Open Access

What is considered cardiotoxicity of anthracyclines in animal studies

Corrigendum in: /10.3892/or.2020.7717

  • Authors:
    • Nikolaos Georgiadis
    • Konstantinos Tsarouhas
    • Ramin Rezaee
    • Haritini Nepka
    • George E.N. Kass
    • Jean‑Lou C.M. Dorne
    • Dimitrios Stagkos
    • Konstantinos Toutouzas
    • Demetrios A. Spandidos
    • Dimitrios Kouretas
    • Christina Tsitsimpikou
  • View Affiliations

  • Published online on: July 14, 2020     https://doi.org/10.3892/or.2020.7688
  • Pages: 798-818
  • Copyright: © Georgiadis et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Anthracyclines are commonly used anticancer drugs with well‑known and extensively studied cardiotoxic effects in humans. In the clinical setting guidelines for assessing cardiotoxicity are well‑established with important therapeutic implications. Cardiotoxicity in terms of impairment of cardiac function is largely diagnosed by echocardiography and based on objective metrics of cardiac function. Until this day, cardiotoxicity is not an endpoint in the current general toxicology and safety pharmacology preclinical studies, although other classes of drugs apart from anthracyclines, along with everyday chemicals have been shown to manifest cardiotoxic properties. Also, in the relevant literature there are not well‑established objective criteria or reference values in order to uniformly characterize cardiotoxic adverse effects in animal models. This in depth review focuses on the evaluation of two important echocardiographic indices, namely ejection fraction and fractional shortening, in the literature concerning anthracycline administration to rats as the reference laboratory animal model. The analysis of the gathered data gives promising results and solid prospects for both, defining anthracycline cardiotoxicity objective values and delineating the guidelines for assessing cardiotoxicity as a separate hazard class in animal preclinical studies for regulatory purposes.

Introduction

Chemotherapeutics cardiotoxicity is a major concern for clinicians treating different kinds of cancer, as it seriously affects their treatment options and the survival of the patient. The cut-off values for the identification of cardiotoxicity caused by chemotherapeutics in humans differ between the American and European guidelines: the definition considers a lower cut-off value of normality for the left ventricular ejection fraction (LVEF) of 50% in Europe (1) and 53% in the USA (2). Both Guidelines emphasize that a drop of LVEF compared to the patient's previous values is also required. This definition is crucial for patients and clinicians, as patients presenting this decline in cardio-imaging indices of cardiac function should be treated with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in combination with β-blockers (3); nevertheless, modifications of anticancer treatment in such patients remain a matter of discussion among different specialists.

In animal studies, where new anticancer substances are evaluated and different agents are tested to overcome anticancer drugs cardiotoxicity, identification of the extent of cardiotoxicity is crucial and necessary for the evaluation of any favourable effects of the counteracting agent (4). In this regard, cardiac imaging is more often used at analogy to the clinical setting. Biomarkers and clinical signs of heart failure are also taken into consideration, but cardiac imaging in animal studies has gained momentum.

Anthracyclines are a class of drugs used in cancer chemotherapy isolated from Streptomyces bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, as well as breast, stomach, uterine, ovarian, bladder cancer, and lung cancers (57). The first anthracycline discovered was daunorubicin (trade name Daunomycin), which is produced naturally by Streptomyces peucetius, a species of actinobacteria. Clinically, the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin. Anthracyclines, which are considered as well-established cardiotoxic compounds causing myocardial suppression in a considerable number of patients, are also used in animal studies as an easy and low-cost method to introduce a model of dilated cardiomyopathy (8), as opposed to interventional research animal models of infarction and myocardial ischaemia [e.g., permanent ligation of the left anterior descending artery (LAD) or cryo-pen application on the surface of the heart leading to cryo-scar ischemia]. Different animal species and various anthracyclines dosing and administration schemes have been applied in the literature for the development of anthracyclines cardiotoxicity (9) and monitoring of the progress thereof, as well as testing different compounds/schemes for ameliorating myocardial damage. To monitor cardiotoxicity caused by anthracyclines, cardiac imaging is primarily used and secondarily, biochemical markers.

At the same time, other pharmaceutical compounds, such as anabolic steroids, along with everyday chemicals, such as metals and pesticides, have been implicated to adversely affect cardiac pathology causing function impairment (10). Toxicity and risk for human health posed by chemicals are well controlled at a European level through a thoroughly developed regulatory network. Nevertheless, cardiotoxicity is not described as a separate hazard class and no specific classification criteria are available in order to legally classify chemicals well in advance as cardiotoxic and avoid potential long-term cardiovascular complications, which could significantly burden any national health system.

But, what is considered cardiotoxicity of anticancer agents and specifically anthracyclines when parameters of cardiac imaging are monitored in animal studies? Is there a uniformity in animal models of anthracyclines cardiotoxicity induction and most importantly, do all studies describe the same decline of myocardial function? Addressing these issues could be of wider use both in clinical medicine and practice, when assessing agents employed for salvation to cardiotoxic complications during oncology treatment, for example, as well as to regulators, when trying to establish reference values in echocardiographic function representing cardiotoxicity induced in animals by chemicals.

In the current in depth review, the identification of most commonly used metrics of myocardial function in animal studies of anthracycline induced cardiotoxicity are presented, along with the range of these values differentiating normal cardiac function from animals with pathological echocardiographic findings indicative of anthracycline cardiotoxicity as per author presentation.

