Reviews: Exercise: Friend or Foe?

REVIEWS
Exercise: friend or foe?

Frida J. Dangardt, William J. McKenna, Thomas F. Lscher and John E. Deanfield
Abstract | Physical activity and exercise have been associated with reduced cardiovascular risk, morbidity,
and mortality, as well as all-cause mortality, both in the general population and in patients with various forms
of cardiovascular disease. Increasing amounts of exercise are associated with incremental reductions in
mortality, but considerable benefits have been found even with a low level of exercise. Exercise is beneficial
for most individuals, but risks exist. Exercise is associated with reduced long-term morbidity and mortality,
but acute exercise can transiently increase the risk of fatal or nonfatal cardiovascular events. Although tragic,
these events are very rare, and even to some extent preventable with screening programmes. Low-intensity
physical activity is important and beneficial to all individuals, including those with a high risk of adverse
cardiovascular events. In individuals who are physically fit and who do not have genetic predisposition to,
or signs of, cardiovascular disease, the greater the intensity and amount of exercise, the greater the health
benefits. Nevertheless, effective strategies to encourage exercise in the population are lacking. A sustained
increase in physical activity is likely to require more than individual advice, and needs to include urban
planningand possibly even legislation.
Dangardt, F.J. etal. Nat. Rev. Cardiol. advance online publication 25 June 2013; doi:10.1038/nrcardio.2013.90
Introduction
The inspiration for the Olympic marathon is the legend
of Pheidippides (530490BC), who died upon reaching Athens after running the 40km from Marathon to
announce the Greek victory over Persia. Some sources
indicate that Pheidippides had previously run the
240km from Marathon to Sparta, to request help from
the Spartans in the battle of Marathon, and that he was,
in fact, a professional running courier. If true, this fact
might help to explain his sudden death, as evidence of
myocardial remodelling has been shown in extreme
endurance athletes, which can increase the risk of fatal
arrhythmias.1 By contrast, some researchers believe that
the human body is well-adapted to endurance running.2,3
In the Hellenic era, Hippocrates and followers were convinced of the importance of physical activity to maintain
health and fight disease, but the popularity of this belief
subsequently declined. In 1953, however, Morris and colleagues published research on the benefits of physical
activity on the reduction of coronary heart disease.4
Ideally, the legacy of the London 2012 Olympic Games
will consist not only of sporting excellence, but also an
effort to increase the level of physical activity and sportin
the general population, with subsequent improvement
in public health. This outcome will require coordinated
strategies from the health-care profession, as well as societal and political commitment.5 Delivery of this legacy
will need to be safe and to include a strategy to identify
individuals at high risk of adverse effects from exercise,
such as sudden cardiac death (SCD) and cardiovascular
events or injuries.611
Competing interests
The authors declare no competing interests.
The benefits and risks of exercise in patients have been

examined in a wealth of observational and interventional
studies. Most population reports, however, are observational and must be interpreted with caution, because of
potential confounding factors, such as socioeconomic
status, genetic background, diet, psychological state,
and environmental influences. With a shortage of randomized, controlled trials, the possibility of reverse causality needs to be consideredhealthy individuals might
find exercising easier than unhealthy individuals do, as
opposed to exercise improving health. Another issue in
these studies is the quantification of physical activity
and exercise, which most often involves self-reporting.
Questionnaires are often associated with over-reporting
of physical activity,12 and the data obtained do not correlate well with those gathered using objective measures,
such as with an accelerometer,13,14 or by measurement of
cardiorespiratory fitness.15
In this Review, we discuss the effects of increased
physical activity and exercise on cardiovascular health.
The benefits and risks will be considered for the general
population, as well as for patients with diagnosed cardiovascular disease, with recommendations for screening
and whether to exercise. Strategies to increase physical
activity in the adult population as safely and effectively
as possible are considered.
Health benefits of physical activity

Increased physical activity or exercise has been shown
to decrease cardiovascular risk, morbidity, and mortality,1622 as well as all-cause mortality.2325 In a prospective
cohort study of 416,175 individuals, all-cause mortality
was 40% and 32% lower in the groups who underwent
NATURE REVIEWS | CARDIOLOGY
National Centre
forCardiovascular
Prevention and
Outcomes, 170
Tottenham Court Road,
London W1T7HA, UK
(F.J. Dangardt,
J.E.Deanfield).
TheHeart Hospital,
University College
London, 1618
Westmoreland Street,
London W1G8PH, UK
(W.J. McKenna).
University Hospital
Zurich,Rmistrasse100,
CH8091 Zurich,
Switzerland
(T.F.Lscher).
Correspondence to:
J.E. Deanfield
j.deanfield@
ich.ucl.ac.uk
ADVANCE ONLINE PUBLICATION | 1

2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
Key points
An increased level of physical activity decreases cardiovascular risk factors in
the general population
The largest benefits of exercise occur when individuals who are least fit
become physically active, even to a low intensity
Controlled exercise is safe and beneficial even for patients with cardiac disease
The risk of adverse events is associated with strenuous exercise, not lowintensity physical activity
The effects of resistance and endurance training have been shown to be
similarly beneficial
Robust strategies are needed to increase physical activity at a population level;
implementation might require supportive legislation
1.0
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0.8
0.6
0.4
0.2
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Inactive
Low
Medium High
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high
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Figure 1 | Relationship between level of physical activity and reduction in

mortalityfrom various causes. Increased physical activity is associated with an
incremental reduction in a | all-cause mortality, as well as death from b | cancer,
c|cardiovascular disease, and d | diabetes mellitus. Reprinted from Wen, C.P.
etal. Minimum amount of physical activity for reduced mortality and extended life
expectancy: a prospective cohort study. Lancet 378, 12441253 (2011). With
permission from Elsevier.
5060min of vigorous or moderate exercise daily,

respectively, than in the inactive group. 35 The results
were adjusted for age, sex, education, physical labour
at work, smoking, alcohol intake, fasting blood glucose
level, systolic blood pressure, total-cholesterol level, BMI,
diagnosed diabetes mellitus or hypertension, and history
of cancer. The reductions in mortality increased with
the intensity of exercise, but even low levels of exercise
were associated with reductions in all-cause mortality,
as well as death from cancer, cardiovascular disease, or
diabetes(Figure1).35
The association between duration of physical activity and reduction in all-cause mortality seems to follow
a doseresponse relationship (Figure2).35 Importantly,
vigorous exercise is effective, but might not be suitable
or safe for some individuals. Nevertheless, health benefits
can be safely achieved by a modest increase in physical
activity, which is less time-consuming than vigorous

