Chapter 15

Physical Exercise Is a Potential “Medicine”

for Atherosclerosis

Jian Yang, Richard Y. Cao, Rongrong Gao, Qiongyao Mi,

Qiying Dai, and Fu Zhu

Abstract  Cardiovascular disease (CVD) has been recognized as the number one
killer for decades. The most well-known risk factor is atherosclerosis. Unlike the
acuity of CVD, atherosclerosis is a chronic, progressive pathological change. This
process involves inflammatory response, oxidative reaction, macrophage activity,
and different interaction of inflammatory factors. Physical exercise has long been
known as good for health in general. In recent studies, physical exercise has been
demonstrated to be a therapeutic tool for atherosclerosis. However, its therapeutic
effect has dosage-dependent effect. Un-proper over exercise might also cause dam-
age to the heart. Here we summarize the mechanism of Physical exercise’s benefi-
cial effects and its potential clinical use.

Keywords  Exercise • Cardiovascular disease • Atherosclerosis

J. Yang • R.Y. Cao • F. Zhu (*)

Department of Rehabilitation, Shanghai Xuhui Central Hospital/Shanghai
Zhongshan-Xuhui Hospital, Fudan University/Shanghai Clinical Research Center,
Chinese Academy of Sciences, 996 Middle Huaihai Road, Shanghai 200031, China
e-mail: [email protected]
R. Gao
Department of Cardiology, First Affiliated Hospital of Nanjing Medical University,
Nanjing 210029, China
Q. Mi
Department of Rehabilitation, Shanghai Xuhui Central Hospital/Shanghai
Zhongshan-Xuhui Hospital, Fudan University/Shanghai Clinical Research Center,
Chinese Academy of Sciences, 996 Middle Huaihai Road, Shanghai 200031, China
School of Life Science, Shanghai University, Shanghai 200444, China
Q. Dai
Department of Cardiology, First Affiliated Hospital of Nanjing Medical University,
Nanjing 210029, China
Metrowest Medical Center, Framingham, MA 01702, USA

© Springer Nature Singapore Pte Ltd. 2017 269

J. Xiao (ed.), Exercise for Cardiovascular Disease Prevention and Treatment,
Advances in Experimental Medicine and Biology 999,
DOI 10.1007/978-981-10-4307-9_15
270 J. Yang et al.

1  Introduction

Cardiovascular disease (CVD) remains the leading cause of death in the world. The
dramatic clinical events, such as unstable angina (UA), myocardial infarction (MI)
and stroke are all caused by atherosclerotic process. Atherosclerosis can start to form
as early as childhood, and progress to adulthood [1]. Over the last several decades,
people have become more obese and less physically active. Thus, the incidence of
disease related to metabolic dysfunction, such as diabetes, hypertension and hyper-
lipidemuia, has been increased dramatically. In addition, according to the WHO data-
base, about 80% of CVD related mortalities are caused by unhealthy behaviors, such
as high fat diets, physical inactivity, alcohol abuse and so on. It has been accepted that
changing lifestyle could reduce the incidence of these disease. One of the most cost-
effective intervention is physical exercise [2, 3]. Recent studies have revealed that
physical exercise decreases CVD related morbidity and mortality through systemic
and cardiac-specific adaptations. Furthermore, physical exercise has been proven to
be a very promising tool in both primary and secondary prevention of CVD [4–6].
Atherosclerosis has been considered as a chronic inflammatory artery disease,
which is responsible for approximate 50% of deaths worldwide. Risk factors to ath-
erosclerotic diseases include smoking, diabetes, hypertension, hyperlipidemia and
lack of physical activity [7]. This process is initiated by circulating plasma low-­
density lipoprotein (LDL) entering the sub-endothelial space in the blood vessel. In
artery with normal endothelial function, LDL would be cleared. However, if endothe-
lial malfunction exists, the balance of entering and clearance would be broken and
LDL would keep accumulating. With time goes by, the accumulated LDL would
build up plaque inside the arterial wall, which could result in narrowing of the lumen.
Consequently, the narrowed lumen reduces blood supply to the end organs. In some
circumstances, the plaque could become vulnerable and finally ruptures. The ruptured
plaque could lead to thrombus formation, which critically obstructs the blood flow.
To date, it has been well established that atherosclerosis is the result of interac-
tions of increased oxidative stress, inflammation, macrophage dysfunction, endo-
thelial injury, lipid deposition, and genetic predisposition [8, 9]. Physical inactivity
has been widely believed to be an independent risk factor for atherosclerosis and
cardiovascular complications [10]. It contributes to the accumulation of visceral fat
and the activation of inflammatory pathways that promote the development of meta-
bolic disorders [11–13]. Nevertheless, evidence suggested that physical exercise
was able to reverse this pathological changes [14, 15].

