European Heart Journal (2014) 35, 30773082
doi:10.1093/eurheartj/ehu390
New directions for warm-up angina?
Researchers at National Institute for Health Research Biomedical
Research Centre at Guys and St Thomas Hospital, London, examine
new ideas for helping patients with coronary heart disease to warm up
and exercise without adverse effects
For nearly 250 years it has been known that, in patients with angina
pectoris, a period of exercise inducing chest pain makes it easier to
exercise later without pain. The first known observations were
made by British physician Dr William Heberden (who gave his
name to Heberdens nodes in rheumatic joint diseases). As cardiac
rehabilitation for coronary artery disease has become commonplace,
it has become a pressing question to make use of the phenomenon of
what is now called warm-up angina or warm-up ischaemia, but the
road to clear-cut advice is paved with obstacles. Patients who have
recently suffered a myocardial infarction are naturally wary of indu-
cing chest pain, whilst their physicians are caught between a rock
and a hard place. Recommend too much exercise and they risk
adverse events, yet recommend too little and they are perhaps not
offering the optimal rehabilitation package.
In an attempt to cast light on the counter-intuitive findings first
noted by Heberden, a team at Kings College, London, UK, led by Pro-
fessors Michael S. Marber and Simon R. Redwood, has been studying
the physiology and haemodynamics of the processes involved. The
research unit is based at Guys and St Thomas Hospital, London,
and its National Institute for Health Research (NIHR) Biomedical Re-
search Centre. One of their experimental set-ups involves an exer-
cise bicycle placed on a table in the catheterization laboratory.
Cath lab bicycle in action
Cath lab bicycle recordings
(credit Dr James Clark)
(credit Dr James Clark)
Their long-term goals are to elucidate the mechanisms of warm-up
angina and thereby to identify the points at which pharmacological
intervention might be able to achieve the same benefits at less risk
than intense exercise. Such a treatment would be directed at redu-
cing occurrence of angina-induced malignant ventricular arrhythmia
and LV dysfunction, and thereby perhaps sudden death. Current
AHA guidelines recommend moderately intense exercise (40 60%
of VO2 max) that at no time crosses a threshold set at a heart rate
of 10 bpm less than that at which angina or ST depression of 1 mm
occurs.1
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: journals.permissions@oup.com.
Evidence for the safety of endurance exercise in patients with
angina, following a period of warm up (510 min), was published 6
years ago in EHJ by Noel et al.2 In a study of 22 patients exercising
to the point of myocardial ischaemia, Noel et al. showed that, with ap-
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propriate ECG monitoring, there was no evidence of arrhythmia,
troponin-related myocardial damage, or left-ventricular dysfunction.
Yet such a short-term relatively small study did not provide evidence
of benefits over a less-intense exercise regimen based on the above
AHA guidelines, as Professor Marber et al. have pointed out: Unfor-
tunately, despite heroic efforts, the predicted benefits of prolonged
ischaemia were not apparent.
Recently, one of the Kings College team, Dr
Rupert Williams, reviewed the field. He said: I
believe that there is benefit to be gained from
high-intensity cardiac rehabilitation, given the
cardio-protective effects seen from exercising to
ischaemia in warm-up angina studies, though the
objective proof is not yet there. A recent study
showed high-intensity cardiac rehabilitation is as safe as moderate-
intensity cardiac rehabilitation, although it was underpowered.3
He points out that warm-up angina is strictly defined in terms of find-
ings at a second period of exercise of either reduced ischemia (in
terms of ST depression) or a higher ischaemic threshold (defined
as an increased rate pressure product [HR x SBP] for a certain ST
depression, usually 1 mm). The period between the two exercise
efforts is important, and should be about 15 min and no longer
than 60 min.
Some of the key research on warm-up ischaemia has been carried
out by Dr Peter Bogaty at the Quebec Heart Institute, Ste-Foy,
Quebec, Canada. He and his team tried to induce warm-up angina
without exercising to ischaemia, but failed to observe the effect
unless exercise was taken to this point, as evidenced by ST depres-
sion. Short-term exercise capacity was increased by exercising
below the ischaemic threshold, but true warm-up in terms of
reduced ischaemia was observed only when the threshold was
reached.
