REVIEWS

PREVENTION OF CVD

Exercise benefits in cardiovascular

disease: beyond attenuation
of traditional risk factors
Carmen Fiuza-​Luces1,2,12*, Alejandro Santos-​Lozano3,4,12, Michael Joyner5,
Pedro Carrera-​Bastos6,7, Oscar Picazo7, José L. Zugaza8,9,10, Mikel Izquierdo   11,
Luis M. Ruilope1 and Alejandro Lucia1,4
Abstract | Despite strong scientific evidence supporting the benefits of regular exercise for the
prevention and management of cardiovascular disease (CVD), physical inactivity is highly
prevalent worldwide. In addition to merely changing well-​known risk factors for systemic CVD,
regular exercise can also improve cardiovascular health through non-​traditional mechanisms.
Understanding the pathways through which exercise influences different physiological systems is
important and might yield new therapeutic strategies to target pathophysiological mechanisms in
CVD. This Review includes a critical discussion of how regular exercise can have antiatherogenic
effects in the vasculature, improve autonomic balance (thereby reducing the risk of malignant
arrhythmias), and induce cardioprotection against ischaemia–reperfusion injury , independent
of effects on traditional CVD risk factors. This Review also describes how exercise promotes a
healthy anti-​inflammatory milieu (largely through the release of muscle-​derived myokines),
stimulates myocardial regeneration, and ameliorates age-​related loss of muscle mass and
strength, a frequently overlooked non-​traditional CVD risk factor. Finally , we discuss how the
benefits of exercise might also occur via promotion of a healthy gut microbiota. We argue,
therefore, that a holistic view of all body systems is necessary and useful when analysing the role
of exercise in cardiovascular health.

Physical activity
Any bodily movement
produced by skeletal muscles
that requires energy
expenditure.
Moderate-​to-vigorous
physical activity
(MVPA). Any activity with an
energy expenditure of
≥3 metabolic equivalents
(for example, brisk walking);
the WHO minimum
recommendations are 150 min
of MVPA each week (or 20 min
or 10,000 steps on most days
of the week) for adults and
60 min of active playing on
most days of the week for
children and adolescents.
*e-​mail: carmen.fiuza@
universidadeuropea.es
https://doi.org/10.1038/
s41569-018-0065-1
Most of the protein-​c oding genes in the human
genome were subjected to selection pressure during
the pre-​industrial era, when physical activity was an
integral part of daily life and, moreover, was needed for
survival1. Thus, humans are genetically adapted to per-
form physical activity on a regular basis, and failure
to do so — as occurs today in a large proportion of
­people worldwide2 — creates a mismatch3 that results in
chronic maladaptation4.
Determining the amount of physical activity that is
adequate for maintenance of health and that is in accord-
ance with our biological makeup is possible by analysing
the habits of traditional populations that still follow a pre-
industrial lifestyle. To standardize physical activity levels,
researchers have used the so-​called physical activity ratio
(PAR), calculated as the daily total energy expenditure of
an individual divided by the daily basal metabolic rate
(both in kJ/min)5. A PAR value of 1.40–1.69 represents
the inactive to lightly active lifestyle that is character-
istic of Western societies, whereas values of 1.70–1.99
and ≥2.00 represent moderately active and vigorously
active lifestyles, respectively5. Among hunter–gatherers,
the Hadza people of Tanzania, who show an absence of
cardiovascular disease (CVD) risk factors, have an aver-
age PAR of 1.78 in women and 2.26 in men5. Moreover,
Hadza people spend on average 950 min each week per-
forming moderate-​to-​vigorous physical activity (MVPA)1,
which is approximately sixfold greater than the mini-
mum of 150 min each week that is recommended for
adults by the WHO6. A high PAR is also characteristic of
forager–horticulturalist, pastoralist, and traditional farm-
ing popu­lations. The Tsimané people of Bolivia, who still
follow a forager–horticulturalist lifestyle and have a low
incidence of coronary atherosclerosis and a near-​absence
of CVD risk factors (except for high serum C-​reactive
protein (CRP) levels as measured by high-​sensitivity test-
ing, owing to high rates of infectious diseases)7, have a PAR
of 2.02–2.15 in men and 1.73–1.85 in women5. Moreover,
the estimated PAR is 1.70 in non-​Westernized horticul-
turalists from Kitava, Papua New Guinea, who reportedly
have a very low incidence of stroke, ischaemic heart
disease, diabetes mellitus, and metabolic syndrome8.

Nature Reviews | Cardiology

Reviews

Key points more-​intense stimuli and, therefore, more-​profound

• Regular exercise induces antiatherogenic adaptations in vascular function and
structure, irrespective of traditional cardiovascular disease (CVD) risk factors.
• Regular exercise training improves cardiac parasympathetic regulation, thereby
conferring protection against malignant arrhythmias, and also provides
cardioprotection against ischaemia–reperfusion injury.
• Muscle-​derived myokines are responsible for many of the beneficial effects of
exercise, particularly by promoting a healthy anti-​inflammatory milieu.
• Exercise can improve myocardial regeneration capacity, in part through stimulation
of circulating angiogenic cells.
• Loss of muscle strength and mass is a forgotten hallmark of — and, in fact, a risk factor
for — CVD that can be largely reversed with resistance (strength) training, including
in elderly individuals.
• Regular exercise can promote a healthy gut microbiota while protecting the
permeability and function of the gut barrier.
These examples illustrate that a very active lifestyle
that is well above the minimum WHO recommendations
has been a normal characteristic throughout human
evolution1. Nonetheless, technological improvements
over the past ~350 generations (that is, during the agricul-
Physical inactivity
Also termed ‘lack of physical
tural, industrial, and, most recently, digital revolutions)
activity’; defined as not meeting have led to substantial decreases in human physical
the WHO-​recommended activity levels. Indeed, physical inactivity is now the
minimum levels of moderate-​ fourth leading cause of death worldwide9. Approximately
to-vigorous physical activity
one-​third of adults worldwide2 (~50% of adults in the
(note, physical inactivity is
not a synonym for sedentary USA10) do not meet the minimum WHO recommen-
behaviour). dations for MVPA; the trend towards inactivity starts
in adolescence (age 13–15 years)2, leading to a subopti-
Exercise mal cardiovascular phenotype and an increased risk of
Also termed ‘exercise training’;
a subset of physical activity
cardiometabolic disorders2,4.
that is planned, structured, and Most epidemiological studies in very large population
repetitive and has a final or an cohorts (such as those showing an inverse association
intermediate objective of between physical activity and risk of CVD) usually
improving or maintaining
measure physical activity levels from questionnaires.
physical fitness. In this Review,
the terms ‘exercise’ and By contrast, the majority of studies analysing specific bio-
‘exercise training’ are used logical and/or molecular outcomes and mechanisms in
interchangeably to refer to the smaller cohorts of humans or animal models (including
cardiovascular adaptations those discussed in this Review) typically investigate the
produced by this specific type
of physical activity; a single
effects of purposefully designed exercise programmes11.
bout of exercise is referred Exercise is a proxy for (but not a perfect surrogate of)
to as ‘acute exercise’. physical activity, given that exercise is believed to induce
author addresses
1
Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain.
2
CIBER de Enfermedades Raras (CIBERER), Madrid, Spain.
3
i+HeALTH Research Group, Department of Health Sciences, European University been proved useful to increase cardiorespiratory fitness
Miguel de Cervantes, Valladolid, Spain.
4
Research Institute of the Hospital 12 de Octubre (i+12), Madrid, Spain.
5
Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, only one metabolic equivalent (MET) might decrease the
MN, USA.
6
Centre for Primary Health Care Research, Lund University/Region Skåne, Skåne University
Hospital, Malmö, Sweden.
7
NutriScience — Education and Consulting, Lisbon, Portugal.
8
Achucarro — Basque Center for Neuroscience, Bilbao, Spain.
9
Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of
Science and Technology, University of the Basque Country, Leioa, Spain.
10
IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
11
Department of Health Sciences, Public University of Navarre, CIBER of Frailty and
Healthy Aging (CIBERFES), Navarrabiomed, Pamplona, Spain.
12
These authors contributed equally: Carmen Fiuza-Luces, Alejandro Santos-​Lozano.
biological adaptations than physical activity. Indeed, an
efficient and successful exercise training modality for
improving cardiovascular health12 that is gaining popu­
larity in Western society, partly owing to its low time
commitment (sessions last <20 min) despite its high
physiological demand, is high-​intensity interval training
(HIIT), a form of interval exercise13. Thus, in this Review,
the terms ‘physical activity’ and ‘exercise’ should be inter-
preted according to their Glossary definitions. In addi-
tion, aerobic exercise (also termed ‘endurance exercise’)
rather than other exercise modalities, is specifically
implied by the term ‘exercise’, unless otherwise specified.
The health benefits of regular physical activity are
irrefutable14 (Fig. 1). Even low physical activity loads below
the minimum WHO recommendations can provide
major benefits, such as improved cardiometabolic bio-
markers (diastolic blood pressure and HDL cholesterol
levels) in adolescents15 or reduced all-​cause mortality in
adults16,17. For instance, exercising for only 15 min daily
was associated with a 14% reduction in the risk of all-​
cause death compared with inactivity in an Asian adult
population18, and compared with never running, running
for 5–10 min daily at slow speeds (<6 mph) was associ-
ated with a considerably reduced risk of death from
CVD in US adults19. Of note, however, whether the lev-
els of activity below WHO recommendations can also
influence the numerous non-​traditional mechanisms
reviewed in our Review (such as myokine release, haemo­
dynamics, or heart electrophysiology) remains to be
demonstrated. Nevertheless, the findings that regular
physical activity reduces the risk of CVD worldwide are
particularly persuasive20. Such benefits are essentially
independent of country, income, or the type of physi-
cal activity (recreational or work-​related) but are largely
dose-​dependent, with strong benefits (namely, a 14%
reduction in the risk of CVD) reported at physical activity
levels that are fivefold greater than the WHO-​established
minimum20. Likewise, other studies have reported that
the benefit threshold for reducing all-​cause mortality cor-
responds to high doses (3–5-fold greater than the WHO
minimum recommended level) of physical activity21.
Promotion of regular physical activity worldwide
is needed to decrease the substantial global economic
burden (including direct health-​care costs, productivity
losses, and reductions in disability-​adjusted life-​years)
attributable to physical inactivity22. In turn, regular phys-
ical activity is the only behavioural intervention that has
(CRF), a strong indicator of good metabolic health, low
morbidity, and low risk of death23. An increase in CRF of
risk of CVD by 15%24. CRF declines with age, physical
inactivity, and sedentary behaviour (such as long sitting
time)24,25, and sitting time is positively associated with
CVD mortality26, whereas achieving moderate-​to-high
CRF levels (that is, ≥8 METs, with 8 METs being the
metabolic cost of jogging for the average person) is asso-
ciated with a reduced risk of CVD events24. Furthermore,
high levels of physical activity (~60–75 min daily) seem
to eliminate the positive association between time spent
sitting and risk of death27. In summary, although low