2  Physical Activity and Atherosclerosis

Atherosclerosis is a complicated process involving various reactions. It is started

from LDL entering the sub-endothelial space in the blood vessel, which is later
oxidized by reactive oxygen species (ROS). Oxidized LDL upregulates adhesion
molecules and induces the expression of chemotactic agents in endothelial cells
15  Physical Exercise Is a Potential “Medicine” for Atherosclerosis 271

[16]. These factors are able to recruit inflammatory cells to the vessel wall, which in
turn can induce cascade expression of inflammatory factors, such as MCP-1, and
cytokines including interferon Gamma (IFN-y), tumor necrosis factor-α (TNF-α)
and interleukin-6 (IL-6) [17, 18]. Later on, smooth muscle cells (SMC) migrate
from the tunica media into the intimal or sub-endothelial space and participate in the
reaction. Finally, a fibrous cap would be built [19].
Recent studies demonstrated that physical inactivity can lead to the accumula-
tion of visceral fat and consequently result in the activation of oxidative stress and
inflammation cascade, which eventually enhances the progression of atherosclero-
sis [20]. Regular physical exercise confers plentiful effects in restraining the athero-
genic process, which involved arterial wall remodeling, plaque size modulation,
macrophage function regulation and inflammatory reaction control [21]. In animal
study, regular physical exercise corrects cardiovascular and metabolic risk factors to
baseline level in obese rats that were fed on a high-fat diet [22]. On the other hand,
exercise can prevent the conversion of plaques into a vulnerable phenotype [23],
which is the main trigger of acute coronary syndrome. Randomized clinical trials
have validated the role of physical exercise in primary and secondary prevention of
atherosclerosis, CVD, and decrease mortality among adults [24, 25].

2.1  Physical Exercise Reduces Atherosclerosis Process

Physical exercise prevents atherosclerotic plaque development and induces the

regression of coronary stenosis possibly by preventing and reducing inflammatory
reaction, oxidative stress and regulating endothelial function. Besides, physical
exercise can normalize blood pressure, insulin resistance, serum lipid level [15],
which all are crucial factors during atherosclerosis development.

2.2  Physical Exercise Exerts Anti-inflammatory Effects

Chronic inflammation is one of the most important features of atherosclerosis and

persists throughout the whole process. It starts with the release of pro-inflammatory
factors including cytokines and nuclear factor-κB (NF-κB). NF-κB, a pro-­
inflammatory transcription factor, can upregulate the transcription of other pro-­
inflammatory molecules, such as tumor necrosis factor-α (TNF-α), interleukins
(IL-1β, and IL-6), cyclo-oxygenase-2 (COX-2), and nitric oxide synthase (iNOS).
Apart from this, it is also associated with oxidative stress production and disease
related to aging [26–28]. One study showed that combination of exercise and Korean
red ginseng supplement or exercise alone could decrease serum CRP, NF-kB, TNF-­
α, COX-2, IL-6, ICAM-1 and VCAM-1 in aorta of D-gal induced aging atheroscle-
rotic rats [29]. Another report showed that higher intensity exercise enhanced
NF-κB activation, which consequently bring adverse effect to CVD [30, 31].
272 J. Yang et al.