By carrying out extremely accurate haemodynamic measure-
ments, the Kings College group are hoping to elucidate some
aspects of warm-up angina. The exercise bicycle on the Cath lab
table, for example, is being used to study patients receiving an angio-
plasty. During the procedure, before the coronary artery stenosis is
3078
treated, the patient undergoes two periods of exercise with a
wire placed beyond the stenosis to monitor pressure and flow.
Dr Williams said that during the second period, coronary blood
flow increases and microvascular resistance decreases, despite a
reduction in perfusion pressure. Also, the augmentation indexa
measure of wave reflection and arterial stiffnessdecreases on
second exercise, which indicates a relative reduction in afterload.
There is, therefore, still great uncertainty about the mechanism of
warm-up angina. One possibility is that it is a direct effect of dilatation
of muscular conduit arteries during the first exercise period, especial-
ly the femoral and brachial arteries, thereby reducing the augmenta-
tion index on second exercise. Much interest has also been expressed
in the apparent similarities between warm-up angina and ischaemic
preconditioning, in which non-lethal ischaemia is associated with
reduced infarct size in a subsequent myocardial infarction.
However, the mechanisms seem to be different. At a molecular
level, one possible mechanism, according to Dr Williams, is
opening of potassium channels in myocyte mitochondria and the
Kings College group is hoping to test this idea with appropriate ago-
nists, using cardiac MRI as a marker of perfusion.
Refining electrocardiography interpretation
criteria in elite athletes: redefining the limits
of normal
Better criteria for identifying athletes at risk of sudden cardiac death
are discussed
Sudden cardiac death (SCD) is the leading cause of non-traumatic
mortality in young (,35 years old) athletes. A vast majority of
cases are due to a diverse spectrum of inherited and congenital
cardiac conditions that are readily detectable through a combination
of history, examination, and 12-lead electrocardiography (ECG).
Sudden death is usually the first manifestation in up to 80% of athletes
and therefore some form of screening is necessary to identify those at
risk. Consequently, an increasing number of sporting bodies and sci-
entific organizations, including the European Society of Cardiology
(ESC), recommends pre-participation cardiovascular evaluation of
athletes using ECG prior to clearance to compete.1 One study has
demonstrated that ECG-based screening may indeed save lives.2
A major reservation to ECG screening is the generation of false-
positive results, which arise from the overlap between physiological
manifestations of the athletes heart and pathological cardiac
conditions. To facilitate the distinction between physiological and
pathological ECG patterns, the ESC produced guidelines for inter-
pretation of an athletes ECG in 2010.1 However, these have consist-
ently been associated with an unacceptably high false-positive rate
of between 10 and 20%.3 Furthermore, the ESC recommendations
are derived entirely from non-elite Caucasian (white) athletes4
and fail to account for ECG patterns in the most highly trained ath-
letes or the influence of ethnicity on the athletes heart, particularly
CardioPulse
Outlining advice he gives to his patients, he said: I always tell them
to warm up before exercise, especially if going out in cold weather
which may place additional strain on their heart. People were
scared of intense exercise in the past, but I believe it potentially
offers cardioprotective effects, provided the build-up to intense
exercise is slow and guided by the cardiac rehabilitation team. Most
importantly I would like to emphasise the benefits of exercise and
cardiac rehabilitation, which is currently an under-prescribed asset.
Conflict of interest: none declared.
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References
References are available as Supplementary material at European Heart Journal online.
with respect to athletes of African/Afro-Caribbean ethnicity (black
athletes).
Black athletes form an increasing population of sportsmen com-
peting at the highest levels in Western countries. Data now unequivo-
cally demonstrate that black athletes exhibit significantly greater
electrical and structural adaptations in response to exercise com-
pared with white athletes,5 8 placing them at higher risk of false-
positive results and potential false disqualification from sport.
Previous research from our group has demonstrated that up to
25% of black athletes exhibit T-wave inversions. Majority of these is
confined to the anterior leads V1 V45 7 and do not represent
significant pathology.6 The recently published Seattle Criteria9 has
aided the interpretation of an athletes ECG, in part by recognition
of anterior T-wave inversion as a normal pattern in black athletes.
However, as with the ESC recommendations, these criteria are
largely consensus based.
