Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity
- Aarti Asnani, MD
Aarti Asnani, MD
- Harvard Medical School
- Tomas G Neilan, MD
Tomas G Neilan, MD
- Assistant Professor of Medicine
- Harvard Medical School
- Marielle Scherrer-Crosbie, MD, PhD
Marielle Scherrer-Crosbie, MD, PhD
- Professor of Medicine
- Division of Cardiology
- University of Pennsylvania
- Debasish Tripathy, MD
Debasish Tripathy, MD
- Professor and Chair, Department of Breast Medical Oncology
- The University of Texas MD Anderson Cancer Center
- Section Editors
- Stephen S Gottlieb, MD
Stephen S Gottlieb, MD
- Section Editor — Heart Failure
- Professor of Medicine
- University of Maryland School of Medicine
- Harold Burstein, MD, PhD
Harold Burstein, MD, PhD
- Section Editor — Breast Cancer
- Associate Professor of Medicine
- Harvard Medical School
- Richard A Larson, MD
Richard A Larson, MD
- Editor-in-Chief — Hematology
- Section Editor — Leukemia
- Professor of Medicine
- University of Chicago Pritzker School of Medicine
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 .
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 .
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 . 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 . The Top2-beta-doxorubicin-DNA complex can induce DNA double-strand breaks, leading to cell death . 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 . Other mechanisms proposed to contribute to anthracycline cardiotoxicity include mitochondrial iron accumulation  and dysregulation of cardiomyocyte autophagy .
- Khouri MG, Douglas PS, Mackey JR, et al. Cancer therapy-induced cardiac toxicity in early breast cancer: addressing the unresolved issues. Circulation 2012; 126:2749.
- Tan TC, Neilan TG, Francis S, et al. Anthracycline-Induced Cardiomyopathy in Adults. Compr Physiol 2015; 5:1517.
- Singal PK, Deally CM, Weinberg LE. Subcellular effects of adriamycin in the heart: a concise review. J Mol Cell Cardiol 1987; 19:817.
- Adderley SR, Fitzgerald DJ. Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2. J Biol Chem 1999; 274:5038.
- Dowd NP, Scully M, Adderley SR, et al. Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo. J Clin Invest 2001; 108:585.
- Singal PK, Iliskovic N, Li T, Kumar D. Adriamycin cardiomyopathy: pathophysiology and prevention. FASEB J 1997; 11:931.
- Li T, Singal PK. Adriamycin-induced early changes in myocardial antioxidant enzymes and their modulation by probucol. Circulation 2000; 102:2105.
- Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998; 339:900.
- Martin E, Thougaard AV, Grauslund M, et al. Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy. Toxicology 2009; 255:72.
- Tewey KM, Rowe TC, Yang L, et al. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 1984; 226:466.
- Capranico G, Tinelli S, Austin CA, et al. Different patterns of gene expression of topoisomerase II isoforms in differentiated tissues during murine development. Biochim Biophys Acta 1992; 1132:43.
- Lyu YL, Kerrigan JE, Lin CP, et al. Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res 2007; 67:8839.
- Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012; 18:1639.
- Ichikawa Y, Ghanefar M, Bayeva M, et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 2014; 124:617.
- Li DL, Wang ZV, Ding G, et al. Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification. Circulation 2016; 133:1668.
- Ewer MS, Ali MK, Mackay B, et al. A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin. J Clin Oncol 1984; 2:112.
- Doroshow JH. Doxorubicin-induced cardiac toxicity. N Engl J Med 1991; 324:843.
- Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003; 97:2869.
- Drafts BC, Twomley KM, D'Agostino R Jr, et al. Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease. JACC Cardiovasc Imaging 2013; 6:877.
- Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2014; 27:911.
- Qin A, Thompson CL, Silverman P. Predictors of late-onset heart failure in breast cancer patients treated with doxorubicin. J Cancer Surviv 2015; 9:252.
- Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991; 324:808.
- Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016; 37:2768.
- Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 2004; 109:2749.
- Lipshultz SE, Rifai N, Sallan SE, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 1997; 96:2641.
- Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015; 131:1981.
- Isner JM, Ferrans VJ, Cohen SR, et al. Clinical and morphologic cardiac findings after anthracycline chemotherapy. Analysis of 64 patients studied at necropsy. Am J Cardiol 1983; 51:1167.
- Nakamae H, Tsumura K, Terada Y, et al. Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Cancer 2005; 104:2492.