exercise and, therefore, is more practical and widely
applicable to the general population.32
Inactivity has been estimated to be responsible for
almost 10% of premature deaths worldwide, corresponding to >5million deaths per year. WHO data suggest that
>500,000 deaths per year could be avoided if levels of
inactivity were reduced by 10%. 36 The doseresponse
relationship for the mortality-lowering effect of regular
physical activity is particularly pronounced when
moving from being sedentary to a low or moderate level
of exercise, and only a small additional reduction in risk
occurs with further increases in level of activity. Energy
expenditure of only 1,000kcal per week from exercise
has been estimated to produce a reduction of 2030%
in all-cause mortality, compared with inactive individ
uals.25,35,37 In a meta-analysis of 38 studies, including a
total of >271,000 individuals, moderate and vigorous
levels of activity produced a 24% and 35% reduction in
all-cause mortality, respectively, in men, and a 31% and
44% reduction in women.25 The associations seem to be
even stronger for men aged >65years, with a relative risk
reduction of 33% with moderate activity, and 45% with
vigorous activity, using age-adjusted estimates.25
Cancer
A broad range of benefits of increased physical activity
and regular exercise has been reported. In observational
studies, exercise has been shown to reduce the risk of
various types of cancer, and physical inactivity might
contribute to 10% of breast or colon cancer worldwide.38
In a review of 27 studies of cancer survivors, physical
activity was found to reduce all-cause mortality by up to
60%.39 The risk of death from cancer was reduced by up
to 51% and 61% in survivors of breast or colon cancer,
respectivly.39 The risk of death from ovarian or prostate
cancer might also be reduced by increased physical activity in cancer survivors.39 The few randomized controlled
trials on the effects of exercise in cancer survivors have
shown beneficial effects on various biomarkers, such as a
decreased level of circulating insulin, improved insulinrelated pathways, and reduced inflammation,39 as well as
improved cardiorespiratory fitness and reduced symptoms of cancer.40 However, no randomized, controlled
studies have been conducted on the effects of exercise
on mortality or the recurrence of cancer.
Psychiatric health
Exercise therapy has been found to be as effective as cognitive therapy in the treatment of mild psychiatric conditions, particularly mild depression.41,42 In a review of
the psychological benefits of exercise in cross-sectional
and experimental studies, symptoms of depression were
reduced after aerobic exercise in both men and women
in all adult age groups, and the effects were greatest
among individuals with clinical depression.42 Beneficial
effects of exercise on premenstrual syndrome, selfesteem, mood state, stress responsiveness, and anxiety
were also reported.42 Exercise has also been shown to
improve cognition and to prevent the development
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Osteoporosis and obesity

Exercise has been shown to reduce the risk of osteo
porosis.37,4648 Weight-bearing and impact exercise seem
particularly effective in preventing the loss of bone mass
that occurs as a result of ageing, and can also improve
bone density regardless of age or sex.49,50 Exercise can
both prevent the development of obesity and form part
of a weight-loss strategy. In individuals who are obese,
either resistance or cardiorespiratory training confers
cardiovascular benefits, which are enhanced if these
training modalities are combined.18,5153
Cardiovascular disease
Various studies, reviews, and consensus reports have
been published on the cardiovascular benefits of physical activity and exercise.1622 The positive effects include
improved cardiovascular risk factors, such as decreased
blood pressure, decreased levels of LDL cholesterol
and triglycerides, an increased level of HDL cholesterol, a decreased level of inflammatory markers such
as Creactive protein, and improved insulin resistance.37,47 The benefits are considerable, even with a low
or moderate level of physical activity. In a meta-analysis
of 49 studies involving >700,000 individuals, a 2550%
reduction in adverse cardiovascular events was reported
in individuals who routinely participated in physical
activity, compared with sedentary individuals.11 Exercise
capacity is a strong predictor of the risk of death in
patients referred for clinical exercise testing, regardless of
the underlying risk factors,26 and is possibly even morestrongly associated with reduced risk of cardiovascular
disease or events than measures of physical activity.15
In a study involving 961 individuals (aged 1824years
at follow-up), change in physical activity during the
6year follow-up was inversely associated with changes
in serum insulin and triglycerides levels.21 In another
study involving 162 adolescents (aged 1619years at
follow-up), a decrease in physical activity over a 3year
period was associated with increased arterial stiffness.59
Low-to-moderate intensities of exercise (3579% of
age-predicted maximum heart rate) can lower systolic
blood pressure by 3.510.5mmHg.37 Either aerobic or
anaerobic exercise-training has been shown to improve
glucose uptake and insulin sensitivity,5356 as well as to
decrease cardiovascular morbidity (including the incidence of myocardial infarction) and mortality.35,37,6062
In a study of 28,345 women, the risk of a cardiovascular
event decreased linearly with increased levels of activity.61 The relative contributions of changes in the following factors to the decrease in risk were attributed
as follows: inflammatory and haemostatic biomarkers (32.6%), blood pressure (27.1%), LDL-cholesterol
50
Reduction in all-cause mortality (%)
of Alzheimer disease in elderly individuals, possibly

through influences on brain plasticity, neurogenesis, and
repair.43,44 Patients with severe psychiatric disease have
an increased risk of obesity, diabetes, and cardiovascular
disease. Exercise in patients receiving pharmacological
treatment for psychiatric illness might reduce their risk
of cardiovascular disease.45
Vigorous
Moderate
Total
40
35%
29%
30
20%
20
14%
10
0
0
10
20
50
30
40
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80
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90
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Figure 2 | Relationship between daily duration of physical activity and reduction in

all-cause mortality. Reprinted from Wen, C.P. etal. Minimum amount of physical
activity for reduced mortality and extended life expectancy: a prospective cohort
study. Lancet 378, 12441253 (2011). With permission from Elsevier.
and HDL-cholesterol levels (19.1%), apolipoprotein