www.nature.com/nrcardio
 Reviews

Interval exercise
Exercise that typically involves
short, repeated bouts of
intense effort (for example, fast
running or intensive bicycling)
interspersed with short
recovery periods (each lasting
a few minutes or less); common
variants are high-​intensity
interval training (HIIT), in which
near maximal effort is
expended in exercise bouts of
1 min, interspersed with 1-min
recovery periods, and sprint
interval training (SIT), in which
supramaximal effort is
expended in exercise bouts of
~30 min, interspersed with
recovery periods lasting a
few minutes.
Aerobic exercise
Exercise involving dynamic
movements and large muscle
groups that predominantly rely
on aerobic metabolism for
fuelling muscle contractions;
examples include jogging,
running, swimming, and rowing.
Myokine
A cytokine or peptide
produced by skeletal muscle
cells and subsequently
released into the circulation,
where it exerts endocrine or
paracrine effects in other cells,
tissues, or organs.
levels of regular physical activity (that is, below WHO
minimum recommendations) can benefit cardiovascular
health, a dose–response relationship has been reported.
However, some researchers are currently questioning the
benefits of very high doses of regular physical activity or
exercise (Box 1).
The biological mechanisms underpinning the cardio­
metabolic benefits of an active lifestyle remain to be
fully elucidated. The well-​documented association of
regular physical activity with a decreased incidence
of traditional CVD risk factors (such as hypertension,
dyslipidaemia, and diabetes mellitus) suggests that regu­
lar physical activity can protect against the formation
of intraluminal blood clots28. However, regular physical
activity or exercise can also exert direct beneficial effects
beyond favourable changes in serum lipid profiles and
blood pressure. For example, regular physical activity or
exercise has direct structural and functional benefits in
the vasculature, including cardiac preconditioning and
improved autonomic balance.
In this Review, we describe the various benefits of
exercise in the context of CVD: antiatherogenic effects
in blood vessels, including improvements in vascular
endothelial function and structural vascular adap-
tations (enlargement of conduit arteries, increases
in the collagen and elastin content of atherosclerotic
plaque, and development of coronary collateral blood
vessels); a healthy autonomic balance (regular exercise
increases vagal tone to the heart and prevents malignant
arrhythmias); and cardioprotection against ischaemia–
reperfusion injury. We also discuss the progress in our
understanding of the direct effects of exercise in the
release of muscle-​derived myokines, which induce a
healthy anti-​inflammatory milieu, and the promotion
of a healthy gut microbiota. The mechanisms by which
exercise stimulates myocardial repair and attenuates
sarcopenia (and how these effects can benefit cardio-
metabolic health as we age) are also discussed. Of note,
although some of the discussed mechanisms could also
mediate the benefits of exercise in various other disease
conditions not directly linked to CVD, this Review
focuses exclusively on CVD.
Antiatherogenic vascular adaptations
Repetitive exposure to haemodynamic stimuli during
exercise can lead to antiatherogenic adaptations in vas-
cular function and structure, irrespective of traditional
CVD risk factors29 (Fig. 2).
Functional adaptations. Vascular endothelial dysfunc-
tion has an important role during the development of
atherosclerosis up to the final stage of atherosclerotic
plaque rupture. Normal vascular endothelial func-
tion can be restored not only through drug treatment
(for example, with statins)30 but also through exercise.
Indeed, a meta-​analysis from 2015 revealed that exer-
cise intensity improves vascular endothelial function
in a dose-​dependent manner, at least for aerobic activ-
ities31. Importantly, exercise training improves vascular
endothelial function in the absence of changes in serum
lipid levels, blood pressure, glucose tolerance, or BMI32.
Improvements in vascular endothelial function
induced by acute, moderate-​intensity exercise are largely
caused by an increase in shear stress, which stimulates

'ZGTEKUG +PETGCUGFTKUMQHCVTKCNȰDTKNNCVKQPCPF 2J[UKECNCEVKXKV[

RQVGPVKCNHQTCEWVGVTCPUKGPVUVTWEVWTCN
CPFQTHWPEVKQPCNKORCKTOGPV %GKNKPIGHHGEV

QTGXGPTGXGTUGGHHGEVKPRCVKGPVUYKVJ
4GIWNCTUVTGPWQWUGPFWTCPEG ECTFKQXCUEWNCTFKUGCUG
GZGTEKUG
HQTGZCORNGOCTCVJQPU
QTWNVTCOCTCVJQPU %CTFKQXCUEWNCTJGCNVJ $GKPIXGT[CEVKXG

VJCVKUGZEGGFKPI9*1TGEQOOGPFGF

2J[UKECNCEVKXKV[NGXGNU
'PFWTCPEGGZGTEKUGVTCKPKPI NGXGNUD[ŰsHQNF
'ZGTEKUGKPVGPUKV[

HQTGZCORNGLQIIKPIHQT
sOKPűFC[UGCEJYGGM $GKPICEVKXG

VJCVKUOGGVKPIVJGOKPKOWO9*1
TGEQOOGPFGFNGXGNUQHRJ[UKECNCEVKXKV[
5VTGPIVJVTCKPKPI

HQTGZCORNGNKHVKPIYGKIJVU
sFC[UGCEJYGGM $GKPIUQOGYJCVCEVKXG

VJCVKURGTHQTOKPIUQOGRJ[UKECNCEVKXKV[
DWVCVNGXGNUEQPUKFGTCDN[DGNQYVJG
'PFWTCPEG UVTGPIVJVTCKPKPI 9*1TGEQOOGPFGFOKPKOWO

$GKPIXGT[KPCEVKXG

Fig. 1 | Cardiovascular benefits of regular exercise and physical activity.
Current epidemiological evidence suggests that regular physical activity or
inactivity (right panel) and exercise (left panel) influence cardiovascular
health in several ways, including proven beneficial effects (green arrows),
proven deleterious effects (red arrows), and potential deleterious effects (red
dashed arrow). The well-documented benefits of regular physical activity on
cardiovascular heath can be obtained even with activity levels well below
the minimum WHO recommendations (namely , 150 min of moderate-​
to-vigorous physical activity (MVPA) each week , or 20 min MVPA daily , or
10,000 steps on most days of the week for adults; 60 min MVPA daily for
adolescents) as well as at levels up to approximately five times above these
recommendations. A benefit ceiling (albeit not an adverse effect) can be
reached at even higher MVPA levels in healthy individuals, although a
potential deleterious effect has been reported in patients with
cardiovascular disease at relatively moderate activity levels (~14,000 steps
daily). In turn, purposefully designed programmes of exercise training
( >3 days each week), especially those combining endurance (such as jogging)
and strength (such as weight lifting) training, are the most effective in
improving cardiovascular health, particularly via the non-​traditional
mechanisms reviewed here. By contrast, long-​term participation in strenuous
endurance exercise (such as training for and competing in ultramarathons)
does not provide additional cardiovascular benefits and can be associated
with transient cardiac alterations and an increased risk of atrial fibrillation
compared with the age-matched general population.

Nature Reviews | Cardiology

Reviews

Cardiorespiratory fitness
The capacity of the circulatory
and respiratory systems to
supply oxygen to skeletal
muscles during sustained
physical activity; the primary
measure is maximal oxygen
consumption (VO2 max)
reached during graded exercise
testing until exhaustion.
endothelium-​dependent vasodilatation through the
increased synthesis of nitric oxide (NO) 33 (Fig.  2) .
In patients with CVD, repetitive increases in shear stress
induced by a 4-week moderate-​intensity exercise training
programme improved endothelium-​dependent vasodila­
tation in coronary conduit and resistance vessels34 and
enhanced NO bioavailability by increasing the expres-
sion and activation of endothelial nitric oxide synthase
(eNOS), an effect mediated by the phosphoinositide
reduces the probability of flow-​limiting stenosis. The
ability of exercise training to alter conduit arterial wall
characteristics might also modulate the development of
atherosclerotic plaques.
Atherosclerotic plaque. Irrespective of changes in
serum lipid profiles, exercise training increases the col-
lagen and elastin content of atherosclerotic plaques42
(Fig. 2). In patients with CVD, a high CRF is associated

Metabolic equivalent 3-kinase (PI3K)–RAC-​ α serine/threonine-​ protein
(MET). A unit for quantifying kinase (AKT) signalling pathway35. However, contro-
cardiorespiratory fitness: 1 MET versy exists regarding a potential detrimental effect of
is equivalent to the basal excessive exercise on vascular function (for example, in
metabolic rate (consumption of
3.5 ml O2/kg/min, on average).
elite athletes) through increased oxidative damage to the
vascular endothelium36. Conversely, endurance training
Sedentary behaviour might also improve endothelial function by decreasing
Any waking activities chronic inflammation (as discussed below, in the sec-
conducted in a sitting,
tion on myokines). These functional adaptations precede
reclining, or lying posture and
characterized by an energy
structural adaptations, particularly in conduit arteries.
expenditure ≤1.5 metabolic
equivalents. Structural adaptations. An early observation of vessel
enlargement resulting from intense exercise training
Sarcopenia
Derived from the Greek ‘sarx’
was described in an autopsy report on Clarence DeMar,
(flesh) and ‘penia’ (loss); seven-​time winner of the Boston marathon, who had
sarcopenia is the age-​induced “unusually large coronary arteries”37. Subsequent stud-
loss of muscle mass and ies showed that regular exercise training is associated
function, which typically
with increased coronary artery size and dilatation
manifests as reduced gait speed.
capacity38,39. Indeed, the diameters of large peripheral
Shear stress arteries (the aorta, carotid, and subclavian arteries) are
The frictional force exerted by larger in athletes than in sedentary individuals40, and
blood flow on the endothelium exercise training in general increases the luminal diam-
of vessel walls.
eter of conduit arteries29 (Fig. 2). Exercise training also
reduces the wall thickness of conduit arteries supplying
both active and non-​active areas41 (Fig. 2). This remod-
elling of the arterial wall and tissue organization might
enable arterial wall tension to be sustained despite the
decrease in wall thickness29. Importantly, this remodel-
ling process also indicates that even when atherosclero-
sis is present, the presence of a marked luminal reserve
Box 1 | is ‘over-​exercise’ possible?
Some researchers have questioned the cardiovascular benefits of very high amounts of
exercise and have introduced the concept of cardiac overuse injury (or ‘over-​exercise’)
to refer to all the potential deleterious cardiac consequences of repeated exposure to
strenuous endurance exercise (SEE), such as marathons and ultramarathons151.
Although the long-​term clinical consequences of SEE on cardiac structure remain to
be fully elucidated, the bulk of the evidence supports the hypothesis that the acute
alterations produced by a bout of SEE (for example, an impairment of right ventricular
function observed after an ultramarathon run) are essentially transient152.
In addition, although long-​term exposure to SEE can increase the risk of atrial
fibrillation, the numerous benefits of SEE (which are generally those of endurance
exercise and/or physical activity, as discussed in this Review) outweigh its potential
negative cardiovascular effects152. For example, the results of a meta-​analysis showed
that former elite athletes had lower CVD mortality than the general population46.
Conversely, although very high levels of leisure-​time physical activity (≥10-fold greater
than the minimum WHO recommendation) are not associated with increased all-​cause
mortality in the general population21, the evidence is controversial for patients with
CVD. A reverse J-​shaped association has been reported between physical activity level
and CVD mortality in individuals with coronary heart disease (although the least active
patients also had increased hazards)153, and the health benefits of physical activity
against CVD mortality in heart attack survivors seem to reach a maximum threshold at
fairly moderate loads: 10.7 km daily of brisk walking, or the equivalent of ~14,000 steps154.
with a high fibrous volume and/or cap thickness of
coro­nary plaques43, and regular exercise decreases both
the necrotic core area and plaque burden44. Although
research from 2017 showed a higher prevalence of coro­
nary artery calcification and atherosclerotic plaques in
veteran male athletes (who had lifelong experience of
endurance training) than in age-​matched but less-​trained
men, the veteran athletes also had a more benign plaque
composition (that is, fewer mixed plaques and more
calcified-​only plaques)45. This observation provides
biological support for the aforementioned meta-​analytic
evidence that top-​level athletes have a lower risk of death
from CVD than the general population46.
Collateralization. The development of coronary col-
lateral blood vessels and, consequently, of increased
perfusion of the collateralized myocardium is another
well-​documented structural adaptation to aerobic train-
ing that limits myocardial infarction (MI) lesion size if a
coronary artery is blocked and is one of several findings
supporting the implementation of exercise programmes
in the management of CVD47 (Fig. 2).
The aforementioned adaptive responses to exercise
can also limit age-​related increases in vascular and car-
diac stiffness48. Importantly, reduced vascular stiffness
protects vital organs (particularly the brain and kidneys,
and probably also the heart) against the development of
heart failure with preserved ejection fraction (HFpEF)49.
Together, these adaptations are thought to ensure ade-
quate blood flow to these organs over time and, there-
fore, reduce the risk of acute ischaemic events and limit
the damage caused by such events, if they occur.
Autonomic balance
Ventricular fibrillation in the context of coronary artery
disease remains a leading cause of sudden cardiac death
and of all-​cause and cardiovascular mortality worldwide50.
Beyond the improvements in blood flow to the heart,
other important mechanisms by which regular exer-
cise protects against life-​threatening arrhythmias exist,
some of which involve the autonomic nervous system.
Heart rate variability (HRV) is a measure of effer-
ent vagal nerve activity to the heart51. In this regard, low
HRV is a marker of autonomic dysfunction that might
be associated with impaired cardiovascular health and
poor outcomes, including, for instance, an increase in
mortality in patients after MI or in patients with heart
failure52 or a substantial increase in the incidence of a
first cardiovascular event in populations without known
CVD53. Regular exercise improves HRV, including in
patients with heart failure54 or diabetes mellitus55. Elegant
research in dogs subjected to experimental MI has shown
that exercise training improves cardiac parasympathetic

