Cardiovascular Effects and Benefits of Exercise

Abstract

It is widely accepted that regular physical activity is beneficial for cardiovascular health. Frequent exercise is robustly associated with a decrease in cardiovascular mortality as well as the risk of developing cardiovascular disease. Physically active individuals have lower blood pressure, higher insulin sensitivity, and a more favorable plasma lipoprotein profile. Animal models of exercise show that repeated physical activity suppresses atherogenesis and increases the availability of vasodilatory mediators such as nitric oxide. Exercise has also been found to have beneficial effects on the heart. Acutely, exercise increases cardiac output and blood pressure, but individuals adapted to exercise show lower resting heart rate and cardiac hypertrophy. Both cardiac and vascular changes have been linked to a variety of changes in tissue metabolism and signaling, although our understanding of the contribution of the underlying mechanisms remains incomplete. Even though moderate levels of exercise have been found to be consistently associated with a reduction in cardiovascular disease risk, there is evidence to suggest that continuously high levels of exercise (e.g., marathon running) could have detrimental effects on cardiovascular health. Nevertheless, a specific dose response relationship between the extent and duration of exercise and the reduction in cardiovascular disease risk and mortality remains unclear. Further studies are needed to identify the mechanisms that impart cardiovascular benefits of exercise in order to develop more effective exercise regimens, test the interaction of exercise with diet, and develop pharmacological interventions for those unwilling or unable to exercise.

Full text

MINI REVIEW
published: 28 September 2018
doi: 10.3389/fcvm.2018.00135
Frontiers in Cardiovascular Medicine | www.frontiersin.org 1September 2018 | Volume 5 | Article 135
Edited by:
Jacob Haus,
University of Michigan, United States
Reviewed by:
Abbi D. Lane-Cordova,
University of South Carolina,
United States
Dae Yun Seo,
Inje University College of Medicine,
South Korea
*Correspondence:
Matthew A. Nystoriak
matthew.nystoriak@louisville.edu
Specialty section:
This article was submitted to
Cardiovascular Metabolism,
a section of the journal
Frontiers in Cardiovascular Medicine
Received: 14 June 2018
Accepted: 07 September 2018
Published: 28 September 2018
Citation:
Nystoriak MA and Bhatnagar A (2018)
Cardiovascular Effects and Benefits of
Exercise.
Front. Cardiovasc. Med. 5:135.
doi: 10.3389/fcvm.2018.00135
Cardiovascular Effects and Benefits
of Exercise
Matthew A. Nystoriak*and Aruni Bhatnagar
Division of Cardiovascular Medicine, Department of Medicine, Diabetes and Obesity Center, Institute of Molecular Cardiology,
University of Louisville, Louisville, KY, United States
It is widely accepted that regular physical activity is beneficial for cardiovascular health.
Frequent exercise is robustly associated with a decrease in cardiovascular mortality
as well as the risk of developing cardiovascular disease. Physically active individuals
have lower blood pressure, higher insulin sensitivity, and a more favorable plasma
lipoprotein profile. Animal models of exercise show that repeated physical activity
suppresses atherogenesis and increases the availability of vasodilatory mediators such
as nitric oxide. Exercise has also been found to have beneficial effects on the heart.
Acutely, exercise increases cardiac output and blood pressure, but individuals adapted
to exercise show lower resting heart rate and cardiac hypertrophy. Both cardiac and
vascular changes have been linked to a variety of changes in tissue metabolism and
signaling, although our understanding of the contribution of the underlying mechanisms
remains incomplete. Even though moderate levels of exercise have been found to
be consistently associated with a reduction in cardiovascular disease risk, there is
evidence to suggest that continuously high levels of exercise (e.g., marathon running)
could have detrimental effects on cardiovascular health. Nevertheless, a specific dose
response relationship between the extent and duration of exercise and the reduction in
cardiovascular disease risk and mortality remains unclear. Further studies are needed
to identify the mechanisms that impart cardiovascular benefits of exercise in order to
develop more effective exercise regimens, test the interaction of exercise with diet, and
develop pharmacological interventions for those unwilling or unable to exercise.
