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IJC Heart & Vasculature 50 (2024) 101332
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IJC Heart & Vasculature

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Doxorubicin-induced cardiotoxicity and risk factors

Carl Belger 1, Carmelita Abrahams 1, Aqeela Imamdin , Sandrine Lecour *
Cardioprotection Group, Cape Heart Institute, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
A R T I C L E I N F O A B S T R A C T
Keywords: Doxorubicin (DOX) is an anthracycline antibiotic widely used as a chemotherapeutic agent to treat solid tumours
Doxorubicin and hematologic malignancies. Although useful in the treatment of cancers, the benefit of DOX is limited due to
Chemotherapy its cardiotoxic effect that is observed in a large number of patients. In the literature, there is evidence that the
Toxicity
presence of various factors may increase the risk of developing DOX-induced cardiotoxicity. A better under
Diabetes
Cardiovascular risk
standing of the role of these different factors in DOX-induced cardiotoxicity may facilitate the choice of the
therapeutic approach in cancer patients suffering from various cardiovascular risk factors.
In this review, we therefore discuss the latest findings in both preclinical and clinical research suggesting a link
between DOX-induced cardiotoxicity and various risk factors including sex, age, ethnicity, diabetes, dyslipi
daemia, obesity, hypertension, cardiovascular disease and co-medications.
1. Introduction [9]. The American Society of Echocardiography and the European As
sociation of Cardiovascular Imaging define clinical cardiotoxicity as a
Cancer is a life-threatening disease characterized by unregulated cell 10 % point decrease in LVEF from baseline to a value below 53 % and
growth and the formation of malignant tumours. In 2020, an estimated subclinical cardiotoxicity as preserved LVEF with a 15 % reduction in
19.3 million people were diagnosed with cancer worldwide and nearly Global Longitudinal Strain (GLS) with/without an increase in serum
10 million cancer deaths were recorded [1,2]. There are multiple biomarkers for cardiac injury such as troponin [10]. However, it is
treatment strategies for cancer that have contributed to steadily important to note that most research studies have used their own defi
decrease its fatality rate since the 1960s [3]. However, following nition when referring to cardiotoxicity. Cardiotoxicity can occur at any
treatment, many cancer survivors may experience significant side- time during or after treatment and is separated into three classes: acute,
effects of the therapy. early and late onset or chronic cardiotoxicity [9]. Acute cardiotoxicity
One such treatment is Doxorubicin (DOX), an anthracycline anti occurs during treatment and often presents as supraventricular ar
biotic frequently used as a chemotherapy for the treatment of solid tu rhythmias, electrocardiograph (ECG) changes and left ventricular
mours and hematogenous malignancies [4]. However, its use is limited dysfunction [9]. These symptoms usually regress, however it may also
due to many cancer survivors developing congestive heart failure (CHF) progress into early or late cardiotoxicity [11]. Early cardiotoxicity oc
when receiving this treatment [5]. In an Italian cohort of 2625 cancer curs within the first year of treatment while late cardiotoxicity occurs
patients treated with anthracyclines, 9 % of the patients experienced several years later, but both are associated with the development of CHF
cardiotoxicity with a mean follow up time of 5.2 years (98 % of which [9,11,12].
occurred in the first year) [6]. Similarly, in a group of patients under Monitoring left ventricular systolic function with imaging modalities
going anticancer therapy in Spain with a mean follow up of 2 years, 37.5 and cardiovascular biomarkers before and after completion of anthra
% of patients experienced cardiotoxicity [7]. cycline based chemotherapy is therefore recommended to detect early
An early indicator for DOX-induced cardiotoxicity is a decrease in myocardial damage (see Table 1). Although several imaging modalities
left ventricular ejection fraction (LVEF) from baseline [8]. The European exist, serial monitoring with two-dimensional (2D) echocardiography is
Society of Cardiology (ESC) defines clinical cardiotoxicity as a 10 per routinely used in the clinical setting due to its widespread availability,
centage (%) point decrease in LVEF from baseline to a value below 50 % avoidance of exposure to radiation, ability to obtain haemodynamic
* Corresponding author at: Hatter Institute and Cape Heart Institute, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Observatory
7935, South Africa.
E-mail address: Sandrine.lecour@uct.ac.za (S. Lecour).
1
Shared first co-authorship.
https://doi.org/10.1016/j.ijcha.2023.101332
Received 24 July 2023; Received in revised form 14 December 2023; Accepted 16 December 2023
Available online 27 December 2023
2352-9067/© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
C. Belger et al. IJC Heart & Vasculature 50 (2024) 101332
parameters and to assess cardiac structures [6,13,14]. However, one related to oxidative stress, where the serum level of myeloperoxidases
main challenge with 2D echocardiography is that it is not sensitive increased during anthracycline treatment but was not associated with
enough to detect small changes in LVEF [see review [13]]. 2D Speckle left ventricular dysfunction [15]. However, patients with baseline levels
tracking echocardiography to measure myocardial global longitudinal of myeloperoxidase above the median had more severe myocardial
strain (GLS) is a more sensitive method to detect a reduction in injury after anthracycline treatment [15]. Furthermore, in a meta-
myocardial contractility prior to the onset of left ventricular systolic analysis, there was no change in serum levels of galectin-3 while mye
dysfunction [14]. In a population of breast cancer patients receiving an loperoxidase increased earlier than cardiac troponin I and NT pro-BNP
anthracycline based chemotherapy regimen, there was a >10 % reduc during anthracycline therapy and was associated with an increased
tion in LVEF in 23.3 % of patients at 3 months and in 25.3 % of patients risk for cardiotoxicity [21].
at 6 months, however, LVEF remained above 50 % throughout follow up Unfortunately, these conventional modalities to detect cardiotoxicity
with no patients diagnosed with cardiotoxicity according to the crite are only positive after damage to the myocardium has already been
rion. On the other hand, a greater than 15 % reduction in GLS was done. Currently, there is a need to identify patients at risk prior to the
observed in 61.6 % of patients at 3 months, and a relative but significant onset of any clinical manifestations [see review [22]]. A recent assess
decrease in GLS in the whole population throughout follow up thus ment for a biomarker utilizing technology within the omics field shows
indicating that GLS is more sensitive to detect myocardial injury at an promise to offer a more targeted approach to identify patients at risk for
earlier timepoint following treatment [14]. Probing for cardiovascular developing anthracycline cardiotoxicity before and early during treat
biomarkers during treatment may assist to identify myocardial injury ment [see reviews [22,23]]. Briefly, genomic studies have identified
prior to the onset of changes in left ventricular function and could several single nucleotide polymorphisms (SNPs) and microRNAs that are
therefore assist in predicting patients at risk for a subsequent decline in associated with a greater risk for the development of anthracycline-
left ventricular function [15]. The cardiac biomarker, high sensitivity induced cardiotoxicity. In preclinical models, the use of a metab
troponin I, is released upon myocardial injury early during treatment olomic approach has allowed to identify more than 39 metabolites that
and has demonstrated to predict a subsequent decline in LVEF [16]. are able to predict cardiotoxicity earlier than other biochemical or his
Similarly, the neurohormone N-terminal pro-brain natriuretic peptide topathological analysis [see review [22]].