www.nature.com/nrcardio
 Reviews

+ORTQXGFXCUEWNCTGPFQVJGNKCNHWPEVKQP 8CUEWNCTTGOQFGNNKPICPIKQIGPGUKU
'PNCTIGFEQPFWKVCTVGTKGU
↑ 01 ↑ #PVKKPȱCOOCVQT[
TGFWEGFYCNNVJKEMPGUUCPF
O[QMKPGU KPETGCUGFNWOKPCNFKCOGVGT
↑ G015
5JGCTUVTGUU %QTQPCT[
EQNNCVGTK\CVKQP
'PFQVJGNKCN EGNNU

#WVQPQOKEDCNCPEG
5VCDKNK\GF
RNCSWGNGUKQPU

%CTFKCERTGEQPFKVKQPKPI
↑ 01
↓5[ORCVJGVKEVQPG ↓β#FTGPGTIKE ↑ 4+5-
VQVJGJGCTV TGEGRVQT
UGPUKVKXKV[ ↑ %CNEKWO
↑8CICNVQPGVQVJGJGCTV /KVQEJQPFTKQP

Fig. 2 | Main benefits of regular exercise on blood vessels, autonomic balance, and cardiac preconditioning.
Cumulative exposure to haemodynamic stimuli during aerobic exercise induces antiatherogenic adaptations in vascular
function (left upper panel) and structure (right upper panel), irrespective of traditional cardiovascular risk factors. Of note,
these benefits have been mainly reported with dynamic endurance (aerobic) exercise involving large muscles, such as
jogging, running, or bicycling in humans or forced treadmill running, swimming, or voluntary wheel running in rodents.
Improvements in vascular endothelial function are largely attributable to increased shear stress, which stimulates
vasodilatation via release of nitric oxide (NO). Regular exercise also decreases chronic inflammation through the
release of myokines. These functional adaptations precede structural adaptations, particularly in conduit arteries, which
enlarge with exercise. Regular exercise increases atherosclerotic plaque collagen and elastin content, decreases necrotic
core volumes, and reduces overall plaque burden. Another structural adaptation to aerobic training is coronary
collateralization, which increases myocardial perfusion. Beyond improved blood flow to the heart, regular exercise might
protect against life-​threatening arrhythmias via improved cardiac autonomic balance (left lower panel). Regular exercise
prevents fatal arrhythmias by inducing cardiac preconditioning (right lower panel), which protects the heart against
ischaemia–reperfusion injury. Cardioprotection can be induced by a single bout of exercise and can be maintained for
months with regular exercise; the mechanisms reportedly involved include increased cardiac storage of NO metabolites,
activation of pro-​survival kinases of the reperfusion injury salvage kinase (RISK) pathway , and improved calcium-​retaining
capacity of mitochondria. eNOS, endothelial nitric oxide synthase.

regulation (reflected by increased HRV), restores normal
β-​adrenergic receptor balance (by reducing β2-adrenergic
receptor sensitivity and expression), and protects against
ventricular fibrillation51,56.
In the context of the above observations, vagal tone
might be improved with exercise training because
blood vessels in barosensitive areas of the carotid arter-
ies become more compliant than in their pre-​training
state and, thus, are able to distend more in response to
an increase in blood pressure57,58. This change, in turn,
increases afferent signalling to the brainstem and evokes
reflex increases in vagal (parasympathetic) nerve activity
to the heart while simultaneously suppressing sympa-
thetic activity to the heart58 (Fig. 2). Endurance training
can also induce adaptations in the cardiovascular cen-
tres of the brainstem that inhibit sympathetic activity59.
Together, these peripheral and central effects increase
vagal tone and protect against fatal arrhythmias.
In dogs that are susceptible to ischaemia-​induced
ventricular fibrillation following experimental MI,
endurance exercise training led to other adapta-
tions, including the normalization of repolarization
abnormali­ties, as shown in vivo by electrocardiographic
recordings and in vitro by measuring myocyte action
potential duration 60. These animals also showed
improved myocyte calcium handling owing to restor­
ation of ryanodine receptor (RyR) channel activity,
which was mediated by the exercise-​induced reduction
in calcium/calmodulin-​dependent protein kinase type II
(CaMKII)-mediated hyperphosphorylation of RyR
at Ser2814, resulting in the prevention of calcium ion
leakage from the sarcoplasmic reticulum. These changes
limited the propagation of unstable electrical signals in
the heart, thereby preventing malignant arrhythmias.
Cardiac preconditioning
Regular exercise can also prevent fatal arrhythmias by
inducing cardiac preconditioning (Fig. 2). Exposure of
the heart to ischaemia and then reperfusion initiates
a cascade of events that culminate in tissue damage,
known as ischaemia–reperfusion injury. Crucial con-
tributors to this process include dysregulated calcium
signalling and oxidative damage, in addition to mito-
chondrial dysfunction61. Even a single bout of exercise
can protect the heart against ischaemia–reperfusion
injury, and this cardioprotection can be maintained
for months with regular exercise. Key cardioprotective
mechanisms of exercise include an increased capacity
to withstand oxidative stress, upregulated expression of
sarcolemmal ATP-​sensitive potassium channel subunits,
and mitochondrial adaptations (particularly increased
resistance to injury of these organelles via improvements
in their tolerance to apoptotic stimuli or in their capacity
for scavenging endogenous reactive oxygen species)61.
Cardiac preconditioning refers to the phenomenon
whereby brief periods of ischaemia before prolonged

Nature Reviews | Cardiology

Reviews
occlusion are cardioprotective, as they reduce the
subsequent MI lesion size or the risk of ventricular
fibrillation62. Exercise can induce cardiac precondi-
tioning62, although this phenomenon is still widely
under-​recognized. Preclinical research in rodents has
revealed that cardioprotection occurs within 1–5 days
of acute exercise63,64, a time period that is too short to
induce improvements in traditional CVD risk factors62.
The hypothesis that exercise induces the immediate
attenuation of cardiac ischaemia is supported by a
meta-​analysis of data from 1,053 patients with angina
who underwent sequential exercise stress testing65.
Compared with the values obtained at their first exercise
stress test, these individuals showed a significant delay
in onset of ST-​segment depression (91 s, P < 0.001) and
a decrease in peak ST-​segment depression (−0.38 mm)
on a second exercise stress test. Similarly to ischae-
mia, exercise also elicits cardioprotection against
necrosis, which is partly mediated by δ-​opioid recep-
tor activation66. In addition to opioids, several factors
that trigger preconditioning (such as adenosine and
bradykinin) are released in a dose-​dependent manner
during exercise66.
The cardiac preconditioning effects of exercise —
including β3-adrenergic receptor-​mediated upregu-
lation of cardiac eNOS expression, which results in
increased cardiac storage of NO metabolites such as
nitrite and nitrosothiols — are sustained for several days
in exercised mice67. Furthermore, the finding that even
moderate-​intensity exercise produces MI-​sparing effects
in rats68,69 suggests that the presence of ischaemia during
exercise is not obligatory for achieving cardioprotection
via exercise-​induced cardiac preconditioning62. A study
in obese mice found that exercise training induced
robust cardiac preconditioning effects, notably a 67%
reduction in MI lesion size, independent of changes in
traditional CVD risk factors (for example, body mass and
blood levels of insulin, glucose, or cholesterol)70. Several
mechanisms were reportedly involved: the activation of
pro-​survival kinases of the so-​called reperfusion injury
salvage kinase (RISK) pathway, namely, increased phos-
phorylation of PI3K, AKT, extracellular-​signal-regulated
kinase 1 (ERK1; also known as MAPK3) and ERK2 (also
known as MAPK1), 70 kDa ribosomal protein S6 kinase
(p70S6K; also known as S6K1), 5ʹ-AMP-​activated pro-
tein kinase (AMPK), and glycogen synthase kinase 3β
(GSK3β); decreased levels of phosphatases, including
phosphatase and tensin homologue (PTEN), mitogen-​
activated protein kinase phosphatase 3 (MKP3; also
known as DUSP6), and protein phosphatase 2C (PP2C);
and an improved capacity of mitochondria to retain cal-
cium ions mediated via an increase in the calcium con-
centration required to open mitochondrial permeability
transition pores (mPTPs).
Myokines
Chronic systemic inflammation is emerging as a CVD
risk factor71. Indeed, pro-​inflammatory cytokines have
been associated with increases in the risk of both coro-
nary heart disease (independently of conventional CVD
risk factors)72 and type 2 diabetes mellitus73. The adipose
tissue actively secretes bioactive substances, referred
to as adipokines or adipocytokines, which can have
either pro-​inflammatory or anti-​inflammatory effects.
Obesity-​driven adipose tissue dysfunction contrib-
utes to the development of CVD through upregulation
of pro-​inflammatory adipokines and downregulation
of anti-​inflammatory adipokines74. By contrast, exercise
training produces beneficial anti-​inflammatory effects28,
including, for example, a decrease in serum CRP
levels in healthy individuals75 and decreases in both
CRP and IL-6 plasma levels in patients with type 2
diabetes mellitus76.
The exercise milieu. Skeletal muscle is an endocrine
organ that can produce and release myokines into the
bloodstream (particularly during muscle contrac-
tion), where they function locally and/or systemically
to elicit myriad beneficial effects, including decreased
inflammation and insulin resistance28 (Fig. 3). The anti-​
inflammatory milieu created by exercise training is
believed to be mediated largely by myokines (Fig. 3),
which protect arteries against the progression of athero-
sclerosis and stenosis and preserve the stable phenotype
of pre-​existing atherosclerotic plaques77.
IL-6 is a pro-​inflammatory cytokine involved in T cell
differentiation and activation that is mainly derived
from immune cells or adipocytes. Elevated levels of cir-
culating IL-6 (standard mean difference 1.49, 95% CI
1.04–1.93 compared with healthy adults) are associated
with several chronic conditions, including type 1 diabe-
tes mellitus78 and increased intima–media thickness in
individuals with (or at risk of) CVD, as well as in appar-
ently healthy individuals79, and also with an increased
risk of death from CVD and all-​cause death in the gen-
eral elderly population80. Paradoxically, when released by
contracting muscles, IL-6 has health-​promoting effects
that seem to be dose-​dependent, as the benefits increase
with increasing duration81 and intensity82 of exercise
(Fig. 3). IL-6 exerts a strong anti-​inflammatory effect by
inducing the release of other circulating cytokines that
have anti-​inflammatory properties, specifically IL-1
receptor antagonist (IL-1RA) and IL-10, from blood
mononuclear cells83. IL-6 might also exert direct anti-​
inflammatory effects by decreasing circulating levels
of tumour necrosis factor (TNF)84. Furthermore, IL-6
induces other healthy metabolic effects that, in turn,
decrease the risk of CVD, such as increasing lipolysis
and fat oxidation in adipose tissue85 or reducing skeletal
muscle insulin resistance86.
Of note, in preclinical models, the release of the
muscle-​d erived myokine IL-15 has been shown to
conserve metabolic homeostasis by decreasing white
adipose tissue mass87, increasing glucose tolerance88,
and facilitating glucose uptake by muscle tissue 89
(Fig. 3). Irisin has also been proposed as a candidate
myokine that is present in human blood, as higher
circulating levels of irisin have been reported in aero­
bically trained individuals than in their sedentary
counterparts90. However, concerns have been raised
regarding inconsistencies between mouse and human
data91 and methodological issues, such as potential cross
reactivity of the commercially available anti-​irisin anti-
bodies with other proteins92. Preclinical data indicate
www.nature.com/nrcardio
 Reviews