Keywords: physical activity, endothelium, blood flow, atherosclerosis, coronary artery disease
INTRODUCTION
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide.
In the United States, CVD accounts for ∼600,000 deaths (25%) each year (1,2), and after
a continuous decline over the last 5 decades, its incidence is increasing again (3). Among
the many risk factors that predispose to CVD development and progression, a sedentary
lifestyle, characterized by consistently low levels of physical activity, is now recognized as a
leading contributor to poor cardiovascular health. Conversely, regular exercise and physical
activity are associated with remarkable widespread health benefits and a significantly lower
CVD risk. Several long-term studies have shown that increased physical activity is associated
with a reduction in all-cause mortality and may modestly increase life expectancy, an effect
which is strongly linked to a decline in the risk of developing cardiovascular and respiratory
diseases (4). Consistent with this notion, death rates among men and women have been
found to be inversely related to cardiorespiratory fitness levels, even in the presence of other
predictors of cardiovascular mortality such as smoking, hypertension, and hyperlipidemia (5).

Nystoriak and Bhatnagar Exercise and Cardiovascular Health
Moreover, better fitness levels in both men and women can
partially reverse the elevated rates of all-cause mortality as well
as CVD mortality associated with high body mass index (6,7).
Recent work from cardiovascular cohorts shows that sustained
physical activity is associated with a more favorable inflammatory
marker profile, decreases heart failure risk, and improves survival
at 30 years follow-up in individuals with coronary artery disease
(8–10).
Despite the robust beneficial effects of physical activity and
exercise on cardiovascular health, the processes and mechanisms
by which frequent physical activity promotes cardiorespiratory
fitness and decreases CVD risk remain unclear. In the past
several decades, considerable research effort has aimed to identify
the major physiological and biochemical contributors to the
cardiovascular benefits of exercise, and as a result, significant
advances have been made from observational and interventional
studies with human participants. In parallel, valuable mechanistic
insights have been garnered from experimental studies in animal
models. Thus, in this review, we provide a synopsis of the
major known effects of exercise and physical activity on principal
factors associated with risk for poor cardiovascular health
including blood lipids, hypertension, and arterial stiffness. For
the purpose of the review, we follow the definition of exercise
as “a subset of physical activity that is planned, structured, and
repetitive and has as a final or an intermediate objective the
improvement or maintenance of physical fitness (11).” These
characteristics distinguish exercise from less structured and
planned physical activity, which is often not solely for the purpose
of maintaining or improving physical fitness. Most long-term
observational studies report levels of physical activity, whereas
more controlled and short duration studies examine the effects
of exercise. Throughout the text, we distinguish between these
two types of activities to the extent possible. We also discuss
the means by which a healthy cardiovascular system adapts to
exercise conditioning as well as recently proposed mechanisms of
adaptation that may work to antagonize cardiovascular disease.