level (15.5%), BMI (10.1%), and haemoglobinA1c or
diabetes(8.9%).61
Genetic determinants of fitness and response to exercise have been suggested to influence the cardiovascularrisk reduction associated with increased physical activity,
but this effect remains unconfirmed, particularly in
women. In a study of 23,016 women showing cardio
vascular benefits of physical activity, muscle strength
was the only genetic score that was independently
inversely associated with cardiovascular risk. No evidence showed that the inverse relationship between physical activity and cardiovascular disease was modified by
any of the genetic scores for physical fitness.63 In another
study, the presence of a polymorphism in the gene for
endothelial nitric oxide synthase did not affectthe beneficial effects of exercise in women.64 However, the positive
response to exercise seems to be greater in women than
in men, at least in terms of protection against cardio
vascular events.65 In a study involving 5,721 women, a
17% decrease in the risk of death was reported with each
1MET (metabolic equivalent of task) increase in exercise
capacity.66 By contrast, in a study involving 6,213 men,
each 1MET increase in exercise capacity produced
only a 12% reduction in mortality.26 In a meta-analysis
of 33 studies, of which 22 included both sexes and 11
included only men, a 13% decreasein all-cause mortality (n=102,980) and a 15% decrease incoronary heart
disease or cardiovascular disease events (n=84,323) with
each 1MET increase in exercise capacity was reported.67
Sex-specific differences in the response to exercise were
not analysed in this study.
Mechanisms of benefit
The effects of exercise on the body are multifactorial
and involve various interconnected systems, including
vascular regulation, the inflammatory system, as well
as lipid, insulin, and glucose metabolism. Reductions
in blood pressure, blood lipid levels, inflammation,

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and insulin resistance have been shown to occur with
exercise.21,37,48,51,5457 The pathways for these effects are
not fully understood, but involve intricate molecular responses to the acute and persistent physiological
changes induced by exercise.68
The acute effects of resistance training include an
increase in peripheral vascular resistance leading to
greater cardiac afterload, and eventually an increase
in parallel sarcomere fibres in the myocardium, which
causes concentric remodelling of the ventricle.68 Other
effects are an increase in skeletal muscle mass, improved
insulin sensitivity and glucose uptake, and upregulated fatty acid metabolism and oxidative phosphorylation resulting from an increase in the number of
mitochondria.56,69
Aerobic or endurance training acutely increases
blood flow and, consequently, the cardiac preload and
end-diastolic volume. These changes can lead to symmetrical enlargement of both right and left ventricles.1
The long-term effects include improvement of endothelial function in both the peripheral and coronary artery
circulation with improved arterial compliance. The sustained decrease in peripheral resistance contributes to
the blood-pressure-lowering effect.70
To improve understanding of the complex effects of
exercise on metabolic factors, novel studies have been
designed to investigate the effects of persistent physical
activity on the metabolome, and determine the influence
on cardiometabolic risk.71 Metabolite profiling was performed in a long-term study involving 16 pairs of twins
with discordance within the pairs in the level of physical activity, and 1,037 age-matched and sex-matched
controls from three community-based cohorts. Active
individuals had a higher level of apolipoproteinA1, a
lower level of apolipoproteinB (and, therefore, a lower
apolipoproteinB/A1 ratio), a higher level of polyunsaturated fatty acids relative to saturated fatty acids, a lower
level of the branched-chain amino acid isoleucine, and
a lower level of the acute-phase reactant 1acid glycoprotein than inactive individuals. These results, which
indicate a healthier metabolite profile in active compared
with inactive individuals,71 were surprisingly consistent
across the various study groups, which suggests that the
benefits of physical activity are generally applicable.
Benefits according to type of exercise

Aerobic and resistance training have different effects on
the cardiovascular system, but both have positive effects
on cardiovascular health. However, the effects of endurance and resistance training have been directly compared
in only a few studies. In a review of 28 randomized, controlled trials comprising a total of 1,012 participants, isometric handgrip training was found to be more effective
in lowering blood pressure than other types of resistance
training, but had no effect on other cardiovascular risk
factors.57 Dynamic resistance training had beneficial
effects on blood lipid levels, blood pressure, and glucose
tolerance.57,72 In a study of 39 patients with type2 diabetes who were randomly allocated to either endurance or
strength training for 4months, a decline in the glycated
haemoglobin (HbA1c) level, blood glucose level, and

insulin resistance was found with strength training, but
not with endurance training.70 Strength training was also
associated with an improvement in blood lipid profile
(increased HDL-cholesterol level, and reduced LDLcholesterol and triglyceride levels), which did not occur
with endurance training.70
Both forms of training have beneficial effects on weight
loss, fat mass, and cardiorespiratory fitness in individuals
who are overweight or obese. In a 12week intervention
study involving 97 individuals who were overweight or
obese (but otherwise healthy), aerobic exercise, resistance training, or combination exercise programmes at
moderate intensity for 30min, 5days per week, improved
the cardiovascular-risk profile compared with individuals who did not exercise.54 More-pronounced changes
in body fat, waist circumference, and oxygen consumption were seen in the combination-exercise group than
in those performing only aerobic or resistance training.
The resistance-training group, however, showed a 25%
decrease in the apolipoproteinB48 level, not seen in the
other groups.54 However, further studies to compare
endurance and resistance training are required to
define the best training strategy for cardiovascular-risk
reduction in the general population.
Benefits of exercise in patients

