Exercise Prevention of Cardiovascular Disease in Breast Cancer Survivors

Abstract

Thanks to increasingly effective treatment, breast cancer mortality rates have significantly declined over the past few decades. Following the increase in life expectancy of women diagnosed with breast cancer, it has been recognized that these women are at an elevated risk for cardiovascular disease due in part to the cardiotoxic side effects of treatment. This paper reviews evidence for
the role of exercise in prevention of cardiovascular toxicity associated with chemotherapy used in breast cancer, and in modifying cardiovascular risk factors in breast cancer survivors. There is growing evidence indicating that the primary mechanism for this protective effect appears to be improved antioxidant capacity in the heart and vasculature and subsequent reduction of treatment-related oxidative stress in these structures. Further clinical research is needed to determine whether exercise is a feasible and effective nonpharmacological treatment to reduce cardiovascular morbidity and mortality in breast cancer survivors, to identify the cancer therapies for which it is effective, and to determine the optimal exercise dose. Safe and noninvasive measures that are sensitive to changes in cardiovascular function are required to answer these questions in patient populations. Cardiac strain, endothelial function, and cardiac biomarkers are suggested outcome measures for clinical research in this field.

Full text

Review Article
Exercise Prevention of Cardiovascular Disease in
Breast Cancer Survivors
Amy A. Kirkham1and Margot K. Davis2
1Rehabilitation Sciences, University of British Columbia, 212–2177 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3
2Division of Cardiology, University of British Columbia, Diamond Health Care Centre, 9th Floor, 2775 Laurel Street,
Vancouver,BC,CanadaV5Z1M9
Correspondence should be addressed to Margot K. Davis; margot.davis@ubc.ca
Received  September ; Accepted  December 
Academic Editor: Christine Brezden-Masley
Copyright ©  A. A. Kirkham and M. K. Davis. is is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
anks to increasingly eective treatment, breast cancer mortality rates have signicantly declined over the past few decades.
Following the increase in life expectancy of women diagnosed with breast cancer, it has been recognized that these women are
at an elevated risk for cardiovascular disease due in part to the cardiotoxic side eects of treatment. is paper reviews evidence for
the role of exercise in prevention of cardiovascular toxicity associated with chemotherapy used in breast cancer, and in modifying
cardiovascular risk factors in breast cancer survivors. ere is growing evidence indicating that the primary mechanism for this
protective eect appears to be improved antioxidant capacity in the heart and vasculature and subsequent reduction of treatment-
related oxidativestress in these str uctures.Further clinical research is needed to determine whether exercise is a feasible and eective
nonpharmacological treatment to reduce cardiovascular morbidity and mortality in breast cancer survivors, to identify the cancer
therapies for which it is eective, and to determine the optimal exercise dose. Safe and noninvasive measures that are sensitive
to changes in cardiovascular function are required to answer these questions in patient populations. Cardiac strain, endothelial
function, and cardiac biomarkers are suggested outcome measures for clinical research in this eld.
1. Introduction
Breast cancer is the most common malignancy among
women worldwide [],andanestimated%ofthepopulation
are survivors of breast cancer []. Advances in breast can-
cer therapy have contributed to dramatic improvements in
survival, but many of these therapies, particularly anthracy-
cline chemotherapy, le-sided radiotherapy, and trastuzumab
targeted therapy, are associated with cardiovascular toxicities
[]. Breast cancer survivors are at increased risk of cardio-
vascular disease-related death compared to women without
breast cancer [], likely due in part to these toxicities. An
increased prevalence of traditional cardiovascular risk factors
in this population at diagnosis, and lifestyle perturbations
associated with cancer treatment also contribute to this
increased risk []. Chemotherapy for breast cancer will
induce menopause in one- to two-thirds of women [],
further increasing cardiovascular risk [,]. As breast cancer
survival rates rise, cardiovascular disease becomes an increas-
ingly important competing risk []. Combined, these factors
contribute to the recent nding that cardiovascular disease
has surpassed breast cancer as the leading cause of death in
older women diagnosed with breast cancer [].