Materials and methods

PubMed electronic database was systematically searched to detect all original research studies published until March 1, 2020, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (11). The specific literature search strategy used was: [AND (“*rats*” OR “*doxorubicin* OR “*echocardiography*” OR “anthracycline” OR “*ejection fraction*”)] either in the Title, or the Abstracts. The reference list of the retrieved studies was further evaluated for the relevance of the subject and the eligibility by screening the titles/abstracts of full papers. The non-English citations (<5) were reviewed separately. Animal data only from rat species were assessed, as it is evident from the search string. All types of citations other than original research studies (e.g., review articles) were excluded. Two authors (NG and CT) independently assessed the title and the abstract content (or both) of each record retrieved to decide which studies should be further evaluated and extracted all data. Disagreements were resolved through consensus or by consultation with a third author (KT). A final draft of the manuscript was prepared after several revisions and approved by all authors. In total, 86 published manuscripts on animal studies were considered for the systematic review (Fig. 1).

Despite the small size of the rat heart and the fast heart rate, echocardiography is systematically used in the evaluation of rat heart function (12). Data for 2 main indices of LV contractility were extracted from the list of studies.

The first index is LV fractional shortening (FS) and is calculated by the formula: FS (%) = [LV end-diastolic diameter (LVDd) minus LV end-systolic diameter (LVDs)]/LVDd × 100.

LVEF is the second and more common, index of LV contractility. EF can be calculated from the equation: EF (%) = [(LVDd3 - LVDs3) / LVDd3] × 100 (13) or from the equation: EF (%) = (LVEDV-LVESV)/LVEDV × 100, where LVEDV is the LV end-diastolic volume and LVESV is LV end-systolic volume (12).

Results

A summary of the studies reviewed in the present report is presented in Table I.

Table I.

Treatment protocol and main findings of the studies that examined anthracyclines cardiotoxicity in rats reviewed in the present report.

Table I.

Treatment protocol and main findings of the studies that examined anthracyclines cardiotoxicity in rats reviewed in the present report.