- Guglin M, Aljayeh M, Saiyad S, et al. Introducing a new entity: chemotherapy-induced arrhythmia. Europace 2009; 11:1579.
- Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med 1996; 125:47.
- Barrett-Lee PJ, Dixon JM, Farrell C, et al. Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk. Ann Oncol 2009; 20:816.
- Wojnowski L, Kulle B, Schirmer M, et al. NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation 2005; 112:3754.
- Steinberg JS, Cohen AJ, Wasserman AG, et al. Acute arrhythmogenicity of doxorubicin administration. Cancer 1987; 60:1213.
- Rudzinski T, Ciesielczyk M, Religa W, et al. Doxorubicin-induced ventricular arrhythmia treated by implantation of an automatic cardioverter-defibrillator. Europace 2007; 9:278.
- Kilickap S, Akgul E, Aksoy S, et al. Doxorubicin-induced second degree and complete atrioventricular block. Europace 2005; 7:227.
- Dazzi H, Kaufmann K, Follath F. Anthracycline-induced acute cardiotoxicity in adults treated for leukaemia. Analysis of the clinico-pathological aspects of documented acute anthracycline-induced cardiotoxicity in patients treated for acute leukaemia at the University Hospital of Zürich, Switzerland, between 1990 and 1996. Ann Oncol 2001; 12:963.
- Luminari S, Montanini A, Caballero D, et al. Nonpegylated liposomal doxorubicin (MyocetTM) combination (R-COMP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL): results from the phase II EUR018 trial. Ann Oncol 2010; 21:1492.
- Tirelli U, Errante D, Van Glabbeke M, et al. CHOP is the standard regimen in patients > or = 70 years of age with intermediate-grade and high-grade non-Hodgkin's lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group. J Clin Oncol 1998; 16:27.
- Cardinale D, Sandri MT, Martinoni A, et al. Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol 2000; 36:517.
- Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91:710.
- Wang L, Tan TC, Halpern EF, et al. Major Cardiac Events and the Value of Echocardiographic Evaluation in Patients Receiving Anthracycline-Based Chemotherapy. Am J Cardiol 2015; 116:442.
- Procter M, Suter TM, de Azambuja E, et al. Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial. J Clin Oncol 2010; 28:3422.
- Romond EH, Jeong JH, Rastogi P, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2012; 30:3792.
- Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000; 342:1077.
- Sawaya H, Sebag IA, Plana JC, et al. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging 2012; 5:596.
- Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 2009; 339:b4606.
- Armstrong GT, Plana JC, Zhang N, et al. Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging. J Clin Oncol 2012; 30:2876.
- Raj S, Franco VI, Lipshultz SE. Anthracycline-induced cardiotoxicity: a review of pathophysiology, diagnosis, and treatment. Curr Treat Options Cardiovasc Med 2014; 16:315.
- Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006; 355:1572.
- Runowicz CD, Leach CR, Henry NL, et al. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. J Clin Oncol 2016; 34:611.
- Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012; 23 Suppl 7:vii155.
- Daher IN, Kim C, Saleh RR, et al. Prevalence of abnormal echocardiographic findings in cancer patients: a retrospective evaluation of echocardiography for identifying cardiac abnormalities in cancer patients. Echocardiography 2011; 28:1061.
- Hoffmann R, von Bardeleben S, ten Cate F, et al. Assessment of systolic left ventricular function: a multi-centre comparison of cineventriculography, cardiac magnetic resonance imaging, unenhanced and contrast-enhanced echocardiography. Eur Heart J 2005; 26:607.
- Thavendiranathan P, Grant AD, Negishi T, et al. Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy. J Am Coll Cardiol 2013; 61:77.
- Hundley WG, Bluemke DA, Finn JP, et al. In: ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus document on cardiovascular magnetic resonance: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents Lippincott Williams & Wilkins, Baltimore 2010. p.2462.
- Alexander J, Dainiak N, Berger HJ, et al. Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med 1979; 300:278.
- Choi BW, Berger HJ, Schwartz PE, et al. Serial radionuclide assessment of doxorubicin cardiotoxicity in cancer patients with abnormal baseline resting left ventricular performance. Am Heart J 1983; 106:638.
- Friedman MA, Bozdech MJ, Billingham ME, Rider AK. Doxorubicin cardiotoxicity. Serial endomyocardial biopsies and systolic time intervals. JAMA 1978; 240:1603.
- Thavendiranathan P, Poulin F, Lim KD, et al. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 2014; 63:2751.
- Sawaya H, Sebag IA, Plana JC, et al. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol 2011; 107:1375.