Current strategies to mitigate cardiotoxicity associated
with anthracycline treatment include dose reduction, mod-
ied administration methods, liposomal formulations, and
administration of cardioprotective medications []. However,
dose modication may be associated with reduced oncolog-
ical benet [], and pharmacological interventions may be
associated with additional side eects.
Aerobic exercise training and other forms of physical
activity are eective in primary and secondary prevention
of cardiovascular disease and cardiovascular disease-related
death []. For breast cancer survivors, exercise training
issafeandeectiveinimprovingcardiorespiratorytness,
strength, body composition, fatigue, anxiety, depression,
Hindawi Publishing Corporation
Journal of Oncology
Volume 2015, Article ID 917606, 13 pages
http://dx.doi.org/10.1155/2015/917606

Journal of Oncology
and quality of life, and is recommended during and aer
treatment []. However, the eect of aerobic exercise on
cardiovascular function and outcomes during or aer breast
cancer treatment is not well established in humans.
e purpose of this paper is to () review the potential
mechanisms mediating exercise prevention of cardiovascular
toxicity; () review the available evidence for the role of
exercise in prevention of cardiovascular disease in breast
cancer survivors, including predominantly preclinical studies
of the heart and clinical studies of cardiovascular risk factors;
and () suggest outcome measures for translation of the
preclinical ndings to clinical studies.
2. Potential Mechanisms Mediating Exercise
Prevention of Cardiovascular Toxicity
e vast majority of studies investigating exercise prevention
of direct cardiovascular toxicity are in rodent models uti-
lizing the anthracycline agent doxorubicin and compare an
exercise-trained treated group to a sedentary treated group.
e discussion of mechanisms and preclinical evidence refers
to studies with this design unless otherwise noted. e
mechanism underlying the cardioprotective eects of aerobic
exercise before or during treatment with doxorubicin has
not been fully elucidated but is likely to be multifactorial
with summative eects and feedback from diverse processes.
Potential mechanisms by which exercise may act in oppo-
sition to the negative eects of doxorubicin to protect the
heart and vasculature are listed in Tabl e  .ereisavail-
able evidence for exercise protection mechanisms related
to reduced oxidative stress, interruption of topoisomerase-
mediated pathways, cardiomyocyte contractile protein iso-
form shis, and upregulation of heat shock proteins (HSP),
endothelial nitric oxide (NO), and endothelial progenitor
cells.
e most widely supported mechanism by which exer-
cise may prevent doxorubicin cardiotoxicity is through its
antioxidant eects. e production of reactive oxygen species
(ROS) is one of the possible mechanisms for doxorubicin
cardiotoxicity [,]. Although cells are equipped with
an endogenous antioxidant system to protect against ROS,
cardiomyocytes have only one fourth of the antioxidative
capacity of the liver and other tissues [], making them
particularly vulnerable to oxidative stress. Exercise-induced
enhancement of cardiomyocyte antioxidant capacity may
prevent ROS-induced damage associated with doxorubicin
treatment []. Compared with untrained animals, exercise-
trained rodents have increased levels of antioxidant activity
and reduced levels of oxidative stress markers following
doxorubicin exposure [–]. However this mechanism may
not play a role in cardioprotection when exercise is of
low intensity and duration []. Reduced levels of protein
turnover via the ubiquitin-proteasome pathway, an important
mechanism for degradation of cellular proteins with oxidative
damage, have been demonstrated in exercise-trained rodents
compared to sedentary rodents []. is nding provides
further support for exercise protection via reduced oxidative
stress.
