Doxorubicin Cardiotoxicity: Pathophysiology Updates
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(2020) 22:52
Cardio-Oncology (M Fradley, Section Editor)
Doxorubicin Cardiotoxicity: Pathophysiology Updates Christopher W. Hoeger, MD1,2 Cole Turissini, BA1 Aarti Asnani, MD1,2,* Address 1 CardioVascular Institute, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, CLS-911, Boston, MA, 02115, USA *,2 Harvard Medical School, Boston, MA, USA Email: [email protected]
* Springer Science+Business Media, LLC, part of Springer Nature 2020
This article is part of the Topical Collection on Cardio-Oncology Keywords Doxorubicin I Anthracycline I Cardioprotection I Dexrazoxane I Oxidative stress
Abstract Purpose of review Doxorubicin has long been known to cause cardiotoxicity, yet our understanding of its pathophysiologic mechanisms remains incomplete. This review aims to update readers on the most recent evidence supporting candidate mechanisms and proposed treatments for doxorubicin cardiotoxicity. Recent findings Doxorubicin causes cardiotoxicity via traditional mechanisms, such as oxidative stress, DNA and mitochondrial damage, and iron overload, as well as through novel pathways such as autophagy and CYP1 induction. The relative importance of each pathway and how these pathways interact with each other is not well-understood. Novel approaches to cardioprotection are needed. Summary Novel mechanisms of doxorubicin cardiotoxicity represent exciting opportunities for prevention and treatment of this entity. Further studies are needed to translate recent findings into clinical use.
Introduction Anthracyclines are chemotherapeutic agents that have been used to treat a broad range of malignancies for the past several decades. Doxorubicin is a potent anthracycline used in the treatment of breast cancer, leukemia, lymphoma, and sarcoma. It is welldocumented that doxorubicin administration can result in cardiotoxicity, which in adults typically manifests as a
subacute dilated cardiomyopathy that typically occurs within the first year after treatment and can result in long-term congestive heart failure [1•]. The incidence of anthracycline cardiotoxicity is dose-dependent and ranges from 5 to 10% of patients on standard dosing regimens (up to 400 mg/m2) to 20% of patients after a cumulative dose of 700 mg/m [2]. In general, higher
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rates of cardiotoxicity are typically observed in patients with older age or pre-existing cardiovascular disease [3]. Effective use of anthracyclines is thus limited by their potential for cardiotoxicity, which may restrict treatment options for common malignancies. A number of potential mechanisms of doxorubicin cardiotoxicity have been previously identified, including oxidative stress and nitric oxide metabolism, DNA and
(2020) 22:52
mitochondrial damage, iron overload, and cell death through dysregulation of autophagy, necrosis, and apoptosis (Table 1). The relative importance and interrelationship of these mechanisms are not yet well understood. Despite this uncertainty, recent investigations into the mechanisms of doxorubicin
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