PLASMA LIPIDS AND ATHEROGENESIS
Given the centrality of plasma lipids as key determinants of CVD
risk, many studies have tested whether regular engagement in
physical activity may lower CVD risk by affecting the levels of
circulating lipoproteins. These studies have found that endurance
training is associated with elevated levels of circulating high
density lipoprotein (HDL) and, to a lesser extent, a reduction in
triglyceride levels (12)—both changes that can reduce the risk of
coronary heart disease (13). Nonetheless, results concerning the
effects of physical activity on plasma lipids have been variable and
confounded by an apparent dependence on the type, intensity,
and duration of exercise as well as diet (14). In addition, early
studies aimed at determining effects of physical activity on
low density lipoprotein (LDL) levels did not test the dose-
dependence of exercise. However, a study of subjects with mild
to moderate dyslipidemia, randomized into high amount/high
intensity (23 kcal/kg/wk, jogging), low amount/high intensity
(14 kcal/kg/wk, jogging), and low amount/moderate intensity
(14 kcal/kg/wk, walking) exercise training groups over a 6 months
period, found a dose-dependent effect of exercise on plasma
levels of LDL, triglycerides, and large particle, very low density
lipoprotein (VLDL) (15). Increasing levels of exercise over time
were also found in this study to increase HDL from baseline
(pre-exercise regimen) levels. Although higher levels of HDL
are associated lower CVD risk (16,17), recent work suggests
that some pharmacological interventions that elevate plasma
HDL levels fail to reduce the risk of major cardiovascular events
(18,19). Nevertheless, HDL particle size is a key determinant
of ATP binding cassette transporter A1 (ABCA1)-mediated
cholesterol efflux (20), indicating that HDL particle size may be
an important correlate of CVD risk. Hence, an increase in the
size of LDL and HDL particles and a decrease in VLDL particle
size, rather than HDL levels per se, upon exercise training (15)
may impart CVD risk protection. In agreement with this view a
recent study investigating the dose-dependent effects of exercise
on cholesterol efflux in 2 randomized trials consisting of six
distinct exercise doses reported a significant increase in HDL
cholesterol and efflux capacity with exercise, albeit in the high
amount/high intensity intervention groups only (21). Thus, even
though exercise alters plasma lipid profile and increases HDL
concentration and particle size, moderate exercise may produce
only limited effects on HDL functionality and the contribution
of changes in plasma lipoprotein concentration, structure, and
function to overall reduction in CVD risk by exercise remains
unclear.
In addition to changes in plasma lipids, exercise could directly
impact the homeostasis of the arterial wall to antagonize the
progression of atherosclerotic disease and thereby contribute
to the well-documented reduction in coronary artery disease
in people with active lifestyles, when compared with sedentary
individuals (22–25). Even in people with symptomatic coronary
artery disease, an increase in regular physical activity can improve
VO2max and, at high doses (∼2,200 kcal/week), promote
regression of atherosclerotic lesions (26). In patients with stable
CAD, 4 weeks of rowing or cycling led to enhanced vasodilatory
responses to acetylcholine, which was associated with increased
total endothelial nitric oxide synthase (eNOS) expression and
eNOS, and protein kinase B (Akt) phosphorylation (27).
That exercise stimulates NO production is supported by
animal studies. For instance, it has been reported that carotid
arteries from exercised ApoE−/−mice exhibit elevated eNOS
expression and suppressed neointimal formation after injury
when compared with those from sedentary ApoE−/−control
mice (28). In contrast, aorta from sedentary mice kept in normal
housing conditions exhibit increased vascular lipid peroxidation
and superoxide levels, which may contribute to endothelial
dysfunction and lesion formation, when compared with mice
subjected to 6 weeks of voluntary wheel running (29). Regular,
but not intermittent, physical activity in high cholesterol diet-
fed LDLR-null mice has also been found to rescue aortic valve
endothelial integrity, reduce inflammatory cell recruitment, and
prevent aortic valve calcification (30), which raises the possibility
that exercise may reduce the development and progression
of degenerative aortic valve disease. Despite this evidence, it
remains unclear to what extent salutary changes in blood lipids
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Nystoriak and Bhatnagar Exercise and Cardiovascular Health
and vascular function contribute to the cardiovascular benefits of
exercise and further studies are required to quantify both lipid-
dependent and lipid-independent effects of physical activity.
INSULIN SENSITIVITY
The association between blood lipids and cardiovascular health
is highly influenced by systemic insulin sensitivity, and resistance
to insulin signaling is known to promote the development of
heart disease, in part by altering the blood lipid profile (31).
