 26, 2007
1774
apy, HIV infection, and cardiovascular risk. The
Strategies for Management of Antiretroviral Ther-
apy (SMART) study demonstrated that interrup-
tion of antiretroviral therapy was associated with
an increased risk of opportunistic disease or
death.
5
Furthermore, the drug-conservation strat-
egy in the SMART trial was associated with a
60% increase in the risk of cardiovascular dis-
ease during a mean follow-up of only 16 months,
indicating that effective viral suppression actu-
ally may reduce short-term cardiovascular risk.
These findings mirror those of AIDS Clinical
Trials Group Study 5152S, which assigned HIV-
positive patients who had not previously received
antiretroviral therapy to one of three drug regi-
mens, each omitting one aspect of the therapy
(one omitting a protease inhibitor, another omit-
ting a nucleoside reverse-transcriptase inhibitor,

and a third omitting a nonnucleoside reverse-
transcriptase inhibitor). The study showed that
after 24 weeks of therapy, endothelial dysfunc-
tion improved to a similar degree in all groups,
despite significant differences in lipoprotein lev-
els.
6
The implication of these studies is that
short-term use of antiretroviral therapy reduces
cardiovascular risk.
However, the long-term effects of such therapy
on cardiovascular disease are unclear, and the
report by the Data Collection on Adverse Events
of Anti-HIV Drugs (DAD) study group in this is-
sue of the Journal is informative.
7
Among the
23,437 patients who were followed for a median
of 4.5 years, there were 345 myocardial infarc-
tions. After adjustment for cardiovascular risk
factors (excluding lipids), patients receiving pro-
tease inhibitors had an increase in the risk of
myocardial infarction of 16% per year (P<0.001),
as compared with an increase of only 5% per year
(P = 0.17) among patients receiving nonnucleoside
reverse-transcriptase inhibitors. Adjusting for lip-
id levels, hypertension, and diabetes mellitus re-
duced the relative risk for use of protease inhib-
itors to 10% (P = 0.002) and for nonnucleoside
reverse-transcriptase inhibitors to 0% (P = 0.92).

The authors concluded that increased exposure
to protease inhibitors was associated with an in-
creased risk of myocardial infarction, a finding
that was partly explained by dyslipidemia, and that
“no evidence of such an association” was seen
for nonnucleoside reverse-transcriptase inhibitors.
The conclusions regarding protease inhibitors
are sound and are supported by the results of
the AIDS Clinical Trials Group Study 5078, which
showed that the use of the protease inhibitor
ritonavir had a small but statistically significant
effect on the progression of carotid-wall thickness
among patients with HIV infection.
8
Collective-
ly, these studies indicate that the short-term and
long-term risks of antiretroviral therapy may
differ.
How should physicians interpret these data?
First, it is critically important to recognize that
the magnitude of increased cardiovascular risk ob-
served with protease inhibitors is not high, espe-
cially as compared with the effect of other cardio-
vascular risk factors. The relative risk per year
of exposure to protease inhibitors was 1.16,
which is considerably smaller than the relative
risk of increasing age (1.39), male sex (1.91), cur-
rent smoking (2.83), and history of cardiovascu-
lar disease (4.3) (all P<0.001). Whether the use of
nonnucleoside reverse-transcriptase inhibitors is

associated with a lower risk of myocardial infarc-
tion than the use of protease inhibitors is less
certain. The incidence rates of myocardial infarc-
tion according to years of exposure to protease
inhibitors and nonnucleoside reverse-transcrip-
tase inhibitors overlap, and the relative risks ap-
pear to be quite unstable, with significant over-
lap noted through year 4, followed by a sudden
decrease in risk in the group receiving nonnucle-
oside reverse-transcriptase inhibitors by year 5.
Because of the low number of myocardial infarc-
tions and the short duration of follow-up of pa-
tients receiving nonnucleoside reverse-transcrip-
tase inhibitors, the trend is unclear. In the analysis
restricted to patients who had not previously re-
ceived treatment with the other drug class, the
confidence intervals were so wide that strong
conclusions cannot be drawn.
A second important point is that the incidence
of myocardial infarction among patients exposed
to protease inhibitors for more than 6 years was
only 0.6% per year, a rate similar to that of car-
diovascular events in the viral-suppression group
of the SMART study (0.8%).
5
This level of cardio-
vascular risk would be considered low or at most
moderate, depending on a patient’s risk-factor
burden.
9

Thus, there does not appear to be an
epidemic on the horizon — simply a risk that
needs to managed. Given the much greater car-
diovascular risks associated with diabetes melli-
tus and with smoking (and the high prevalence
of smoking among HIV-infected patients), per-
Downloaded from www.nejm.org on February 18, 2008 . Copyright © 2007 Massachusetts Medical Society. All rights reserved.
editorials
n engl j med 356;17 www.nejm.org april 26, 2007
1775
haps more effort should be spent assisting our
patients with smoking cessation and the preven-
tion of diabetes, rather than our focusing so in-
tently on the dyslipidemic effects of antiretroviral
therapy, especially since uncontrolled viremia is
a greater risk factor for death from cardiovascu-
lar causes than are the metabolic changes asso-
ciated with such therapy.
Aggressive treatment of HIV clearly is the
main clinical priority, and such therapy appears
to reduce cardiovascular risk, at least in the short
term. With increased exposure to antiretroviral
therapy, there is increased exposure to cardiovas-
cular risk factors. Being treated with a protease
inhibitor may increase cardiovascular risk mod-
estly; however, longer-term studies are needed to
understand the significance of this observation
and to determine which drugs within the classes
of protease inhibitors and nonnucleoside reverse-
transcriptase inhibitors may contribute to the

problem. Patients with HIV infection are living
longer — that’s the good news. But the longer
you live, the more likely it is that heart disease
will develop, so the treatment of modifiable risk
factors is prudent.
Dr. Stein reports receiving consulting fees from Abbott and Bristol-
Myers Squibb and grant support from Bristol-Myers Squibb. No other
potential conflict of interest relevant to this article was reported.
From the University of Wisconsin School of Medicine and Public
Health, Madison.
Passalaris JD, Sepkowitz KA, Glesby MJ. Coronary artery
disease and human immunodeficiency virus infection. Clin Infect
Dis 2000;31:787-97.
Maggi P, Fiorentino G, Epifani G, et al. Premature vascular
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Stein JH. Managing cardiovascular risk in patients with HIV
infection. J Acquir Immune Defic Syndr 2005;38:115-23.
Bozzette SA, Ake CF, Tam HK, Chang SW, Louis TA. Cardio-
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Stein JH, Cotter BR, Parker RA, et al. Antiretroviral therapy
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center trial (Adult AIDS Clinical Trials Group Study A5152s).
Circulation 2005;112:II-237. abstract.

The DAD Study Group. Class of antiretroviral drugs and
the risk of myocardial infarction. N Engl J Med 2007;356:1723-
35.
Currier J, Kendall M, Henry K, et al. 3-Year follow-up of ca-
rotid intima-media thickness in HIV-infected and uninfected
adults: ACTG 5078. Presented at the 13th Conference on Retro-
viruses and Opportunistic Infections, Denver, February 5–8, 2006.
abstract.
Grundy SM, Cleeman JI, Merz CN, et al. Implications of
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110:227-39. [Erratum, Circulation 2004;110:763.]
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