Coronary artery disease
In patients with coronary artery disease, the benefits of
exercise in cardiac rehabilitation are well established.
Exercise should be introduced early after an acute cardio
vascular event, once the patient is considered stable, as
part of the strategy to prevent future events.7376 In a
review of 47 studies in which a total of 10,427 patients
were randomly allocated to exercise rehabilitation or
standard care, exercise reduced all-cause and cardio
vascular mortality, as well as admissions to hospital. 77
Both all-cause and cardiovascular mortality can be
reduced by up to 25% with long-term exercise programmes in patients with coronary artery disease.73,77
Admissions to hospital can be reduced by up to 30%.77
The exercise regimes are most-commonly individualized
to patients after clinical assessment and exercise testing,
and can consist of both cardiorespiratory and resistance
training.77,78 A weakness of most of the studies is that the
patients included were predominantly middle-aged men
at fairly low cardiovascular risk. Studies of exercise in
women and high-risk individuals with coronary artery
disease are lacking.
Heart failure
In patients with heart failure and coronary artery disease,
evidence consistently shows the benefits of exercise as
part of treatment and rehabilitation programmes, and
the risk is very small if current recommendations are
followed.7881 In patients with congestive heart failure,
skeletal muscle strength is a better predictor than peak
oxygen consumption of survival;82 this finding indicates
that resistance training might be more beneficial than
endurance training in these patients.
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Exercise-based interventions can reduce hospitali
zations for heart failure, and improve quality of life in
low-to-moderate risk patients with systolic heart failure
in NYHA classIIIII, but do not seem to affect all-cause
mortality.83 In a meta-analysis of 19 randomized controlled studies involving 3,647 patients with heart failure
in NYHA classIIV, and data from the HFACTION
trial (n=2,331),84 hospitalizations for heart failure, but
not all-cause admissions to hospital, were reduced with
exercise.85 An improvement in health-related quality of
life was also reported. With the exclusion of data from
the HFACTION trial, a reduction in long-term mortality was found, but this result might have been influenced by the inconsistency of death reports.85 Another
meta-analysis of nine studies and 801 patients showed
reduced mortality with exercise, as well as prolonged
time to admission to hospital.86
In the HFACTION trial, 84 2,331 patients (28%
women, median age 59years) were randomly allocated
to receive either standard care only or in combination
with 36 sessions of aerobic exercise training followed
by home-based training. Standard care included a recommendation for 30min of exercise daily. No reduction in all-cause mortality or rate of hospitalization was
reported, but after adjusting for highly prognostic variables, such as duration of exercise testing, left ventricular
ejection fraction, depression score, and history of atrial
fibrillation or flutter, an 11% decrease in all-cause mortality or hospitalization was reported, as well as a 15%
decrease in cardiovascular mortality or hospitalization
for heart failure. 84 In a Review article, Downing and
Balady concluded that challenges remain in the routine
application of exercise therapy, despite increasing evidence of beneficial effects on exercise.81 These challenges
include acceptance and use of exercise as an adjunctive
intervention in the management of patients with heart
failure, and tailoring of exercise programmes to address
the needs of subgroups of patients.81 Improving shortterm and long-term adherence to exercise training and
a physically active lifestyle remains an important goal.
Congenital heart disease

The authors of current guidelines recommend exercise
in patients with congenital heart disease,87,88 mostly at a
similar level to that recommended for the general public.
Poor cardiorespiratory fitness is common in this group
of patients, and can contribute to reduced survival. 88
Children and adolescents with septal defects, mild aortic
stenosis, mild-to-moderate aortic regurgitation, isolated
bicuspid aortic valve, coarctation of the aorta, mild and
stable aortic dilatation or aneurysm, mild pulmonary
hypertension, an implanted device (such as a pacemaker
or defibrillator), tetralogy of Fallot, or Ebstein anomaly
(without substantial tricuspid regurgitation) are advised
to exercise to normal levels.88 This recommendation
means 60min per day of moderate-to-vigorous cardio
respiratory physical activity, and unrestricted participation
in competitive sport. Limitations are applied to weightbased musculoskeletal activities, but this form of physical activity is also considered safe in most individuals, if
very high-intensity training is avoided.88 Children with

congenital heart disease can be over-restricted by their
parents and teachers, which can contribute to a reduced
level of physical activity and exercise capacity later in life.
In adults with congenital heart disease, the recommendations for exercise depend on the haemodynamic situation, the risk of arrhythmias and acute decompensation,
and a patients ability to exercise. The risk of SCD during
exercise is mostly very small. Competitive sports should
be avoided by patients with Eisenmenger syndrome,
coronary artery anomalies, Ebstein anomaly, or transposition repaired by atrial switch or Rastelli procedure,
owing to their morphological severity and complexity, as
well as their tendency to induce serious arrhythmias.87
Otherwise, the recommendations for adults with congenital heart disease are similar to those for children
with congenital heart diseasecardiorespiratory exercise
should be performed at a similar level to that recommended for healthy adults, but resistance training should
be avoided in some individuals.87
Bicuspid aortic valve is the most-common form of
congenital heart disease, and whether patients with
this condition should participate in competitive sports
is often debated. In a prospective study, 30 competitive athletes with a bicuspid aortic valve showed similar
increases in left ventricular volume and aortic diameter as nonathletic patients with a bicuspid aortic valve
during the 5year follow-up.89 In the 56 athletes with a
normal, tricuspid aortic valve, no increase in left ventricular volume or aortic diameter was observed.89 These
data suggest that exercise does not contribute to disease
progression in patients with a bicuspid aortic valve, at
least in the short or medium term.
The use of exercise in rehabilitation of patients with
congenital heart disease is not well investigated, but
given that children with congenital heart disease now
usually survive to adulthood, concern is increasing about
additional problems that might arise from acquired
cardiovascular disease. Exercise might have an important role in reducing risk factors for atherosclerosis, and
requires further study.
Dilated cardiomyopathy
Exercise in patients with dilated cardiomyopathy
improves cardiac function and is beneficial for cardiac
rehabilitation.81,90,91 In a study of 24 middle-aged patients
(aged 5312years) with dilated cardiomyopathy, participants were randomly allocated to standard care or
an 8week supervised exercise programme followed by
6months of self-regulated training.90 The investigators
reported improvements in left ventricular end-systolic
volume and left ventricular ejection fraction, as indicators of improved cardiac function.90 The results agreed
with those from a study of 15 middle-aged patients
(aged 582years; eight men, seven women) diagnosed
with dilated cardiomyopathy and in NYHA classIIII.91
The exercise programme consisted of 20min of cycling
at 7080% of maximum heart rate five times per week
for 8weeks. Exercise improved the left ventricular ejection fraction by 16% at rest and by a further 20% during

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a
3%
SCD in US athletes
SCD in Italy
6%
10%
24%
14%
4%
5%
52%
19%
10%
10%
6%
11%
20%
2%
3%
SCD in Australia
52%
SCD in US military recruits
9%
16%
12%
29%
1%
40%
12%
9%
1%
10%
5%
2%
Cardiomyopathy
Myocarditis
Valvular disease
Atherosclerotic CAD
25%
19%
8%
Anomalous coronaries
Aortic aneurysm or dissection
Other structural cause
Structurally normal
2%
Figure 3 | Causes of SCD in various populations. a | Study of 134 cases of SCD