Resistance of adipocytes to the effects of insulin and resulting
reduction in glucose uptake leads to the increased release of free
fatty acids and greater production and release of triglycerides,
and VLDL by the liver (32). In addition, reduced HDL in the
insulin resistant state, resulting in part from increased activity
of cholesteryl ester transfer protein (CETP), and transfer of
cholesteryl esters from HDL to triglyceride-rich lipoproteins (33),
suppresses reverse cholesterol transport from the arterial wall and
promotes atherosclerotic plaque formation.
Insulin signaling within the vascular endothelium promotes
Akt-dependent phosphorylation and activation of eNOS, which
produces the vasodilator - NO. This, however, is antagonized by
the activation of the Ras-RAF-MAPK pathway that stimulates
cell growth and differentiation and increases the production
of the potent vasoconstrictor - endothelin-1 (ET-1) (34,35).
During diabetes, selective inhibition of the PI3K-Akt-eNOS
pathway, together with compensatory hyperinsulinemia leads to
unmasking and stimulation of the MAPK-mediated production
of endothelin-1 (ET-1) (36,37), and vascular smooth muscle
proliferation, which could contribute to atherosclerotic plaque
development and peripheral artery disease (38,39). Enhanced
endothelial production and secretion of ET-1, along with
heightened sympathetic activity may represent key contributing
factors in enhanced vasoconstriction of small diameter arteries
and arterioles in the insulin-resistant state, thereby increasing
systemic vascular resistance to blood flow and elevating arterial
blood pressure. In addition, as a hallmark of diabetes and insulin-
resistance, elevated blood glucose levels also accelerate the
formation of advanced glycation end products (AGEs), proteins
and lipids that have undergone non-enzymatic glycation and
oxidation, leading to cross-linking of collagen and elastin fibers
and loss of vascular compliance (i.e., arterial stiffening) (40,41).
A number of studies have shown that individuals with
insulin-dependent and non-insulin-dependent diabetes mellitus
have improved sensitivity to insulin and improved glycemic
control after exercise training (42–44). Indeed, it has been
found that even a single low-intensity (50% VO2max,
350 kcal expended) exercise session results in significantly
improved insulin sensitivity and fatty acid uptake upon
examination on the following day (45). Studies in animal
models of exercise suggest that increased physical activity
can improve insulin sensitivity in adipose tissue, skeletal
muscle, and endothelium (46–49), which are major contributors
to systemic insulin resistance in individuals with type 2
diabetes. While our understanding of the precise cellular
and molecular mechanisms involved in the enhancement of
insulin signaling following exercise has been hampered by
inconsistent results across species and exercise protocols, it
appears that exercise conditioning is associated with adaptive
remodeling in the expression or regulation of one or more
components of the insulin receptor/insulin receptor substrate
(IRS)/PI3K/Akt signaling cascade (50–52). During exercise,
insulin levels are slightly reduced and frequently contracting
muscle exhibits greater glucose uptake via enhanced insulin-
independent sarcolemmal translocation of GLUT4 glucose
transporters (53–55). Moreover, muscle damage associated with
eccentric exercise can paradoxically cause insulin resistance via
TNF-α-mediated reductions in PI3K activity (56–59). Thus,
further research is required to elucidate how certain exercise
regimens can promote tissue-specific adaptations in insulin-
signaling and how these pathways may be targeted to reverse
insulin-resistance and associated cardiovascular complications of
diabetes.
BLOOD PRESSURE
During exercise, increases in cardiac stroke volume and heart rate
raise cardiac output, which coupled with a transient increase in
systemic vascular resistance, elevate mean arterial blood pressure
(60). However, long-term exercise can promote a net reduction in
blood pressure at rest. A meta-analysis of randomized controlled
interventional studies found that regular moderate to intense
exercise performed 3–5 times per week lowers blood pressure
by an average of 3.4/2.4 mmHg (61). While this change may
appear small, recent work shows that even a 1 mmHg reduction
in systolic BP is associated with 20.3 fewer (blacks) or 13.3 fewer
(whites) heart failure events per 100,000 person-years (62). Thus,
reductions in blood pressure observed when exercise is included
as a behavioral intervention along with dietary modification and
weight loss (63,64) could have a significant impact on CVD
incidence.