PublicationNo. of animals/rat strain/sexAnthracycline administeredAnthracycline total doseDurationSummary of findingsCalculations
Zhang et al (14)30/Sprague DawleyDoxorubicin1 mg/kgDaily dosesCardiac dysfunctionValues calculated
rats/male(brand name Adriamycin) for 2 weeks(parameters monitored:manually by the
diastolic left ventricularauthors of this
internal dimension, systolicreview
left ventricular internal
dimension, LVEF and LVFS)
Tian et al (15)70/Sprague DawleyDoxorubicin3.0 mg/kgOnce a weekCardiomyopathyValues provided
rats/Male for 6 weeks in the manuscript
Andreadou et al (16)90/Wistar rats/maleDoxorubicin18 mg/kg, ip6 equal dosesCardiomyopathyValues provided
for 2 weeks(parameters monitored:in the manuscript
cardiac geometry, function
and histopathology)
Oliveira et al (17)20/Wistar rats/maleDoxorubicin5 mg/kg, ipOnce a weekVentricular dysfunctionValues provided
for 4 weeks in the manuscript
Hydock et al (18) 46/Sprague-DawleyDoxorubicin10 mg/kg ipAcuteParameters altered:Values provided
rats/Male administrationLVFS and LVPWTin the manuscript
(bolus)
Fernandez-Fernandez36/Sprague-Dawley ratsDoxorubicin18 mg/kgOver 12 daysCardiac function alteredValues provided
et al (19)Wistar rats Fischer-344 (LVFS, left ventricularin the manuscript
rats/NM developed pressure,
contractility and relaxation,
cardiac capillary permeability)
Todorova et al (20)27/Fisher 344 rats/femaleDoxorubicin12 mg/kgTwice per weekParameters monitored:Values provided
(1.5 mg/kg each)for 4 weeksPlasma levels of troponin Iin the manuscript
Left ventricle (LV) function,
LV PWT, LV volume,
LVEF, LVFS
Vasić et al (21)68/Wistar rats/maleDoxorubicin15 mg/kg ipEvery other dayParameters monitored:Values provided
for 2 weeks Echocardiography,in the manuscript
serum cardiac troponins,
heart rate variability and
blood pressure variability
Mathias et al 22)64/Wistar rats/maleDoxorubicin20 mg/kg ipAcute administrationAltered LVFSValues provided
(a single injection) in the manuscript
Wang et al (23) 40/Sprague-DawleyDoxorubicin15 mg/kg ipAcute administrationAltered LVEF, LVFSValues calculated
rats/male(brand name Adriamycin) (a single injection)and LV outflowmanually by the
authors of this
review
Arozal et al (24) 25/Sprague-DawleyDaunorubicin3 mg/kg/dayEvery other dayAltered cardiac functionValues provided
rats/male (18 mg/kg total dose)for 12 days(haemodynamic statusin the manuscript
and echocardiography)
Argun et al (25)40/10-week-oldDoxorubicin4 mg/kg/dose toTwice a weekParameters monitored:Values provided
Wistar albino rats/male a cumulative dosefor 2 weeksSerum BNP and C-typein the manuscript
of 16 mg/kg, ip natriuretic peptide
LV functions by
echocardiography
and histological
assessment
Tatlidede et al (26)32/Wistar albino rats ofDoxorubicin20 mg/kg, ipEvery other dayParameters monitored:Values provided
both sexes for 2 weeksBP and HR,in the manuscript
echocardiography
Lactate dehydrogenase
Razmaraii et al (27)24/adult Wistar rats/maleDoxorubicin2 mg/kg/48 hOver a 12-day periodParameters monitored:Values provided
LVSP, LVDP, rate ofin the manuscript
rise/drop of LV pressure,
LVEF, LVFS, contractility
Gziri et al (28)43/ pregnant WistarDoxorubicin10 or 20 mg/kg i.v.On 18th day ofAltered left ventricularValues provided
rats/female pregnancyfunctionin the manuscript
Oliveira et al (29)29/adult Wistar rats/maleDoxorubicinAccumulated doses ofFour weeklyMyocardial fibrosisValues provided
8 (n=8), 12 (n=7), andinjectionsAltered left ventricularin the manuscript
16 (n=7) mg/kg, ipover 8 weekssystolic function
Carvalho et al (30)64/Wistar rats/maleDoxorubicin20 mg/kg, ipAcuteLVEF monitoredValues provided
administration in the manuscript
(a single injection)
Stewart et al (31)72/Sprague DawleyDoxorubicin15 mg/kg, ipAcute administrationParameters monitored:Values provided
rats/male (a bolus injection)LV septal and PWT,in the manuscript
LVESd, LVEDd, mitral
and aortic valve blood
flow profiles, heart dimensions
Polegato et al (32)35/Wistar rats/maleDoxorubicin20 mg/kg, ipAcute administrationParameters monitored:Values provided
(a single dose)LVFS, isovolumetricin the manuscript
relaxation time and
myocardial passive stiffness
Lee et al (33)20/Sprague Dawley rats/maleDoxorubicinCumulative dose:Once every two daysImpaired LV functionValues calculated
20 mg/kg, ipfor 6 timesand performancemanually by the
authors of this
review
Cheah et al (34)29/Wistar rats/maleDoxorubicin5 mg/kg, ivAcute administrationParameters monitored:Values provided
(a single dose)BP, HR, LVED volume,in the manuscript
other echocardiographic
parameteres
Li et al (35)48/adult Sprague-DawleyDoxorubicinCumulative dose:Over a 4-week periodParameters monitored:Values provided
rats/male 16 mg/kg, ip serum BNP levelin the manuscript
LVEDd, LVESd, LVEF, LVFS
Dundar et al (36)28/adult Wistar albinoDoxorubicin15 mg/kg, ipAcute administrationParameters monitored:Values provided
rats/female (a single dose)LVIDd and LVISdin the manuscript
via the parasternal long
axis two-dimensional images.
LVFS and LVEF
Barış et al (37) 31/Sprague-DawleyDoxorubicin25 mg/kg, ipFor 12–14 daysParameters monitored:Values provided
rats/male left ventricular ejection fin the manuscript
raction (LVEF), LVFS and
mitral lateral annulus (s’)
velocity + left ventricular
end-diastolic and end-systolic
diameters
Lu et al (38) 60/Sprague-DawleyDoxorubicin2.5mg/kg/week, ipFor 6 weeksParameters monitored:Values provided
rats/male LVFS and LVEFin the manuscript
O'Connell et al (39)115/adult Wistar rats/maleDoxorubicin2.5 mg/kg, ip6 doses over a periodParameters monitored:Values provided
(cumulative doseof 2 weeksleft ventricular systolicin the manuscript
15 mg/kg) and diastolic dimensions and
2 mg/kg, ip (cumulativeOnce a weekEF
dose 18 mg/kg)for 9 weeks
Chang et al (40)71/Sprague-Dawley rats/nmDoxorubicin3 mg/kg/day, ivOnce a weekParameters monitored:Values provided
for 6 weeksSWT and PWT, LVEDin the manuscript
dimensions, LVES dimensions,
LVEF
Teng et al (41) 46/Sprague-DawleyDoxorubicin2 mg/kg, ipOnce a week for 8Parameters monitored:Values provided
rats/male weeksLVED dimensions, LVESin the manuscript
dimensions, FS
Kim et al (42) 61/Sprague-DawleyDoxorubicin1.25 mg/kg, ipEvery other day forLV systolic/diastolicValues provided
rats/male 1 month (16 times)dysfunctionin the manuscript
Kondru et al (43)24/Wistar rats/maleDoxorubicin2 mg/kg, ipOnce in a weekMyocardial dysfunctionValues calculated
for 5 weeks manually by the
authors of this
review
Moriyama et al (44)66/Crl:CD(SD) rats/maleDoxorubicin2 mg/kg, ivOnce weekly,Parameters monitored:Values provided
for 6 weeksLVEDd, LVESd, LVFSin the manuscript
Burdick et al (45)20/Crl:CD(SD) rats/maleDoxorubicin2 mg/kg, ipOnce a weekParameters monitored:Values calculated
for 6 weeksLVFSmanually by the