that peroxisome proliferator-​activated receptor-​γ co-​
activator 1α (PGC1α)-induced expression of irisin might
help to combat obesity by stimulating the browning of
white adipose tissue and activating the thermogen­
esis programme, which promote energy expenditure93
(Fig. 3). Indirect evidence for a protective role of irisin
against the development of CVD comes from the find-
ing that centenarians without CVD have approximately
twofold higher blood levels of irisin than young adults
with precocious MI94.
Other myokine candidates include meteorin-​like
protein (METRNL), which is an exercise-​related factor
that (similarly to irisin) improves glucose tolerance and
stimulates thermogenesis, albeit through a different
mechanism: increased expression of genes associated
with brown fat thermogenesis and anti-​inflammatory
cytokines95 (Fig. 3). Moreover, fibroblast growth fac-
tor 21 (FGF21) has also been proposed as a myokine
that is induced by the PI3K–AKT pathway96. FGF21
protects muscle tissue against insulin resistance97 and
augments brown fat thermogenesis in concert with
irisin98 (Fig. 3).
Myocardium and vessels. Myokines might also elicit
direct benefits to the cardiovascular system (Fig.  3).
In mice, follistatin-​related protein 1 (FSTL1) improves
endothelial cell function and promotes revascularization
in ischaemic tissue by activating eNOS via the PI3K–
AKT pathway99. Similarly, irisin might also improve
arterial relaxation through both endothelium-​dependent
(NO-​mediated) and endothelium-​independent (calcium
influx-​inhibiting) mechanisms100, and protects against
endothelial injury and atherosclerosis through activation
of PI3K–AKT and eNOS signalling101. In addition to its
known association with improved whole-​body insu-
lin resistance102, apelin exerts direct beneficial cardio­
vascular effects, including vasodilatation, increased
myocardial contractility, and angiogenesis103.
A holistic view. The myokine–CVD research field
is growing rapidly, and new candidates are regularly
emerging. Another myokine candidate is musclin
(also known as osteocrin), which seems to increase
CRF in preclinical models by increasing mitochondrial
biogenesis104. Beyond myokines, working muscles can

&KTGEVECTFKQXCUEWNCTDGPGȰVU %8&

HQTGZCORNG↑GPFQVJGNKCNHWPEVKQP
↑CTVGTKCNTGNCZCVKQP↑O[QECTFKCN
↑)NWEQUG EQPVTCEVKNKV[↑CPIKQIGPGUKUCPFQT
JQOGQUVCUKU TGXCUEWNCTK\CVKQP
.KXGT 2CPETGCU (56.
+TKUKP +.4#
%JTQPKEU[UVGOKE
+PUWNKP #RGNKP +. KPȱCOOCVKQP
/WUENG
()( +. 60(
+. ↑2TQKPȱCOOCVQT[
)NWEQUG
CFKRQMKPGU
+. ()(
+. +TKUKP &[UHWPEVKQPCN9#6
↑/WUENGOCUU ↑8KUEGTCN9#6
+. /'640.
9#6
.+( %QPVTCEVKPI
OWUENGU $TQYPKPI
/WUENKP ↑6JGTOQIGPGUKU

↑%4( 1DGUKV[
9#6OCUU
↑/KVQEJQPFTKCN
5CTEQRGPKC DKQIGPGUKU

Fig. 3 | Cardiovascular benefits of muscle-​derived myokines. Skeletal muscle is an endocrine organ that produces and
releases myokines into the bloodstream, particularly during muscle contraction, where they elicit beneficial local and/or
systemic cardiovascular effects. The benefits depicted here were mainly elucidated from research into the effects of
dynamic endurance (aerobic) exercise in animals and humans, although some myokines might specifically be induced by
resistance exercise. The anti-​inflammatory milieu created by exercise training protects arteries against atherosclerosis
and helps to stabilize pre-​existing atherosclerotic plaques. The release of IL-6 by contracting muscles increases the levels
of the anti-​inflammatory cytokines IL-1 receptor antagonist (IL-1RA) and IL-10 and decreases circulating levels of the
pro-​inflammatory cytokine tumour necrosis factor (TNF). Myokines improve cardiometabolic health through several
mechanisms: IL-6, IL-15, and fibroblast growth factor 21 (FGF21) reduce skeletal muscle insulin resistance, which improves
glucose homeostasis; irisin, meteorin-​like protein (METRNL), and FGF21 stimulate browning of white adipose tissue (WAT),
activating thermogenesis and promoting energy expenditure, which reduces obesity ; leukaemia inhibitory factor (LIF),
IL-4, IL-6, IL-7 , and IL-15 stimulate skeletal muscle growth and maintenance, which is especially important to protect
elderly individuals against sarcopenia and the accumulation of visceral fat, two important risk factors for cardiovascular
disease (CVD); and musclin increases mitochondrial biogenesis and cardiorespiratory fitness (CRF). Myokines might have
direct cardiovascular benefits: follistatin-​like protein 1 (FSTL1) improves endothelial cell function and promotes
revascularization in ischaemic tissue; irisin improves arterial relaxation and protects against endothelial injury and
atherosclerosis; and apelin promotes vasodilatation, increased myocardial contractility , and angiogenesis. Solid and
dashed arrows denote increasing and decreasing effects, respectively.

Nature Reviews | Cardiology

Reviews
Resistance exercise
Movement performed against
a specific external force that is
regularly increased during
training; examples include
weightlifting and exercises
using resistance machines.
Muscle strength
The ability of a muscle to exert
force on physical objects;
muscle strength is determined
by the mass of the muscle and
its ability to recruit motor units.
also secrete other molecules with potential cardiometa-
bolic beneficial effects, such as β-​aminoisobutyric acid
(BAIBA), a metabolite formed by the catabolism of thy-
mine that promotes the browning of white adipocytes
and improves glucose homeostasis105 (Fig. 3).
Some anabolic myokines, including IL-4, IL-6, IL-7,
IL-15, and leukaemia inhibitory factor (LIF)28, are also
involved locally in muscle growth, hypertrophy, and
maintenance (Fig. 3). The roles of these myokines are
important to consider given that sarcopenia is com-
monly associated with CVD, particularly in elderly indi-
viduals106. By contrast, high muscle mass might protect
against the accumulation of visceral fat, which is a CVD
risk factor (discussed below)107,108.
The majority of research on myokines has focused
on endurance exercise, and the myokines induced by
resistance exercise (also known as strength exercise) are
only now being explored109. An important message aris-
ing from these studies is that a holistic, integrative vision
of cardiovascular health is necessary to fully elucidate
the cardioprotective roles of exercise-​induced myok-
ines, given that substantial myokine-​mediated crosstalk
exists between skeletal muscle and several other tissues,
including not only the cardiovascular system but also
the adipose tissue.
Myocardial regeneration
Impaired myocardial regenerative capacity is one of the
deleterious consequences of MI that worsens clinical out-
comes after heart failure, particularly in elderly patients
aged >60 years110. Unfortunately, no major advances
have been made in this area, and all-cause mortality at
≤1 year after MI remains high110. Thus, novel therapeutic
approaches are needed to mitigate the adverse remod-
elling of the left ventricle that occurs after MI110. In this
regard, meta-analytic evidence shows that exercise train-
ing following MI has salutary effects on left ventricular
(LV) remodelling, notably by reducing LV end-systolic
volume, a strong predictor of mortality after MI111.
Exercise benefits can last ≥3 months and are maximized
with the early commencement of training (that is, from
1 week after MI)111. Improvements in vascular endothelial
function, autonomic balance, and myocardial contractil-
ity and reductions in myocardial wall stress are among
the suggested mechanisms underpinning these bene-
fits111. Other postulated mediators of exercise-induced
myocardial repair after MI are increased activation of
telomerase in damaged cardiac tissues, particularly
in elderly individuals110, or neuregulin 1 (NRG1)-
dependent activation of receptor tyrosine-protein
kinase ERBB2 and ERBB4 signalling112. The precise role
of the myokine FSTL1 in exercise-induced myocardial
repair remains to be elucidated owing to the potential
myocardium-regenerating effects of FSTL1 in general,
particularly when released from the epicardium113.
Circulating angiogenic cells. Exercise can serve as a
coadjuvant in regenerative medicine therapy through
its stimulating effects on a subset of stem cells, termed
circulating angiogenic cells (CACs; also known as circu-
lating progenitor cells or circulating endothelial cells),
levels of which are inversely associated with the risk of
CVD114. Although the exercise-​induced engraftment
of CACs in the injured myocardium remains to be defini­
tively shown, regular exercise does increase the number
and/or function of CACs in individuals with CVD or
related conditions (namely, metabolic syndrome or obe-
sity)28. Notably, intense exercise, particularly that suffi-
cient to induce transient myocardial ischaemia, seems
to be the most potent stimulus for the release of CACs
into the blood28,115.
The mechanisms postulated to mediate exercise-​
induced proliferation and release of CACs involve, among
others, proangiogenic factors such as hypoxia-​inducible
factor 1α (HIF1α) or vascular endothelial growth factor
(VEGF), IL-6, and increased NO levels (derived from the
bone marrow, endothelium, or CACs themselves)28.
Loss of muscle strength
In addition to low levels of physical activity or CRF, low
muscle strength is also associated with CVD develop-
ment, CVD mortality, and CVD-​related outcomes in
adults, adolescents, and children across a wide range of
ages and populations116,117 (Fig. 4). For instance, baseline
handgrip strength was associated with CVD events and
hospitalization in patients (men and women, average age
64 years) with diabetes mellitus118 and with CVD mortal-
ity in patients with prediabetes or diabetes mellitus aged
≥50 years119. Associations have also been reported for
1 repetition maximum (1RM) measures of leg or bench
press and the incidence of metabolic syndrome in men
aged 20–80 years120.
Sarcopenia. The strength of skeletal muscle largely
depends on the mass of this tissue. In this context,
low muscle mass is an independent predictor of major
adverse cardiovascular events in patients with chronic
kidney disease121 and is associated with coronary artery
calcification in healthy middle-​aged adults122 and with
increased CVD mortality in individuals with known
CVD risk factors aged ≥65 years123 (Fig. 4). Conversely,
high muscle mass might protect against ischaemic stroke
in community-​dwelling adults124, and a high middle-​arm
circumference is an independent predictor of survival in
patients aged >70 years125.
Accelerated sarcopenia is prevalent among patients
with HFpEF126 and can contribute to the development
of this condition by promoting cardiovascular remod-
elling and dysfunction127. Pathological mechanisms
implicated in the deleterious cardiovascular effects of
sarcopenia include systemic inflammation, which can be
due (at least in part) to myokine dysregulation127 (Fig. 4).
Systemic inflammation might induce coronary micro-
vascular endothelial inflammation and reduce NO bio-
availability128 (with impairment of endothelial function
in patients with HFpEF and sarcopenia)129.
As skeletal muscle is the major site of dietary glucose
utilization, loss of this tissue contributes to dysglycae-
mia and insulin resistance, which in turn are associated
with mitochondrial and endothelial dysfunction and with
LV hypertrophy127. Skeletal muscle loss can also lead to
a decreased release of muscle-​derived carnitine (a modi-
fied amino acid that is mostly accumulated in cardiac and
skeletal muscles and, among other metabolic functions,
www.nature.com/nrcardio
 Reviews