Lower ambulatory blood pressure, associated with chronic
aerobic and resistance exercise, is thought to be driven largely
by a chronic reduction in systemic vascular resistance (65).
Contributing to this effect, shear forces, as well as released
metabolites from active skeletal muscle during exercise, signal
the production and release of nitric oxide (NO) and prostacyclin
from the vascular endothelium, which promotes enhanced
vasodilation via relaxation of vascular smooth muscle cells
(66). This effect is especially significant because a reduction
in eNOS activity that occurs with aging or due to NOS3
polymorphism, has been reported to contribute to hypertension
(67–69). Long-term exercise training increases eNOS expression
as well as NO production in hypertensive individuals, consistent
with the blood pressure lowering effect of physical activity
(70). An important role of NO in mediating the vascular
effects of exercise is further supported by results showing that
rats with hypertension induced by chronic NOS inhibition
undergoing a swimming exercise regimen for 6 weeks have
significantly elevated eNOS protein expression and improved
acetylcholine-induced vasodilation (71). Thus, improvements in
NO production and bioavailability appear to represent significant
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factors that contribute to improved endothelium-dependent
vasodilation following exercise training, which can reduce resting
vascular resistance and lower blood pressure. However, in
addition to NO-mediated reductions in resistance vascular tone,
adaptive reductions in sympathetic nerve activity, prevention or
reversal of arterial stiffening, and suppression of inflammation
are also likely contributors to the blood pressure lowering effects
of exercise, although the impact of exercise on these outcomes
may be population specific (e.g., at-risk versus healthy adults)
(72–74). As with changes in blood lipid profile, it remains unclear
to what extent the blood pressure lowering effects of exercise can
account for the beneficial effects of exercise on CVD risk and
mortality.
CARDIAC ADAPTATIONS
During exercise, the heart is subjected to intermittent
hemodynamic stresses of pressure overload, volume overload,
or both. To normalize such stress and to meet the systemic
demand for an increased blood supply, the heart undergoes
morphological adaptation to recurrent exercise by increasing
its mass, primarily through an increase in ventricular chamber
wall thickness. This augmentation of heart size is primarily
the result of an increase in the size of individual terminally
differentiated cardiac myocytes (75). Adaptive remodeling of the
heart in response to exercise typically occurs with preservation
or enhancement of contractile function. This contrasts with
pathologic remodeling due to chronic sustained pressure
overload (e.g., during hypertension or aortic stenosis), which can
proceed to a loss of contractile function and heart failure (76).
Recent work in experimental animal exercise models has
identified several cellular and molecular alterations involved in
the physiologic growth program of the heart that accompanies
exercise conditioning. Whereas pathologic remodeling of the
heart is associated with a reduction in oxidative energy
production via fatty acid oxidation and more reliance on
glucose utilization, mitochondrial biogenesis and capacity for
fatty acid oxidation are enhanced following exercise (77,78).
A recent study suggests that changes in myocardial glycolytic
activity during acute exercise and the subsequent recovery
period can also play an important role in regulating the
expression of metabolic genes and cardiac remodeling (79).
Possibly upstream of these metabolic changes, studies have
also revealed a dominant role for IGF-1 and insulin receptor
signaling, via the PI3K/Akt1 pathway leading to the activation
of transcriptional pathways associated with protein synthesis
and hypertrophy (80,81). Untargeted approaches have identified
other major determinants of transcriptional programs that drive
the exercise-induced hypertrophic response. For instance, it has
been reported that exercise-induced reduction in the expression
of CCAAT-enhancer binding protein β(C/EBPβ) relieves its
negative regulation by CBP/p300-interactive transactivator with
ED-rich carboxy-terminal domain-4 (Cited4) (82). Activation
of Cited4 has been found to be necessary for exercise-induced
cardiac hypertrophy, and cardiac-specific overexpression of
the gene is sufficient to increase heart mass and protect
against ischemia/reperfusion injury (83). Other transcriptional
pathways known to be activated by pathologic stimuli and
cardiac hypertrophy, such as NFATc2, are decreased in exercise
models (79,84), suggesting that some signaling pathways
activated during exercise-induced growth program may directly
antagonize specific factors that promote pathological remodeling.