authors of this
review
Ammar et al (46)50/Wistar rats/maleDoxorubicin2.5 mg/kg, ip3 times a weekParameters monitored:Values calculated
for 2 weeksLVED dimensionsmanually by the
and LVSD dimensions, FSauthors of this
review
Calvé et al (47) 21/Sprague-DawleyDoxorubicin3 mg/kgAcute administrationParameters monitored:Values provided
rats/female (on postnatalIVSd, LVPWd, LVIDd,in the manuscript
day 26th)LVISd
Shen et al (48) 150/Sprague-DawleyDoxorubicin1 mg/kg, ipTwice a weekParameters monitored:Values provided
rat/male 2 mg/kg, ip (cumulativeOnce a weekLVESd, LVEDd, LVEFin the manuscript
dose 12 mg/kg)for 6 weeks
Wu et al (49)32/Sprague-Dawley rat/maleDoxorubicin2.5 mg/kg, ipEvery second dayParameters monitored:Values calculated
(cumulative dosefor 6 timesLVEDP, LVESP and leftmanually by the
15 mg/kg) ventricular pressureauthors of this
(±dP/dtmax), LVEF and LVFSreview
Shoukry et al (50)32/Wister rats/maleDoxorubicin2.5 mg/kg, ip2 weeksParameters monitored:Values calculated
LVIDd, LVIDs, LVFS andmanually by the
LVEFauthors of this
review
Niu et al (51)26/Sprague DawleyDoxorubicinEach dose consisted ofFor 2 weeks on daysParameters monitored:Values provided
rats/male 1, 1, 2, 2, 3, 3, 41st, 3rd, 5th, 7th,IVSd, IVSs, LVPWd andin the manuscript
and 4 mg/kg, ip9th, 11th, 13th andLVPWs, LVIDd, LVIDs
(cumulative dose15th, respectivelywere measured on left
20 mg/kg) ventricular long-axis areas.
LVEF and LVFS
Boutagy et al (52)20/Wistar ratsDoxorubicin2.15 mg/kg, ipEvery 3 daysImpaired systolic function andValues calculated
  (Crl:Wl)/male (cumulative dosefor 21 daysLV volumes and dimensions.manually by the
15 mg/kg) Parameters monitored:authors of this
echocardiographic variablesreview
(LVEF, global longitudinal strain,
global radial strain, LVEDV,
LVESV, relative PWT
Lee et al (53)150/Fischer rats/maleDoxorubicin2.5 mg/kg, ipEvery other dayAltered LV functionValues calculated
(cumulative dosefor 2 weeksParameters monitored:manually by the
15 mg/kg) LVFS, LVEDd and LVESd,authors of this
LV end diastolic volumereview
(LVEDV), right basal
ventricular diastolic diameter
(RVD1), and the RV fractional
area change (RVFAC)
da Silva et al (54)52/Wistar rats/femaleDoxorubicin1.25 mg/kg, ipThree times a weekParameters monitored:Values calculated
for 2 weeksaorta-to-left atrial diametermanually by the
ratio, LVESd, LVEFauthors of this
review
Mao et al (55) 160/Sprague-DawleyDoxorubicin2 mg/kg, ipOnce a week forParameters monitored:Values provided
rats/male 8 consecutive weeksLVEDd, LVESd, LVPWT,in the manuscript
interventricular septum
thickness (IVST), LVEF, LVFS
Deng et al (56) 42/Sprague-DawleyDoxorubicin2.5 mg/kg, ip6 injectionsParameters monitored:Values calculated
rats/male(brand name Adriamycin)(cumulative 15 mg/kg)over 2 weeksLV dimensions, LVFS, LVEFmanually by the
authors of this
review
Bertinchant et al (57)45/Wistar rats/maleDoxorubicin1.5 mg/kg, iv,Once a week forParameters monitored:Values provided
(cumulative doseup to 8 weeksLVEDd, LVESd and LVFSin the manuscript
12 mg/kg)
Sun et al (58) 70/Sprague-DawleyDoxorubicin2.5 mg/kg, ipOnce a week forParameters monitored:Values provided
rats/male 6 consecutive weeksLVEF, LVEDd, LVESdin the manuscript
and LVFS
Guerra et al (59)12/SHR rats/maleDoxorubicin1.5 mg/kg, ipOnce a weekParameters monitored:Values provided
(cumulative dosefor 9 weeksLVEDd, LVESd and LVEFin the manuscript
13.5 mg/kg)
Gao et al (60)90/Wistar albino rats/maleDoxorubicin2 mg/kg, ipEvery 3 daysParameters monitored:Values calculated
for 30 daysThe interventricular septalmanually by the
thickness at diastole, leftauthors of this
ventricular internal diameterreview
in diastole and systole,
LVPWd at diastole, EF, FS
Chen et al (61) 60/Sprague-DawleyDoxorubicin2.5 mg/kg, ip6 injectionsParameters monitored:Values calculated
rats/male over 2 weeksLVAW, LVPWT, LVIDdmanually by the
were measured in systoleauthors of this
and diastole.review
EF, FS and LV volume at
end-systole and end-diastole
Li et al (62) 56/Sprague-DawleyEpirubicin8 mg/kg, ipEvery five days forParameters monitored:Values calculated
rats/male a total of threeLV dimensions and wallmanually by the
injectionsthickness, EF, FSauthors of this
review
Schwarz et al (8) 60/Sprague-DawleyDoxorubicin2.5 mg/kg, ivOnce a weekLeft ventricular end-systolicValues provided
rats/female(brand name Adriamycin) for 10 weeksand end-diastolic diameters, FSin the manuscript
Leontyev et al (63) 46/Sprague-DawleyDoxorubicin2.5 mg/kg, ipOnce a weekLV end-systolic diameterValues provided
rats/male for 9 weeks(LVESD) and LV end-diastolicin the manuscript
diameter (LVEDD) + FS
Merlet et al (64) 158/Sprague-DawleyDoxorubicin2.5mg/kg, ip6 injectionsLV end-diastolic and -systolicValues calculated
rats/male (total 15 mg/kg)over 2 weeksdiameters (LVEDD andmanually by the
LVESD), diastolic posteriorauthors of this
wall thicknesses (dPWth).review
+ LV end diastolicand systolic
volumes (LVEDV and VESV)
to assess LV ejection fraction
(LVEF), whereas LV shortening
fraction (LVSF)
Ozkanlar et al (65) 40/Sprague-DawleyDoxorubicin2.5 mg/kg, ivOnce a weekLeft ventricular ejectionValues provided
rats/male for 3 weeksfraction (LVEF) and leftin the manuscript
ventricular fractional shortening
(LVFS)
Hong et al (66) 12/Sprague-DawleyDoxorubicin5 mg/ weekOnce a weekFS and ejection fraction +Values provided
rats/male(brand name Adriamycin) for 3 weeksinterventricular septalin the manuscript
dimension diastole; LV
internal dimension diastole;
LV posterior wall dimension
diastole; interventricular
septal dimension systole;
LV internal dimension
systole; LV posterior
wall dimension systole
Teraoka et al (67)75/Wistar rats/maleDoxorubicin1 mg/kg, ip15 times over aLV diameter of the systoleValues provided
(brand name Adriamycin)(cumulative doseperiod of 3 weeksLVDs + LV diameter ofin the manuscript
15 mg/kg) the diastole LVDd.
+ %fractional shortening
Hamed et al (68)130/Wistar ratsDoxorubicinCumulative dose of3 weeksLV diameterValues provided
(Harlan)/male 15 mg/kg in systole (LVIDs)in the manuscript
LVIDd, LV diameter in diastole;
IVSd, intra ventricular septum
in diastole
LV posterior wall thickness
in diastole (LVPWd)
Gabrielson et al (69) 21/Sprague-DawleyDoxorubicinCumulative dose of 15Six or three weeklyInterventricular septumValues calculated
rats/female or 7.5 mg/kgdoses, respectivelydiastole (IVSd) andmanually by the
left ventricular posteriorauthors of this
wall thickness at end diastolereview
(PWTED)
+ LV chamber diameters were
measured at the end of diastole
(LVEDd) and systole
(LVESd). EF%
Yu et al (70) 63/Sprague-DawleyDoxorubicin2.5 mg/kg, ipOnce a weekLV shortening (LVFS) wasValues provided
rats/male for 6 weekscalculated as (LVEDd-in the manuscript
LVESd)/LVEDd 9 100,