(NT pro-BNP) is released from cardiomyocytes in response to expansion Understanding the mechanisms how DOX targets cancer cells and
and pressure overload [17]. Serum levels of NT pro-BNP increased induces cardiotoxicity is key to ensure its efficacy while protecting pa
during anthracycline treatment, an effect that was associated with a tients against the side effects of DOX. As largely reviewed in the litera
decline in left ventricular fractional shortening and ejection fraction ture, DOX kills cancer cells through two main mechanisms. Firstly, by
[17]. In a different study, serum levels of NT pro-BNP increased prior to intercalation with deoxyribonucleic acid [24], leading to double
a decline in LVEF [18]. In contrast, others observed an increase in car stranded breaks and secondly, by topoisomerase inhibition [25,26].
diac troponins I, T and NT pro-BNP during anthracycline treatment, Some mechanisms involved in DOX-induced cardiotoxicity may be
however it was not related to changes in left ventricular dysfunction distinct from its anti-cancer therapeutic mechanisms while others may
[19]. The discrepancies in findings between studies could be related to overlap [26]. There are two well-theorized mechanisms of DOX-induced
sample size, differences in the timing of assessment for left ventricular cardiotoxicity. Firstly, upon its administration, DOX undergoes one
function and the biomarkers or differences in the dosage of anthracy electron reduction producing the reactive oxygen species (ROS), su
cline treatment administered where a higher cumulative dosage would peroxide anion and hydrogen peroxide [27,28]. ROS react with iron
have a stronger biomarker response [19]. Other biomarkers have also (Fe2+ and Fe3+) to produce the highly toxic hydroxyl radical promoting
been considered including galectin-3, c-reactive protein and myeloper oxidative stress causing damage to DNA, proteins and lipids leading to
oxidase [15,20]. Galectin-3 is related to cardiac remodelling and fibrosis cell death [28,29]. Secondly, DOX increases intracellular iron concen
and c-reactive protein is involved in systemic inflammation. Both were tration through inhibiting the iron regulatory protein-1 (IRP-1) [30].
increased in patients receiving anthracycline treatment; however, the IRP-1 regulates the expression of genes involved in iron metabolism and
effect was not associated with left ventricular dysfunction [15,19]. homeostasis, thus its inhibition leads to increased intracellular iron
Similar observations were made with myeloperoxidase, an enzyme levels and consequently, oxidative stress [31]. Cardiac tissue has a
Table 1
Current tools available for the early detection of anthracycline cardiotoxicity.
Measurement Advantage Limitation
Imaging modalities
2D echocardiography LVEF Accessible Sensitivity
Haemodynamics Cardiac No exposure to radiation Interobserver variability
structures
3D echocardiography LVEF Reduced variability compared to 2D Costly
Haemodynamics Cardiac echocardiography Operator dependence
structures Limited availability
2D speckle tracking GLS Sensitivity Strain packages for different manufacturers vary.
echocardiography Predict subsequent decline in LVEF Abnormal strain cut off values yet to be standardized.
MUGA scan LVEF Reproducibility Radiation

Limited structural and functional information on other
cardiac structures.
CMR imaging LVEF Reproducible Costly
Fibrosis Characterization of myocardial tissue Limited availability
Oedema
Biomarkers
Troponin I Myocardial injury Sensitivity Standardization for routine clinical use yet to be
Reproducible determined.
Minimally invasive
Availability
CMR: Cardiac Magnetic Resonance; GLS: Global Longitudinal Strain; LVEF: Left Ventricular Ejection Fraction; MUGA: Multigated acquisition. [Adapted from: [13,16]].
2
relatively low anti-oxidative defence system which makes it more sus DOX-induced cardiotoxicity, the most common one being cumulative
ceptible to DOX-induced ROS damage compared to other tissues [32]. In dosage [5]. Adult and paediatric cancer patients are most at risk when
addition, DOX itself reduces the expression of anti-oxidative enzymes, cumulative dosage exceeds 400–700 mg/m2 and 300 mg/m2, respec
glutathione and catalase, further impeding its anti-oxidative defence tively [58]. However, subclinical cardiac dysfunction has also been
system and leaving the heart vulnerable to oxidative stress [33]. These observed at a lower dosage [58]. The method of administration also
two mechanisms are known as the “ROS and iron” hypothesis and are plays a role, where a greater risk is associated with bolus infusion
widely believed to be the major causes of DOX-induced cardiotoxicity, compared to continuous infusion [59]. Other than the clinical applica
although many other mechanisms exist [26] [see review [34]]. tion, there are factors related to the patient profile which act as con
Other mechanisms include targeting signalling molecules involved in founders, increasing susceptibility to DOX-induced cardiotoxicity.
apoptosis such as the pro-apoptotic gene P53, inhibition of the T-cell Individuals who bear these risk factors can be considered for other
survival factor GATA-4 and degradation of the cell cycle regulator p300 therapies while those who continue to receive DOX will need to be
[35–38]. DOX upregulates intracellular protein degradation by closely monitored to recognize and treat cardiotoxicity. In this mini-
increasing the activity of the ubiquitin–proteasome system (UPS) review, we therefore discuss important risk factors that may favour
causing degradation of essential proteins [39]. The oxidative stress also the risk of DOX-induced cardiotoxicity, including sex, age, ethnicity,
promotes dysfunction of the mitochondria [40]. This results in mito diabetes, dyslipidaemia, obesity, hypertension, cardiovascular disease,
chondrial swelling and apoptosis, cristae disruption, increased number and co-medications (Fig. 1).
of lysosomes and chromatin shrinkage [41–44]. Finally, DOX has car
diotoxic mechanisms that overlap with its anticancer functions. For 2. Sex
example, DOX causes more severe DNA damage through topoisomerase
IIα than topoisomerase IIβ, the former being highly expressed in cancer Sex is a well-known risk factor for cardiovascular diseases in humans.
cells and immature human-induced pluripotent stem cell-derived car It is estimated that 290 million women and 260 million men live with
diomyocytes [45,46]. Based on the current understanding of the sig heart disease globally [60]. Contrastingly, an estimated 9.8 million men
nalling pathways involved in DOX-induced cardiotoxicity, several died of heart disease in 2019 compared to 9.2 million women [60]. Men
cardioprotective intervention strategies are currently explored to miti also have a higher incidence of cancer worldwide as well as a higher
gate its cardiotoxic effect [see review [47]]. Briefly, modifying the total mortality due to cancer [61]. It is therefore important to consider
administration of anthracycline chemotherapy which includes lower sex-based susceptibility with cancer treatment as one sex may be more at
accumulative dosage, slow infusion, and treatment with liposomal DOX, risk of cardiotoxic effects caused by DOX (see Fig. 2).
has demonstrated to be of clinical benefit [48–50]. Concurrent or sub Sex hormones are an important mechanism behind these differences
sequent treatment with pharmacological therapies such as dexrazoxane, since cardiac cells express both oestrogen receptors (ER) and androgen
inhibitors of the renin-angiotensin-aldosterone system, beta adreno receptors (AR), thus making these cells specifically prone to changes
ceptor blockers are also investigated in clinical trials [19,51–55]. Un function to the levels of circulating sex hormones [62]. Oestrogen,
fortunately, many clinical trials aiming to reduce or prevent the onset of specifically, has shown cardioprotective effects, in part due to preven
cardiotoxicity are neutral despite strong preclinical studies, highlighting tion of apoptosis as well as alleviation of left ventricular hypertrophy
flaws in the translation from bench to bedside [56,57]. [63]. Oestrogen modulates a variety of cardioprotective pathways such
There are well known risk factors associated with the development of as the phosphatidylinositol-3-kinase (PI3K) pathway and the
Fig. 1. Major risk factors for DOX-induced cardiotoxicity. Abbreviations: ACE = Angiotensin Converting Enzyme, ARB = Angiotensin Receptor Blockers, CCB =
Calcium Channel Blockers, DOX = Doxorubicin, MRT = Mediastinal Radiation Therapy, ROS = Reactive Oxygen Species, SGLT2 = Sodium Glucose Transporter 2.