Being able to regulate the activity of cytokines may contribute to the protective
effect of physical exercise [32, 33]. TNF-α levels are found to be increased in
patients with atherosclerosis [34–36]. It activates and accelerates atherogenesis pro-
cess by promoting thrombosis, vascular remodeling, inflammation, endothelium
apoptosis, oxidative stress and impairing NO bioavailability [35, 37, 38]. Apart
from that, TNF-α precipitates in the secretion of adhesive molecules, thus encourag-
ing recruitment of inflammatory cells [36]. Overexpression of TNF-α is implicated
in damaged arterial wall and unstable plaque [39]. The reduction of TNF-α could be
achieved by lipopolysaccharide-stimulated monocytes in whole blood from healthy
subjects [40]. Further study looking into physical exercise and TNF-α found that
physical exercise could prevent the elevation of circulating TNF-α [41]. Other stud-
ies also showed that physical exercise decreases cytokines, in particular TNF-α
[42–44], which is a crucial risk actor in atherosclerosis development and vascular
function. TNF-α plays a central role in vascular inflammation, involved in oxidative
stress, apoptosis and also thrombogenesis [45–47].
IL-6 has received increasing attention as it interprets the anti-inflammatory effect
of physical exercise in patients with CVD [48, 49]. In contrast to TNF-α, IL-6 inhib-
its the endotoxin-induced increase of TNF-α [41], induces concentrations of two
other anti-inflammatory cytokines: IL-1Ra (IL-1 receptor antagonist) and IL-10,
and has a central role in exercise-induced leukocyte trafficking [50]. Furthermore,
IL-6 has vital effect on atherosclerosis by producing CRP.  CRP can increase the
levels of reactive oxygen species (ROS) and NF-κB. Both of them can precipitate
inflammation [32, 51]. Also, CRP is associated with higher cardiovascular risks [32,
52]. A recent review has summarized that physical exercise could lower the effects
of CRP on inflammation of atherosclerosis [53]. Increasing evidence has clarified
that physical activity ameliorated activation of inflammation, by decreasing level of
TNF-α, IL-1β, and IL-6. In addition, it activates matrix metalloproteinase 9, thus in
turn attenuates fibrosis, in an MI animal model [50, 54].
IL-18 is another pleiotropic inflammatory cytokine, which was found to be
increased in the serum of type II diabetes patients. It revealed itself a predictor of
cardiovascular death and future CVD [55]. Besides, it worsens the plaque burden
and is related to left ventricular myocardial dysfunction [56]. IL-18 can be reduced
by an exercise intervention without weight change [57, 58].
In summary, physical exercise is an effective way to decrease the key inflamma-
tory factors like TNF-α, CRP, IL-6 and IL-18, suppressing atherosclerosis from a
molecular level.

2.3  Physical Exercise Exerts Antioxidant Effects

Oxidative stress is another important pathology change in atherosclerosis. It has

been well established that physical exercise has a strong negative effect on oxidative
stress [59–62]. Oxidative stress is defined as an imbalance between the excessive
production of oxidant compounds plus the insufficient anti-oxidant defense
15  Physical Exercise Is a Potential “Medicine” for Atherosclerosis 273

systems, which may cause tissue injury. It can produce endothelial dysfunction and
accelerate atherosclerosis in patients with CVD.
Oxidized LDL (OxLDL), formed under oxidative stimulation, can enhance local
inflammatory response. Lots of factors contributing to the formation of
OxLDL. Systemic diseases like diabetes, chronic kidney disease are well known to
induce OxLDL [63]. Air pollution, which is usually neglected, is also a strong
inducer for systemic oxidative stress [64]. Physical exercise has been proven to
ameliorate systemic inflammation and oxidative burden via acting on NO [65, 66].
It has been well studied that NO is involved in the oxidation of LDL-cholesterol
[67, 68]. Decreased endothelial NO bioavailability may be the earliest indication of
atherosclerosis [69]. Reduction of endothelial NO bioavailability is closely related
to vasoconstriction, platelet adherence and aggregation, leukocytes adherence, and
increased proliferation of SMC [70]. These effects all contribute to the pathogenesis
of atherosclerosis. Decreased expression of endothelial NO synthase (eNOS), loss
of eNOS activity, and accelerated NO degradation by ROS are associated with sup-
pressed NO bioactivity [71, 72]. Exercise readjusts the balance between NO genera-
tion and NO inactivation [73]. Among many enzymatic systems that are able to
produce ROS, NADPH oxidase appears to be the most significant one [74, 75].
Physical inactivity increases the activity of NADPH oxidase, followed by enhanced
O2− and ROS production. It finally will lead to endothelial dysfunction and athero-
sclerotic lesion progression [76]. To sum up, the mechanism of exercise modulating
oxidative stress are as follows: (1) increases eNOS expression and/or eNOS Ser1177
phosphorylation [mediated by an increase in Akt expression and/or phosphoryla-
tion]; (2) increases antioxidant superoxide dismutase (SOD) expression; (3)
decreases NADPH oxidase activity and expression of its subunits (gp91phox,
p22phox and nox4), leading to reduced ROS generation [77–82].
Last but not the least, hyperhomocysteinemia(HHcy) is an unneglectable risk
factor for atherosclerosis and oxidative stress. HHcy also involved in vascular
responses and endothelial injury [83]. It could enhance propensity for plaque rup-
ture and promote vascular SMCs proliferation [84–87]. Studies have elucidated that
HHcy induces oxidative stress/ROS through induction of thrombin and activation of
PAR-4 and NADPH oxidase 1, or oxidation of reactive sulfhydryl groups in the
presence of molecular oxygen [83, 88, 89]. Exercise is found to be effective in sup-
pressing HHcy induced destruction. Firstly, exercise can reduce HHcy-mediated
oxidative stress and atherogenesis, either directly by reducing Hcy levels or indi-
rectly by enhancing PON1 levels. PON1 is a calcium-dependent esterase belonging
to the PON family of proteins and is strongly associated with HDL level. PON1 can
reduce cellular oxidative stress as well as the rate of cholesterol biosynthesis after
entry into the macrophages [90–92]. Secondly, exercise can upregulate kidney beta-
ine homocysteine S-methyltransferase level, which removes Hcy through the non-
classical remethylation pathway [93]. In turn, HHcy can also restrict the physical
activity capacity. Therefore, it is inevitable to correct the HHcy before the exercise
regimen to exert its full potential [94–96].
Physical Exercise Regulates Endothelial Function
274 J. Yang et al.