involving competitive US athletes aged <25years.95 Most were men (90%) and
collapsed during or after exercise (90%). Hypertrophic cardiomyopathy was the
most-common cause of SCD, whereas structurally normal hearts were rarely
observed (3%). b | Review of all 273 cases of SCD in Italians aged <35years in the
Veneto region, between 1979 and 1998.140 The majority of SCDs occurred during
normal daily activity, whereas 4% occurred during or after exercise. The mostcommon causes of SCD in this population were obstructive CAD and arrhythmogenic
right ventricular cardiomyopathy. c | Study of 427 cases of SCD in individuals aged
<35years over a 10year period in eastern Sydney, Australia.141 More than half of
the SCDs were attributed to cardiac causes, whereas a structurally normal heart
with normal toxicology was reported in 29% of individuals. Death occurred during
exercise in 10.8% of cases. d | Review of 126 cases of SCD among US military
recruits aged <35years.142 In 86% of cases, death occurred during or after
exercise. Half of the SCDs were attributed to an identified cardiac abnormality,
whereas in 35% of cases, no abnormalities were detected during the post-mortem.
Abbreviations: CAD, coronary artery disease; SCD, sudden cardiac death.
physical exercise.91 These changes were accompanied by

an 8% improvement in 6min walking test distance and,
equally importantly, a substantial increase in qualityof-life score. No significant alteration was observed in
the level of cardiac high-energy phosphates during rest
or physical exercise, which indicates that no detrimental change in cardiac energy metabolism occurred.91
These studies were small, and large, randomized trials
are needed to test the effects of exercise in patients with
dilated cardiomyopathy.
Cardiovascular risks of exercise

Exercise is beneficial for most individuals at a population level, but risks exist for particular individuals. In a
systematic review of 51 studies, Goodman and colleagues

researched the frequency of adverse events during lowintensity, everyday physical activity, such as gardening or
walks; high-intensity exercise training, with the objective
to increase fitness; and clinical exercise testing of either
referred patients or healthy athletes.7 The investigators
reported an incidence of 0.41.0 deaths per 10,000 exercise tests of patients screened or referred for cardio
vascular testing, and a complication rate (myocardial
infarction or dangerous arrhythmias) of 1.18.9 per
10,000 tests, partly depending on the risk category of the
patients and the year of the study. In the older studies,
the risk profile of the population was slightly different
from in newer studiesfor example, the rate of smoking
decreased over time. The complication rate during exercise testing in athletes and healthy individuals ranges
from 0 to 0.8 per 10,000 tests, respectively.7 In exercise
training or physical activity of moderate-to-high intensity,
the risk of a fatal event ranges from 0.0003 per 10,000h
(data from 2006, in women aged 3055years) to 0.45
per 10,000h (data from 1971, in men aged >30years).7
These data highlight precisely the risk paradox: despite
consistent evidence of a reduced risk of long-term morbidity and mortality with exercise, evidence also shows
that an acute bout of exercise transiently increases the risk
of fatal or nonfatal cardiovascular events. These events
are tragic, but occur rarely in athletes during or immediately after exercise, with an incidence of <13 in 100,000
individuals per year.10,34 The incidence of SCD seems to
be lower in the general population under normal conditions (daily activity and rest, not involving physical
exertion) than in athletes, with estimates of 0.100.16
in 100,000 individuals per year,92 presumably because of
lower amounts of vigorous exercise undertaken by the
general population. The risks of exercise, regardless of
intensity, are very small for the general population, up to
a threshold of about 60min daily of very high-intensity
exercise, at which point, detrimental effects might be seen
in predisposedindividuals.93
SCD in the young

In young individuals (aged <3035 years), inherited cardiomyopathies (such as hypertrophic, dilated,
orarrhythmogenic right ventricular cardiomyopathy),
arrhythmia syndromes (such as catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, or
Brugada syndrome), and anomalous coronary arteries
are the most-common causes of SCD.10,92,94 Data from
specialist centres suggest that the most-common underlying cause of SCD in young individuals is hypertrophic
cardiomyopathy in the USA, and arrhythmogenic right
ventricular cardiomyopathy in Europe (Figure3).95 These
studies emanate from centres of excellence in the respective diseases. However, other studies reveal that, in up to
one-third of SCDs of young individuals, no abnormalities are detected at post-mortem examination, a situation
defined as sudden arrhythmic death syndrome.92
The paradox of a fit, young athlete dying suddenly
tends to be widely reported, but sudden arrhythmic death
syndrome mostly occurs in young men during sleep or
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Acute exercise
Hypercoagulable
state
Inflammatory
factors
Catecholamines
Immediately after exercise
Na+/K+
imbalance
Sympathetic activity
Vagal withdrawal
Abrupt cessation
of activity
Heart rate
Systolic blood pressure
Venous return
Myocardial oxygen cost
Cardiac output
Arterial
blood pressure
Undetected CHD
Myocardial irritability
Ischaemia
Altered conduction
velocity
Peripheral arterial
vasodilatation
Altered
depolarization/repolarization
Coronary perfusion
Plaque stability
Undetected CHD
Ventricular ectopy
Undetected CHD
Figure 4 | Factors contributing to exercise-induced cardiovascular risk during and after vigorous physical activity in
individuals with undetected CHD. Abbreviation: CHD, coronary heart disease. 2008 Canadian Science Publishing or its
licensors. Reproduced with permission from Goodman, J.M., Thomas, S.G. & Burr, J. Evidence-based risk assessment and
recommendation for exercise testing and physical activity clearance in apparently healthy individuals. Appl. Physiol. Nutr.
Metab. 36 (Suppl.1), S14S32 (2011). Originally published in Franklin, B.A. Cardiovascular events associated with
exercise: the riskprotection paradox. J. Cardiopulm. Rehabil. 25(4), 189195 (2005); reproduced with permission from
Wolters Kluwer Health.
while they are inactive.97 This pattern is corroborated by

data from a study of 174 occurrences of SCD in a population of 6.6million individuals aged 240years.98 In this
study, 76% of the SCDs occurred in men, 90% in individuals aged 1840years, and 72% at home. In adults
(aged 1840years), only 9% of the SCDs occurred during
moderate-to-vigorous exercise, whereas 33% of the SCDs
in children and adolescents (aged 218years) occurred
during moderate-to-vigorous exercise. Underlying
structural heart disease (most-commonly dilated cardio
myopathy) was present in 72% of individuals, and had
previously been undiagnosed in 78%.98
In an epidemiological study of sudden arrhythmic
death syndrome in England, data showed an annual mortality of 500600 deaths in individuals aged <35years;
18% of these individuals had no family history of premature SCD.92 Only 22% of relatives of these individuals,
assessed using electrocardiography and family history,
were found to have an inherited cardiac disease, mostcommonly long QT syndrome. 97 However, thorough
assessment, involving exercise testing and cardiacultrasonography, revealed features of inherited cardiac
disease in 4053% of relatives. 96,99 A family history
of premature SCD aged <35years should trigger the
evaluation of first-degree relatives for inherited forms
of heart-muscle, arrhythmic, and vascular disease. 100
Observational studies from clinics where the families
of individuals who have experienced SCD are evaluated
have shown positive results, including the successful
detection of inheritable causes of SCD, preventive treatment with blockers, low requirements for implantation
of a cardioverterdefibrillator, and no fatal arrhythmias in relatives without an implantable cardioverter

defibrillator.100 These findings underscore the importance
of raised awareness of inherited cardiovascular disease in
both the medical and lay communities, and strengthen
the argument for the establishment of specialist clinics.
SCD in the middle-aged