3
Fig. 2. Signalling pathways targeted by different risk factors in DOX-induced cardiotoxicity.
extracellular signal-regulated kinase (ERK) 1/2 pathway, both involved DOX with adrenergic-induced cardiac stress was shown to be reduced in
in apoptosis prevention and improved mitochondrial function [64,65]. castrated male mice compared to non-castrated males, but no changes
Other than sex hormones, differences in health are further influenced by were seen in ovariectomized females [76]. Pre-exposure to DOX did not
sex-specific lifestyle habits and risk factors such as smoking, diet, stress cause any sex-specific changes in cardiac function, but coupled with
and alcohol consumption [66]. Additionally, sex-linked genes such as Y- cardiac stress, DOX caused persistent cardiac atrophy in male mice only,
linked DDX3Y and X-linked XIST have also been linked to susceptibility which could not be prevented by gonadectomy, thus illustrating sexually
to cardiomyopathies, indicating that genetics may play a further role in dimorphic responses to DOX cardiotoxicity [76]. A study examining the
sexual dimorphism in DOX-induced cardiotoxicity [67]. effect of DOX treatment on cardiac contractile properties in gonadec
Most animal studies investigating the effects of DOX have generally tomized rats showed that oestrogen (but not progesterone) was able to
been assessed in male rodents to reduce the variability of results caused restore contractility in ovariectomized female rats, whereas testosterone
by fluctuating oestrogen levels in female rodents [68]. However, DOX was unable to restore contractility in castrated males [77].
induced greater myocardial injury in certain strains of male mice and Literature exploring sex differences in DOX induced cardiotoxicity in
rats compared to females. Comparing 10 collaborative cross mouse humans is scarce, with very few studies including adult participants.
strains receiving 25 mg/kg DOX, the authors observed no changes in Notably, there is a difference in findings between adult and paediatric
susceptibility between sexes in six strains, male susceptibility in three cancer patients.
strains and female susceptibility in one strain [69]. Indeed, troponin-T Most studies report young girls being more at risk of cardiotoxicity
levels, used as a measurement of cardiac injury, were higher in male compared to young boys [78–80]. This increased risk could theoretically
B6C3F1 mice compared to female mice when cumulative DOX dose relate to the low levels of oestrogen in the female body at a pre-
exceeded 21 mg/kg [70]. Similarly, LVEF was significantly reduced in pubescent age [81]. It is also hypothesized that females have a lower
male Wistar rats but not in females when DOX was given at a cumulative clearance of DOX than males due to their higher levels of fat mass since
dose of 14 mg/kg [71]. In addition, male rats had a 50 % mortality DOX clearance is reduced in obese patients [82,83]. A study analysing
compared to no deaths in females [71]. In another adult rat model, male 150 children between the ages of 11 weeks and 21 years old treated with
rats had significantly more severe cardiomyopathy scores and myocar DOX, revealed a positive association between the female sex and cardiac
dial lesions compared to females [72]. Finally, in a study where cumu dysfunction [78]. The two tests used in this study were resting and ex
lative dose was 16 mg/kg, female Wistar Kyoto rats were better ercise gated nuclear angiography, and ECG monitoring of cycle ergo
protected against DOX-induced weight loss, blood pressure increase, metry [78]. A similar study evaluating 106 children diagnosed with
cardiac dysfunction, and nephrotoxicity compared to male mice [73]. DOX-induced cardiotoxicity, positively correlated female sex with a
The majority of evidence suggests that male rodents are more at risk of higher risk of cardiotoxicity [79]. This study used patient records to
cardiotoxicity than female rodents. measure heart failure, cardiac-related deaths, and irregular cardiac
In rodent studies, there is also strong evidence to support female function [79]. Using mortality records, young girls may be more at risk
hormones as role-players in maintaining cardiac function with DOX of death due to cardiotoxicity than boys [80]. Contrastingly, in other
treatment, particularly after cardiac stress. Female ovariectomised rats paediatric studies, neither sex was a risk factor for DOX-induced car
treated with a subclinical dose of DOX and subject to cardiac stress in the diotoxicity and in others, adult females were at higher risk [78,84–86].
form of swim training showed divergence from non-ovariectomised rats These differences could be due to the cumulative dosage, grouping of
in maintenance of cardiac function, thus indicating that ovarian hor paediatric and adult patients, the number of individuals of each sex in
mones may play a role in reducing DOX-induced cardiotoxicity [74]. each study or a different definition used to define cardiotoxicity.
Similarly the use of oestrogen therapy in ovariectomized rats together In adults, one study reported a positive correlation between male sex
with DOX, improved DOX treatment-induced a decrease in ejection and risk of cardiac disease when 77 % of patients received DOX treat
fraction [75]. Treatment with oestrogen was also able to prevent the ment [87]. These data are only partially reliable since baseline rates of
release of B-myosin heavy chain in cardiac tissue, which is known to be heart disease are higher in males than females and can thus skew the
expressed in adult hearts during heart failure. In a study examining both results. Furthermore, not all patients in the cohort received DOX therapy
male and female gonadectomized mice, the hypertrophic response to and this may possibly interfere with the resultant correlation. Similarly,
4
141 adult patients with a median age of 54 and a cumulative dose of 300 inflammation, and anti-oxidant activity caused by DOX in a rat model
mg/m2 of DOX indicated male sex as risk factor for subclinical cardio using 72 male rats sorted into three age categories - young, adult, and
myopathy, which was defined by decreased left ventricular fractional elderly [99]. This sentiment is echoed in anthracycline clinical trial data
shortening [88]. Finally, a significantly larger proportion of men which indicates an increased risk of cardiotoxicity with increasing pa
developed symptomatic HF and experienced cardiac-related deaths tient age [98,100]. Additionally, increasing patient age has been asso
compared to women in a larger anthracycline study where 89 % of pa ciated with decreased DOX clearance, resulting in a higher risk of
tients received DOX [89]. cardiomyopathy [101].