Endothelial cell integrity is crucial for preserving vascular homeostasis. It allows

the continuous adjustment of vascular tone, regulation of leukocyte traffic, and also
maintenance of blood fluidity [97]. Endothelial dysfunction refers to an injury of
endothelium-dependent vasorelaxation. Vulnerable plaques are sites of active
inflammation and oxidative stress. They are most likely to locate where there is
impaired endothelial function. Endothelial dysfunction presents in all stages of ath-
erosclerosis process. The impaired endothelial cells release lower levels of NO,
thrombomodulin, prostacyclin and tissue plasminogen activator but increase the
release of endothelin-1, angiotensin II, plasminogen activator inhibitor (PAI)-1 [98,
99]. However, clinical and experimental findings clearly demonstrate that physical
exercise can counteract these destructive effects [100, 101]. Researchers found that
a primary target of the physical exercise intervention appears to be the impaired
endothelial function [102, 103].
Inflammatory factors like NO and CRP are crucial in endothelial homeostasis.
Loss of NO bioactivity seems as an early event in the pathogenesis of atherosclero-
sis [69]. CRP is produced in response to IL-6, and its pro-atherogenic effects are
applied through damaging the endothelial function. Both of them could be down-
regulated by physical exercise.
Interestingly, researchers also found that endothelial impairment is accompanied
by increased blood pressure, insulin resistance and dyslipidemia [104, 105]. This
suggests that the concurrent appearance of these risk factors might share a common
mechanism. Given this information, physical exercise preserves endothelial func-
tion by controlling blood pressure through regulation of AII receptor (type I) and
increasing skeletal muscle endothelial nitric oxide synthase content [106, 107]. By
controlling one factor, physical exercise helps to decrease the risk for all other
chronic metabolic disease. Besides, another study demonstrated that acute dynamic
resistance exercise can decrease resting blood pressure and reactivity to phenyleph-
rine and increased endothelium-dependent relaxation [108].
In patients with CVD, physical exercise reverses endothelial dysfunction and
increases CBF [109–111]. While in patients with Type 2 diabetes and obesity, simi-
lar results have been observed [112, 113] but without concomitant changes in tradi-
tional risk factors. All these results encourage physical exercise for both treatment
and prevention of these endothelial function-centered disease [114–117].

2.4  Physical Exercise Reduces Endothelial Adhesiveness

Endothelial adhesiveness plays important role in the development of atherosclero-

sis. Within a week after the initiation of a high-cholesterol diet, monocytes adher-
ence to the endothelium and starts to migrate. It leads to the development of intimal
lesions, which contain sub-endothelial macrophage-derived foam cells, small num-
bers of non-lipid-filled macrophages and T lymphocytes [118, 119]. Under normal
physiologic conditions, endothelial cell does not secrete factors that induce the
adhesion molecules. Once activated by cytokines, oxLDL, or ROS, endothelial cells
15  Physical Exercise Is a Potential “Medicine” for Atherosclerosis 275