Our experience of screening several thousand elite athletes over
almost 2 decades led us to suspect that in exercising individuals,
several additional ECG patterns that are considered abnormal by
current recommendations may simply be markers of cardiac enlarge-
ment or represent normal variants when found in isolation in an
otherwise healthy athlete (Figure 1, orange circle). Specifically,
these patterns include voltage criteria for left and right atrial
CardioPulse
Figure 1 Refined ECG criteria for screening athletes. Taken from Sheikh et al.12
enlargement, right-ventricular hypertrophy, and left- and right-axis
deviation; together, these constitute over 60% of all abnormalities.
Two studies published by our group in 2012 confirmed our suspi-
cions: although comprising a high burden of positive ECGs in elite ath-
letes, no evidence was found to support these five patterns to signify
serious cardiac disease.10,11
Our observations led us to devise a set of refined ECG screening
criteria (Figure 1) whereby the above-mentioned ECG patterns, in-
cluding anterior T-wave inversion in black athletes, were regarded
as normal finings if observed in isolation in an otherwise asymptom-
atic athlete with no relevant family history or examination findings.
On the basis of our own experience and in conjunction with the
Bethesda guidelines, we also increased the cut-off for an abnormal
corrected QT interval (QTc) to 470 ms in male and 480 ms in
female athletes.
In the current study, the impact of our refined criteria on the false-
positive ECG rate was assessed in a large cohort of black (n 1208)
and white (n 4297) athletes undergoing pre-participation screen-
ing with history, examination, and 12-lead ECG between 2000 and
2012.12 The ECGs of all athletes were re-evaluated using the
refined criteria, ESC recommendations, and Seattle Criteria, to de-
termine the number of positive results requiring athletes to
undergo further investigations. All three ECG criteria were also
applied to a cohort of 103 young, asymptomatic athletes with
HCM to determine the number of individuals in which suspicion of
the condition was correctly raised by each criterion.
The ESC recommendations resulted in a staggering 40.4% of black
athletes exhibiting an abnormal ECG requiring further investigation
prior to being given clearance to compete. Importantly, almost one
in five white athletes (16.2%) also tested positive on the basis of
the ESC recommendations. The Seattle criteria reduced the
number of positive ECGs to 18.4% in black athletes and 7.1% in
white athletes. However, the refined criteria further reduced
3079
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abnormal ECGs to 11.5% in black athletes and 5.3% in white athletes.
Significantly, all three criteria identified 98.1% of athletes with HCM.
Overall, the study detected 40 athletes with pathology. Of these
individuals, 25 were diagnosed with only minor congenital or valvular
abnormalities. The remaining 15 were diagnosed with serious path-
ology, defined as a condition implicated as a recognized cause of
exercise-related SCD. All 15 cases were identified by a combination
of history and 12-lead ECG, with 14 (93.3%) identified on the basis of
ECG alone.
During the screening period, a significant proportion of athletes
(n 3087) were required to undergo echocardiography as a stand-
ard part of their clubs screening policy, regardless of history, exam-
ination, or ECG findings. This cohort was used to determine the
sensitivity and specificity of the screening process using each of the
three ECG screening criteria. The refined criteria improved specifi-
city in black athletes from 40.3% using the ESC recommendations
to 84.2%, and in white athletes from 73.8% using the ESC recommen-
dations to 94.1%. Importantly, sensitivity for detecting all cardiac con-
ditions, including HCM, remained 70% in black and 60% in white
athletes, regardless of the criterion employed. Exclusion of minor
pathology from our calculations resulted in a dramatic improvement
in sensitivity to 100% in both black and white athletes without a com-
promise in specificity.
The results of this study have furthered our understanding of
benign vs. abnormal ECG patterns in athletes, and will have a signifi-
cant impact on reducing the burden of false-positive results during
pre-participation screening whilst maintaining sensitivity for serious
cardiac conditions. Indeed, the ECG correctly identified 93.3% of
serious cardiac pathology that may otherwise have not been
detected. Further work should focus on reproducing our results in
other centres screening large cohorts of elite athletes, and on
further improving ECG specificity in black athletes, a significant pro-
portion of whom continue to exhibit positive ECG results.