In addition to metabolic and molecular remodeling, exercise
can also promote functional adaptation of the heart, which
may ultimately increase cardiac output and reduce the risk of
arrhythmia. Clinical studies have shown that exercise-trained
individuals have improved systolic and diastolic function (85,
86), while results of studies using animal models of exercise
show that endurance exercise promotes enhanced cardiomyocyte
contraction-relaxation velocities and force generation (87–90).
This effect of exercise on cardiomyocyte contractile function
may be related to alterations in the rise and decay rates of
intracellular Ca2+transients, possibly due to enhanced coupling
efficiency between L-type Ca2+channel-mediated Ca2+entry
and activation of subsarcolemmal ryanodine receptors (RyR;
i.e., calcium-induced calcium release), and increased expression
and activity of the sarcoendoplasmic reticulum Ca2+ATPase
(SERCA2a) and sodium-calcium exchanger (NCX) (88,91,92).
In addition, the sensitivity of the cardiomyocyte contractile
apparatus may also become more sensitive to Ca2+, thus
producing a greater force of contraction at a given [Ca2+]i,
following exercise, (93). These changes may at least partially
depend on upregulation of the Na+/H+antiporter and altered
regulation of intracellular pH.
During pathologic remodeling of the heart, electrical
instability can result from a lack of upregulation of key
cardiac ion channel subunits associated with action potential
repolarization relative to an increase in myocyte size (94). In
contrast, increased myocyte size in physiological hypertrophy is
associated with the upregulation of depolarizing and repolarizing
currents, which may be protective against abnormal electrical
signaling in the adapted heart (95,96). For example, cardiac
myocytes isolated from mice after 4 weeks of swim training
were found to have elevated outward K+current densities (i.e.,
Ito,f, IK,slow , Iss, and IK1 ) and increased expression of underlying
molecular component Kv and Kir subunits in parallel with
increases in total protein levels (96). Interestingly, a follow
up study found that while increases in K+channel subunit
expression following exercise training requires PI3K, these
changes occur independently of Akt1 and hypertrophy (97).
BLOOD AND VASCULATURE
The oxygen carrying capacity of blood, determined by the
number of circulating erythrocytes and their associated
intracellular hemoglobin concentration, is an important
determinant of exercise performance and resistance to fatigue
(98). High endurance athletes commonly have “athlete’s anemia,”
possibly due to loss of erythrocytes, or low hematocrit secondary
to an expansion of plasma volume (99). Yet, overall total
erythrocyte mass is increased in athletes, especially those
who train at high altitude (100). This is in part due to a
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dose-dependent effect of O2on hypoxia-inducible factor (HIF)-
mediated erythropoietin production as well as upregulation
of erythropoietin receptors, iron transporters, and transferrins
(101). Multiple studies have shown that hematopoiesis is
enhanced immediately following exercise (102,103). Intense
exercise is associated with the release of a variety of stress and
inflammatory factors that are active on the bone marrow such
as cortisol, IL-6, TNF-α, PMN elastase, and granulocyte colony
stimulating factor (104–106). Although HPCs appear to modestly
decline in the period immediately following an exercise session
in conditioned runners, one study found that circulating CD34+
hematopoietic progenitor cell counts were 3- to 4-fold higher in
runners vs. non-runners at baseline (102), which may represent
an adaptive response that facilitates tissue repair. A subsequent
study found that a bout of intense exercise was associated with
a release of CD34+/KDR+endothelial progenitor cells from the
bone marrow and that this effect was enhanced in individuals
with elevated LDL/HDL and LDL/TC profiles (107). Likewise, a
significant increase in the number of circulating EPCs, associated
with increased levels of VEGF, HIF-1α, and EPO was found
within hours after varying intensities of resistance training in
women (108). Nonetheless, the physiological significance of
these responses remains unclear, as the effects of exercise on
angiogenesis and the wound healing response have not been
systematically studied.