will start to express cell adhesion molecules (CAMs), such as ICAM-1, VCAM-1,
E-selectin, and P-selectin. They are all essential to the recruitment of inflammatory
cells [120]. While physical exercise has a positive effect in the circulating CAMs.
Circulating ICAM-1, VCAM-1, and P-selectin are found to be significantly
decreased after 2 weeks of exercise training [121–123]. Similarly, physical exercise
performed 5 times per week for 6–8 weeks decreases circulating P-selectin andV-
CAM-­1 levels [124]. Shear stress induced during physical exercise could probably
contribute to these effects [125]. Besides, apart from the direct impact on CAMs
expression, physical exercise might also have indirect beneficial effects throughout
the reduction of agonists of CAM synthesis [43, 126, 127].
Endothelin-1 (ET-1), which is expressed by vascular endothelial cells, has strong
constrictor and proliferative activity on SMCs. Because of this, it has been implicated
in modulation of vascular contraction and progression of atherosclerosis. Its produc-
tion has been found to be elevated in human atherosclerotic lesions [128–130]. It was
found that in healthy adults, physical exercise is able to suppress its level [131, 132].
In all, by reducing the soluble adhesion molecules which may represent the inter-
action between activated monocytes/macrophages and endothelial cells and ET-1
concentration, physical exercise might be considered as an effective non-­
pharmacological intervention to reduce endothelial adhesiveness.

2.5  Physical Exercise Regulates Macrophages Function

Macrophage has been studied for centuries for its role in inflammatory response. In
addition to modulating immune reaction, it is also noticed to take great part in the
atherosclerotic process. Macrophage is able to modulate lipid metabolism. During
the early phase of plaque formation, macrophages become foam cells when it can
not process OxLDL.  Foam cells are the hallmarks of atherosclerotic lesions and
vulnerability [133, 134]. Macrophages have been parsed into at least two
subtypes(M1 and M2), each of which have specific roles in atherosclerosis [135–
138]. M1 macrophages produce high levels of pro-inflammatory factors like CD40,
CD80, IL-6, TNF-α, iNOS [139]. While M2 macrophages leads to more foam cell
formation with higher phagocytic nature and greater ability to import OxLDL. Foam
cell–prone M2 macrophages level is higher than pro-inflammatory M1 macrophages
in the early atherosclerotic lesions; but the ratio reverses as the lesion progresses
[140]. In addition, macrophages express MMPs to stable plaques during atherogen-
esis [141–143]. Additionally, HHcy may be a primary cause for the macrophages
dysfunction that leads to the effect on atherosclerosis [142, 144].
Physical exercise prevents foam cell formation. It accelerates the transportation
of cholesterol from macrophages to the liver which has been considered as the ini-
tial step of atherosclerosis [145]. Moreover, physical exercise encourages accumu-
lation of collagen and elastin by modulating serum level of MMPs and TIMP-1.
This greatly keep the plaque stability and reduce in lesion incidence and arterial
stenosis [146–148].
276 J. Yang et al.