3080
Performance enhancing agents and the heart
* Professor Josef Niebauer, Salzburg, Austria, presented
the latest evidence at EuroPRevent 2014
Doping is the use of drugsthat appear on the World
Anti-Doping Agencys List of Prohibited Sub-
stances. Even though the use of performance-
enhancing drugs and the application of, for example, novel materials
for sporting equipment is done for the same reason, i.e. to gain an
edge over others, it is rightly banned and considered unethical
because it exposes athletes to health risks and in the end may take
their lives.
Leisure time athletes and competitive athletes use performance-
enhancing drugs, hoping to gain an edge over their competitors.
More often than not athletes are aware of the potential hazards,
and use such drugs to reach a goal they feel they are unable to
reach without illegal substances. By taking this short-cut, they
accept that this may expose them to severe and possibly deadly
health risks. Protagonists of the legalized use of currently prohibited
substances will have to understand that health risks cannot be fully
controlled and that athletes will always be exposed to an unjustifiable
risk which may not only be associated with increased morbidity but
eventually reduced life expectancy.
Doping is a phenomenon not limited to elite sport, but it is actu-
ally more common in leisure time athletes. It has been reported
that up to 20% of members of fitness clubs and up to 60% of
those who train to increase muscle mass take performance enhan-
cing substances.
Substances that induce cardiovascular complications and may thus
be first noticed by a cardiologist include among others anabolic sub-
stances, peptide hormones, and stimulants.
Anabolic steroids are most commonly used to increase muscle
mass, but they also result in concentric left-ventricular hypertrophy
without a concomitant increase in left-ventricular diameter, which
can be documented by echocardiography. Since the rate of apoptosis
is increased, myocardial fibrosis and necrosis may accidentally be
found in myocardial biopsies or cardiac magnetic tomographic
imaging performed for other reasons.
During routine medical screening, arterial hypertension or dyslipi-
daemia, i.e. elevated levels of LDL and homocysteine as well as dimin-
ished levels of HDL, may be detected and might lead to the suspicion
*Source: Wild&Team/SALK; free for use.
CardioPulse
References
References are available as Supplementary material at European Heart Journal online.
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of anabolic steroid use, especially in muscular athletes. Combined
with the reported endothelial dysfunction, the risk of atherosclerosis
is increased and has been well documented in users of anabolic ster-
oids. Furthermore, diastolic and systolic dysfunction may be picked
up during echocardiography.
Unfortunately, anabolic drug use remains undetected in the vast
majority of these athletes and this may first become apparent when
end organ damage, e.g. myocardial or cerebrovascular events,
occurs as a result of increased platelet activity, reduced fibrinolytic
activity, and subsequent thromboembolic events.
Peptide hormones such as erythropoietin (Epo), insulin-like
growth factor 1 (IGF-1), human growth factor (hGH), and human
chorionic gonadotropin (hCG) are also widely used and may
induce myocardial hypertrophy, interstitial myocardial fibrosis,
arrhythmias, heart failure, and diabetes mellitus. Epo is still popular
among endurance athletes, because it increases haemoglobin mass.
Risks of elevated haematocrit, increased blood viscosity, and result-
ing thromboembolic events as myocardial infarction or stroke are
well known even among athletes and coaches, but are neglected in
order to take a reputed short-cut to success.
Last but not the least, stimulating substances like amphetamines or
its derivatives ephedrine or cathine are widely used, despite the fact
that they induce tachycardias and arrhythmias which have led to
sudden cardiac death.
Unfortunately, the use of performance-enhancing drugs is rather
common in both leisure time and also competitive athletes. Since
many of these substances lead to cardiovascular and cerebrovascular
manifestations, cardiologists have the privilege to be among the first
to take a note of it. By bringing these life-threatening effects to the at-
tention of the athlete, end-organ damage can be prevented and lives
can possibly be saved.
CardioPulse
Sudden cardiac death in young competitive
athletes
Dr Michael Papadakis explains the essentials of cardiovascular
screening in first-degree relatives
The sudden death of a young athlete from a cardiac disorder is par-
ticularly emotive and is often associated with considerable media
coverage, drawing attention to the athletic prowess of the individual
and the number of life years lost. The majority of sudden cardiac
deaths (SCDs) in the young are secondary to previously quiescent,
inherited cardiac diseases that can potentially be detected during
life, galvanizing discussions relating to primary and secondary preven-
tion of similar catastrophes.
