What is considered cardiotoxicity of anthracyclines in animal studies
Corrigendum in: /10.3892/or.2020.7717
- Authors:
- Published online on: July 14, 2020 https://doi.org/10.3892/or.2020.7688
- Pages: 798-818
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Copyright: © Georgiadis et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
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 (5–7). 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. |
In Figs. 2–5, 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
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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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