Trevi R. Mancilla, Brian Iskra, Gregory J. Aune
ABSTRACT
Doxorubicin‐induced cardiotoxicity in childhood cancer survivors is a growing problem. The population of patients at risk
for cardiovascular disease is steadily increasing, as five‐year survival rates for all types of childhood cancers continue
to improve. Doxorubicin affects the developing heart differently from the adult heart and in a subset of exposed patients,
childhood exposure leads to late, irreversible cardiomyopathy. Notably, the prevalence of late‐onset toxicity is increasing
in parallel with improved survival. By the year 2020, it is estimated that there will be 500,000 childhood cancer survivors
and over 50,000 of them will suffer from doxorubicin‐induced cardiotoxicity.
The majority of the research to‐date, concentrated on childhood cancer survivors, has focused mostly on clinical outcomes
through well‐designed epidemiological and retrospective cohort studies. Preclinical studies have elucidated many of the cellular
mechanisms that elicit acute toxicity in cardiomyocytes. However, more research is needed in the areas of early‐ and late‐onset
cardiotoxicity and more importantly improving the scientific understanding of how other cells present in the cardiac milieu
are impacted by doxorubicin exposure.
The overall goal of this review is to succinctly summarize the major clinical and preclinical studies focused on doxorubicin‐induced
cardiotoxicity. As the prevalence of patients affected by doxorubicin exposure continues to increase, it is imperative that
the major gaps in existing research are identified and subsequently utilized to develop appropriate research priorities for
the coming years. Well‐designed preclinical research models will enhance our understanding of the pathophysiology of doxorubicin‐induced
cardiotoxicity and directly lead to better diagnosis, treatment, and prevention. © 2019 American Physiological Society. Compr Physiol 9:905‐931, 2019.
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Figure 1. Summary of myocardial cellular effects and the injury response induced by doxorubicin. Color key—blue: absence abrogates cardiac dysfunction or protects from apoptosis. Green: Inhibition of pathway or downregulation of expression. Yellow: Mediates apoptotic response. Red: Expression increases or enhances cardiac dysfunction. Orange: Absence enhances cardiac dysfunction. (Interestingly, p53 both increases in expression, while global knockdown abrogates the cardiotoxic response.) Adapted from Lindsey et al. (170).
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Teaching Material
T. R. Mancilla, B. Iskra, G. J. Aune. Doxorubicin-Induced Cardiomyopathy in Children. Compr Physiol 9: 2019, 905-931.
Didactic Synopsis
Major Teaching Points:
- Anthracyclines have been unequivocally linked to cardiovascular disease later in life.
- Acute cardiotoxicity, which occurs during the first year of treatment, has a low incidence in the pediatric population due to dosing regimens that limit total cumulative dose delivered and infrequent pre-existing cardiovascular disease in children.
- Chronic cardiotoxicity can take decades to develop and the pathological mechanisms are not fully understood.
- Doxorubicin has multiple mechanisms of action and the effect depends on the cell type.
- Superoxide production and disruption of the electron transport chain leads to mitochondrial dysfunction.
- Doxorubicin intercalates DNA and inhibits topoisomerase II leading to DNA damage and the DNA damage response.
- Early detection of cardiac damage that indicates initiation of a progressive process leading to chronic cardiotoxicity is needed. Ejection fraction determined by echocardiography is not sensitive enough and a molecular or more sensitive imaging biomarker is urgently needed.
Didactic Legends
The figure—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legend published in the article. The following legend to the same figures is written to be useful for teaching.
Figure 1 Teaching Points: DOX has been shown to have a myriad of effects on the different cell types of the heart. The figure above summarizes some of the known expression changes induced by DOX in each cell type. The diagram also illustrates that the preponderance of research has been conducted on the cardiac myocyte.
How to Cite
Trevi R. Mancilla, Brian Iskra, Gregory J. Aune. Doxorubicin‐Induced Cardiomyopathy in Children. Compr Physiol 2019, 9: 905-931. doi: 10.1002/cphy.c180017