(TCKNV[ .QYOWUENG %8&

UVTGPIVJ 'RKFGOKQNQIKECNCUUQEKCVKQP

#FKRQMKPG 5CTEQRGPKE 5CTEQRGPKC ↑ 8KUEGTCNQDGUKV[

F[UTGIWNCVKQP QDGUKV[
CIGTGNCVGF

/[QMKPG
%8& 'PFQVJGNKCN %JTQPKEU[UVGOKE F[UTGIWNCVKQP .QYOWUENG

*(R'( F[UHWPEVKQP KPȱCOOCVKQP OCUU

+PUWNKP 4GUKUVCPEG
UVTGPIVJ
TGUKUVCPEG VTCKPKPI

Fig. 4 | interplay between muscle strength, muscle mass, and CVd.
Low muscle strength in adults is associated with the development of
cardiovascular disease (CVD) and CVD-​related outcomes, including death.
In turn, the strength of skeletal muscle largely depends on its mass, and low
muscle mass is similarly associated with an increased risk of CVD or related
outcomes, especially in elderly individuals. Low muscle strength and mass
both lead to accelerated sarcopenia, which is prevalent in patients with
heart failure with preserved ejection fraction (HFpEF) and contributes to the
development of this condition. Because skeletal muscle is the major site of
dietary glucose utilization and myokine production, loss of this tissue
contributes to dysglycaemia, insulin resistance, and myokine dysregulation,
which in turn are associated with mitochondrial and endothelial
dysfunction and left ventricular hypertrophy. The combination of skeletal
muscle loss and obesity — so-​called sarcopenic obesity — is especially
harmful, as increased fat mass potentially leads to dysregulation of
adipokine secretion and upregulation of pro-​inflammatory adipokines. The
decline in skeletal muscle function associated with sarcopenia contributes
to the development of frailty syndrome. The good news is that resistance
(strength) training has tremendous therapeutic potential, particularly in
patients aged > 60 years with CVD, as it can counteract loss of skeletal
muscle strength and/or mass while improving glycaemic control and
decreasing visceral fat. Increases in muscular strength resulting from
resistance training might also prevent CVD itself. Solid and dashed arrows
denote increasing (or contributing) and decreasing effects, respectively.

transports long-​chain fatty acids into mitochondria for
oxidation to provide energy)127. Of note, l​-carnitine sup-
plementation attenuated cardiac fibrosis by increasing
prostacyclin production through the arachidonic acid
pathway in a preclinical model of hypertensive HFpEF
(Dahl salt-​sensitive rats fed a high-​salt diet) and has been
postulated as a potential therapeutic option for patients
with HFpEF130. The combination of skeletal muscle loss
and obesity — so-​called sarcopenic obesity — is espe-
cially harmful, as increased fat mass deposition potentially
leads to dysregulation of adipokine secretion (upregula-
tion and downregulation of pro-​inflammatory and anti-​
inflammatory adipokines, respectively)74, as mentioned
above127 (Fig. 4). Moreover, adiponectin deficiency can con-
tribute to the development of HFpEF, as this adipokine has
cardioprotective activity; adiponectin increases diastolic
function and decreases cardiac hypertrophy, in addition
to lowering myocardial oxidative stress and improving
intracellular calcium handling131.
The decline in skeletal muscle function that is associ-
ated with sarcopenia and the subsequent risk of disability
is likely to become an increasingly important issue owing
to population ageing and improved survival in patients
with CVD. For instance, elderly patients with diabetes
mellitus have accelerated sarcopenia and a greater decline
in functional capacity than their normoglycaemic peers,
and are at an increased risk of accelerated ageing and the
development of frailty syndrome, as well as falls, institu-
tionalization, and disability132. Thus, the preservation of
functional capacity should be a main focus in the manage-
ment of patients with CVD, particularly those at advanced
ages. In this regard, although elderly individuals might
(like any other adults) clearly benefit from the WHO
recommendations for physical activity (namely, MVPA
≥150 min daily), this minimum level might not be suffi-
cient to attenuate age-related declines in physical function,
for which resistance-based exercises are also needed.
Resistance training. Prescription of resistance (strength)
training remains largely ignored despite its tremendous
therapeutic potential. In patients aged >60 years who
have diabetes mellitus, resistance training counteracts
the losses of skeletal muscle strength and/or mass and
functional capacity and can also improve glycaemic con-
trol while decreasing visceral fat levels132. Meta-analytic
evidence shows that resistance training can improve
mobility in elderly patients with coronary artery dis-
ease133 and in community-dwelling individ­uals 6 months
after a stroke134. Resistance training also lowers the risk
of CVD in healthy adults by decreasing blood pressure,
body fat levels, and plasma triglyceride concentrations135.
Furthermore, human muscle strength remains respon-
sive to resistance training even near the end of life; frail
nonagenarians with multiple comorbidities (including
CVD) showed substantial gains in muscle strength after
only 8 weeks of light-to-moderate resistance training (leg
press) with no other concomi­tant lifestyle (for ­example,
nutritional) or medical interventions136.
Maintaining an adequate level of muscular strength
facilitates the capacity to carry out activities of daily life
and to participate in physical activity, and is also likely
to help to maintain a high CRF level, which is a strong
predictor of decreased CVD mortality24. Increases in
muscular strength resulting from resistance training
might also prevent CVD itself, at least partially through
biological pathways that are not necessarily associated
with CRF or with traditional CVD risk factors. Such
potential mechanisms would have positive effects on
muscle mass and/or muscle quality (that is, increased
strength for the same muscle mass), adipose tissue
(including attenuation of age-​induced increase in vis-
ceral adiposity), and the maintenance of, or increase
in, resting metabolic rate116 (Fig. 4). Other postulated
(albeit less explored) mechanisms include improved vas-
cular endothelial function137, increased blood antioxidant

Nature Reviews | Cardiology

Reviews

Gut microbiota
The collective microorganisms
(bacteria, archaea, fungi, and
viruses) that reside in the
gastrointestinal tract.
Gut microbiome
The collective genomes of the
gut microbiota.
Short-​chain fatty acids
Fatty acids (such as butyrate)
that are produced by the gut
microbiota during the
fermentation of partially
digestible and indigestible
carbohydrates; the highest
levels of short-​chain fatty acids
are found in the proximal
colon, where they are used
locally by enterocytes or
transported across the gut
epithelium into the
bloodstream.
Intestinal permeability
The capacity of material to
pass from the lumen of the
gastrointestinal tract through
the cells lining the gut wall into
the rest of the body.
Lipopolysaccharide
Also known as endotoxin; an
active component of the cell
wall of Gram-​negative bacteria
originating from food intake
and/or the microbiota of the
oral cavity and gut.
defence, and decreased central arterial stiffness116. In
addition, specific resistance exercise-​induced myokines
might also be identified in the future137.
Effects of exercise on the gut
Discoveries in the past decade have shed light on the role
of the gut microbiota in health and disease, including in
CVD. Although the precise mechanisms remain to be
elucidated, specific gut microbiome profiles and microbial
metabolites are associated with CVD138. An unhealthy
phenotype (that is, representing maladaptation) of the
gut microbiota might increase the risk of CVD through
several mechanisms, such as increased production
of the microbial metabolite trimethylamine N-​oxide
(TMAO) 139, increased endotoxaemia 140, increased
bacterial translocation to carotid arterial plaques141,
increased body fat mass, increased and decreased serum
concentrations of triglycerides and HDL, respectively142,
and increased blood pressure 143. Regular exercise,
by ­contrast, modulates the gut microbiota towards a
healthy phenotype.
Having a high CRF138,144, an active lifestyle (that is,
meeting or exceeding the WHO minimum recom-
mendations for MVPA)145, or participating in endur-
ance exercise training146,147 can positively modulate the
human gut microbiota via several possible mechanisms:
increasing bacterial diversity, a parameter that is usually
associated with favourable health outcomes148; increas-
ing faecal concentrations of short-​chain fatty acids such as
butyrate, a commonly used indicator of gut health147,148;
increasing the proportion of health-​promoting bacterial
species (such as Faecalibacterium prausnitzii, Roseburia
hominis, and Akkermansia muciniphila)145; and decreas-
ing the levels of microorganisms associated with obe-
sity and metabolic diseases (such as Eubacterium rectale
and Clostridium coccoidea)144. Interestingly, the benefits
of endurance exercise training on the gut microbiota
seem to be independent of diet and disappear upon
recommencement of a sedentary lifestyle147.
Conversely, an increase in intestinal permeability
resulting from the altered expression of tight-​junction
proteins increases absorption into the circulation of
lipopolysaccharide (also known as endotoxin), which in
turn has been shown to increase systemic inflammation
via activation of Toll-​like receptors (TLRs), particularly
TLR4 (ref.140). In turn, TLR4 activation triggers inflam-
mation and induces the formation of macrophage foam
cells, which are hallmarks of early-​stage atherosclerotic
lesions. Interestingly, lipopolysaccharide levels are ele-
vated in CVD and in some cardiometabolic conditions,
including obesity and diabetes mellitus149. Importantly,
highly endurance-​trained individuals have lower plasma
levels of lipopolysaccharide than their sedentary peers,
and lipopolysaccharide levels are positively correlated
with plasma concentrations of plasminogen activator
inhibitor 1 (PAI1), total cholesterol, and/or LDL chol­
esterol and triglycerides150. In summary, exercise can
promote a healthy gut microbiota while protecting the
intestinal barrier.
Although additional mechanistic information is
needed to elucidate the biological pathways that mediate
the b
­ eneficial effects of exercise on gut health, the afore-
mentioned findings illustrate how the exercise milieu
can benefit many organs beyond the cardiovascular sys-
tem, which in turn can improve cardiometabolic health
in general.
Conclusions
Regular physical activity or exercise induces myriad
physio­logical adaptations that benefit human cardiovas-
cular health either directly or indirectly. Many of these
benefits seem to be independent of traditional CVD risk
factors, blood lipid and glucose levels, obesity, and high
blood pressure. Importantly, skeletal muscle is increas-
ingly considered to be an endocrine organ that (particu-
larly during muscle contraction) can secrete bioactive
substances with salutary cardiovascular effects, the
so-called myokines, many more of which are likely to
be identified in the near future. This fascinating field
should remind us to take a holistic view of the cardio-
vascular system, which cannot be separated from other
organs, notably the skeletal muscle. Unfortunately, the
tremendous potential of resistance (strength) exercise
training for reversing both disease and the effects of age-
ing on muscle mass and function, and thereby indirectly
improving cardiovascular health, is under-recognized in
most clinical settings. Finally, an important consider­
ation is that, as opposed to most drugs, exercise is largely
free of adverse effects, and its benefits are, to a certain
extent, dose-dependent (after gradual habituation to
increasing exercise loads). It is time to view exercise as
medicine for the management of CVD.
A strength of this Review is our integrative vision of
CVD in the context of the whole human body, including
not only the cardiovascular system per se but also the
interplay between the heart and vessels and other tissues
(including skeletal muscle, adipose tissue, and even the
gut), as well as the several approaches (epidemiological,
physiological, and molecular) we have considered. We
believe that such an integrative perspective might be of
great assistance to those readers who do not work in the
field of exercise per se.
Published online xx xx xxxx