where LVEDd is LV
end-diastolic diameter and
LVESD is LV end-systolic
diameter
+ LV ejection fraction
Bai et al (71)RatsDoxorubicin6 injections totalWithin 2 weeksLVEF; LVFS; LVEDdValues provided
15 mg/kg) and LVESdin the manuscript
Lu et al (72) 48/Sprague-DawleyDoxorubicin1 mg/kg on the 2nd and LV internal end-diastolicValues calculated
rats/male 4th days, 2 mg/kg on the diameter (diastolic LVID)manually by the
6th and 8th days, and the posterior wallauthors of this
3 mg/kg on the 10th end-diastolic thicknessreview
and 12th days, and (diastolic LVPW) + LV
4 mg/kg on the 14th diastolic volume (diastolic
and 16th days, ip LVV) and function indexes
(stroke volume, EF and FS)
Wachtman et al (73) 30/Sprague-DawleyDoxorubicin2.5 mg/kg, ivOnce a week forFSValues provided
rats/female a total of 6 doses in the manuscript
Zhang et al (74)40/Wistar outbred rats/maleDoxorubicin2.5 mg/kg, ipThree times per weekThe LV end-systolic diameterValues provided
(brand name Adriamycin)(total 15 mg/kg)for one week. After a(LVSD), the LV end-diastolicin the manuscript
two-week interval,diameter (LVDD), the LV
administration forend-systolic volume (LVSV)
another week. Theseand the LV end-diastolic
steps were conductedvolume (LVDV) + The LV
6 timesejection fraction (LVEF)
and the LV shortening
fraction (LVFS)
Chen et al (75)39/ Wister rats/maleDoxorubicin2.5 mg/kg, ipSix times for 2 weeksLV end diastolic diameterValues provided
(LVEDd), LV end systolicin the manuscript
diameter (LVESd) and ejection
fraction (EF) + FS + LV
systolic pressure (LVSP), LV
end diastolic pressure (LVEDP),
LV maximum dP/dt and
LV minimum dP/dt
Ha et al (76)60/Wistar rats/maleDoxorubicin2 mg/kg, ivOnce a week for 2, 4,LV performanceValues calculated
(brand name Adriamycin) 6 or 8 weeks,LV dimensions (end-diastolicmanually by the
consecutivelyand end-systolic diameter)authors of this
+ EFreview
Emanuelo et al (77) 40/Sprague-DawleyDoxorubicin2.5 mg/kg, ipEvery second dayLV systolic pressure (LVSP)Values calculated
rats/male (total 15 mg/kg)for a period ofDiastolic and systolicmanually by the
2 weeksLV wall thickness, LVEDD,authors of this
and LVESD were measuredreview
  + percent LV FS
Lim (78) 52/Sprague-DawleyDoxorubicin2.5 mg/kg, ipSix timesLVES dimensions, LVEDValues provided
rats/male over 2 weeksdimensions, LVFSin the manuscript
Hydock et al (79) 147/Sprague-DawleyDoxorubicin10 mg/kg, ipAcute administrationSWT during systole (SWs)Values calculated
rats/male (bolus injection)and diastole (SWd), PWT andmanually by the
PWT during diastole (PWd),authors of this
LVEDd, LVESd, FSreview
Xiang et al (80) 37/Sprague-DawleyDoxorubicin2.5 mg/kg, ipOnce a weekLVEDd and LVESd +Values provided
rats/male for 6 weeksLV FS (%)in the manuscript
Kenk et al (81) 94/Sprague-DawleyDoxorubicin2.5 mg/kg, ip6 injectionsLV internal diameterValues provided
rats/male(brand name Adriamycin)(total 15 mg/kg)over 2 weeks(LV diastolic and systolicin the manuscript
dimensions; LVDD and
LVSD), LV posterior
wall (LVPW), and intra-
ventricular septum (IVS)
thickness at end-diastole
and peak systole.
→LV volume in diastole
and systole (LVDV, LVSV),
stroke volume (SV),
EF, FS, and LV mass
Katona et al (82)23/Adult Wistar rats/maleDoxorubicin2.5 mg/kg, ipThree times a weekParameters monitored:Values provided
(brand name Adriamycin) for 2 weeksLVDDd and LVSDd,in the manuscript
FS, LAD, AOD
Hydock et al (83) 49/Sprague-DawleyDoxorubicin1.5 mg/kg i.p ofOnce a day forSeptal wall thickness at systoleValues provided
rats/female (cumulative 15 mg/kg)10 consecutive days(SWs) and diastole (SWd),in the manuscript
posterior wall thickness at
systole (PWs) and diastole
(PWd), LVDs and LVDd,
and FS
Hou et al (84)40/Wistar rats/maleDoxorubicin2.5 mg/kg, ip6 times for 2 weeksLV dimensionsValues provided
(brand name Adriamycin) [end-diastolic diameterin the manuscript
(LVDd) and end systolic
diameter (LVDs)] + % FS
of the LV
Hydock et al (85) 74/Sprague-DawleyDoxorubicin1 mg/kg, ipOnce a day forSeptal wall thicknessValues provided
rats/male (total 10 mg/kg)10 consecutive daysat systole (SWs) and diastolein the manuscript
(SWd), posterior wall thickness
at systole (PWs) and diastole
(PWd), LVDs and LVDd.
+ FS, LV mass and relative
wall thickness (RWT).
Koh et al (86)33/Wistar rats/maleDoxorubicin2 mg/kg, ivOnce a weekLV dimensions (the LVDd,Values provided
(brand name Adriamycin) for 8 weeksLVDs, the intraventricularin the manuscript
septal thickness, and the LV
posterior wall thickness) +
% FS of LV atrial natriuretic
peptide; brain natriuretic peptide
Carresi et al (87)40/Wistar rats/maleDoxorubicin2.5 mg/kg, ip6 times for 2 weeksLVESd; LVEDd; IVSs;Values provided
IVSd, LVPWs and LVPWd;in the manuscript
EF; FS
Ma et al (88)190/Wistar rats/maleDoxorubicin2.5 mg/kg, ip6 times for 2 weeksLVEDD) and LVESDValues provided
+ FS + EF  in the manuscript
Zhang et al (89) 26/Sprague-DawleyDoxorubicin4 mg/kg, ipTwice per weekDiastolic interventricularValues calculated
rats/male (cumulative dosefor 2 weeksseptum thickness (IVSTd),manually by the
16 mg/kg) systolic interventricular septumauthors of this
thickness (IVSTs), + EF + FSreview
Sun et al (90) 32/Sprague-DawleyDoxorubicin20 mg/kg, ipAcute administration(LVEF) from EDV and ESV,Values provided
rats/male 5.0 mg/kg, iv(single dose)+ EDV and ESVin the manuscript
+ LVFS
Zhu et al (91)50/Adult Sprague-DawleyDoxorubicin2 mg/kg/week6 weeksEjection fractionValues provided
rats/male in the manuscript
Croteau et al (92)12/ Fisher rats/maleDoxorubicin2 mg/kg, ivOnce a weekLeft ventricular functionValues provided
for 6 weeksLeft ventricle ejection fractionin the manuscript
Ikegami et al (93) 14/Sprague-Dawley/NMDoxorubicin2.5 mg/kg, ip3 times a weekLVDd and LVFS + FSValues provided
for 2 to 6 weeks in the manuscript
Hiona et al (94)24/Sprague DawleyDoxorubicinCumulative dose ofOnce a weekLVFSValues provided
rats/female 25 mg/kg, ipfor 6 weeks in the manuscript
Tang et al (95) 40/Sprague-DawleyDoxorubicin2.5 mg/kg, ipOnce a day forParameters monitored:Values provided
rats/male a total of 6 timesLVEF, LVIDd, LVIDs,in the manuscript
LVPWd, LVPWs, left ventricle
% EF, and left ventricle % FS
Migrino et al (96)31/Sprague DawleyDoxorubicin2.5 mg/kg, ivOnce a weekFS monitoredValues provided
rats/male for 10 or 12 weeks in the manuscript
Liu et al (97) 24/Sprague-DawleyDoxorubicinEach dose consisted ofAt 1st, 3rd, 5th, 7th,Parameters monitored:Values provided
rats/male(brand name Adriamycin)1, 1, 2, 2, 3 and 3 mg/kg,9th and 11th day,interventricular septumin the manuscript
ip (cumulative doserespectivelythickness of systolic, IVSd,
12 mg/kg) LVIDd, LVISd, LVPW,
LVPWd, EF, FS
Liu et al (98)120/Sprague DawleyDoxorubicin3.3 mg/kg, ivOnce a week Values provided
rats/NM for 4 weeks in the manuscript