Atherosclerotic vascular disease is associated with >80%
of exercise-related SCDs in individuals aged >35years,
and >95% of SCDs in individuals aged >40years. 7 In
male marathon runners aged >40years, only 59 cardiac
arrests or SCDs occurred among 10.9million registered
race participants in the USA between 2000 and 2009,101
which indicates that the risk of a major cardiovascular
event is low. Nevertheless, strenuous exercise (such as
marathon running) is not recommended in physically
unfit, middle-aged, or elderly individuals without previous cardiovascular screening and appropriate training.101
The adverse consequences of exercise, such as cardiac
events or SCD, are most common in unfit individuals
who start exercising.8
In individuals with undetected cardiovascular disease,
several possible factors might trigger an adverse event
during physical exertion, such as plaque rupture or
arrhythmia. Sympathetic activation, which increases
susceptibility to potentially fatal ventricular arrhythmias through an increase in circulating catecholamines,
the activation of platelets, and a decrease in plaque stability are the main risks in undetected coronary heart
disease(Figure4).7,102

REVIEWS
Possible consequences of long-term, extreme endurance training include cardiac remodelling, fibrosis, and
the development of arrhythmias.103 The extreme effort of
a marathon, Ironman triathlon, or similar competition can
lead to transient acute volume overload of the atria and
right ventricle, with transient reduction in right ventricular ejection fraction and elevation of cardiac biomarker
levels, all of which return to normal within 1week.104 After
months to years of repetitive injury, this process, in some
individuals, can lead to patchy myocardial fibrosis, particularly in the atria, interventricular septum, andright
ventricle, which creates the substrate for atrial and ventricular arrhythmias. Data show a fourfold to fivefold
increased prevalence of atrial fibrillation in endurance
athletes, but the familial or genetic risk of supraventricular
arrhythmias was not evaluated.105,106 The importance of the
familial nature of atrial fibrillation has been recognized,
with at least a twofold increased risk in individuals with
a first-degree relative who has the arrhythmia.107 Obesity,
hypertension, and diabetes are also common risk factors
for atrial fibrillation, and can be reduced by exercise.107
Heart failure and coronary artery disease

In a study of the effects and safety of exercise in 232 patients
with heart failure, only one substantial cardiovascular event
occurred during 5years, as a result of hypotension.79 In the
HFACTION study,84 1,159 patients in exercise-training
programmes were compared with 1,171 patients receiving standard care. The incidence of exercise-related death
was the same in each group (n=5). Nevertheless, more
patients in the training group than in the standard-care
group required hospitalization (n=37 versus n=22).84 In
a meta-analysis of 22 studies including a total of 3,826
participants with heart failure, outpatientexercise-training
programmes were found to improve exercise capacity, exercise performance, and quality of life, without an increased
rate of adverse events.108
Cardiomyopathy and congenital heart disease
Competitive sports are not recommended for most
patients with cardiomyopathy, or many with congenital
heart disease, given the elevated risk of severe arrhythmias
and cardiac decompensation.87,88 Patients with hypertrophic cardiomyopathy, arrhythmogenic right ventricular
cardiomyopathy, an untreated coronary artery anomaly,
long QT syndrome, Brugada syndrome, Eisenmenger
syndrome, idiopathic dilated cardiomyopathy, or dilated
aortic root are generally recommended to avoid extreme
exertion and participation in competitive sports.33 The
risk of exercise is, however, modest in most patients, and
many should be counselled to continue with regular, submaximal exercise programmes.87,88 Low-grade physical
activity, such as walking and decreased sedentary time, is
both safe and beneficial for all patients.
In arrhythmogenic right ventricular cardiomyopathy,
sport and strenuous exercise should be avoided, as they
might increase the risk of SCD by as much as fivefold.109
This increased risk results not only from the stretching
of the right ventricle by acute volume overload during
exertion, but also from sympathetic stimulation, which
can be a major trigger of life-threatening arrhythmias.110