Anthracycline-induced ROS cause lipid peroxidation []
and downregulate expression of the sarcoplasmic reticulum
calcium pump, SERCAa []. Decreased calcium uptake by
SERCAa then leads to an increase in cytosolic calcium [].
ese two changes result in opening of the mitochondrial
permeability transition pore, allowing release of calcium from
the mitochondrial matrix, downregulation of mitochondrial
respiration, and leaking of proapoptotic mitochondrial pro-
teins into the cytosol [,]. A single submaximal exercise
session  hours before doxorubicin treatment prevented
opening of the mitochondria permeability transition pore,
mitigating the downstream eects []. is hypothesis is
supported indirectly by several other studies demonstrat-
ing attenuation of doxorubicin-associated increases in the
proapoptotic proteins caspase- and  in exercise trained
rodents [,,,]. ese ndings may be related to
modulation of defense systems including stress chaperones
like HSPs, or antioxidants, but may not be related to exercise-
induced upregulation of SERCAa [,].
ere is emerging evidence implicating topoisomerase
𝛽, an enzyme regulating DNA unwinding, in doxorubicin-
induced cardiomyocyte mitochondrial dysfunction [],
secondary to downregulation of peroxisome proliferator-
activated receptor-𝛾coactivator (PGC)-𝛼,atranscriptional
coactivator of mitochondrial biogenesis []. Exercise train-
ing upregulates expression of PGC-𝛼in skeletal muscle,
although a similar response in cardiomyocytes has not been
observed [,]. Two recent preclinical studies inves-
tigating the role of PGC-𝛼in exercise cardioprotection
did not demonstrate an interaction between exercise and
doxorubicin [,]. However, the capacity of exercise to
impact topoisomerase 𝛽and PGC-𝛼in cardiomyocytes
requires further investigation before this mechanism can be
dismissed.
In the rodent heart, doxorubicin causes disruption of
cardiac bioenergetics and an associated shi from the 𝛼iso-
form of the contractile protein, myosin heavy chain (MHC),
to the 𝛽isoform which has reduced contractile power [].
Exercise training before [,]andduringdoxorubicin
treatment [,]conservesthe𝛼isoform in rats. However,
healthy human hearts express % of the 𝛼isoform on average,
whilethisisthepredominantisoformexpressedintherat
heart []. erefore the extent and subsequent impact of
a doxorubicin-induced shi in MHC isoform distribution
may be smaller for human myocardium. Clinical research is
required to clarify the role of prevention of MHC isoform
shis in exercise cardioprotection.
HSPs control protein folding and unfolding, and are
upregulated in cardiomyocytes during times of oxidative
stress []. An exercise-induced increase in HSP expression
is hypothesized to play a role in cardioprotection against dox-
orubicin by preserving the integrity and activity of mito-
chondrial respiratory complexes and thereby attenuating
mitochondrial dysfunction []. Although there is some
evidence supporting HSP-mediated cardioprotection [,,
], there are also conicting results [,,].
Breast cancer therapies, including chemotherapy, tar-
geted therapies, and radiotherapy, may be associated with
endothelial dysfunction, a disease process involving impaired

Journal of Oncology 
T : Potential mechanisms for exercise prevention of doxorubicin-related cardiovascular toxicity.
Myocardial target Role of target
Direction of
exercise-induced
change∗
Direction of
doxorubicin-induced
change∗
Evidence of exercise
prevention of
doxorubicin-induced
change
Mechanisms with evidence for their role in exercise prevention
Antioxidant to oxidative
stress ratio
Prevention of oxidative
damage ↑[]↓[]✓[–,]
×[]
Expression of 𝛼:𝛽myosin
heavy chain isoform in
rodents
Motor protein required for
muscular contraction; in a
healthy rodent heart there
is a much higher
concentration of the 𝛼
isoform
↑[]↓[]✓[,–]
×[]
Caspase  and  activity Markers for apoptotic
signaling ↓[]↑[]✓[,,,]
HSP  expression
Controls protein folding
and unfolding in response
to stress
↑[]↑↑ []✓[,]
Mitochondrial permeability
transition pore opening
Regulation of calcium
handling and apoptosis ↓[]↑[]✓[]
Ubiquitin-proteasome
activation
Maintains protein function
and quality control ↓[]↑[]✓[]
Endothelial progenitor cell
level
Physiologic and pathologic
vessel formation ↑[]↓[]✓[]
HSP expression
Controls protein folding
and unfolding in response
to stress
↑[,]=[]✓[]
×[,]
SERCAa expression
Calcium recycling from the
cytosol into the
sarcoplasmic reticulum
↑[]↓[]✓[]
×[,]
Mechanisms with evidence against their role in exercise prevention
HSP  expression
Controls protein folding
and unfolding in response
to stress
↑[]↓[]×[]
AMPK activation Senses and regulates energy
homeostasis ↑[]↓[]×[]
Cardiac progenitor cell
level/heart mass
Physiological turnover of
cardiomyocytes ↑[]↓[]×[]
Expression of PGC-𝛼
Tra n scri ption c oact i v at o r
that regulates
mitochondrial biogenesis
and angiogenesis
=[,]↓[]×[,]
Potential mechanisms for exercise prevention lacking investigation
Neuregulin-/ErbB
signalling
Cardiac cell survival
growth factor ↑[]↓[]0
Expression of GATA-
Transcription factor
involved in cardiac
survival, hypertrophic
growth of the heart
↑[]↓[]0
↑:increase;↓: decrease; =: no change; ✓: evidence available in favor of this mechanism; ×: evidence available against this mechanism; 0: no evidence available.