[i] LV, left ventricular; LVEF, LV ejection fraction; LVFS: LV fractional shortening; BNP, brain natriuretic peptide; PWT, posterior wall thickness; AWT, anterior wall thickness; SWT, septal wall thickness; BP, blood pressure; HR, heart rate; LVSP, LV systolic pressure; LVDP, LV diastolic pressure; LVEDd, LV end-diastolic diameter; LVESd, LV end-systolic diameter; LVEDV, LV end-diastolic volume; LVIDd, LV internal diastolic diameter LVISd, LV internal systolic diameter; LVPWs, LV systolic wall thickness; LVPWd, LV diastolic wall thickness; IVSd, intraventricular septum in diastole; LAD, left atrial diameter; AOD, aortic diameter; ip, intraperitoneally; iv, intravenously; NM, not mentioned; SD, Sprague-Dawley.

In Figs. 25, the normal and suppressed values of the two main echocardiographic indices discussed, %EF and %FS, respectively, are presented. Reported baseline (normal) %EF values in rats vary (55-96.5%). In 78.2% of the studies reviewed, normal values range from 70 to 90%. High %EF values (>90%) are reported in 14% of the studies. In contrast, normal %FS values present even higher variability (25-84.2%). The majority (66.7%) of the values, though, are reported to be within the range of 40 and 60%.