1. Raichlen, D. A. et al. Physical activity patterns and
biomarkers of cardiovascular disease risk in hunter-​
gatherers. Am. J. Hum. Biol. https://doi.org/10.1002/
ajhb.22919 (2017).
2. Hallal, P. C. et al. Global physical activity levels:
surveillance progress, pitfalls, and prospects. Lancet
380, 247–257 (2012).
In this study, the authors examine in detail physical
activity levels worldwide and highlight the
worryingly high proportion (80.3% of total) of
inactive adolescents (aged 13–15 years and doing
less than the WHO-​recommended minimum of
60 min daily of MVPA).
3. Santos-​Lozano, A., Lucia, A., Ruilope, L. &
Pitsiladis, Y. P. Born to run: our future depends
on it. Lancet 390, 635–636 (2017).
4. Booth, F. W., Roberts, C. K., Thyfault, J. P.,
Ruegsegger, G. N. & Toedebusch, R. G. Role of
inactivity in chronic diseases: evolutionary insight and
pathophysio­logical mechanisms. Physiol. Rev. 97,
1351–1402 (2017).
5. Gurven, M., Jaeggi, A. V., Kaplan, H. & Cummings, D.
Physical activity and modernization among Bolivian
Amerindians. PLoS ONE 8, e55679 (2013).
6. World Health Organization. Global Recommendations
on Physical Activity for Health (WHO, 2010).
This manuscript compiles the WHO Physical
Activity for Health recommendations.
7. Kaplan, H. et al. Coronary atherosclerosis in
indigenous South American Tsimane: a cross-​sectional
cohort study. Lancet 389, 1730–1739 (2017).
8. Lindeberg, S., Eliasson, M., Lindahl, B. & Ahren, B.
Low serum insulin in traditional Pacific Islanders — the
Kitava Study. Metabolism 48, 1216–1219 (1999).
9. Kohl, H. W. 3rd et al. The pandemic of physical
inactivity: global action for public health. Lancet 380,
294–305 (2012).
10. Katzmarzyk, P. T., Lee, I. M., Martin, C. K. & Blair, S. N.
Epidemiology of physical activity and exercise training