In childhood cases of cancer treated with DOX or anthracyclines in In adult studies, advancing age was a risk factor for subclinical car
females who go on to become pregnant at a later stage, there is evidence diomyopathy when analysing age as a continuous variable in 141 pa
to suggest that pregnancy exacerbates cardiovascular dysfunction tients with a median age of 54 and a cumulative dose of 300 mg/m2
induced by DOX. A population based-study in Canada has shown a [88]. Supporting this, an increase in age was positively associated with a
higher risk for the development of heart failure, arrhythmias, valvular higher risk of cardiotoxic effects, measured by LVEF, 2 years after
disease, pericardial disease, coronary artery disease, or cardiac-related therapy involving 613 breast cancer patients [102]. Notably, these re
death in patients diagnosed with cancer before the age of 21 when sults only investigated age as a risk factor in women. Finally, a 3–4 year
compared to matched controls without previous cancer diagnoses [90]. long DOX-plus-placebo study involving 620 patients of varying ages
A study conducted in the Netherlands in survivors of childhood cancer, found an increased incidence of CHF in patients above 65 years old
including 74.4 % of the study population who were treated with DOX at compared to those below [5]. It is also important to remember that the
a cumulative mean dosage of 270 mg/m2, found that pregnancy caused presence of co-morbidities (which may contribute to DOX-induced car
left ventricular dysfunction with abnormal baseline longitudinal strain, diotoxicity) is increasing when patients become older.
but individuals with normal baseline values had low risk of left ven With regard to cancer treatment in children, a follow up study was
tricular dysfunction during pregnancy [91]. Interestingly, none of the performed on 115 childhood-cancer survivors where echocardiograms
patients with abnormal baseline went on to develop heart failure with were obtained on average 7.8 years after completion of DOX treatment.
pregnancy, echoing the findings of another study in the Netherlands, The results showed that patients had significantly reduced left ventric
which showed a low risk of developing peripartum anthracycline- ular fractional shortening compared to the predicted normal value
induced congestive heart failure in survivors of childhood cancer [85]. [103]. This paper, among others, has been cited as evidence that chil
A study conducted in the Middle-East followed a group of 37 cancer dren are at a higher risk of cardiotoxic damage compared to other ages.
survivors, who had received DOX treatment <500 mg/m2 in their However, it should be considered that the results were only compared to
childhood (at least 2 years prior), through pregnancy [92]. Fractional predicted healthy values and not DOX-treated individuals of other ages.
shortening [93] was used as the defining measure for cardiac dysfunc Thus, these results in themselves are not categorically conclusive.
tion, and women with normal function at baseline had no change in Overall, chances of heart complications are high during treatment,
cardiac function during pregnancy, while those with cardiac dysfunction since acute cardiotoxicity is quite common, then decrease shortly after
showed further reduced fractional shortening after pregnancy [92]. treatment, since subacute cardiotoxicity is rare, and then increase again
In conclusion, most animal studies elucidate a sexual dimorphism over time as the likelihood of late-onset cardiotoxicity rises [11,104].
related to DOX-induced cardiotoxicity in most mice and rat strains Children are more likely to incur heart complications many years after
wherein females are protected, and males are more at risk. On the other treatment whereas the elderly, usually those above 65 years old, are
hand, clinical results allowing for a correlation between sex and disease more likely to present disease conditions soon after treatment.
in humans are limited and further complicated by puberty and lifestyle
choices between sexes. If young females may be more are risk of 4. Ethnicity
developing cardiac complications than males when treated with
anthracyclines, the data obtained in adults are inconclusive. Further Ethnicity is a well-known cardiovascular risk factor with black Af
large studies are necessary to investigate this correlation which seems to rican individuals being less at risk of coronary heart disease than other
be age dependent [94]. races, but more at risk of presenting with ischemic strokes and intra
cerebral haemorrhages compared to white individuals [105]. On the
3. Age other hand, black Americans have a higher mortality rate due to heart
disease than all other ethnic groups [106]. Similarly, black women in the
Aging is a well-known risk factor for both cardiovascular disease as USA have a two-fold higher rate of chronic hypertension compared to
well as cancer [60,95]. Thus, it would follow that the incidence of DOX- white women [106]. Differences between countries may suggest socio-
induced cardiotoxicity may also increase with age. However, since the economic reasons rather than ethnicity per se. When exploring the
three classes of cardiotoxicity present at different times, it may be that role of ethnicity in DOX-induced cardiotoxicity, it is also key to keep in
certain age groups will be more at risk of one type of cardiotoxicity than mind that the physiology and the pathophysiology of cardiovascular
another. For example, acute and subacute DOX-induced cardiotoxicity disease may differ according to ethnicity [107,108].
are more often seen in older cancer patients whereas paediatric patients Studies separating individuals into groups based on ancestry can give
display acute conditions less frequently but are more prone to late-onset insight into ethnicity as a risk factor. Comparing 100 African American
cardiotoxicity [96]. This is because young individuals can incur car patients receiving DOX with 399 DOX-treated patients of unknown age
diomyocyte damage with no immediate signs of cardiac dysfunction, but and racial distribution, a significantly increased incidence of car
may start to present symptoms as the heart comes under stress with age diotoxicity in the African American patients for all doses of DOX (from
[97]. Older individuals, on the other hand, have hearts more sensitive to 450 mg/m2 to 600 mg/m2) compared to the randomized study popu
damage and are more likely to suffer soon after or during treatment lation was observed [109]. Similarly, an increased risk factor for DOX-
[98]. induced cardiotoxicity was observed in African Americans compared
Investigating the effect of age on DOX-induced cardiotoxicity is to non-African individuals [79]. Furthermore, cancer survivors of Afri
difficult because most publications focus either on paediatric studies or can ancestry had an increased risk of cardiomyopathy compared to those
on adult studies, few including both demographics. Furthermore, 8-year of European ancestry [110]. Recently, a large cohort of 1084 cancer
or longer follow ups are more common in paediatric analyses and near survivors treated with anthracyclines highlighted a higher incidence of
non-existent in older age groups as many elderly individuals have a HF in non-Hispanic blacks, Hispanics and Asians compared to the non-
limited lifespan due to other health factors. In general, in an animal Hispanic white patients [111]. Outside of Western studies, a multi-
study, an increase in age was associated with greater oxidative stress, ethnic Asian study reported that patients of Chinese ethnicity treated
5
with anthracyclines had a significantly lower preponderance of car elucidated but may involve, at least in part, an increase in lipotoxicity,
diotoxicity compared to individuals from the combined group composed hyperglycaemia, and mitochondrial damage caused by both DOX and
of Malay, Indian, Caucasian and foreign national patients [112]. diabetes. More research is necessary regarding the mechanisms under
In summary, all current studies suggest that individuals of African lying diabetes as a confounding factor for DOX-induced cardiotoxicity as
ancestry appear to be more likely to suffer from DOX-induced car this may benefit the management of diabetic patients receiving DOX.
diotoxicity compared to other races while Chinese patients may be at a
lower risk compared to other races. It is important to note that these 6. Dyslipidaemia
correlations have not yet been linked to genetic studies and it is possible
that different socio-economic, factors may explain part of these findings Dyslipidaemia, defined as an abnormal level of cholesterol or fats in
[113]. the blood, is a significant risk factor for cardiovascular disease [127].
