Author: Nicholas Houska, DO - University of Colorado - Childrens Hospital Colorado
A 7-year-old boy with a history of acute lymphoblastic leukemia treated with doxorubicin presents with symptoms of heart failure. Which of the following morphological subtypes of cardiomyopathy is MOST likely to be found in this patient?
EXPLANATION
Anthracyclines are a class of cytotoxic drugs extracted from the Streptomyces bacterium. They are utilized as chemotherapeutic agents and include doxorubicin (the most commonly used), daunorubicin, and epirubicin. First used in the 1960s, anthracyclines remain one of the most commonly used and effective chemotherapeutics for solid and hematological cancers. Anthracyclines are inhibitors of the DNA topoisomerase II enzyme, leading to DNA double-strand breaks and subsequent upregulation of p53, which results in programmed cell death (apoptosis).
Anthracyclines are thought to be the primary drugs related to chemotherapy-induced cardiotoxicity. The risk of cardiotoxicity increases as the total cumulative dose of doxorubicin (Dox) increases, with a 3-5% risk at 400 mg/m2 and 18-48% at 700 mg/m2. Apoptosis-mediated loss of cardiomyocytes and oxidative stress are the main culprits of Dox-induced cardiomyopathy. Extremes of age (less than 5 years of age or greater than 65 of age), preexisting cardiac disease or cardiovascular risk factors, and radiation therapy are additional risk factors for Dox-induced cardiomyopathy.
Anthracycline-induced cardiotoxicity can develop at various time points after the initiation of doxorubicin treatment, leading to a dated classification. Acute cardiotoxicity occurs after a single dose or course with the onset of symptoms within 2 weeks. Early-onset chronic occurs within 1 year and presents as a dilated-hypokinetic cardiomyopathy, with progressive development of heart failure. Late-onset chronic occurs years to decades after completion of doxorubicin therapy. Anthracycline-induced cardiotoxicity is defined as a decrease in left ventricular ejection fraction greater than 10% with a final value less than 53% after exposure. It is typically detected via cardiac imaging such as echocardiography and magnetic resonance imaging, along with monitoring of cardiac biomarkers.
Most guidelines recommend serial monitoring after anthracycline use. While historically, doxorubicin-induced cardiotoxicity has been thought of as irreversible and associated with high mortality, more recent studies are suggesting that there may be some effectiveness of heart failure therapy. Primary prevention includes lifestyle modification of cardiovascular risk factors, limitations on total dosage, and the use of less cardiotoxic analogs such as epirubicin. Additionally, dexrazoxane, an iron-chelating agent that prevents the accumulation of oxygen-free radicals, is often included in chemotherapy regimens to protect against the cardiotoxic effects of anthracyclines. The mainstays of heart failure therapy for anthracycline-mediated dilated cardiomyopathy are angiotensin-converting enzyme inhibitors and beta blockers.
Anthracyclines, and specifically doxorubicin-induced cardiotoxicity, are most commonly associated with a dilated hypokinetic cardiomyopathy (answer B). Hypertrophic cardiomyopathy (answer C) is typically associated with genetic disorders. While restrictive cardiomyopathy (answer A) can develop as a result of anthracycline use, it is much less common and presents years or decades after exposure. Restrictive cardiomyopathy is more commonly associated with deposition disorders such as amyloidosis and hemochromatosis.
REFERENCES
Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of Anthracyclines. Front Cardiovasc Med. 2020;7:26. doi: 10.3389/fcvm.2020.00026.
Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother.2021;139:111708. doi: 10.1016/j.biopha.2021.111708.
Mancilla TR, Iskra B, Aune GJ. Doxorubicin-Induced Cardiomyopathy in Children. Compr Physiol. 2019:12;9(3):905-931. doi: 10.1002/cphy.c180017.