HSP: heat shock protein; SERCA: sarcoplasmic reticulum calcium pump; AMPK: AMP-activated protein kinase; PGC: peroxisome proliferator-activated
receptor-𝛾coactivator.
∗Note: Where possible reference cited provides evidence for the cardiomyocyte response, which may dier from other cell types.

Journal of Oncology
regulation of vascular tone and loss of atheroprotection [].
Flow-mediated dilatation is triggered by shear stress from
increased blood ow through a vessel, resulting in NO-medi-
ated vasodilation []. Doxorubicin impairs both endothe-
lium-dependent (i.e., ow-mediated) and endothelium-
independent vasodilation [,,]. Breast radiation
impairs endothelium-dependent vasodilation in exposed
axillary arteries, causes ultrastructural damage to myocardial
capillaries, and can induce atherosclerosis in coronary arter-
ies [–]. Trastuzumab may cause endothelial dysfunction
through reductions in NO [].
Exercise training improves endothelial dysfunction, pre-
dominantly through increased NO production as a result of
chronic periods of pulsatile blood ow []. In the presence
of the superoxide ROS, NO reacts to form a reactive molecule
that can damage DNA, and this reaction also decreases the
bioavailability of NO []. e upregulation of antioxidative
enzymes associated with exercise training may therefore
promote NO bioavailability by scavenging ROS []. Hay-
ward et al. provided evidence that exercise preconditioning
prior to -uorouracil chemotherapy exposure increased NO
production in rodents [].
Endothelial progenitor cells (EPCs) contribute to main-
taining the integrity of the endothelial cell layer, and lower
levels of circulating EPCs are associated with an increased
risk of cardiovascular events and death []. Exercise stimu-
lates EPC mobilization from the bone marrow []. In human
breast cancer survivors receiving doxorubicin-containing
chemotherapy, exercise has been associated with an increase
in circulating EPCs relative to usual care controls [].
ere are other proposed mechanisms for cardiotoxicity
where exercise training could counteract the doxorubicin-
induced molecular response that have not yet been investi-
gated as mechanisms for exercise cardioprotection. For exam-
ple, pharmacological 𝛼-adrenoceptor activation of the car-
diac transcription factor GATA- has demonstrated cardio-
protective capacity against doxorubicin []. erefore, exer-
cise training, which appears to enhance both 𝛼-adrenoceptor
responsiveness [],andGATA-mRNAlevelintheheart
[] may also exert a cardioprotective eect via a GATA-
 pathway. Another example includes doxorubicin and
trastuzumab downregulation of neuregulin-/ErbB receptor
tyrosine kinase signaling in cardiomyocytes. Neuregulin-
/ErbB signaling plays a critical role in cardiac development
and cardiomyocyte survival and organization []. Intrigu-
ingly, exercise training upregulates expression of neuregulin-
 in rodent cardiomyocytes [], indicating a potential
mechanism for exercise prevention of doxorubicin- and tra-
stuzumab-related cardiotoxicity. Readers are referred to a
more comprehensive review of potential mechanisms for
exercise prevention of targeted cancer therapy-related car-
diotoxicity [].