Dyslipidaemia can result in the build-up of plaques in vessels, thus
5. Diabetes predisposing individuals to ischemic events [128]. Cancer itself can shift
a patient’s lipid profile by decreasing high density lipoprotein (HDL) and
Diabetes is a chronic condition characterized by abnormally high increasing low density lipoprotein (LDL) plasma levels, leading to an
blood glucose levels [114]. Diabetes is significantly related to other increased risk of atherosclerosis [129]. DOX is also known to induce
diseases with an increased risk of both cancer and cardiovascular dis dyslipidaemia in patients post-treatment [130]. As a result, concomitant
eases in diabetic patients [115]. Diabetes can result in diabetic cardio therapies of hypolipidemic drugs are often envisaged [124,131].
myopathy, which is characterised by the presence of cardiac dysfunction A Sri Lankan study has reported dyslipidaemia to be a predictor of
in diabetic patients in the absence of other risk factors such as hyper subclinical cardiotoxicity defined as a >10 % decrease in ejection frac
tension and cardiovascular disease [116]. This condition is caused by a tion, 6 months after completion of anthracycline therapy [132]. The
number of factors including diastolic and systolic stress on diabetic ANTEC study is an ongoing trial that aims to assess the prognostic value
hearts as a result of mitochondrial dysfunction, inflammation, lip of coronary atherosclerotic lesions and the calcium score on CT scan
otoxicity, and cardiomyocyte apoptosis (amongst others) [117]. This prior to anthracycline chemotherapy for the occurrence of cardiotoxicity
predisposition to cardiomyopathy in diabetic individuals may suggest [133]. Hyperlipidaemia has however, been investigated in studies
that diabetic patients could be at a higher risk for developing DOX- combining other cardiovascular risk factors, including hypertension and
induced cardiotoxicity, in which case this treatment strategy should be diabetes, suggesting that these patients had an increased risk of devel
carefully considered for diabetic cancer patients. oping HF induced by anthracyclines compared to those with none of
Indeed, experimental models highlight that diabetes can aggravate these risk factors [134]. In addition, having all three of these risk factors
DOX-induced cardiotoxicity. Interestingly, DOX promotes hyper compounded the risk of HF, indicating that dyslipidaemia contributes to
glycaemia and insulin resistance in non-diabetic Wistar rats [118]. cardiac sensitivity when in combination with hypertension and diabetes
Surprisingly, diabetes in db/db mice does not exacerbate this insulin [134]. However, dyslipidaemia was not analysed as a solitary risk factor
resistance caused by DOX [119]. However, DOX upregulated pro- [134].
inflammatory signalling and downregulated anti-inflammatory signal In summary, although very little data are present in the literature, it
ling in diabetic rat muscle compared to non-diabetic rat muscle [119]. is likely that dyslipidaemia will further enhance anthracycline-induced
Db/db mice also had an increased mortality rate and a decreased in cardiotoxicity.
cardiac contractile function compared to db/+ non-diabetic mice [120].
This is likely attributed to the increase in ROS generated by DOX, 7. Obesity
leading to the activation of pro-inflammatory molecules such as the
signalling factor Nuclear Factor kappa-light-chain-enhancer of activated Obesity is clinically defined as an unhealthy state of excess body fat.
B cells (NFκB) [119,120]. In 2016, 13 % of adults were considered obese globally [135].
Supporting the findings of animal studies, in a recent meta-analysis Animal models use different diets to test the effect of obesity on DOX-
study including 7488 patients, diabetes was associated with an induced cardiotoxicity. A moderately restricted diet in Sprague-Dawley
increased risk of anthracycline-induced cardiac toxicity. Similarly, pa rats showed protection against DOX-induced cardiotoxicity compared to
tients with diabetes have an increased risk of HF after DOX treatment a high fat, obesity-inducing diet which increased sensitivity to car
compared to non-diabetic patients [121]. It is suggested that type 2 diotoxicity [136]. This study also reported that the moderate diet
diabetes is a significant predictor of late-onset DOX-induced HF but not increased signalling in the Janus-kinase/signal transducer and activator
early-onset HF [122]. of transcription 3 (JAK/STAT3) signalling, a well-known car
Interestingly, DOX-induced cardiotoxicity modulates many signal dioprotective pathway [136]. However, this evidence could point to the
ling pathways common to diabetes [123]. DOX inhibits peroxisome contribution of diet to DOX-induced cardiotoxicity rather than the
proliferator activated receptor gamma (PPARγ) and causes lipotoxicity contribution of obesity itself since different diets are known to
in cells. PPARγ is known to relieve hyperglycaemic and high lipid con contribute to heart disease independently of body mass index (BMI)
ditions in diabetes as well as increasing insulin sensitivity, thus DOX [137]. Overweight C57BL/6 mice have also shown systolic dysfunction
inhibiting this pathway would create an excess of lipids causing lip 20 days after DOX administration compared to normal mice who pre
otoxicity [124]. Much like diabetes, DOX is also known to decrease sented with no dysfunction at the end of the treatment [138].
mitochondrial copy number and to reduce mitochondrial function In humans, a meta-analysis of 15 studies involving anthracycline-
[125]. In addition, DOX treatment reduces body weight, raises blood treated breast cancer patients reported that obesity or being over
glucose, and serum lipid levels, effects which are also observed in pa weight were strongly associated with cardiotoxicity [139]. However,
tients with type II diabetes. As a result, lipotoxicity and any toxic effects these results were not able to exclude obesity-related risk factors such as
caused by the abnormal metabolic state of the diabetic patient may be diabetes and pre-existing heart conditions. It is likely that obesity and
worsened by DOX. Additionally, it is proposed that diabetic patients being overweight contribute to DOX-induced cardiotoxicity through a
would be pre-disposed to oxidative and inflammatory damage due to variety of mechanisms, including, but not exclusive to, diabetes and
certain upregulated genes such as S100A8 and S100A9 which are bio hypertension. Later, the same group investigated 929 patients receiving
markers of inflammation that are upregulated in cardiovascular diseases anthracyclines, and found a significant association between obesity and
[120,126]. cardiotoxicity independent of related risk factors [140]. However, only
In summary, diabetes is likely a confounding factor for DOX-induced 7 % of these patients received DOX. The remaining 93 % received other
cardiotoxicity. The mechanism behind this predisposition is not yet fully anthracyclines such as epirubicin. A recent large-scale meta-analysis
6
including patients receiving anthracycline chemotherapy, highlighted predictor of CH within ten years after DOX treatment[87].In contrast,
that obesity was a risk factor for cardiotoxicity while being overweight pre-existing coronary heart disease showed no significant contribution
was not associated with cardiotoxicity [141]. Others found no signifi towards cardiotoxicity two years after DOX treatment in a cohort of 613
cant contribution of a BMI over 25 towards cardiotoxicity [102]. Finally, breast cancer patients [102]. Similarly, patients with latent atheroscle
one study measured body fat percentage using X-ray absorptiometry in rosis did not have an increased risk of chemotherapy-induced car
DOX-treated children and found that doxorubicinol clearance, the major diotoxicity [152]. However, in this latest study, very few breast cancer
metabolite of DOX, was decreased in children with a body fat percentage patients received DOX as a treatment as most patients received trastu
above 30 [142]. Two details should be noted from this study: firstly, zumab, possibly interfering with the correlation between DOX-induced
DOX clearance itself was not significantly different between body fat cardiotoxicity and atherosclerosis [152]. Contradicting data could be
percentage groups and secondly, 4 out of 6 individuals with a body fat attributed to the different types and severities of pre-existing heart
percentage above 30 were, in fact, in the normal BMI range [142]. This disease in each case.
data suggest that body fat percentage, and not BMI, may affect DOX In summary, the severity and nature of pre-existing cardiovascular
pharmacokinetics. Fat cells known as adipocytes directly correlate with disease are likely to influence the possible side effect of DOX treatment.
body fat percentage and are hypothesized to have dysregulated release Severe conditions such as a history of ischemia, heart attacks and strokes
of cytokines in obese individuals [143]. These adipokines have been would need to be weighed carefully when considering DOX as a treat
shown to be protective against DOX cardiotoxicity in mice, perhaps ment whereas latent or underlying conditions may interfere less with the
illuminating a reason for the increased susceptibility in obese mice treatment.