The resistance arterial vascular network also undergoes
functional and structural adaptation to exercise (109). During
acute exercise, small arteries and pre-capillary arterioles that
supply blood to the skeletal muscles must dilate to increase
blood flow through the release of vasodilatory signals (e.g.,
adenosine, lactate, K+, H+, CO2) from active surrounding
muscle (110–112). Repeated exercise leads to an adaptive
response in skeletal muscle arterioles that includes increased
vascular density coupled with greater vasodilatory capacity,
such that enhanced perfusion can occur after conditioning
(113–116). This may be partly due to adaptation of the
endothelium to the complex interplay of recurrent variations
in hemodynamic stresses and vasodilatory stimuli of exercise.
Endothelial synthesis of NO is greatly increased at rest and
during exercise in conditioned individuals/animals (117). A
similar adaptive response to exercise has also been noted in the
coronary vasculature, which must dilate to meet the increased
metabolic demands of the myocardium (118). Exercise-trained
humans and animals demonstrate reduced myocardial blood
flow at rest, which may reflect a reduction in cardiac oxygen
consumption primarily as a result of lower resting heart rate
(119,120). However, a large body of evidence suggests that
multiple mechanisms converge to enhance the ability of the
coronary circulation to deliver a greater supply of oxygen to
the conditioned myocardium during exercise. This includes
structural adaptations consisting of an expansion in the density
of intramyocardial arterioles and capillaries as well as enhanced
microvascular collateral formation (121–124). Additionally, like
skeletal muscle arterioles, coronary arterial network enhances
its responsiveness to vasoactive stimuli via a number of distinct
mechanisms including, but not limited to, augmentation of
endothelial NO production, altered responsiveness to adrenergic
stimuli, or changes in the metabolic regulation of vascular
tone (125–127). In addition, some studies implicate hydrogen
peroxide (H2O2)-mediated vasodilation in opposing exertion-
induced arterial dysfunction in overweight obese adults after
a period of exercise training (128,129), suggesting enhanced
contribution of NO-independent mechanisms to improved
microvascular endothelial function with exercise. Collectively,
these adaptations may act to support enhanced myocardial
function and increased cardiac output during repeated exercise,
and increased total body oxygen demand following exercise
conditioning. Further advancement of our understanding of how
blood flow is improved in response to exercise could lead to
novel therapeutic strategies to prevent or reverse organ failure in
patients resulting from inadequate blood flow.
CONCLUDING REMARKS AND
REMAINING QUESTIONS TO BE
ADDRESSED
Despite the extensive body of knowledge documenting the
unequivocal health benefits of exercise, a vast majority of
Americans do not engage in sufficient physical activity (130).
Nonetheless, mortality risk reduction appears with even small
bouts of daily exercise and peak at 50–60 min of vigorous
exercise each day (131). However, the question remains as
to how much exercise is optimal for cardiovascular health
benefit. Studies in endurance runners show that the frequency
of adverse cardiovascular events in marathoners is equivalent
to that in a population with established CHD, suggesting that
too much exercise may be detrimental (132). An upper limit
for the cardiovascular benefits of exercise is further supported
by a recent study showing that individuals who completed
at least 25 marathons over a period of 25 years have higher
than expected levels of coronary artery calcification (CAC)
and calcified coronary plaque volume when compared with
sedentary individuals (133). A recent investigation also showed
that individuals who maintain very high levels of physical activity
(∼3 times recommended levels) have higher odds of developing
CAC, particularly in white males (134). In contrast, other studies
report greater plaque stability due to calcification in exercisers,
thus indicating that with higher levels of physical activity,
plaque quality may be favorably impacted to lower the risk of
cardiovascular events, despite a higher incidence of plaques and
normal CAC scores (135,136). Nevertheless, as with other effects
of exercise, the shape of the dose-response curve remains obscure
and it is not clear at what levels of intensity and duration the
effects of exercise begin to taper and where they start to become
detrimental. It is also unknown how this threshold of transition
from benefit to harm is affected by personal demographic features
such as age, sex, ethnicity, and baseline CVD risk.