In summary, although evidence exists for several dierent
mechanisms through which exercise protects the heart and
vasculature from doxorubicin-related toxicity, the unifying
feature appears to be increased antioxidant capacity and
reduction of oxidative stress. Several potential mechanisms,
including exercise-induced upregulation of topoisomerase
𝛽/PGC-𝛼, GATA-, and neuregulin-/ErbB warrant fur-
ther investigation to determine their role in cardioprotection.
3. Evidence for Exercise Prevention of
Cardiovascular Disease
3.1. Cardiotoxicity Prevention
3.1.1. Acute Exercise. In animal models, doxorubicin-related
cardiotoxicity can be attenuated by a single exercise session
in close proximity to time of exposure. In the seminal study
in this area, a -minute exercise session completed half an
hour aer doxorubicin exposure reduced mortality [].
ese ndings were extended to demonstrate that an exhaus-
tive exercise session half an hour aer doxorubicin expo-
sure attenuated markers of cardiomyocyte mitochondrial
dysfunction []. Sixty minutes of submaximal exercise
performed  hours prior to doxorubicin prevented or atten-
uated le ventricular (LV) systolic and diastolic dysfunction,
cardiomyocyte mitochondrial apoptosis and dysfunction,
and lipid peroxidation at  days post-treatment in rodents
[,].
e potential of a single exercise session to provide car-
dioprotection is particularly appealing, as regular, supervised
exercise training during chemotherapy may not be feasible
forallpatientsduetodistancefromhometoexercisecenters,
diculty with treatment symptoms, scheduling conict with
work, or family obligations. Ongoing research by our group is
investigating the cardioprotective benet of an acute exercise
session  hours prior to doxorubicin administration in
women with breast cancer.
3.1.2. Exercise Training before Treatment. In animals receiv-
ing high-dose bolus doxorubicin, exercise preconditioning
prevents or attenuates acute (∼ hour post) increases in
cardiac troponin I [,], markers of oxidative stress [–
,,], cardiomyocyte mitochondrial dysfunction [,,
], morphological and histological damage [], markers
of apoptosis [,,], and decreases in HSP expression
[,] and LV systolic function [,]. Similar ndings
have been reported in studies that extended the follow-up
time to – days aer doxorubicin exposure [,,,].
Findings exclusive to studies with longer follow-up include
attenuation of decits in coronary ow [], transmitral, and
transaortic ow [,], as well as transformation to the
𝛽-MHC isoform []. Even at four weeks aer doxorubicin
exposure, the benecial eects of exercise preconditioning on
𝛽-MHC transformation, LV wall thickness, mass and systolic
function, and transmitral/transaortic ow were still apparent
[].
e feasibility of exercise preconditioning in humans
has been questioned, as the interval between breast cancer
diagnosis and treatment is shorter than the length of most
training programs that have been studied ( to  weeks).
However, cardioprotective eects have been reported aer as
little as  days to  weeks of training in rodents [,,].
It should be noted that administered doxorubicin doses in
these studies were higher than comparable human doses. It

Journal of Oncology 
is unclear whether similar benets would be seen in patients
receiving standard treatment doses.
3.1.3. Exercise Training during Treatment. Exercise training
concurrent to chronic doxorubicin treatment in rodents has
been associated with attenuation of LV systolic and diastolic
dysfunction [,,,,], cardiomyocyte apoptosis [],
transformation to 𝛽-MHC [,], reductions in LV wall
thickness []andheartmass[], and decits in coronary
[], transmitral, and transaortic ow [,,].
Exercise training in humans during chemotherapy treat-
ment for breast cancer is feasible and prevents the decrease
in cardiorespiratory tness seen in usual care controls [–
]. Preliminary clinical studies of the eects of exercise
training on cardiac function in humans undergoing breast
cancer treatment have had disappointing results, however. A
small randomized control trial of exercise training compared
to usual care during doxorubicin-containing chemotherapy
for breast cancer found no change in LV ejection fraction
(LVEF) in either group []. A single-arm study investigated
the eects of four months of exercise training in  breast
cancer survivors receiving adjuvant trastuzumab therapy.