[143].
In conclusion, obesity is a risk factor for DOX-induced cardiotoxicity, 10. Co-medications/co-treatments
both on its own and in combination with other comorbidities. Notably,
BMI may be an inaccurate assessment tool, that has been questioned by Many cancer patients treated with DOX often receive multiple
researchers for years [144,145]. A more reliable way to assess the risk of therapies which may interfere with DOX and its side effects. Trastuzu
DOX-induced cardiotoxicity in obese individuals might be to take mab, mediastinal radiation therapy (MRT) and diclofenac sodium are
further measurements where possible such as body fat percentage and example of drugs that may affect patients treated with DOX.
adipokines level. Trastuzumab is an antibody for the human epidermal growth factor
receptor-2 (HER-2), a receptor which precipitates a survival signal in
8. Hypertension both cancer cells and cardiomyocytes. It is often used in cancer therapies
to block this signalling pathway and reduce tumorigenic activity [153].
High blood pressure or hypertension is a common condition which However, this pathway is also involved in cardioprotection. When
severely increases the risk of many diseases, including heart disease trastuzumab was first approved by the Food and Drug Administration
[60]. Both experimental and clinical studies suggest that pre-existing (FDA) in 2001, it was warned against using it with any anthracyclines,
hypertension could potentially increase susceptibility to DOX-induced DOX included. This is because one of the trials for the drug showing a 4-
cardiotoxicity. fold increase in CHF in patients receiving the drug concomitantly with
Spontaneous hypertensive rats treated with DOX presented with anthracycline therapies compared to either drug on its own [154]. This
changes in cardiac electrical activity, a greater weight loss, decreased was confirmed in a recent retrospective study where trastuzumab was
systolic blood pressure, greater cardiac lesions and mortality compared associated with a higher risk of DOX-induced cardiotoxicity [102].
to normotensive rats [146,147]. Similar findings were reported in 73 Trastuzumab may exacerbate the cardiotoxic effects of anthracycline
breast cancer patients receiving varying doses of DOX with pre-existing chemotherapy mainly through interfering with the cell survival signal
arterial hypertension that positively correlated with left ventricular ling pathways in relation to HER2 [see review [155]]. Binding of tras
systolic dysfunction 6 months after treatment [148]. Hypertension was tuzumab on cardiomyocytes HER2 receptors prevents the activation of
found to be a significant risk factor for both early- and late-onset car downstream cell survival pathways in response to DOX-mediated ROS
diotoxicity in 1153 American patients with more than 90 % of these production [156,157] thus potentiating DOX-mediated ROS production,
patients receiving a cumulative dose above 250 mg/m2 [122]. In a oxidative stress and ultimately cardiomyocyte death. DOX in combina
retrospective study involving 58,541 Korean patients receiving DOX, tion with trastuzumab further upregulates the expression of angiotensin
2324 of whom went on to be diagnosed with DOX-induced HF, hyper II (ANG II), an inhibitor of NRG-1, a protein downstream of HER2 [158].
tension was found to be a predictor of HF [149]. A recent systematic ANG II further activates NADPH oxidases within cardiomyocytes,
study screening 1330 papers, highlighted that adult patients with increasing ROS production with subsequent oxidative stress and
elevated blood pressure have an increased vulnerability to cardiotox apoptosis [159]. In addition to inhibiting HER2 mediated cell survival
icity related to anthracyclines [150]. signalling and promoting oxidative stress, trastuzumab alone or in
In summary all data suggest that hypertension is a significant risk combination with DOX further demonstrated to downregulate topo
factor for DOX-induced cardiotoxicity. The mechanism behind this is isomerase IIβ (topIIβ) [160].
likely due to early damage and stress placed on the heart by hyperten MRT is a common anti-cancer therapy, often accompanying DOX
sion prior to treatment, predisposing individuals to further damage, but therapy. Notably, patients receiving both treatments had an increased
thorough investigation has yet to confirm this. incidence of cardiac hospitalizations over a 10-year period compared to
those receiving DOX alone [87,161].
9. Pre-existing cardiovascular diseases Digoxin is a cardiac glycoside drug used to treat heart disease
symptoms such as atrial flutters and HF. Similarly to MRT, digoxin
If DOX treatment leads to cardiovascular diseases in many in increased myocardial damage in rabbits when administered with DOX
dividuals, there is evidence in the literature supporting that pre-existing compared to either on its own [162]. Contrastingly, recent experiments
cardiovascular disease may worsen the effects of DOX-induced car conducted in mice and zebrafishes showed that digoxin may, in fact,
diotoxicity [151]. reduce the cardiotoxicity caused by DOX [163]. This possible interaction
Pre-existing cardiac disease, defined as patients with two or more therefore requires further investigation.
records of ischemia, atherosclerosis and/or other heart disease, was Other drugs given to the patients who are treated for other comor
shown to increase the risk of CHF in DOX-treated cancer patients bidities such as hypertension and diabetes may also interfere with DOX-
compared to individuals with no cardiac comorbidities [121]. Similarly, induced cardiotoxicity (see Table 2). Metformin improves the cancer-
cardiac hospitalization (CH) before cancer diagnosis, was the largest killing activity of DOX and there are convincing preclinical data
7
Table 2
Animal studies testing the effect of co-medications on DOX-induced cardiotoxicity.
Drug/medication Drug concentration DOX Animal Study Outcomes Reference
concentration length from
first dose of
DOX
Digoxin 50ug/kg/d 12 mg/kg once Wistar rats 7 days Digoxin + DOX treated rats had a lower systolic [204]
volume and left ventricular volume in diastole
compared to rats treated with DOX alone.
Atorvastatin 20 mg/kg/d 5 mg/kg/w for 4 Male C57BL/ 6 weeks Atorvastatin with DOX increased LVEF and [177]
weeks 6 mice Survivin levels compared to mice treated with
DOX alone.
Atorvastatin 20 mg/kg/d or 40 mg/ 5 mg/kg/w for 4 Male C57 4 weeks Atorvastatin increased TFEB, reduced myocardial [160]
kg/d weeks mice fibrosis and enhanced lysosome function in mice
receiving DOX alone.
Lovastatin 10 mg/kg/d for 5 or 10 1 × 10 mg/kg Male and 5–10 days Lovastatin attenuated cardiomyocyte damage [205]
days female Balb/ caused by DOX and raised CK-MB and LDH levels
c mice compared to the mice receiving DOX alone.
Lovastatin 3 mg/kg 3× per week for 3 mg/kg/w for 5 Female 3 months Treatment with Lovastatin in DOX treated mice [206]
3 months weeks C57BL/6 protected mice from a decrease in left ventricular
mice posterior wall diameter with no change in
ejection fraction. Lovastatin treatment also
mitigated a decrease in mRNA levels of heat
shock protein Hspa1b.
Fluvastatin 6/mg/kg/d for 7 days 3 × 7.5 mg/kg Male and 1 week Fluvastatin reduced the decrease in iNOS, eNOS, [179]
female NF-κB and caspase 3 caused by DOX treatment.