The proposed preventative strategies focus primarily on averting
further deaths in the context of competitive sport by cardiovascular
evaluation of athletes and the use of automated external defibrilla-
tors in athletic venues.
Pre-participation screening of young athletes with a 12-lead ECG
remains a contentious issue. Despite data from the Italian national
screening programme in athletes reporting a reduction in SCD
with screening, there are concerns relating to false-positive tests,
which may result in unnecessary investigations or erroneous disquali-
fication. However, recent studies in large cohorts of young athletic
individuals have resulted in refinement of the ECG criteria consid-
ered to denote an abnormal result, with a considerable improvement
in the ECG specificity.1
Prompt defibrillation (within 5 min) has been associated with sur-
vival rates in excess of 60% in athletes. A comprehensive medical
action plan that is rehearsed on a regular basis is essential to
ensure the best possible outcome in the context of mass gathering
events in sports arenas.
The SCD of a young individual is the beginning of a long and arduous
road for the grieving family. With media interest focused on the tragic
death, the family remains at the fringes of evolving events, and the
medical community often overlooks the fact that close relatives are at
potential risk of the same fate. The inherited nature of most conditions
predisposing to SCD in the young highlights the importance of perform-
ing comprehensive post-mortem evaluation of the index case as well as
offering cardiovascular screening to all first-degree relatives.
After consent, a blood sample and splenic tissue should be retained
from the deceased to enable genetic testing (molecular autopsy),
which may prove invaluable for cascade familial screening.
Fit teenagers are less likely to have myocardial
infarctions in later life
A large Swedish study discusses the association of fitness during
teenage years and myocardial infarction later in life
Researchers in Sweden have found an association between a
persons fitness as a teenager and their risk of myocardial
3081
Examination of the heart by an experienced cardiac pathologist is
crucial to ensure accurate interpretation of the autopsy findings, as
false conclusions may misguide familial evaluation or offer false re-
assurance to surviving relatives and dissuade physicians from initiating
familial screening. The interpretation of the results is a complex task
as many disorders are rare or exhibit subtle findings at autopsy.
In addition, uncertainty may exist regarding the causal relationship
between the pathological findings and the sudden death.2 A recent
study demonstrated a disparity in 40% of cases as to the potential
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cause of death when comparing cardiac pathologist vs. general path-
ologist reports.3
Familial evaluation should encompass a comprehensive cardiologic-
al assessment of all first-degree relatives. Investigations are guided by
clinical suspicion based on data collected on the deceased, including
pre-morbid history, circumstances of death, and autopsy findings.
It is imperative to emphasize that, in a significant proportion of
SCDs, an obvious cause of death cannot be identified, despite
detailed histopathological and toxicological evaluation. Such deaths
are classified as sudden arrhythmic death syndrome (SADS). Up to
50% of families with an SADS death demonstrate evidence of an
ion-channel disorder following clinical assessment. Most importantly,
25% of SADS relatives are diagnosed with a previously unsuspected
inherited cardiac condition, underscoring the need to refer such fam-
ilies for thorough specialist assessment.2
Interventions ranging from advice for simple lifestyle modification
to the implantation of a prophylactic ICD can reduce the risk of
further fatalities.
References
References are available as Supplementary material at European Heart Journal online.
infarction (MI) in later life. In a study of nearly 750 000 men,
they found that the more aerobically fit men were in late
3082
adolescence, the less likely they were to have an MI 30 or 40 years
later.
The study, published in the European Heart Journal,1 found that the
relationship between aerobic fitness and MI occurred regardless of
the mens body mass index (BMI) when they were teenagers.
However, fit but overweight or obese men had a significantly
higher risk of a MI than unfit, lean men.
Professor Peter Nordstrom, of Umea Uni-
versity, Umea, Sweden, who led the research,
said: Our findings suggest that high aerobic
fitness in late adolescence may reduce the
risk of MI later in life. However, being very fit
does not appear to fully compensate for
being overweight or obese. Our study suggests
that its more important not to be overweight or obese than to be fit,
but that its even better to be both fit and of normal weight.