Exposure to anthracyclines suppresses both echocardiographic indices. In the 86 studies reviewed in the present report, Doxorubicin is almost universally used to induce cardiotoxicity, along with Daunorubicin and Epirubicin in two studies (Table I). The structures of the three anthracyclines used are presented in Fig. 6. Anthracyclines were administered with order of appearance either via intraperitoneal injection, intravenous injection or orally with the feed. The doses were administered once, twice, three times per week. The duration of the dose administration spans from one week to ten weeks. In most of the experiments, the benchmark for terminating the administration was the proof of cardiac toxicity. The echocardiography values suggest that there is no specific dose regime threshold which indicates the establishment of the effect, but it is specific to each experiment and probably dependent on other factors such as age and general condition of the animals.

The suppressed %EF values reported from rats after anthracyclines administration vary from 31 to 91% (Fig. 4). EF values 50–80% are reported in 72.3% of the studies reviewed. Suppression of the %EF due to anthracycline administration varies from 10 to 40% compared to the normal values in more than two thirds of the studies reviewed (71.7%) (Fig. 7). On the other hand, suppressed %FS values ranging from 14 to 71.8%, present a more narrow distribution (%FS values 20–50% in 84.6% of the studies). As shown in Fig. 7, a more equal distribution of the %FS suppression due to anthracycline toxicity is observed with approximately one fourth of the studies reporting 20–30% and 30–40% suppression, respectively. It is evident from Figs 8 and 9 that normal and suppressed %EF and %FS values separate sufficiently well. The rat strain does not seem to influence either the normal or the suppressed %EF and %FS values (Fig. 10).

Only 11 studies used an acute administration scheme, with 3–20 mg/kg bw anthracycline single injection either intravenously or intraperitoneally. Most of the studies used a prolonged administration period, from 2 weeks (33 studies) up to 10 weeks, and cumulative doses ranging from 1 to 20 mg/kg bw. All dosage schemes were carefully selected to induce cardiotoxicity and did not seem to affect the suppression of %EF and %FS monitored.

Discussion

Myocardial contractility suppression due to anthracycline administration is of increasing interest and represents a major challenge in the clinical setting. At the same time in a preclinical stage it serves as a model for the assessment of both new chemotherapeutic and cardioprotective agents to be introduced in clinical practice. The myocardial toxicity of anthracyclines is known to be affected by sex and age, along with a number of cardiovascular risk factors and comorbidities (99). It is found that anthracycline related congestive heart failure reaches 10% of patients older than 65 years at usual doses (100). While in early studies it was thought that EF cannot accurately predict congestive heart failure attributed to doxorubicin (100), current perspective is that anthracycline-related cardiotoxicity is manifested by a progressive continuous decline in LVEF (1) and identifying subclinical myocardial dysfunction related to anthracycline treatment has great therapeutic implications (2).

Preclinical animal studies are essential in cancer chemotherapy research along with the evaluation of the cardiotoxic propensity of the chemotherapeutic agents. The current recommendations for prevention of cardiac events from cancer chemotherapies are largely based on recommendations. The American Society of Clinical Oncology, for example, recommends active screening and prevention of modifiable cardiovascular risk factors, such as tobacco use, high blood pressure, high cholesterol, alcohol use, obesity and physical inactivity (101). A well characterized animal model for defining cardiotoxicity due to chemotherapy and the treatment thereof is of great importance for clinical practice, as it will enable physicians to base their decisions not only on epidemiology but also on observations developed using concrete data from animal studies.

In the present review, the range of the main echocardiographic indices, namely EF and FS, used in describing anthracycline cardiotoxicity in rats was summarized along with the normal values of the said indices presented in the respective studies. In the graphic representation, it seems that normal and suppressed values due to anthracyclines administration for the two echocardiographic indices are well separated. This provides the first evidence for the possibility of setting a cut-off point for defining anthracycline cardiotoxicity in rats with an in-depth future meta-analysis.

In the current study a wide range of EF and FS decline due to anthracycline administration was observed. However, the trends of the said decline are easily identified, especially for FS values, thus rendering the establishment of minimum cut off values of decline feasible. The question remains, as it has also been identified for humans, whether the absolute suppressed values of EF and FS, combined or separately, or the % suppression caused by anthracyclines should be used to describe cardiotoxicity, and which of the two approaches could be more effective in prevention. In our study, it seems that setting a range for % suppression of EF and FS could be more efficient in identifying early cardiotoxicity by counteracting the intra-individual variation of the absolute values.

In the current in depth review analysis, we did not identify differences between rat strains in terms of suppressed EF and FS values due to anthracycline administration. This is an interesting finding as it seems that the usual strains used in rat studies are equally prone to the cardiotoxic anthracycline potential. In animal models of genetically programmed hypertension and heart failure, it is found that doxorubicin administration did not lead to lower myocardial contractility compared to non-genetically modified strains (102). In addition, in the current systematic review, acute and chronic anthracyclines cardiotoxicity models were found equally potent in inducing cardiotoxicity based on evaluated echocardiographic indices.