No evidence for a benefit of exercise in arrhythmogenic
right ventricular cardiomyopathy exists; indeed, data
from animal models indicate a deleterious effect on
myocardial function.111
Hypertrophic cardiomyopathy is common in the
general population, with a reported incidence of up to
1 in 500 adults, most of whom are unaware that they
carry the condition.112 Undetected hypertrophic cardio
myopathy in an athlete can be an important risk factor
for SCD. 33 Extreme exercise or competitive sport is,
therefore, not recommended in individuals diagnosed
with the condition, although the data to support this
advice are not conclusive.94,112114 Nevertheless, in adults
with hypertrophic cardiomyopathy, exercise programmes
are sometimes used, and seem to be both safe and beneficial if strenuous exercise is avoided, and if the risk of
SCD is evaluated beforehand. 79,113 For some patients,
pharmacological treatment or septal-reduction procedures can reduce the risk of exercise-induced obstruction
of the left ventricular outflow tract and can, therefore,
increase exercise tolerance.115
Screening proposals
Screening is controversial but, we believe, necessary
for young athletes to limit the occurrence of avoidable
SCD. 10,33,34 Adolescent and young adults involved in
sport have an estimated 2.8fold greater risk of SCD than
their nonathletic counterparts.116 Electrocardiographic
screening is the most-efficient and cost-effective screening method for risk stratification of SCD in athletes.
Cardiovascular screening before participation in the
USA traditionally involves a personal and family history
and physical examination, without a 12lead electro
cardiogram or other testing. This screening method
is currently recommended by the AHA, although the
power to detect potentially lethal cardiovascular abnormalities is limited.117 In a study of 134 young, US highschool and collegiate athletes who experienced SCD,
only 3% were suspected of having cardiac disease in their
preparticipation medical evaluation, of whom about 1%
eventually received an accurate diagnosis.118
By contrast, the Italian screening programme includes
a personal and family history, physical examination, anda
12lead electrocardiogram. Among 22 athletes with hypertrophic cardiomyopathy, which was detected using electrocardiographic screening at the Centre for Sport Medicine
in Padua, and who were disqualified from competition,
only 23% would have had their condition diagnosed
on the basis of a positive family history, symptoms, or
abnormal physical findings, in the absence of an electro
cardiogram.114 To identify young, nonathletic, high-risk
individuals, an electrocardiogram and family history are
likely to be sufficient, in addition to the referral of family
members of individuals who experience SCD.33,92,97,113,119,120
A screening algorithm is proposed in Figure5.
Screening strategies around the world varyfrom
Italy, where a cardiology clearance certificate is required
to participate in sports from the age of 12years, to the
USA, where no formal testing is required. The Italian
REVIEWS
claim that a reduced incidence of deaths associated
with competitive sport is attributable to their screening programme has been questioned, particularly given
the apparently high mortality,10 which is similar to that
among US athletes.121 Targeted evaluation of at-risk
groups, including those with known, inherited forms
of cardiovascular disease, and young athletes involved
in competitive sport, seems to be feasible. The financial burden of athlete screening might justifiably be
considered a responsibility of sports organizations.
The need for cardiovascular evaluation of middleaged or elderly individuals engaged in leisure-time
sport activities is discussed in a statement from the
exercise physiology and sports cardiology sections of
the European Association of Cardiovascular Prevention
and Rehabilitation.102 The recommendations for screening are based on the preparticipation activity levels and
the planned level of exercise. All individuals should complete a self-assessment questionnaire, and then follow
the resulting recommendations. Sedentary individuals
who want to engage in low-intensity activity and have a
negative self-assessment (that is, no cardiac symptoms
or history of cardiovascular disease) do not need further
evaluation. If the self-assessment is positive (symptoms
or a history of cardiovascular disease), an additional
assessment by a qualified physician, including a personal
and family history, cardiovascular-risk score, physical
examination, and a 12lead electrocardiogram, should
be undertaken. If the risk SCORE (Systematic COronary
Risk Evaluation) is >5%, a maximal exercise test should
be performed before engaging in any level of exercise.
Strategies to promote activity

The development of strategies to encourage people to
incorporate an increased level of physical activity into
their daily lives in a sustainable fashion remains challenging. Understanding exercise behaviour could yield
important information for enhancing the rate of participation in physical activity.58 Evidence suggests that small
health benefits are associated with individual behavioural
counselling to promote a healthy diet and increasedphysical activity among adults, 123 whereas incorporating
physical activity as a natural part of daily activities from
an early age and encouraging childrens natural desireto
play actively are important. For a behavioural change
to succeed on a population level, two strategiesurban
planning and public legislationneed to be considered.
Studies have shown that children are likely to be most
physically active when unsupervised by adults and
allowed to play outdoors.124,125 Parents choices for their
children influence physical activity, with active travelling (running, walking, cycling, or using a scooter)
and organized physical activity resulting in an increase
in overall physical activity for the rest of the day.126
Therefore, increased physical activity can create a virtuous circle. This effect is also true for adults, in whom
active travel to work (by walking, running, or cycling) is
associated with an overall increase in physical activity,127
and adherence to activity recommendations.128 Strategies
to alter commuting patterns might have a favourable
Proband evaluation
Sudden death
Post-mortem report normal
Negative toxicology
Expert pathologists
assessment normal
Mutation analysis in probandsthe molecular

autopsy
If DNA available in sufficient quantity and
quality
LQTS/Brugada/CPVT genes
Concurrent process without delay to
familial evaluation
Familial evaluation
Initial relative evaluation

Historical assessment
Physical examination
Resting ECG
24 h ECG
Exercise ECG
Echocardiogram
Normal heart
If normal ECG findings

present
Abnormal or equivocal
cardiac morphology
If suspicious right ventricular

lead repolarization present
Cardiac magnetic resonance

imaging signal-averaged ECG
Ajmaline test
Inherited heart disease diagnosed?

Mutation analysis in relatives
If relative is diagnosed or suspected of having inherited heart disease, proceed to
appropriate mutation analysis
In an unequivocal (known or highly probable) mutation is detected in proband or relative,
offer family cascade genetic testing and exclude noncarriers from clinical evaluation
If an equivocal mutation (novel or possible) is detected, offer family cascade testing
and clinical evaluation
Figure 5 | Recommended diagnostic algorithm for families of a proband with

sudden arrhythmic death syndrome. Abbreviations: CPVT, cathecholaminergic
polymorphic ventricular tachycardia; ECG, electrocardiogram; LQTS, long QT
syndrome. Reproduced from Behr, E.R. etal. Sudden arrhythmic death syndrome:
familial evaluation identies inheritable heart disease in the majority of families.
Eur. Heart J. 29(13), 16701680 (2008), by permission of Oxford University Press
and the European Society of Cardiology.
impact on the overall level of physical activity.127 Changes

might be achieved with increased access to cycle routes
and the introduction of cycle hire schemesto enableand
encourage people to cycle rather than to use other forms
of private or public transport. One of the problems of
exercise to work is that the strategy does not benefit
those members of the population with the highest
cardiovascular riskindividuals who are unemployed.129
To influence the whole community, including children, stay-at-home parents, and individuals who are
unemployed, other forms of urban planning can be used,
including the provision of well-lit, safe outdoor spaces
and green areas to facilitate activities such as running,
walking, and recreational cycling (Box1). Some might
argue that humans are specifically adapted for movement 2,3,130 and, to encourage this natural behaviour,
easily accessible, pleasant, and secure trails for running,
walking, or cycling are necessary. Easy access to exercise
is likely to appeal to todays busy individuals, such as

REVIEWS
Box 1 | Strategies to promote physicalactivity
Urban planning
Safe and pleasant walkways and cycle routes
Safe and pleasant running trails that are separated
from traffic, well lit, and have safe crossings
More stairways and fewer lifts and escalators in
subways and other public areas
Disability passes required to use lifts
Roads must give way to cycle routes and walkways
Car-free roads in cities
Schools
Mandatory 1h of physical activity daily in the school
curriculum
Mandatory outdoor recess
Free bus passes given only to children who live >3km
from school
Walking school buses (a group of children walking to
school with one or more adults)
Plenty of well-planned and well-equipped parks and
playgrounds
Workplace
Mandatory exercise breaks
Gyms and exercise equipment at the office
Printers in one place, at a distance from work areas
Disability passes required to use lifts
Stand-up desks and active seating
Company-sponsored events, such as races
Company-organized strategies to increase exercise,
such as cycle schemes
full-time working parents, who have limited free time.131