Other remaining questions are: can initiation of regular
exercise, later in life, reverse the consequences of lifestyle
choices made during earlier years of life (e.g., sedentarism,
smoking), and whether the beneficial effects of exercise show
circadian or seasonal dependence such that exercising during
a particular time of day or a particular season imparts more
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Nystoriak and Bhatnagar Exercise and Cardiovascular Health
benefit than under other conditions. A recent study showing
that adherence to a two-year, high-intensity exercise program
decreases left ventricular stiffness in previously sedentary middle-
aged participants (137) suggests that to some extent, beginning
exercise, even late in life can be effective in reversing structural
and functional changes in the cardiovascular system associated
with aging and/or disease states such as heart failure with
preserved ejection fraction. Yet, perhaps the most important
questions relate to the mechanisms by which exercise imparts
it remarkable benefits to cardiovascular health. As discussed
above and summarized in Figure 1, regular physical activity can
ameliorate a variety of CVD risk factors such as dyslipidemia or
hypertension, but a well-powered analysis of the cardiovascular
effects of exercise revealed that reduction in the burden of
classical risk factors can account for only about 59% of the
total reduction in cardiovascular mortality (138). What accounts
for the remaining 41% reduction in risk remains unclear, but
it may be related to changes in systemic inflammation as
well as favorable responses to acute inflammatory challenge.
Indeed exercise has pervasive effects on immune cells—natural
killer cells, neutrophils, monocytes, regulatory T cells, as well
as the balance of T-cell types are all affected by exercise
(139) and it promotes a healthy anti-inflammatory milieu
(140). Nevertheless, how exercise affects inflammation and
FIGURE 1 | Overview of major cardiovascular effects of exercise. Abbreviations: HR, heart rate; LV, left ventricle; eNOS, endothelial nitric oxide synthase; NO, nitric
oxide; VSM, vascular smooth muscle; BP, blood pressure; HDL, high density lipoprotein; LDL, low density lipoprotein; VLDL, very low density lipoprotein; TG,
triglycerides; EPC, endothelial progenitor cell.
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Nystoriak and Bhatnagar Exercise and Cardiovascular Health
immunity and how these changes could account for the
salubrious effects of exercise on cardiovascular disease risk and
mortality are important questions that require additional careful
investigations. Additional work is also required to assess how
nutrition affects exercise capacity as well as the cardiovascular
benefits of exercise and how exercise affects the gut and the
microbiome (139,140). In this regard, it is important to clearly
delineate the extent to which nutritional supplements such as
β-alanine and carnosine, which enhance the buffering capacity
of muscle (141) affect exercise capacity as well as muscle growth
and hypertrophy. Such work is essential and important not
only for a basic understanding of the mechanisms of exercise-
induced protection, but also for developing more effective
exercise regimens, testing the efficacy of combined treatments
involving exercise and dietary supplements, and for devising
appropriate pharmacological interventions for those who would
not or cannot exercise.
AUTHOR CONTRIBUTIONS
All authors listed have made a substantial, direct and intellectual
contribution to the work, and approved it for publication.
FUNDING
This work was supported in part by grants from the National
Institutes of Health (GM103492, HL142710) and the American
Heart Association (16SDG27260070).
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