- Negishi K, Negishi T, Hare JL, et al. Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity. J Am Soc Echocardiogr 2013; 26:493.
- Langeland S, D'hooge J, Wouters PF, et al. Experimental validation of a new ultrasound method for the simultaneous assessment of radial and longitudinal myocardial deformation independent of insonation angle. Circulation 2005; 112:2157.
- Hare JL, Brown JK, Leano R, et al. Use of myocardial deformation imaging to detect preclinical myocardial dysfunction before conventional measures in patients undergoing breast cancer treatment with trastuzumab. Am Heart J 2009; 158:294.
- Ky B, Putt M, Sawaya H, et al. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol 2014; 63:809.
- Daugaard G, Lassen U, Bie P, et al. Natriuretic peptides in the monitoring of anthracycline induced reduction in left ventricular ejection fraction. Eur J Heart Fail 2005; 7:87.
- Sandri MT, Salvatici M, Cardinale D, et al. N-terminal pro-B-type natriuretic peptide after high-dose chemotherapy: a marker predictive of cardiac dysfunction? Clin Chem 2005; 51:1405.
- Skovgaard D, Hasbak P, Kjaer A. BNP predicts chemotherapy-related cardiotoxicity and death: comparison with gated equilibrium radionuclide ventriculography. PLoS One 2014; 9:e96736.
- Toro-Salazar OH, Gillan E, O'Loughlin MT, et al. Occult cardiotoxicity in childhood cancer survivors exposed to anthracycline therapy. Circ Cardiovasc Imaging 2013; 6:873.
- Cottin Y, L'huillier I, Casasnovas O, et al. Dobutamine stress echocardiography identifies anthracycline cardiotoxicity. Eur J Echocardiogr 2000; 1:180.
- Aminkeng F. PDGFRB mutation causes autosomal-dominant Penttinen syndrome. Clin Genet 2015; 88:531.
- Blanco JG, Sun CL, Landier W, et al. Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children's Oncology Group. J Clin Oncol 2012; 30:1415.
- Ng T, Chan M, Khor CC, et al. The genetic variants underlying breast cancer treatment-induced chronic and late toxicities: a systematic review. Cancer Treat Rev 2014; 40:1199.
- Armenian SH, Ding Y, Mills G, et al. Genetic susceptibility to anthracycline-related congestive heart failure in survivors of haematopoietic cell transplantation. Br J Haematol 2013; 163:205.
- Jones LW, Courneya KS, Mackey JR, et al. Cardiopulmonary function and age-related decline across the breast cancer survivorship continuum. J Clin Oncol 2012; 30:2530.
- Stoodley PW, Richards DA, Boyd A, et al. Altered left ventricular longitudinal diastolic function correlates with reduced systolic function immediately after anthracycline chemotherapy. Eur Heart J Cardiovasc Imaging 2013; 14:228.
- Moon TJ, Miyamoto SD, Younoszai AK, Landeck BF. Left ventricular strain and strain rates are decreased in children with normal fractional shortening after exposure to anthracycline chemotherapy. Cardiol Young 2014; 24:854.
- Bayram C, Çetin İ, Tavil B, et al. Evaluation of cardiotoxicity by tissue Doppler imaging in childhood leukemia survivors treated with low-dose anthracycline. Pediatr Cardiol 2015; 36:862.
- Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med 1997; 336:267.
- Guendouz S, Buicuic O, Kirsch M, et al. Restrictive cardiomyopathy associated with left ventricle and left atria endocardial calcifications following chemotherapy. J Am Coll Cardiol 2011; 57:1633.
- Mortensen SA, Olsen HS, Baandrup U. Chronic anthracycline cardiotoxicity: haemodynamic and histopathological manifestations suggesting a restrictive endomyocardial disease. Br Heart J 1986; 55:274.
- RISK FACTORS
- CLINICAL MANIFESTATIONS
- Time course
- Early manifestations
- Late manifestations
- RISK ASSESSMENT AND MONITORING
- Approach to baseline assessment and monitoring
- Guideline recommendations
- Assessment of LVEF
- - Echocardiography
- - Cardiac MR
- - Nuclear imaging
- Endomyocardial biopsy
- Investigational tests
- - Strain and strain rate imaging
- - Troponins
- - Natriuretic peptide
- - Investigational approaches to imaging
- - Other tests
- Approach to diagnosis
- Role of cardiology consultation
- Differential diagnosis
- SUMMARY AND RECOMMENDATIONS