Sprague
Dawley rats
Fluvastatin 100 mg/kg/d for 9 days 20 mg/kg once Male and 5 days Co-treatment of DOX with Fluvastatin increased [207]
female LV pressure and SOD activity compared to DOX
C57BL/6 treatment alone.
mice
Metformin 250 mg/kg/d for 7 days 15 mg/kg once Male Wistar 2 days Pre-treatment with Metformin protected against [166]
rats an increase in LDH, CK-MB, caspase 3 and cardiac
MDA associated with DOX treatment. Metformin
pre-treatment also increased SOD activity in
cardiomyocytes compared to DOX alone.
Metformin 500 mg/kg/d for 7 days 20 mg/kg twice Male Wistar 6 days Treatment with Metformin + DOX resulted in [167]
albino rats lower caspase 3 and TNF-α levels compared to
DOX alone.
Metformin 250 mg/kg for 14 days 6 × 3 mg/kg Female 2 weeks Metformin reduced troponin T levels and [165]
Sprague cardiomyocyte damage caused by DOX.
Dawley rats
Metformin 50 mg/kg/d or 500 mg/ 6 × 3 mg/kg Male Wistar 10 days Co-treatment of Metformin with DOX returned [168]
kg/d for 11 days albino rats glutathione levels to normal or above normal and
reduced cardiomyocyte injury observed with
DOX alone.
Metformin 250 mg/kg/d for 14 days 4 x4mg/kg Male Wistar 2 weeks Metformin protected against reduction in LVEF [164]
albino rats and cardiomyocyte apoptosis caused by DOX
alone
Valsartan (ARB) 15 mg/kg/d for 28 days 5 mg/kg/w for 4 C57BL/6J 4 weeks Valsartan + DOX significantly improved LVEF, [181]
weeks mice reduced cardiac inflammation and myocardial
apoptosis compared to DOX alone. Valsartan +
Tolvaptan was more effective in restoring cardiac
function against DOX cardiotoxicity compared to
Valsartan alone.
Valsartan (ARB) Sacubitril/Valsartan 3 × 15 mg/kg/w Male 6 weeks Valsartan/Sacubitril significantly reduced [184]
60 mg/kg/d for 42 days Sprague- cardiomyocyte apoptosis and cardiac dysfunction
Dawley rats caused by DOX and downregulated related
proteins (BAX, caspase 3, GRP78, PERK)
Valsartan (ARB) 31md/kg/d for 18 days 10 × 1.5 mg/kg/d Male 18 days Valsartan did not significantly change troponin T [183]
Sprague- levels or ROS compared to DOX group.
Dawley rats
Enalapril (ACE inhibitor) 60 mg/ml in drinking 15 mg/kg once or Male C57Bl/ 9 weeks Enalapril protected against DOX induced cardiac [189]
water every other week 4 mg/kg/w for 5 6J mice dysfunction (LV volume) and cardiomyocyte
weeks atrophy in the chronic model (5 × 4 mg/kg/w)
but not in the acute model (1 × 15 mg/kg).
Lisinopril (ACE inhibitor) 1 mg/kg/d for 7 days 2 mg/kg Female New 24 weeks Lisinopril reduced the loss of cardiomyocytes [191]
Zealand caused by DOX treatment and decreased ANP in
white Rabbits the LV.
Captopril + Enalapril (ACE 10 mg/kg/d Captopril + 1 × 15 mg/kg Male rats 30 hours Pretreatment with ACE inhibitors reduced TBARS [188]
inhibitors) 2 mg/kg/d Enalapril for concentration in the heart and ameliorated the
7 days inhibition of SOD and LDH activity caused by
DOX treatment.
Enalapril (ACE inhibitor) 10 mg/kg/d 4.17 mg/kg/w for Female 9 weeks Enalapril significantly attenuated the decrease in [190]
for 70 days 6 weeks Sprague- LV contractility and abolished DOX-induced
Dawley rats increase in free radical formation.
(continued on next page)
8
Table 2 (continued )
Drug/medication Drug concentration DOX Animal Study Outcomes Reference
concentration length from
first dose of
DOX
Fosinopril (ACE inhibitor) 25 mg/kg/d for 28 days 6 × 2.5 mg/kg Male 2 weeks Fosinopril attenuated increased in both heart and [192]
Sprague- LV weights induced by DOX treatment and
Dawley rats lowered LDH and AST activity. Fosinopril also
prevented DOX-induced decreases in Ca2+ uptake
in LV sarcoplasmic reticulum.
Mebudipine + Amlodipine 0.5 mg/kg/ 6 × 2.5 mg/kg Male Wistar 43 days Mebudipine and amlodipine reversed the [199]
(Calcium channel d Mebudipine + 0.35 rats increased plasma BET-1, AST, CK-MB, and LDH
blockers) mg/kg/d amlodipine for caused by DOX treatment.
14 days
Spironolactone (Potassium- 40 mg/kg/d for 14 days 10 mg/kg/d for Male 2 weeks Spironolactone attenuated the decrease in LVEF [208]
sparing diuretic) 14 days Sprague- and fractional shortening FS as well as the
Dawley rats increase in cardiac fibrosis, apoptotic cell
number, and cardiac collagen volume fraction
caused by DOX treatment.
Empagliflozin (SGLT2 10 mg/kg/ 5 mg/kg/w for 5 Male C57Bl/ 6 weeks Empagliflozin attenuated a decrease in LVEF, [173]
inhibitor) + Furosemide d empagliflozin or weeks 6 mice longitudinal shortening and circumferential
(Loop diuretic) 20 mg/kg/d furosemide strain and decreased myocardial fibrosis
for 35 days associated with DOX treatment. Furosemide did
not have any effect.
Hydrochlorothiazide 10 mg/kg/d for 7 days 3 mg/kg/w for 5 Wistar albino 30 days Co-treatment of DOX with Hydrochlorothiazide [196]
(Diuretic) weeks rats increased SOD and catalase activity and decrease
TBARS levels compared to DOX alone.
Nifedipine (Calcium channel 10 mg/kg/d for 14 days 3 × 6 mg/kg C57BL/J6 2 weeks Nifedipine reduced DOX-induced cardiomyocyte [201]
blocker) mice injury and apoptosis as well as reduced
phosphorylation of CaMKII and NF-κB.
Verapamil (Calcium channel 25 mg/kg/d for 12 days 12 × 5 mg/kg Male Swiss 4 weeks Verapamil reduced DOX-induced cardiotoxicity [200]
blocker) albino mice through decreased levels of TNF-α and
malondialdehyde in heart tissues coupled with
decreased serum activity of CK-Mb and LDH.
Dapagliflozin (SGLT2 1 mg/kg/d for 14 days 6 × 2.5 mg/kg Male 15 days Co-treatment of DOX with Dapagliflozin [174]
inhibitor) Sprague- significantly reduced plasma cardiac troponin T,
Dawley pro-BNP and TNF-α levels compared to DOX
albino rats alone.
Empagliflozin (SGLT2 10 mg/kg/d for 10 days 7 × 2.17 mg/kg/d Female 1 week Co-treatment of DOX with Empagliflozin [172]
inhibitor) C57BL/6 increased EF and prevented the reduction of
mice radial and longitudinal strain compared to DOX
alone. Empagliflozin also reduced expression of
pro-inflammatory cytokines, NLRP3, MyD88 and
NF-κB in the heart.