Currently, when assessing chemicals toxicity, cardiac effects if monitored and detected in animal studies, mainly on the tissue level, are considered by the authorities, but cardiotoxicity, as such, is not described as a separate hazard class of chemical substances through the available regulations, both at a European level and world-wide. Therefore, chemicals other than pharmaceutical agents are recognised to be cardiotoxic after having exerted such deleterious effects on humans, based on epidemiological studies. In a previous review of our research team, the cardiac pathology and function impairment due to exposure to pesticides revealed that several cardiovascular complications have been reported in animal models including electrocardiogram abnormalities, myocardial infarction, impaired systolic and diastolic performance and histopathological findings, such as haemorrhage, vacuolization, signs of apoptosis and degeneration (103). In addition, there is evidence that short and/or long-term exposure to anabolic androgenic steroids is linked to a variety of cardiovascular complications which could be identified by using echocardiography or biochemical markers (10,104,105). The published data suggest clearly that there is a need to establish regulatory criteria for assessing cardiotoxicity as an inherent property of a chemical substance well in advance, and characterize the risk of exposure to such chemicals through a well-developed regulatory network based on animal models, as is the case for other human health hazard classes, such as carcinogenicity. Regulatory established criteria will enable international organizations to early identify cardiotoxic effects and classify chemicals in order to avoid long-term cardiovascular complications. Specific classification criteria should be developed based on anatomical, histopathological, echocardiographic and biochemical criteria in animals developed in a way that could exclude confounding factors in the development of the observed cardiotoxicity. The results of the present study are promising in identifying echocardiographic criteria in rats for the establishment of cardiotoxicity. Further studies and meta-analyses are needed in order to evaluate other species, commonly used in research, and explore the possibility of early recognizing the onset of cardiotoxicity, possibly through monitoring of biochemical markers based on understanding of the mode of action.

Acknowledgements

Not applicable

Funding

No funding was received.

Availability of data and materials

Not applicable

Authors' contributions

All authors have read and approved the final version of this manuscript. This report is part of the PhD Thesis of NG supervised by DS, KTo and DK and performed in the University of Thessaly. NG: organization and performing of the research, collecting data, writing of the research article. KT, CT: conceptualization of the project, setting criteria for the research, verification of the results, reviewing the manuscript, the statistics and the reference list, overall project management. RR, HN, GENK, JLCMD: data extraction, evaluation of the results, statistical analysis. DAS, DS, KTo, DK, CT: overall project overview, data assessment, evaluation of the results, evaluation of the applicability of the findings, reviewing and writing of the research article and plan assessment.

Ethics approval and consent to participate

Not applicable

Patients consent for publication

Not applicable

Competing interests

DAS is the Editor-in-Chief for the journal, but had no personal involvement in the reviewing process, or any influence in terms of adjudicating on the final decision, for this article. The positions and opinions presented in this article are those of the authors (NG, GENK, JLCMD) alone and are not intended to represent the views or any official position or scientific works of the European Agencies EFSA and ECHA. The other authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

LV

left ventricular

LVEF

LV ejection fraction

LVFS

LV fractional shortening

BNP

brain natriuretic peptide

PWT

posterior wall thickness

AWT

anterior wall thickness

SWT

septal wall thickness

BP

blood pressure

HR

heart rate

LVSP

LV systolic pressure

LVDP

LV diastolic pressure

LVEDd

LV end-diastolic diameter

LVESd

LV end-systolic diameter

LVEDV

LV end-diastolic volume

LVIDd

LV internal diastolic diameter

LVISd

LV internal systolic diameter

LVPWs

LV systolic wall thickness

LVPWd

LV diastolic wall thickness

IVSd

intraventricular septum in diastole

LAD

left atrial diameter

AOD

aortic diameter

ACEIs

angiotensin converting enzyme inhibitors

ARBs

angiotensin II receptor blockers

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September-2020
Volume 44 Issue 3

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Spandidos Publications style
Georgiadis N, Tsarouhas K, Rezaee R, Nepka H, Kass GE, Dorne JLC, Stagkos D, Toutouzas K, Spandidos DA, Kouretas D, Kouretas D, et al: What is considered cardiotoxicity of anthracyclines in animal studies Corrigendum in /10.3892/or.2020.7717. Oncol Rep 44: 798-818, 2020
APA
Georgiadis, N., Tsarouhas, K., Rezaee, R., Nepka, H., Kass, G.E., Dorne, J.C. ... Tsitsimpikou, C. (2020). What is considered cardiotoxicity of anthracyclines in animal studies Corrigendum in /10.3892/or.2020.7717. Oncology Reports, 44, 798-818. https://doi.org/10.3892/or.2020.7688
MLA
Georgiadis, N., Tsarouhas, K., Rezaee, R., Nepka, H., Kass, G. E., Dorne, J. C., Stagkos, D., Toutouzas, K., Spandidos, D. A., Kouretas, D., Tsitsimpikou, C."What is considered cardiotoxicity of anthracyclines in animal studies Corrigendum in /10.3892/or.2020.7717". Oncology Reports 44.3 (2020): 798-818.
Chicago
Georgiadis, N., Tsarouhas, K., Rezaee, R., Nepka, H., Kass, G. E., Dorne, J. C., Stagkos, D., Toutouzas, K., Spandidos, D. A., Kouretas, D., Tsitsimpikou, C."What is considered cardiotoxicity of anthracyclines in animal studies Corrigendum in /10.3892/or.2020.7717". Oncology Reports 44, no. 3 (2020): 798-818. https://doi.org/10.3892/or.2020.7688