2.6  P
 hysical Exercise Preserves Atherosclerotic Plaque
Stability

Most of the acute coronary syndrome (ACS) occurs because of plaque rupture.
Plaque rupture exposes sub-endothelial to various of thrombogenic factors in the
blood. Thrombus forms immediately after the exposure, leading to acute myocar-
dial infarction or stroke [16, 18]. The vulnerability renders plaques to rupture. A
vulnerable atherosclerotic plaque has thin fibrous cap, large lipid core (>50% total
plaque surface), high inflammatory cell burden but low volume of SMCs [149].
Physical exercise has shown its capacity to slow the progression of atherosclero-
sis via promoting plaque stability and preventing plaque rupture in animal studies
[76, 106, 150, 151]. ApoE −/− mouse model has been commonly used in athero-
sclerosis studies. Using this model, swimming training was applied to study its
effect on the plaque. After swimming training, it is observed that the plaques are
more stable by thicker fibrous cap, less adventitia inflammation, decreased media
degeneration and inflammatory macrophage plaque content [106]. Physical exercise
regulates plaque size and its rupturing potential through regulation of matrix con-
tent and matrix regulators [151]. Physical exercise decreases MMP-2, MMP-3, and
MMP-8 levels as well as IL-6. Besides, collagen, elastin, and TIMP-2 (inhibitor of
MMP-2 and MMP-9) were also found to be increased in parallel with the change of
fibrous cap thickness [147, 151]. In other studies, MMPs, TIMP-1 are also found to
be modulated by physical exercise [152].
Apart from the ability to modifying lipoproteins, macrophages can worsen the
plaque status by producing MMPs, which is known to degrade collagen in plaque
[153]. Collagen is the basic structure to keep the atherosclerotic plaque well-formed.
Destruction of the collagen would lead to thrombogenic disasters as mentioned
above. Physical exercise could prevent this from happening by modifying macro-
phage function.
Pro-inflammatory enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2)
is a novel marker for plaque inflammation and rupture-prone plaques [154].
Lp-PLA2 binds to ApoB-containing lipoproteins and degrades oxidized phospho-
lipids in LDL-cholesterol. Elevated level of Lp-PLA2 can be detected within the
necrotic core and macrophages of vulnerable plaques, but not in early stable plaques
[154]. Furthermore, Lp-PLA2 predicts mortality in MI and post-MI patients [155].
Physical exercise has negative effects on this new biomarker, however, clinical evi-
dence remains insufficient [156, 157]. In one clinical study, patients with dyslipid-
emia have suppressed level of Lp-PLA2 after strict lifestyle modification [158].
High plasma Hcy concentration is associated with atherosclerotic plaque rupture
and morbidity in type 2 diabetes patients, and is considered as an independent risk
factor for CVD [84–86, 159–161]. It encourages plaque maturation by activating
SMCs and promoting macrophage differentiation. While physical exercise can
potentially reduce the detrimental effects of HHcy on macrophages. It should be
noted that this effect has not be tested in vivo so far.
15  Physical Exercise Is a Potential “Medicine” for Atherosclerosis 277

3  Physical Exercise, Can One Overdose?

With all the evidence above, the agreement that physical exercise can be applied to
treat atherosclerosis can be reached. Like regular medicine, physical exercise also
has dosage effect. Different dosage of physical exercise refers to the time and
strength spent on exercise. Regular intense exercise brings cardiac adaptations
which comprises the clinical constellation of findings known as the athlete’s heart
[162–165]. However, increasing studied found that these adaptations may also have
deleterious effects. For example, some reports have claimed that atherosclerotic
plaques are present in the carotid or peripheral arteries of 90% of marathon runners
at the age of 50–75 [166, 167].
Regular and moderate-intensity exercise, on the other hand, reduces cardiovas-
cular morbidity and mortality. It could be served as primary and secondary preven-
tion of CVD [165, 168–171]. Vigorous exercise training will cause sport-specific
hemodynamic alterations, leading to profitable structural and functional adaptations
in athletes [172–174]. Chronic exposure to high levels of exercise training, which is
equivalent to “exercise overdose”, may bring some adverse effects. Long term stress
on the heart will cause cardiac remodeling. The clinical presentation could be atrial
fibrillation and cardiomyopathy [175, 176]. “Overdosed” exercise does more harm
than good. To testify this, 40 elite endurance athletes were included in one study. A
decreased right ventricular systolic function and increased cardiac injury biomark-
ers were detected right after completion of an ultra-endurance exercise. Although in
this study short-term recovery appears complete, chronic structural changes and
reduced RV function have been observed in some athletes [176, 177].

4  Summary

In summary, regular physical exercise is highly beneficial in reducing the risk of

atherosclerosis development, and the underlying mechanism could be concluded as
followings: (1) reducing of pro-inflammatory cytokines; (2) counteracting oxidative
stress via decreasing ROS production, Hcy level, NADPH oxidase activity and
increasing NO availability; (3) improving endothelial function; (4) decreasing
endothelial adhesiveness by modulating the expression of ICAM-1, VCAM-1,
E-selectin, P-selectin and ET-1; (5) regulating macrophage function and suppress-
ing the foam cell formation; (6) lowering LDL and triglyceride levels. (7) preserv-
ing atherosclerotic plaque stability. Similar to medicine, the beneficial effect of PE
has dosage effect. Overdosing would also bring “toxicity”. Vigorous exercise train-
ing could adversely affect cardiac function and ameliorate all these beneficial
effects. More clinical trials regarding to the proper exercise training are needed to
establish a more mature physical exercising treatment system.
278 J. Yang et al.

Acknowledgements  This work was supported by the grants from Shanghai Key Discipline
Construction Grant (ZK2012A40) and National Natural Science Foundation of China (81672260).

Competing Financial Interests  The authors declare no competing financial interests.

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