Enhancing accessibility has been shown to be an effective
strategy to increase physical activity.132 These concepts of
urban planning to promote an active society are being
introduced in many places around the world, and involve
several approaches, such as congestion charges as well
as bicycle hire and routes. Evidence of the effect of such
approaches on public health is needed.31,32,133,134
Other measures can be implemented in schools and
workplaces to promote a physically active day. Actions
taken to increase activity in the public are clearly not sufficient, as the level of physical activity remains low,135 and
the level of inactivity remains high.136 In a study of 1,094
children from three European countries, the rate of obesity
was directly associated with time spent engaging in physical activity, as well as the time spent for outdoor play and
walking to school.125 In another study of 2,529 children,
those who had a yard near home in which they could
play, or who frequently visited parks or playgrounds, were
more likely to have >2h per weekday of outdoor play at
home than those who did not have access to these outdoor
spaces.137 Having a playground at school was associated
with increased time spent outside during the school day.137
These findings suggest that the outside environment, both
at home and at school, is important for increasing the
level of physical activity in children. Novel approaches,
including active transport to school, are suggested in Box1.
Workplace-based physical-activity interventions are
beginning to emerge, with conflicting results. Some
show improvements in blood pressure and BMI, but not
an actual increase in physical activity,138 whereas others
show both increased measures of physical activity and

improved levels of cardiovascular risk factors. Various
interventions have been tested, including knowledge
quizzes, team challenges, letters of management support,
newsletters, and fridge magnets, to allow self-monitoring
of physical activity, as well as actual exercise activities, but
the key to success seems to be the creation of a culture of
physical activity at the workplace. Novel approaches to
increase workplace activity are proposed in Box1.
Lessons can be learned from the introduction of legislation to decrease cigarette smoking. Public campaigns over
at least 3decades that emphasized the dangers of cigarette
smoking were unsuccessful.139 By contrast, legislation,
which has included the banning of smoking in the workplace, restaurants, bars, and public areas, has succeeded
in decreasing both the number of smokers and cigarette
consumption.27 This change has had a substantial publichealth benefit over a short period of time not only for
smokers, but also for passive smokers in the population.
An obesity epidemic has continued despite extensive
campaigns about the dangers of childhood obesity and the
consequences of obesity in adulthood. The numbers are
now reaching a point where being obese or overweight is
more common than being a healthy weight,28 and effective measures for individuals and at a population level to
counteract this trend are urgently needed. The development of successful strategies is more difficult for obesity
than for cigarette smoking, and requires advice on both diet
and physical activity or exercise. Evidence shows that the
built environment surrounding us is linked to our level of
physical activity,29 and consequently to obesity and morbidity,30 and that urban strategies to improve the environment
(Box1) can have favourable effects on public health.31
Conclusions
An increased level of physical activity is important and
beneficial for all individuals, including those at high risk
of adverse cardiovascular events, if undertaken sensibly.
Even a small increase in physical activity has beneficial
effects on cardiovascular morbidity and mortality, and
can benefit even patients with severe heart conditions. In
individuals who are physically fit, without signs of cardiovascular disease, the greater the amount of exercise, the
greater the health benefits. Nevertheless, effective strat
egies to promote physical activity in the general popu
lation are lacking. A sustained increase in physical activity
is likely to require more than individual advice, and might
need to include urban planning and even legislation.
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checked for additional studies missed in the initial search.
Abstracts and unpublished studies were not considered.
Only papers published in English were evaluated.
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Author contributions
F.J. Dangardt researched data for the article.
F.J.Dangardt, W.J. McKenna, and J.E. Deanfield
contributed substantially to discussions of its
content. F.J. Dangardt wrote the manuscript, and
W.J. McKenna, T.F. Lscher, and J.E. Deanfield
reviewed/edited the article before submission.


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REVIEWS

Exercise: friend or foe?

The benefits and risks of exercise in patients have been

Health benefits of physical activity

NATURE REVIEWS | CARDIOLOGY

ADVANCE ONLINE PUBLICATION | 1

Figure 1 | Relationship between level of physical activity and reduction in

5060min of vigorous or moderate exercise daily,

activity, which is less time-consuming than vigorous

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Osteoporosis and obesity

of Alzheimer disease in elderly individuals, possibly

Figure 2 | Relationship between daily duration of physical activity and reduction in

and HDL-cholesterol levels (19.1%), apolipoprotein

NATURE REVIEWS | CARDIOLOGY

ADVANCE ONLINE PUBLICATION | 3

Benefits according to type of exercise

haemoglobin (HbA1c) level, blood glucose level, and

Benefits of exercise in patients

4 | ADVANCE ONLINE PUBLICATION

Congenital heart disease

very high-intensity training is avoided.88 Children with

NATURE REVIEWS | CARDIOLOGY

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Figure 3 | Causes of SCD in various populations. a | Study of 134 cases of SCD

physical exercise.91 These changes were accompanied by

Cardiovascular risks of exercise

systematic review of 51 studies, Goodman and colleagues

SCD in the young

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Immediately after exercise

Myocardial oxygen cost

while they are inactive.97 This pattern is corroborated by

of a cardioverterdefibrillator, and no fatal arrhythmias in relatives without an implantable cardioverter

SCD in the middle-aged

NATURE REVIEWS | CARDIOLOGY

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Heart failure and coronary artery disease

can be a major trigger of life-threatening arrhythmias.110

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Strategies to promote activity

Mutation analysis in probandsthe molecular

Initial relative evaluation

If normal ECG findings

If suspicious right ventricular

Cardiac magnetic resonance

Inherited heart disease diagnosed?

Figure 5 | Recommended diagnostic algorithm for families of a proband with

impact on the overall level of physical activity.127 Changes

NATURE REVIEWS | CARDIOLOGY

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full-time working parents, who have limited free time.131

show both increased measures of physical activity and

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La Gerche, A. etal. Exercise-induced right

sedentary, overweight or obese postmenopausal

NATURE REVIEWS | CARDIOLOGY

37. Kokkinos, P. & Myers, J. Exercise and

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73. Piepoli, M.F. etal. Secondary prevention through

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in dilated cardiomyopathy. J. Am. Coll. Cardiol. 51,

121. Harmon, K.G., Asif, I.M., Klossner, D.

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