www.nature.com/nrcardio

in the United States. Prog. Cardiovasc. Dis. 60, 3–10
(2017).
11. Tremblay, M. S. et al. Sedentary Behavior Research
Network (SBRN) — Terminology Consensus Project
process and outcome. Int. J. Behav. Nutr. Phys. Act.
14, 75 (2017).
Herein, the Sedentary Behavior Research Network
presents a Terminology Consensus Project to
standardize important definitions related to
physical inactivity and activity or sedentary time.
12. Karlsen, T., Aamot, I. L., Haykowsky, M. & Rognmo, O.
high intensity interval training for maximizing health
outcomes. Prog. Cardiovasc. Dis. 60, 67–77 (2017).
13. Gillen, J. B. & Gibala, M. J. Is high-​intensity interval
training a time-​efficient exercise strategy to improve
health and fitness? Appl. Physiol. Nutr. Metab. 39,
409–412 (2014).
14. Warburton, D. E. & Bredin, S. S. Reflections on
physical activity and health: what should we
recommend? Can. J. Cardiol. 32, 495–504 (2016).
15. Carson, V. et al. Light-​intensity physical activity and
cardiometabolic biomarkers in US adolescents.
PLoS ONE 8, e71417 (2013).
16. Zhao, G. et al. Leisure-​time aerobic physical activity,
muscle-​strengthening activity and mortality risks
among US adults: the NHANES linked mortality study.
Br. J. Sports Med. 48, 244–249 (2014).
17. Ekelund, U. et al. Physical activity and all-​cause
mortality across levels of overall and abdominal
adiposity in European men and women: the European
Prospective Investigation into Cancer and Nutrition
Study (EPIC). Am. J. Clin. Nutr. 101, 613–621 (2015).
18. Wen, C. P. et al. Minimum amount of physical activity
for reduced mortality and extended life expectancy:
a prospective cohort study. Lancet 378, 1244–1253
(2011).
19. Lee, D. C. et al. Leisure-​time running reduces all-​cause
and cardiovascular mortality risk. J. Am. Coll. Cardiol.
64, 472–481 (2014).
This study is a good example of the growing evidence
that even low physical activity loads, below the WHO
minimum recommendations, can also provide major
benefits; notably, running 5–10 min per day at slow
speeds ( < 6 mph) was associated with a considerably
reduced risk of CVD death in US adults.
20. Lear, S. A. et al. The effect of physical activity on
mortality and cardiovascular disease in 130 000
people from 17 high-​income, middle-​income, and
low-​income countries: the PURE study. Lancet 390,
2643–2654 (2017).
This epidemiological study (n = 168,916 participants)
found that higher recreational and non-​recreational
physical activity levels were associated with a lower
risk of death and cardiovascular events, irrespective
of country income.
21. Arem, H. et al. Leisure time physical activity and
mortality: a detailed pooled analysis of the dose–
response relationship. JAMA Intern. Med. 175,
959–967 (2015).
This population-​based, prospective analysis of US
and European cohorts (total n = 661,137 men and
women aged 21–98 years) shows that meeting the
minimum international recommendations for MVPA
is associated with virtually the maximum longevity
benefit and that the benefit threshold was quite
high at ~3–5 times the recommended minimum,
and no excess risk was found at ≥10 times the
minimum.
22. Ding, D. et al. The economic burden of physical
inactivity: a global analysis of major non-communicable
diseases. Lancet 388, 1311–1324 (2016).
23. Harber, M. P. et al. Impact of cardiorespiratory fitness
on all-​cause and disease-​specific mortality: advances
since 2009. Prog. Cardiovasc. Dis. 60, 11–20
(2017).
24. Kodama, S. et al. Cardiorespiratory fitness as a
quantitative predictor of all-​cause mortality and
cardiovascular events in healthy men and women:
a meta-​analysis. JAMA 301, 2024–2035 (2009).
25. Kulinski, J. P. et al. Association between
cardiorespiratory fitness and accelerometer-​derived
physical activity and sedentary time in the general
population. Mayo Clin. Proc. 89, 1063–1071 (2014).
26. Hamilton, M. T., Hamilton, D. G. & Zderic, T. W. Role of
low energy expenditure and sitting in obesity, metabolic
syndrome, type 2 diabetes, and cardiovascular disease.
Diabetes 56, 2655–2667 (2007).
27. Ekelund, U. et al. Does physical activity attenuate, or
even eliminate, the detrimental association of sitting
time with mortality? A harmonised meta-​analysis of
data from more than 1 million men and women.
Lancet 388, 1302–1310 (2016).
Nature Reviews | Cardiology
28. Fiuza-​Luces, C., Garatachea, N., Berger, N. A. &
Lucia, A. Exercise is the real polypill. Physiology 28,
330–358 (2013).
29. Green, D. J., Hopman, M. T., Padilla, J., Laughlin, M. H.
& Thijssen, D. H. Vascular adaptation to exercise in
humans: role of hemodynamic stimuli. Physiol. Rev.
97, 495–528 (2017).
30. Sahebkar, A. et al. Statin therapy reduces plasma
endothelin-1 concentrations: a meta-​analysis of 15
randomized controlled trials. Atherosclerosis 241,
433–442 (2015).
31. Ashor, A. W. et al. Exercise modalities and endothelial
function: a systematic review and dose–response
meta-​analysis of randomized controlled trials. Sports
Med. 45, 279–296 (2015).
32. Green, D. J., O’Driscoll, G., Joyner, M. J. & Cable, N. T.
Exercise and cardiovascular risk reduction: time to
update the rationale for exercise? J. Appl. Physiol.
(1985) 105, 766–768 (2008).
33. Erkens, R. et al. Modulation of local and systemic
heterocellular communication by mechanical forces:
a role of endothelial nitric oxide synthase. Antioxid.
Redox Signal. 26, 917–935 (2017).
34. Hambrecht, R. et al. Effect of exercise on coronary
endothelial function in patients with coronary artery
disease. N. Engl. J. Med. 342, 454–460 (2000).
In this study in patients with coronary endothelial
dysfunction, a 4-week exercise intervention
improves endothelium-​dependent vasodilatation,
both in epicardial coronary and resistance vessels.
35. Hambrecht, R. et al. Regular physical activity improves
endothelial function in patients with coronary artery
disease by increasing phosphorylation of endothelial nitric
oxide synthase. Circulation 107, 3152–3158 (2003).
This study shows that, in patients with stable
coronary artery disease, a 4-week exercise training
programme improves agonist-​mediated
endothelium-​dependent vasodilatory capacity.
36. Durand, M. J. & Gutterman, D. D. Exercise and
vascular function: how much is too much? Can. J.
Physiol. Pharmacol. 92, 551–557 (2014).
37. Currens, J. H. & White, P. D. Half a century of running.
Clinical, physiologic and autopsy findings in the case of
Clarence DeMar (“Mr. Marathon”). N. Engl. J. Med.
265, 988–993 (1961).
38. Haskell, W. L. et al. Coronary artery size and dilating
capacity in ultradistance runners. Circulation 87,
1076–1082 (1993).
39. Nguyen, P. K. et al. Physical activity in older subjects is
associated with increased coronary vasodilation: the
ADVANCE study. JACC Cardiovasc. Imag. 4, 622–629
(2011).
40. Zeppilli, P. et al. Echocardiographic size of
conductance vessels in athletes and sedentary people.
Int. J. Sports Med. 16, 38–44 (1995).
41. Thijssen, D. H., Cable, N. T. & Green, D. J. Impact of
exercise training on arterial wall thickness in humans.
Clin. Sci. 122, 311–322 (2012).
42. Shimada, K. et al. Atherosclerotic plaques induced by
marble-​burying behavior are stabilized by exercise
training in experimental atherosclerosis. Int. J. Cardiol.
151, 284–289 (2011).
43. Yoshikawa, D. et al. Association of cardiorespiratory
fitness with characteristics of coronary plaque:
assessment using integrated backscatter intravascular
ultrasound and optical coherence tomography. Int. J.
Cardiol. 162, 123–128 (2013).
44. Madssen, E. et al. Coronary atheroma regression and
plaque characteristics assessed by grayscale and
radiofrequency intravascular ultrasound after aerobic
exercise. Am. J. Cardiol. 114, 1504–1511 (2014).
45. Aengevaeren, V. L. et al. Relationship between lifelong
exercise volume and coronary atherosclerosis in
athletes. Circulation 136, 138–148 (2017).
46. Garatachea, N. et al. Elite athletes live longer than the
general population: a meta-​analysis. Mayo Clin. Proc.
89, 1195–1200 (2014).
47. Heaps, C. L., Robles, J. C., Sarin, V., Mattox, M. L. &
Parker, J. L. Exercise training-​induced adaptations in
mediators of sustained endothelium-​dependent coronary
artery relaxation in a porcine model of ischemic heart
disease. Microcirculation 21, 388–400 (2014).
48. Seals, D. R., Desouza, C. A., Donato, A. J. & Tanaka, H.
Habitual exercise and arterial aging. J. Appl. Physiol.
(1985) 105, 1323–1332 (2008).
49. Bhella, P. S. et al. Impact of lifelong exercise “dose” on
left ventricular compliance and distensibility. J. Am.
Coll. Cardiol. 64, 1257–1266 (2014).
50. Glinge, C., Sattler, S., Jabbari, R. & Tfelt-​Hansen, J.
Epidemiology and genetics of ventricular fibrillation
during acute myocardial infarction. J. Geriatr. Cardiol.
13, 789–797 (2016).
Reviews
51. Billman, G. E. et al. Exercise training-​induced
bradycardia: evidence for enhanced parasympathetic
regulation without changes in intrinsic sinoatrial node
function. J. Appl. Physiol. (1985) 118, 1344–1355
(2015).
This study is an illustrative example of the relevant
work performed over the years by G. E. Billman’s
group in dog models, showing the anti-​
arrhythmogenic and salutary effects of moderate
endurance exercise training through enhanced
cardiac parasympathetic regulation.
52. Sessa, F. et al. Heart rate variability as predictive
factor for sudden cardiac death. Aging 10, 166–177
(2018).
53. Hillebrand, S. et al. Heart rate variability and first
cardiovascular event in populations without known
cardiovascular disease: meta-​analysis and dose-​
response meta-​regression. Europace 15, 742–749
(2013).
54. Pearson, M. J. & Smart, N. A. Exercise therapy
and autonomic function in heart failure patients:
a systematic review and meta-​analysis. Heart Fail. Rev.
23, 91–108 (2018).
This meta-​analysis shows that endurance exercise
training improves parasympathetic tone and
reduces sympathetic activity in patients with heart
failure, which is in line with the findings of the
aforementioned mechanistic studies in canine
models by G. E. Billman’s group.
55. Villafaina, S., Collado-​Mateo, D., Fuentes, J. P.,
Merellano-​Navarro, E. & Gusi, N. Physical exercise
improves heart rate variability in patients with type 2
diabetes: a systematic review. Curr. Diab. Rep. 17,
110 (2017).
56. Billman, G. E. Cardiac autonomic neural remodeling
and susceptibility to sudden cardiac death: effect of
endurance exercise training. Am. J. Physiol. Heart
Circ. Physiol. 297, H1171–H1193 (2009).
57. Joyner, M. J. & Green, D. J. Exercise protects the
cardiovascular system: effects beyond traditional risk
factors. J. Physiol. 587, 5551–5558 (2009).
58. Deley, G., Picard, G. & Taylor, J. A. Arterial baroreflex
control of cardiac vagal outflow in older individuals can
be enhanced by aerobic exercise training.
Hypertension 53, 826–832 (2009).
59. Mueller, P. J. Physical (in)activity-​dependent
alterations at the rostral ventrolateral medulla:
influence on sympathetic nervous system regulation.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 298,
R1468–R1474 (2010).
60. Bonilla, I. M. et al. Endurance exercise training
normalizes repolarization and calcium-​handling
abnormalities, preventing ventricular fibrillation in a
model of sudden cardiac death. J. Appl. Physiol.
(1985) 113, 1772–1783 (2012).
This preclinical study finds that exercise training
could prevent ischaemia-​induced ventricular
fibrillation owing to a combination of beneficial
effects on cellular electrophysiology and calcium
handling.
61. Frasier, C. R., Moore, R. L. & Brown, D. A. Exercise-​
induced cardiac preconditioning: how exercise
protects your achy-​breaky heart. J. Appl. Physiol.
(1985) 111, 905–915 (2011).
This detailed review discusses how exercise training
evokes sustainable protection against cardiac
ischaemia–reperfusion injury through several
mechanisms, such as improved oxidant buffering
capacity, decreased cellular and/or mitochondrial
calcium overload, and preservation of bioenergetics.
62. Thijssen, D. H. J., Redington, A., George, K. P.,
Hopman, M. T. E. & Jones, H. Association of exercise
preconditioning with immediate cardioprotection:
a review. JAMA Cardiol. 3, 169–176 (2017).
63. Demirel, H. A. et al. Short-​term exercise improves
myocardial tolerance to in vivo ischemia–reperfusion
in the rat. J. Appl. Physiol. (1985) 91, 2205–2212
(2001).
64. Hamilton, K. L. et al. Short-​term exercise training can
improve myocardial tolerance to I/R without elevation
in heat shock proteins. Am. J. Physiol. Heart Circ.
Physiol. 281, H1346–H1352 (2001).
65. Lalonde, F., Poirier, P., Sylvestre, M. P., Arvisais, D. &
Curnier, D. Exercise-​induced ischemic preconditioning
detected by sequential exercise stress tests: a meta-​
analysis. Eur. J. Prev. Cardiol. 22, 100–112 (2015).
66. Miller, L. E. et al. Involvement of the δ-​opioid receptor
in exercise-​induced cardioprotection. Exp. Physiol.
100, 410–421 (2015).
67. Calvert, J. W. et al. Exercise protects against
myocardial ischemia-​reperfusion injury via stimulation
of β3-adrenergic receptors and increased nitric oxide
Reviews
signaling: role of nitrite and nitrosothiols. Circ. Res.
108, 1448–1458 (2011).
This preclinical study shows that a 4-week exercise
programme protects the heart against myocardial
ischaemia–reperfusion injury, in part by stimulating
β3-adrenergic receptors and increasing cardiac
storage of NO metabolites.
68. Bowles, D. K., Farrar, R. P. & Starnes, J. W. Exercise
training improves cardiac function after ischemia in
the isolated, working rat heart. Am. J. Physiol. 263,
H804–H809 (1992).
69. Lennon, S. L. et al. Exercise and myocardial tolerance
to ischaemia-​reperfusion. Acta Physiol. Scand. 182,
161–169 (2004).
70. Pons, S. et al. Regular treadmill exercise restores
cardioprotective signaling pathways in obese mice
independently from improvement in associated co-​
morbidities. J. Mol. Cell. Cardiol. 54, 82–89 (2013).
71. Dregan, A., Charlton, J., Chowienczyk, P. &
Gulliford, M. C. Chronic inflammatory disorders
and risk of type 2 diabetes mellitus, coronary heart
disease, and stroke: a population-​based cohort study.
Circulation 130, 837–844 (2014).
72. Kaptoge, S. et al. Inflammatory cytokines and risk of
coronary heart disease: new prospective study and
updated meta-​analysis. Eur. Heart J. 35, 578–589
(2014).
73. Liu, C. et al. Adiponectin, TNF-​α and inflammatory
cytokines and risk of type 2 diabetes: a systematic
review and meta-​analysis. Cytokine 86, 100–109
(2016).
74. Fuster, J. J., Ouchi, N., Gokce, N. & Walsh, K. Obesity-​
induced changes in adipose tissue microenvironment
and their impact on cardiovascular disease. Circ. Res.
118, 1786–1807 (2016).
75. Fedewa, M. V., Hathaway, E. D. & Ward-​Ritacco, C. L.
Effect of exercise training on C reactive protein:
a systematic review and meta-​analysis of randomised
and non-​randomised controlled trials. Br. J. Sports
Med. 51, 670–676 (2017).
76. Hayashino, Y. et al. Effects of exercise on C-​reactive
protein, inflammatory cytokine and adipokine in
patients with type 2 diabetes: a meta-​analysis of
randomized controlled trials. Metabolism 63,
431–440 (2014).
77. Niessner, A. et al. Endurance training reduces
circulating inflammatory markers in persons at risk
of coronary events: impact on plaque stabilization?
Atherosclerosis 186, 160–165 (2006).
78. Chen, Y. L. et al. Correlation between serum
interleukin-6 level and type 1 diabetes mellitus:
a systematic review and meta-​analysis. Cytokine 94,
14–20 (2017).
79. Zhang, B. et al. Correlative association of interleukin-6
with intima media thickness: a meta-​analysis. Int. J.
Clin. Exp. Med. 8, 4731–4743 (2015).
80. Li, H., Liu, W. & Xie, J. Circulating interleukin-6 levels
and cardiovascular and all-​cause mortality in the
elderly population: a meta-​analysis. Arch. Gerontol.
Geriatr. 73, 257–262 (2017).
81. Fischer, C. P. Interleukin-6 in acute exercise and
training: what is the biological relevance? Exerc.
Immunol. Rev. 12, 6–33 (2006).
82. Ostrowski, K., Schjerling, P. & Pedersen, B. K. Physical
activity and plasma interleukin-6 in humans — effect
of intensity of exercise. Eur. J. Appl. Physiol. 83,
512–515 (2000).
83. Steensberg, A., Fischer, C. P., Keller, C., Moller, K. &
Pedersen, B. K. IL-6 enhances plasma IL-1RA, IL-10,
and cortisol in humans. Am. J. Physiol. Endocrinol.
Metab. 285, E433–E437 (2003).
This study is an example of work by B. K.
Pedersen’s group representing a paradigm shift
regarding the role of IL-6; when released from
working muscles, this molecule can have
anti-inflammatory rather than pro-​inflammatory
effects.
84. Starkie, R., Ostrowski, S. R., Jauffred, S., Febbraio, M.
& Pedersen, B. K. Exercise and IL-6 infusion inhibit
endotoxin-​induced TNF-​α production in humans.
FASEB J. 17, 884–886 (2003).
85. Pedersen, B. K. & Febbraio, M. A. Muscle as an
endocrine organ: focus on muscle-​derived
interleukin-6. Physiol. Rev. 88, 1379–1406 (2008).
86. Lambernd, S. et al. Contractile activity of human
skeletal muscle cells prevents insulin resistance by
inhibiting pro-​inflammatory signalling pathways.
Diabetologia 55, 1128–1139 (2012).
87. Nielsen, A. R. et al. Association between
interleukin-15 and obesity: interleukin-15 as a
potential regulator of fat mass. J. Clin. Endocrinol.
Metab. 93, 4486–4493 (2008).
88. Kim, H. J. et al. Effect of treadmill exercise on
interleukin-15 expression and glucose tolerance in
Zucker diabetic fatty rats. Diabetes Metab. J. 37,
358–364 (2013).
89. Busquets, S., Figueras, M., Almendro, V.,
Lopez-Soriano, F. J. & Argiles, J. M. Interleukin-15
increases glucose uptake in skeletal muscle.
An antidiabetogenic effect of the cytokine.
Biochim. Biophys. Acta 1760, 1613–1617 (2006).
90. Jedrychowski, M. P. et al. Detection and quantitation
of circulating human irisin by tandem mass
spectrometry. Cell Metab. 22, 734–740 (2015).
91. Raschke, S. et al. Evidence against a beneficial effect
of irisin in humans. PLoS ONE 8, e73680 (2013).
92. Albrecht, E. et al. Irisin — a myth rather than an
exercise-​inducible myokine. Sci. Rep. 5, 8889 (2015).
93. Bostrom, P. et al. A PGC1-α-​dependent myokine that
drives brown-​fat-like development of white fat and
thermogenesis. Nature 481, 463–468 (2012).
94. Emanuele, E. et al. Serum irisin levels, precocious
myocardial infarction, and healthy exceptional
longevity. Am. J. Med. 127, 888–890 (2014).
95. Rao, R. R. et al. Meteorin-​like is a hormone that
regulates immune-​adipose interactions to increase
beige fat thermogenesis. Cell 157, 1279–1291 (2014).
96. Izumiya, Y. et al. FGF21 is an Akt-​regulated myokine.
FEBS Lett. 582, 3805–3810 (2008).
97. Lee, M. S. et al. Fibroblast growth factor-21 protects
human skeletal muscle myotubes from palmitate-​
induced insulin resistance by inhibiting stress kinase
and NF-​κB. Metabolism 61, 1142–1151 (2012).
98. Lee, P. et al. Irisin and FGF21 are cold-​induced
endocrine activators of brown fat function in humans.
Cell Metab. 19, 302–309 (2014).
99. Ouchi, N. et al. Follistatin-​like 1, a secreted muscle
protein, promotes endothelial cell function and
revascularization in ischemic tissue through a nitric-​
oxide synthase-​dependent mechanism. J. Biol. Chem.
283, 32802–32811 (2008).
100. Jiang, M., Wan, F., Wang, F. & Wu, Q. Irisin relaxes
mouse mesenteric arteries through endothelium-​
dependent and endothelium-​independent
mechanisms. Biochem. Biophys. Res. Commun. 468,
832–836 (2015).
101. Lu, J. et al. Irisin protects against endothelial injury
and ameliorates atherosclerosis in apolipoprotein
E-​null diabetic mice. Atherosclerosis 243, 438–448
(2015).
102. Besse-​Patin, A. et al. Effect of endurance training on
skeletal muscle myokine expression in obese men:
identification of apelin as a novel myokine. Int. J.
Obes. 38, 707–713 (2014).
This study shows that endurance exercise training
upregulated the expression of apelin in the muscle
of individuals with obesity, and the authors
postulate that this molecule is a novel myokine.
103. Zhong, J. C. et al. Targeting the apelin pathway
as a novel therapeutic approach for cardiovascular
diseases. Biochim. Biophys. Acta 1863, 1942–1950
(2017).
104. Subbotina, E. et al. Musclin is an activity-​stimulated
myokine that enhances physical endurance. Proc. Natl
Acad. Sci. USA 112, 16042–16047 (2015).
105. Roberts, L. D. et al. β-​Aminoisobutyric acid induces
browning of white fat and hepatic β-​oxidation and is
inversely correlated with cardiometabolic risk factors.
Cell Metab. 19, 96–108 (2014).
106. Chin, S. O. et al. Sarcopenia is independently
associated with cardiovascular disease in older Korean
adults: the Korea National Health and Nutrition
Examination Survey (KNHANES) from 2009. PLOS
ONE 8, e60119 (2013).
107. Medina-​Inojosa, J. R. et al. Association between
adiposity and lean mass with long-​term cardiovascular
events in patients with coronary artery disease: no
paradox. J. Am. Heart. Assoc. 7, e007505 (2018).
108. Shah, R. V. et al. Visceral adiposity and the risk of
metabolic syndrome across body mass index: the
MESA Study. JACC Cardiovasc. Imag. 7, 1221–1235
(2014).
109. Norheim, F. et al. Proteomic identification of secreted
proteins from human skeletal muscle cells and
expression in response to strength training. Am. J.
Physiol. Endocrinol. Metab. 301, E1013–E1021
(2011).
In this study, the authors show that muscle
strength training increases the levels of several
secretory muscle proteins in humans, many of
which are candidate myokines.
110. Sanchis-​Gomar, F. & Lucia, A. Acute myocardial
infarction: ‘telomerasing’ for cardioprotection.
Trends Mol. Med. 21, 203–205 (2015).
111. Haykowsky, M. et al. A meta-​analysis of the effects
of exercise training on left ventricular remodeling
following myocardial infarction: start early and go
longer for greatest exercise benefits on remodeling.
Trials 12, 92 (2011).
112. Cai, M. X. et al. Exercise training activates neuregulin
1/ErbB signaling and promotes cardiac repair in a rat
myocardial infarction model. Life Sci. 149, 1–9 (2016).
113. Sanchis-​Gomar, F., Perez-​Quilis, C. & Lucia, A.
Overexpressing FSTL1 for heart repair. Trends Mol.
Med. 22, 353–354 (2016).
114. Bakogiannis, C. et al. Circulating endothelial
progenitor cells as biomarkers for prediction of
cardiovascular outcomes. Curr. Med. Chem. 19,
2597–2604 (2012).
115. Adams, V. et al. Increase of circulating endothelial
progenitor cells in patients with coronary artery
disease after exercise-​induced ischemia. Arterioscler.
Thromb. Vasc. Biol. 24, 684–690 (2004).
116. Artero, E. G. et al. Effects of muscular strength on
cardiovascular risk factors and prognosis.
J. Cardiopulm. Rehabil. Prev. 32, 351–358 (2012).
117. Celis-​Morales, C. A. et al. Associations of grip strength
with cardiovascular, respiratory, and cancer outcomes
and all cause mortality: prospective cohort study of
half a million UK Biobank participants. BMJ 361,
k1651 (2018).
118. Hamasaki, H. et al. Association of handgrip strength
with hospitalization, cardiovascular events, and
mortality in Japanese patients with type 2 diabetes.
Sci. Rep. 7, 7041 (2017).
119. Lopez-​Jaramillo, P. et al. Association of handgrip
strength to cardiovascular mortality in pre-​diabetic
and diabetic patients: a subanalysis of the ORIGIN
trial. Int. J. Cardiol. 174, 458–461 (2014).
120. Jurca, R. et al. Association of muscular strength with
incidence of metabolic syndrome in men. Med. Sci.
Sports Exerc. 37, 1849–1855 (2005).
121. Harada, K. et al. Impact of skeletal muscle mass on
long-​term adverse cardiovascular outcomes in patients
with chronic kidney disease. Am. J. Cardiol. 119,
1275–1280 (2017).
In this study, low skeletal muscle mass is proved to
be an independent predictor of major adverse
cardiovascular events in patients with chronic
kidney disease.
122. Ko, B. J. et al. Relationship between low relative
muscle mass and coronary artery calcification in
healthy adults. Arterioscler. Thromb. Vasc. Biol. 36,
1016–1021 (2016).
123. Spahillari, A. et al. The association of lean and fat
mass with all-​cause mortality in older adults: the
Cardiovascular Health Study. Nutr. Metab. Cardiovasc.
Dis. 26, 1039–1047 (2016).
124. Minn, Y. K. & Suk, S. H. Higher skeletal muscle mass
may protect against ischemic stroke in community-​
dwelling adults without stroke and dementia:
The PRESENT project. BMC Geriatr. 17, 45 (2017).
125. Kamiya, K. et al. Prognostic usefulness of arm and calf
circumference in patients ≤ 65 years of age with
cardiovascular disease. Am. J. Cardiol. 119, 186–191
(2017).
126. Bekfani, T. et al. Sarcopenia in patients with heart
failure with preserved ejection fraction: impact on
muscle strength, exercise capacity and quality of life.
Int. J. Cardiol. 222, 41–46 (2016).
127. Kinugasa, Y. & Yamamoto, K. The challenge of frailty
and sarcopenia in heart failure with preserved ejection
fraction. Heart 103, 184–189 (2017).
In this report, the authors explain the possible
mechanisms linking myokines, sarcopenia, and the
development of HFpEF.
128. Paulus, W. J. & Tschope, C. A novel paradigm for heart
failure with preserved ejection fraction: comorbidities
drive myocardial dysfunction and remodeling through
coronary microvascular endothelial inflammation.
J. Am. Coll. Cardiol. 62, 263–271 (2013).
129. Dos Santos, M. R. et al. Sarcopenia and endothelial
function in patients with chronic heart failure: results
from the Studies Investigating Comorbidities
Aggravating Heart Failure (SICA-​HF). J. Am. Med. Dir.
Assoc. 18, 240–245 (2017).
130. Omori, Y. et al. L-​Carnitine prevents the development
of ventricular fibrosis and heart failure with preserved
ejection fraction in hypertensive heart disease.
J. Hypertens. 30, 1834–1844 (2012).
131. Tanaka, K. et al. Effects of adiponectin on calcium-​
handling proteins in heart failure with preserved
ejection fraction. Circ. Heart Fail. 7, 976–985
(2014).
132. Cadore, E. L. & Izquierdo, M. Exercise interventions in
polypathological aging patients that coexist with
www.nature.com/nrcardio