Despite exercise training, trastuzumab was associated with
LV dilatation and reduced LVEF []. However the exercise
training dose may have been insucient, as participants did
not attend % of exercise sessions. More sensitive measures
of cardiac function and a higher exercise dose are likely
required in order to demonstrate a cardioprotective benet
in clinical studies.
3.1.4. Exercise Training aer Treatment. Although H´
eon et al.
have reported reduced markers of cardiomyocyte apoptosis
and oxidative stress in rodents undergoing exercise training
two weeks aer the completion of doxorubicin administra-
tion [], to our knowledge the eects of post-treatment
exercise on cardiac function have not been studied.
3.1.5. Summary of Cardiotoxicity Prevention Evidence. In
summary, acute and chronic exercise before, during or aer
doxorubicin treatment in rodents consistently results in pre-
vention or attenuation of doxorubicin-induced deleterious
eects to cardiomyocyte morphology and biochemistry, as
well as cardiac function. Preclinical experimental research is
needed to determine whether exercise can provide cardiopro-
tection from cancer therapies other than doxorubicin.
3.2. Vascular Toxicity Prevention. Few studies have investi-
gated the eects of exercise on vascular function during breast
cancer treatment. Six weeks of exercise training, initiated
four weeks aer doxorubicin treatment, was associated with
improved endothelium-independent but not endothelium-
dependent vasodilation, and with reduced mortality in rats
with cardiac dysfunction []. Similarly, eight, but not four
weeks of exercise training prior to exposure to -uorouracil
chemotherapy was associated with enhanced endothelium-
dependent vasodilation in rats []. In humans, two small
randomized trials of the eect of exercise training during
doxorubicin-containing chemotherapy on endothelial func-
tion have had conicting results [,]. To advance under-
standing of exercise prevention of cardiovascular disease
in breast cancer survivors, future exercise cardioprotection
studies should include measurement of vascular function in
addition to the cardiac measures.
3.3. Cardiovascular Risk Factors Modication. Traditional
cardiovascular risk factors should be monitored and managed
in breast cancer patients who receive cardiotoxic cancer
therapies to prevent additional injury []. Exercise can
favorably improve a number of cardiovascular risk factors
including hypertension, raised cholesterol/lipids, overweight
and obesity, raised blood glucose or diabetes, and cardiores-
piratory tness [].
Hypertension is more than twice as prevalent among
breast cancer survivors aged  and older as it is among the
general population [], and may be caused by chemotherapy
agents used to treat breast cancer including cyclophos-
phamide, cisplatin and carboplatin []. Chemotherapy for
breast cancer is also associated with elevations in triglyceride
levels [], while tamoxifen treatment may reduce levels
of protective high density lipoprotein (HDL) []. Prior
to treatment, breast cancer survivors may already have a
suboptimal lipid prole including higher total cholesterol,
triglyceride, and low density lipoprotein levels, and lower
HDL levels than healthy controls [–]. A similar pattern
occurs with overweight or obesity, where overweight, a risk
factor for development of breast cancer [], is oen an issue
prior to treatment, and chemotherapy treatment perpetuates
the problem via its association with greater weight gains
than other treatments in the year following diagnosis [].
erefore, it is not surprising that almost half of breast
cancer survivors are overweight or obese []. Treatment
also has lasting adverse eects on peak oxygen consumption
(VO2), the gold standard measurement of cardiorespiratory
tness []. Chemotherapy causes a –% reduction in
peak VO2[,], and following breast cancer treatment
completion, remains an average of % lower than that
of healthy sedentary controls []. Furthermore, the level
of cardiorespiratory tness amongst breast cancer survivors
appears to mediate incidence of cardiovascular disease and
risk factors []. Lastly, breast cancer survivors are at an
increased risk for diabetes from two up to  years following
diagnosis [], and its presence increases the risk of mortality
in this population []. In early stage breast cancer survivors,
high blood insulin levels, indicative of insulin resistance,
are associated with obesity, poor lipid proles [], distant
recurrence and death [].
