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Anthracycline-Induced Cardiotoxicity

Kesavan Shan, MD; A. Michael Lincoff, MD; and James B. Young, MD
[+] Article, Author, and Disclosure Information

From The Cleveland Clinic Foundation, Cleveland, Ohio. Requests for Reprints: A. Michael Lincoff, MD, Director, Experimental Interventional Laboratory, Department of Cardiology, F25, The Cleveland Clinic Foundation 9500 Euclid Avenue, Cleveland, OH 44195. Current Author Addresses: Dr. Shan: Baylor College of Medicine, Section of Cardiology, 6550 Fannin MS SM 677, Houston, TX 77030. Drs Lincoff and Young: Department of Cardiology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Clevelane, OH 44195.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1996;125(1):47-58. doi:10.7326/0003-4819-125-1-199607010-00008
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Purpose: To review the current understanding of the clinical significance, detection, pathogenesis, and prevention of anthracycline-induced cardiotoxicity.

Data Sources: A MEDLINE search of the English-language medical literature and a manual search of the bibliographies of relevant articles, including abstracts from national cardiology meetings.

Study Selection: Pertinent clinical and experimental studies addressing the clinical relevance, pathogenesis, detection, and prevention of anthracycline cardiotoxicity were selected from peer-reviewed journals without judgments about study design. A total of 137 original studies and 9 other articles were chosen.

Data Extraction: Data quality and validity were assessed by each author independently. Statistical analysis of combined data was inappropriate given the differences in patient selection, testing, and follow-up in the available studies.

Data Synthesis: Anthracycline-induced cardiotoxicity limits effective cancer chemotherapy by causing early cardiomyopathy, and it can produce late-onset ventricular dysfunction years after treatment has ceased. Detection of subclinical anthracycline-induced cardiomyopathy through resting left ventricular ejection fraction or echocardiographic fractional shortening is suboptimal. Conventional doses of anthracycline often lead to permanent myocardial damage and reduced functional reserve. Underlying pathogenetic mechanisms may include free-radical-mediated myocyte damage, adrenergic dysfunction, intracellular calcium overload, and the release of cardiotoxic cytokines. Dexrazoxane is the only cardioprotectant clinically approved for use against anthracyclines, and it was only recently introduced for selected patients with breast cancer who are receiving anthracycline therapy.

Conclusions: A rapidly growing number of persons, including an alarming fraction of the 150 000 or more adults in the United States who have survived childhood cancer, will have substantial morbidity and mortality because of anthracycline-related cardiac disease. The development of effective protection against anthracycline-induced cardiotoxicity will probably have a significant effect on the overall survival of these patients.


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Figure 1. Reproduced from Von Hoff and colleagues with permission of .
Cumulative probability of developing doxorubicin-induced congestive heart failure (CHF) plotted against total cumulative dose of doxorubicin in all patients receiving the drug (3941 patients; 88 cases of congestive heart failure).[6]Annals of Internal Medicine
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Figure 2. Light microscopy. Section of left ventricle from a 57-year-old woman with adriamycin-induced cardiomyopathy showing marked myofibril loss and vacuolar degeneration ( ). (Hematoxylin and eosin stain. Original magnification, × 400). Electron microscopy. Cardiac myocyte showing adriamycin-induced cardiotoxicity with extensive loss of myofilaments (large arrows). Unaffected myocytes are shown in lower left. Small arrow denotes normal myocyte. (Original magnification, × 2800).
Changes characteristic of adriamycin-induced cardiotoxicity. Top.arrowBottom.
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Figure 3. Percentage of patients with abnormal fractional shortening at long-term follow-up over time after completion of therapy. Adapted from Steinherz and colleagues with permission of The Journal of the American Medical Association. White bars = mild reduction in fractional shortening (25% to 28%); striped bars = moderate reduction in fractional shortening (21% to 24%); black bars = severe reduction in fractional shortening (≤ 20%).
Late-onset ventricular dysfunction over time.[16]
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