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Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity

Aarti Asnani, MD
Tomas G Neilan, MD
Debasish Tripathy, MD
Marielle Scherrer-Crosbie, MD, PhD
Section Editors
Stephen S Gottlieb, MD
Harold Burstein, MD, PhD
Richard A Larson, MD
Deputy Editors
Susan B Yeon, MD, JD, FACC
Sadhna R Vora, MD


The anthracyclines and related compounds (doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone) are among the chemotherapeutic agents implicated in cardiotoxicity. Anthracycline therapy is associated with an increase in the risk for developing heart failure with significant associated morbidity and mortality [1].

The mechanism, clinical manifestations, risk factors, monitoring, and diagnosis of anthracycline-induced cardiotoxicity will be reviewed here. Prevention and management of anthracycline cardiotoxicity and cardiovascular complications of other classes of chemotherapy agents are discussed separately. (See "Prevention and management of anthracycline cardiotoxicity" and "Cardiotoxicity of nonanthracycline cancer chemotherapy agents" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)


Anthracyclines appear to affect cardiac function mainly through mechanisms that involve reactive oxygen species formation, induction of apoptosis, DNA damage through interaction with topoisomerase II, and inhibition of protein synthesis [2].

Myocyte damage has previously been attributed to the production of toxic oxygen-free radicals (ROS) and an increase in oxidative stress, which cause lipid peroxidation of membranes, leading to vacuolization, irreversible damage, and myocyte replacement by fibrous tissue [3-7]. However, oxidative stress is unlikely to be the sole mediator of cardiomyocyte damage, as treatment with scavengers of ROS have not consistently prevented doxorubicin-related cardiotoxicity [8,9].

Later studies implicate the topoisomerase-II (Top2) enzyme. In cancer cells, doxorubicin targets the enzyme Top2 [10]. Doxorubicin binds both Top2 and DNA to form the ternary Top2-doxorubicin-DNA cleavage complex, which triggers cell death. Adult mammalian cardiomyocytes express Top2-beta, but not Top2-alpha [11]. The Top2-beta-doxorubicin-DNA complex can induce DNA double-strand breaks, leading to cell death [12]. The hypothesis that doxorubicin-mediated cardiomyopathy is mediated by Top2-beta in cardiomyocytes is supported by murine studies showing that cardiomyocyte-specific deletion of the gene Top2b (which encodes the Top2-beta enzyme) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for the formation of reactive oxygen species, and protects mice from the development of doxorubicin-induced progressive heart failure [13]. Other mechanisms proposed to contribute to anthracycline cardiotoxicity include mitochondrial iron accumulation [14] and dysregulation of cardiomyocyte autophagy [15].  


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Literature review current through: Mar 2017. | This topic last updated: Apr 03, 2017.
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