A number of exercise intervention studies in human
breast cancer survivors have included cardiovascular risk
factors as outcome measures. Exercise interventions in breast
cancer survivors have consistently reported decreases in
systolic blood pressure of – mmHg both during [–]
and aer [,–]treatment.Reportedeectsonblood
lipids following an exercise intervention with or without
dietary intervention include signicant positive eects on
triglycerides [,], and HDL [], or no eect [,,

Journal of Oncology
]. Numerous exercise interventions have measured weight
or body composition change with mixed results, showing
either no eect or weight reduction []. Small feasibility
studies have demonstrated that the combination of exercise
with a diet intervention could be more eective in reducing
weight in breast cancer survivors [,]. Exercise training
during chemotherapy or radiation treatment for breast cancer
at minimum can prevent the peak VO2decline occurring in
usual care controls [], or improve peak VO2[,,,,
]. Exercise training following completion of breast cancer
treatment improves peak VO2[,,]. Only one []
of six randomized controlled trials to examine the eect of
an exercise intervention on insulin and/or insulin resistance
demonstrated statistically signicant changes [,,–
]. is same study also reported improvements in fasting
blood glucose [].
In summary, exercise interventions appear to have clin-
ically meaningful eects on blood pressure and peak VO2,
whereas the eects on blood lipids, weight, and insulin/
glucose and potential development of diabetes are less clear.
e strong established relationships between both blood
pressure and peak VO2and cardiovascular disease devel-
opment and mortality in noncancer populations [,–
] provide convincing support for the role of exercise in
prevention of cardiovascular disease in human breast cancer
survivors.
4. Translation of Preclinical Findings to
Clinical Studies
Substantial preclinical evidence supports the role of exercise
in prevention of cardiovascular disease toxicity, and there is
some evidence for modication of cardiovascular risk factors
in clinical trials. Further clinical research is warranted to
determine whether exercise is a feasible and eective method
for the reduction of cardiovascular morbidity and mortality
in breast cancer survivors. Barriers to the translation of
preclinical ndings to human models include the need for
more sensitive outcome measures and uncertainty regarding
the optimal exercise dose.
Demonstration of the cardioprotective benets of exer-
cise in rodents has typically required euthanasia. One of the
greatest barriers to this research in humans is identication
of a noninvasive and sensitive outcome measure. ree-
dimensional echocardiography-derived LVEF has emerged
as a more reliable measure of LV function in patients
receivingchemotherapycomparedtotraditionaltwo-
dimensional imaging [], although this does not necessarily
imply greater sensitivity to early changes in function.
Echocardiography-derived LV global longitudinal strain and
strain rate are able to detect changes in cardiac function
during chemotherapy, radiation and trastuzumab treatment
before changes in LVEF are detectable []. In noncancer
populations, cardiac strain responds to exercise training
[]. Our research group is conducting an ongoing study
to determine whether exercise training can prevent the
doxorubicin-related decline in cardiac strain parameters
in women with breast cancer. ese parameters are widely
available in conjunction with standard echocardiography
[]; with acceptable inter- and intra-observer variability
(% and .%, resp.) []. Global longitudinal strain
is predictive of all-cause mortality for a number of other
cardiac conditions [–], and may be a stronger predictor
of outcomes than LVEF [,], but its relationship with
clinical outcomes other than LVEF in breast cancer survivors
is unknown.
Endothelial function is another attractive clinical out-
come measure because dysfunction is an early process in
the development of cardiovascular disease, and in noncancer
populations, responds to pharmacological [,]and
exercise [] interventions. Endothelial function can be easily
measured in humans with a reactive hyperemia test, in which
a cu is inated around the arm to occlude blood ow for
 minutes. With release, the sudden increase in blood ow
causes vasodilatation, which can be measured with ultra-
sound or peripheral arterial tonometry [].