diabetes mellitus: improving functional status and
quality of life. Age 37, 64 (2015).
133. Yamamoto, S., Hotta, K., Ota, E., Mori, R. &
Matsunaga, A. Effects of resistance training on muscle
strength, exercise capacity, and mobility in middle-​
aged and elderly patients with coronary artery disease:
a meta-​analysis. J. Cardiol. 68, 125–134 (2016).
134. Mehta, S. et al. Resistance training for gait speed and
total distance walked during the chronic stage of
stroke: a meta-​analysis. Top. Stroke Rehabil. 19,
471–478 (2012).
135. Cornelissen, V. A., Fagard, R. H., Coeckelberghs, E. &
Vanhees, L. Impact of resistance training on blood
pressure and other cardiovascular risk factors: a meta-​
analysis of randomized, controlled trials. Hypertension
58, 950–958 (2011).
136. Serra-​Rexach, J. A. et al. Short-​term, light- to moderate-​
intensity exercise training improves leg muscle strength
in the oldest old: a randomized controlled trial. J. Am.
Geriatr. Soc. 59, 594–602 (2011).
137. Maeda, S. et al. Resistance exercise training reduces
plasma endothelin-1 concentration in healthy young
humans. J. Cardiovasc. Pharmacol. 44 (Suppl. 1),
S443–S446 (2004).
138. Jie, Z. et al. The gut microbiome in atherosclerotic
cardiovascular disease. Nat. Commun. 8, 845 (2017).
139. Koeth, R. A. et al. Intestinal microbiota metabolism of
L-​carnitine, a nutrient in red meat, promotes
atherosclerosis. Nat. Med. 19, 576–585 (2013).
140. Patel, P. N., Shah, R. Y., Ferguson, J. F. & Reilly, M. P.
Human experimental endotoxemia in modeling the
pathophysiology, genomics, and therapeutics of innate
immunity in complex cardiometabolic diseases.
Arterioscler. Thromb. Vasc. Biol. 35, 525–534 (2015).
141. Lanter, B. B., Sauer, K. & Davies, D. G. Bacteria
present in carotid arterial plaques are found as biofilm
Nature Reviews | Cardiology
deposits which may contribute to enhanced risk of
plaque rupture. MBio 5, e01206–e01214 (2014).
142. Fu, J. et al. The gut microbiome contributes to a
substantial proportion of the variation in blood lipids.
Circ. Res. 117, 817–824 (2015).
143. Wilck, N. et al. Salt-​responsive gut commensal
modulates TH17 axis and disease. Nature 551,
585–589 (2017).
144. Yang, Y. et al. The association between cardiorespiratory
fitness and gut microbiota composition in
premenopausal women. Nutrients 9, E792 (2017).
145. Bressa, C. et al. Differences in gut microbiota profile
between women with active lifestyle and sedentary
women. PLoS ONE 12, e0171352 (2017).
This paper reports novel evidence for an
interdependence between some genera of gut
bacteria and sedentary behaviour, and further
shows that the dose and type of exercise can
influence the composition of the gut microbiota.
146. Petersen, L. M. et al. Community characteristics of the
gut microbiomes of competitive cyclists. Microbiome
5, 98 (2017).
147. Allen, J. M. et al. Exercise alters gut microbiota
composition and function in lean and obese humans.
Med. Sci. Sports Exerc. 50, 747–757 (2018).
148. Estaki, M. et al. Cardiorespiratory fitness as a
predictor of intestinal microbial diversity and distinct
metagenomic functions. Microbiome 4, 42 (2016).
149. Kallio, K. A. et al. Endotoxemia, nutrition and
cardiometabolic disorders. Acta Diabetol. 52,
395–404 (2015).
150. Lira, F. S. et al. Endotoxin levels correlate positively
with a sedentary lifestyle and negatively with highly
trained subjects. Lipids Health Dis. 9, 82 (2010).
151. O’Keefe, J. H., Franklin, B. & Lavie, C. J. Exercising
for health and longevity versus peak performance:
Reviews
different regimens for different goals. Mayo Clin. Proc.
89, 1171–1175 (2014).
152. Sanchis-​Gomar, F., Perez, L. M., Joyner, M. J.,
Lollgen, H. & Lucia, A. Endurance exercise and the
heart: friend or foe? Sports Med. 46, 459–466
(2016).
153. Mons, U., Hahmann, H. & Brenner, H. A reverse
J-shaped association of leisure time physical activity
with prognosis in patients with stable coronary heart
disease: evidence from a large cohort with repeated
measurements. Heart 100, 1043–1049 (2014).
154. Williams, P. T. & Thompson, P. D. Increased
cardiovascular disease mortality associated with
excessive exercise in heart attack survivors. Mayo
Clin. Proc. 89, 1187–1194 (2014).
Acknowledgements
Research in the field of exercise and health by A.L. and M.I.
is funded by Fondo de Investigaciones Sanitarias (Instituto de
Salud Carlos III) and Fondos FEDER (grant #PI15/00558 and
PI17/01814). C.F.-L. has a Juan de la Cierva postdoctoral
fellowship from the Spanish Ministry of Economy, Industry,
and Competitiveness (#JCI-2016-30253). The authors thank
K. McCreath for editorial assistance.
Author contributions
All authors contributed to researching data for this article,
discussions of its content, writing the paper, and review
and/or editing of the manuscript before submission.
Competing interests
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.