Prof Nordstrom and his colleagues analysed data from 743 498
Swedish men who underwent medical examinations at the age of
18 when they were conscripted into the Swedish armed forces
between 1969 and 1984. Aerobic fitness was measured by a cycle
test where the resistance was gradually increased until they were
too exhausted to continue.
The researchers found that every 15% increase in aerobic fitness
was linked to an 18% reduced risk of MI 30 years later, after
adjusting for various confounding factors including socioeconomic
background and BMI. The results also suggested that regular cardio-
vascular training in late adolescence was independently associated
with an 35% reduced risk of an early MI in later life.
There were 7575 MIs in 620 089 men during the total follow-up
time where aerobic fitness was measured, which means the cumulative
incidence was about 1222 per 100 000 men, explained Prof Nord-
strom. There were 271 005 men (43.7%) who were normal weight
or lean, and who had an aerobic fitness that was better than the
average. Among these lean, fit men there were 2176 MIs, resulting in
a cumulative incidence of about 803 MIs per 100 000 men. Thus, the
cumulative incidence of MIs was reduced by about 35% in this group.
However, he warned that the study showed only that there was an
association between fitness and a reduction in myocardial infarction,
and it could not show that being aerobically fit caused the reduced
risk of myocardial infarction.
The relationship between aerobic fitness and heart disease is
complex and may well be influenced by confounding factors that
were not investigated in this study. For instance, some people may
have a genetic predisposition to both high physical fitness and a
low risk of heart disease. In a recent study of twins, we found that
78% of the variation in aerobic fitness at the time of conscription is
related to genetic factors.
CardioPulse contact: Andros Tofield, Managing Editor. Email: docandros@bluewin.ch
CardioPulse
At the time of the mens conscription they had a full medical exam-
ination, which included checking blood pressure, weight, height and
muscle strength, as well as aerobic fitness. During the cycle test for
aerobic fitness, the resistance was gradually increased at the rate of
25 Watts/min2 until the men were too exhausted to continue. The
final work rate (maximum watts) was used for the analysis. The
average work rate for the men was 250 Watts.
The men were followed for an average of 34 years (ranging from 5
to 41 years) until the date of an MI, death, or 1 January 2011, which-
ever came first. To investigate the link between aerobic fitness and
risk of a later MI, the mens results were divided into five groups.
Compared with men in the highest fifth for aerobic fitness, men in
the lowest fifth had 2.1-fold increased risk of an MI during the follow-
up period, after adjusting for BMI, age, place, and year of conscription.
To investigate the joint effect of BMI and fitness with respect to risk
of MIs, BMI were divided into four groups that matched the World
Health Organizations BMI definitions: underweight/lean (BMI
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,18.5 kg/m2), normal weight (BMI between 18.5 and 25 kg/m2),
overweight (BMI between 25 and 30 kg/m2) and obese (BMI
.30 kg/m2). In all four BMI groups, the risk of a later MI was increased
significantly when comparing the least fit with the fit. However, the
fittest obese men had nearly double (71%) the risk of an MI than
did the most unfit, but lean men, and more than four-fold increased
risk compared with the fittest lean men. A similar pattern was seen
for overweight men when compared with normal weight men.
There are some limitations to the research. These include the fact that
the mens BMI, fitness, and blood pressure was only measured at the
time of conscription so it is not known if and how these factors might
have changed in later years; the research was carried out in young
men and may not apply to women or the elderly; and the effect of
smoking could be evaluated only in a sub-group of 23 000 men.
Prof Nordstrom said: As far as we know, this is the first study to
investigate the links between an objective measure of physical
fitness in teenagers and risk of MI in the general population.
Further studies are needed to investigate the clinical relevance of
these findings, but given the strong association that we have found,
the low cost and easy accessibility of cardiovascular training, and
the role of heart disease as a major cause of illness and death world-
wide, these results are important with respect to public health.
Note: One watt one joule per second.
Andros Tofield
Reference
1. Hogstrom G, Nordstrom A, Nordstrom P. High aerobic fitness in late adolescence is
associated with a reduced risk of MI later in life: a nationwide cohort study in men.
Eur Heart J 2014;35:3133 3140.