Cardiac biomarkers may play a role in predicting and
identifying cardiotoxicity []. N-terminal prohormone
brain natriuretic peptide (NT-proBNP) is frequently elevated
during and aer anthracycline treatment in adults [–
]. ere is mixed evidence regarding its ability to predict
cardiac dysfunction following anthracycline treatment [–
], as several studies where trastuzumab treatment followed
anthracycline treatment, do not report a predictive ability of
NT-proBNP [,–]. Due to inter-individual variations
in kinetics, several measurements may be required to capture
an elevation in cardiac troponins in patients receiving anthra-
cyclines [,,,,,–], but the occurrence
of an elevation in troponin I is predictive of chemotherapy
and trastuzumab-related decreases in LVEF [,], and
cardiacevents[]. Exercise in heart failure patients does not
change levels of NT-proBNP []orcardiactroponinI[],
but chronic heart failure has a dierent pathophysiology than
the acute eects of cardiotoxic cancer therapies. Nonetheless,
cardiacbiomarkersmayprovetobeaneectiveoutcome
measure for exercise cardioprotection interventions due to
their accessibility and reliability as a marker of cardiotoxicity.
Another important factor in the eective translation of
preclinical ndings to humans is the exercise intervention
design. While preclinical and clinical experimental studies
demonstrate that high intensity aerobic exercise results in
greater cardiac benets than moderate or low intensity [,
], the strenuous exercise prescription applied in most pre-
clinical studies (ve days a week, moderate to high intensity,
– minutes) would likely not be tolerable for humans
undergoing chemotherapy treatment []. One rodent study
implemented a more clinically feasible and practical exercise
prescription and doxorubicin treatment protocol involving
 minutes of low intensity exercise, performed ve days
per week during chronic low dose doxorubicin treatment
[]. Although the lower doxorubicin dose failed to induce
the MHC isoform shi and lipid peroxidation reported
with higher doses, the lower exercise dose was protective
against LV dysfunction and cardiomyocyte apoptosis []. In
heart failure patients, moderate intensity exercise performed
three days per week has been shown to improve systolic
function []. erefore, the required exercise dose for

Journal of Oncology 
cardioprotection likely involves three to ve days per week
of moderate to high intensity aerobic exercise of at least 
minutes in duration, but greater benets will likely occur with
higher doses. e optimal prescription requires a balance of
patient tolerance with protective ecacy.
5. Conclusion
Breast cancer therapy has ecacious antitumor eects, but
is associated with increased risk of cardiovascular disease.
A considerable body of research, including preclinical stud-
ies and clinical trials, indicates that exercise may be an
eective nonpharmacological method of attenuating the
harmful eects of breast cancer therapies on the heart and
vasculature, of modifying cardiovascular risk factors, and
potentially reducing cardiovascular morbidity and mortality
in this vulnerable population. e mechanisms for exercise
prevention appear to be predominantly related to an increase
in antioxidant capacity and associated reduction in oxidative
stress. Clinical trials are needed to investigate the role of
exercise in the prevention of direct cardiovascular toxicity
of breast cancer treatment and the eect on cardiovascular
eventsandmortality.eroleofexerciseintheprevention
of cardiovascular disease in other cancer populations also
warrants further research, as the detrimental combination
of a high incidence of baseline risk factors combined with
cancer treatment cardiovascular toxicity may be common
to multiple cancer types. Echocardiographic quantication
of LV global longitudinal strain and strain rate, endothelial
function quantication, and measurement of circulating car-
diac biomarkers are safe, noninvasive measures that may be
sensitive and eective outcome measures for clinical studies
of exercise prevention of breast cancer treatment-related
cardiovascular toxicity. e exercise frequency, intensity, and
duration demonstrating cardioprotection in most preclinical
studies may need to be modied to accommodate human
patient tolerability during ongoing cancer treatment.
Conflict of Interests
e authors declare that there is no conict of interests
regarding the publication of this paper.
Acknowledgments
Amy Kirkham is supported by a Canada Graduate Scholar-
ship from the Canadian Institute of Health Research. Margot
Davis is supported by a Vancouver Coastal Health Research
Institute Mentored Clinician Scientist award.
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