Empagliflozin (SGLT2 10 mg/kg for 7 days 7 × 2.57 mg/kg/ Male 2 weeks Co-treatment of DOX with empagliflozin lowered [24]
inhibitor) Sprague- LVEDD and LVESD and infiltrative cell
Dawley rats proliferation while increasing normal cell
morphology and LVEF compared to DOX alone.
ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; AST = aspartate amino transferase; CaMKII = Ca2+/calmodulin-dependent protein kinase
II; CK-MB = creatine kinase myocardial band; DIC = DOX-induced cardiotoxicity; DOX = doxorubicin; eNOS = endothelial nitric oxide synthase; iNOS = inducible
nitric oxide synthase; LDH = lactate dehydrogenase; LVEDD = left ventricular end-diastolic diameter; LVEF = left ventricular ejection fraction; LVESD = left ven
tricular end-systolic diameter; MyD88 = Myeloid differentiation primary response 88; NF-κB = nuclear factor kappa-B; NLRP3 = NLR family pyrin domain containing
3; pro-BNP = pro b-type natriuretic peptide; ROS = reactive oxygen species; SGLT2 = sodium/glucose transporter 2; SOD = superoxide dismutase; TBARS = thio
barbituric acid reactive substances; TFEB = transcription factor EB; TNF-α = Tumour necrosis factor alpha.
suggesting that it may also reduce its cardiotoxicity. In rodents, Met ranging from 3 mg/kg to 20 mg/kg (Table 2). While receiving the
formin alleviates LVEF reduction and cardiomyocyte damage caused by treatment prior and post-DOX has been shown to prevent cardiac
DOX [164,165]. Cellular mechanisms affected by metformin during damage associated with DOX, it is suggested that the prophylactic
DOX treatment include increasing antioxidants glutathione and super treatment is more effective [179]. The mechanism behind this protec
oxide dismutase [165–168]. tion is thought to relate to the anti-apoptotic, anti-inflammatory and
Other drugs used in treatment of diabetes are sodium-glucose antioxidant activities of the drugs [177,179]. A retrospective study
cotransporter-2 (SGLT2) inhibitors. Randomized control trials high conducted in the USA suggests that co-treatment of statins with
light a cardioprotective role of these drugs in non-chemotherapeutic anthracyclines reduced hospitalization due to HF [180]. In contrast, a
patients [169–171]. Current animal studies using the specific SGLT2 double-blind, randomized placebo study reported that atorvastatin did
inhibitors empagliflozin and dapagliflozin indicate that these drugs can not affect the decline in LVEF consecutive to the DOX treatment [56].
limit myocardial fibrosis and improve LVEF in the presence of DOX Larger clinical trials are required to confirm the benefit of statins against
[24,172–174]. This benefit was associated with reduced cellular DOX-induced cardiotoxicity.
expression of markers of cardiac injury and inflammation such as NLR Valsartan is an angiotensin receptor blocker commonly used in pa
family pyrin domain containing 3 (NLRP3), NF-κB and troponin T. The tients suffering from hypertension, heart failure and diabetic kidney
protective effects of SGLT2s are possibly related to their reduction of disease [181]. In rodents, valsartan improves cardiac function in DOX-
intracellular calcium and antioxidant properties [175–178]. treated animals while others suggest that Valsartan alone is not
Statins such as atorvastatin, lovastatin and torvastatin have all been enough to alleviate chemical damage caused by DOX [182,183]. Indeed,
shown to reduce DOX-induced cardiotoxicity in mice at concentrations valsartan, when given in combination with other drugs such as sacubitril
9
and tolvaptan, significantly reduced cardiac damage caused by DOX of multiple factors that can increase the risk for DOX-induced car
[181,182,184]. Several clinical trials have confirmed the efficacy of diotoxicity are very valuable to favour a personalized approach in the
sacubitril/valsartan in alleviating DOX induced HF by reducing LVEF treatment regime of breast cancer patients, with the aim to maximize the
when given during and after treatment with anthracyclines chances of recovery of the cancer patients while minimizing the risk of
[93,185,186]. side-effects of the therapy.
Angiotensin Converting Enzyme (ACE) inhibitors may also benefit
cancer patients treated with anthracyclines. Randomized control studies 12. Ethics approval and consent to participate
have reported ACE inhibitors to reduce cardiotoxicity induced by
chemotherapy, indicating the potential of these drugs to protect against Not applicable.
DOX-induced cardiotoxicity [20,53,187]. Rodent studies using the ACE
inhibitors enalapril, lisinopril, captopril, and fosinopril have identified 13. Consent for publication
possible preventative protective effects of these drugs against DOX-
induced cardiotoxicity [188–192]. Clinical studies have led to mixed Not applicable.
results. For example, in a randomized control study with a follow up
period of 26 months, patients receiving enalapril with DOX or dauno Credit authorship contribution statement
rubicin showed better outcomes in terms of cardiac biomarkers and
reduction in LVEF compared to controls [193]. A multi-study cohort, Carl Belger: Conceptualization, Writing – original draft, Writing –
with a maximum follow-up of 21 months reported no difference in LVEF review & editing. Carmelita Abrahams: Conceptualization, Supervi
or risk of new heart failure diagnosis when an ACE inhibitor was given in sion, Writing – review & editing. Aqeela Imamdin: Writing – review &
patients receiving anthracycline therapy [194]. More studies with editing. Sandrine Lecour: Conceptualization, Funding acquisition, Su
longer follow up would be helpful to assess the effect of ACE inhibitors pervision, Validation, Writing – review & editing.
on chronic cardiotoxicity in DOX patients.
Diuretics are another first-line treatment for hypertension. In ani Declaration of competing interest
mals, eplerenone and furosemide showed no beneficial effect against
DOX-induced cardiotoxicity [173,189]. On the other hand, co-treatment The authors declare that they have no known competing financial
of DOX with spironolactone in rodents showed promising reduction in interests or personal relationships that could have appeared to influence
cardiac biomarkers and an improvement in physical outcomes the work reported in this paper.
[195,196]. In clinical studies, spironolactone protected against reduced
LVEF caused by DOX treatment compared to controls [197]. Of impor Acknowledgements
tant note, hypertensive patients receiving DOX and thiazide diuretics
had higher prevalence of HF compared to patients receiving renin The research of SL is supported by the the Cancer Association of
angiotensin system inhibitors and calcium channel blockers (CCBs) South Africa, the South African National Research Foundation and the
[198]. University of Cape Town.
In rodent studies, mebudipine, amlodipine, nifedipine and verapamil
were all protective against DOX-induced cardiotoxicity [199–201]. This References
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IJC Heart & Vasculature 50 (2024) 101332

Contents lists available at ScienceDirect

IJC Heart & Vasculature

Doxorubicin-induced cardiotoxicity and risk factors

MUGA scan LVEF Reproducibility Radiation

Fig. 2. Signalling pathways targeted by different risk factors in DOX-induced cardiotoxicity.

10.1002/1097-0142(19850615)55:12%3C2761::AID-CNCR2820551206%3E3.0. [130] M. Klinnikova, E. Lushnikova, E. Koldysheva, T. Tolstikova, I. Sorokina,

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