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Anthracycline‐Induced Cardiomyopathy in Adults

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Anthracyclines are one of the most commonly used antineoplastic agent classes, and a core part of the treatment in breast cancers, hematological malignancies, and sarcomas. Their benefit is decreased by their well‐recognized cardiotoxicity. The purpose of this review is to outline the presentation, mechanisms, diagnosis, and treatment of anthracyclines‐induced cardiotoxicity. Symptomatic heart failure occurs in 2% to 5% of patients treated with anthrayclines and may be higher in older patients or patients with cardiovascular risk factors. The mechanisms involved in anthracycline‐induced cardiotoxicity involve myocyte loss by apoptosis in the presence of a limited regenerative capacity. Once symptomatic, anthracycline‐induced cardiotoxicity is associated with markedly decreased survival. Left ventricular ejection fraction (LVEF), mostly determined using echocardiography, is used to monitor patients treated with anthracyclines. As more than 1/3 of patients treated with anthracyclines do not recover their baseline LVEF once it is decreased, more sensitive echocardiographic indices of LV function such as myocardial deformation or biomarkers have been studied in patients monitoring. Cardioprotective treatments such as angiotensin‐converting enzyme inhibitors, beta‐blockers, iron chelators, statins, and metformin are also the topic of research efforts. © 2015 American Physiological Society. Compr Physiol 5:1517‐1540, 2015.

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Figure 1. Figure 1. Three‐dimensional echocardiographic measurement of LVEF in patient receiving anthracycline‐based regimen. LVEF decreased from 61% to 39% (22 point reduction to EF below the lower limit of normal).
Figure 2. Figure 2. Diagnosis of subclinical LV dysfunction. Global longitudinal strain reduction in patient receiving anthracycline‐based regimen. Global longitudinal strain is −20.6% at baseline (Fig. 2a) and −16.3% after receiving 450 mg/m2 of doxorubicin (Fig. 2b), a 21% reduction (20.6 − 16.3/20.6 = 20.8%).
Figure 3. Figure 3. Comparative CMR imaging methods of detection of myocardial fibrosis in a healthy control (A and C) and an asymptomatic subject treated 5 years previously with anthracyclines (B and D). Sequence A and B show standard LGE imaging for detection of replacement myocardial fibrosis and are both normal. Figure C and D show the results from measurement of diffuse myocardial fibrosis and calculation of the ECV using a Look‐Locker sequence. The normal patient had an ECV of 0.27 (C, normal range 0.23‐0.32). The patient with prior anthracycline treatment had an elevated ECV of 0.35 (D).
Figure 4. Figure 4. T‐2 weighted imaging for cardiac edema. Comparative T‐2 weighted cardiac images from a patient after anthracyclines (A) showing regions of increased signal intensity, highlighted using the arrows, as compared to a normal patient (B).
Figure 5. Figure 5. Algorithm proposed in the Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy of the American Society of Echocardiography and the European Association for Cardiovascular Imaging when a patient is scheduled to be treated with anthracyclines.

Figure 1. Three‐dimensional echocardiographic measurement of LVEF in patient receiving anthracycline‐based regimen. LVEF decreased from 61% to 39% (22 point reduction to EF below the lower limit of normal).

Figure 2. Diagnosis of subclinical LV dysfunction. Global longitudinal strain reduction in patient receiving anthracycline‐based regimen. Global longitudinal strain is −20.6% at baseline (Fig. 2a) and −16.3% after receiving 450 mg/m2 of doxorubicin (Fig. 2b), a 21% reduction (20.6 − 16.3/20.6 = 20.8%).

Figure 3. Comparative CMR imaging methods of detection of myocardial fibrosis in a healthy control (A and C) and an asymptomatic subject treated 5 years previously with anthracyclines (B and D). Sequence A and B show standard LGE imaging for detection of replacement myocardial fibrosis and are both normal. Figure C and D show the results from measurement of diffuse myocardial fibrosis and calculation of the ECV using a Look‐Locker sequence. The normal patient had an ECV of 0.27 (C, normal range 0.23‐0.32). The patient with prior anthracycline treatment had an elevated ECV of 0.35 (D).

Figure 4. T‐2 weighted imaging for cardiac edema. Comparative T‐2 weighted cardiac images from a patient after anthracyclines (A) showing regions of increased signal intensity, highlighted using the arrows, as compared to a normal patient (B).

Figure 5. Algorithm proposed in the Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy of the American Society of Echocardiography and the European Association for Cardiovascular Imaging when a patient is scheduled to be treated with anthracyclines.
 1.Adderley SR, Fitzgerald DJ. Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2‐mediated induction of cyclooxygenase‐2. J Biol Chem 274: 5038‐5046, 1999.
 2.Armenian SH, Gelehrter SK, Chow EJ. Strategies to prevent anthracycline‐related congestive heart failure in survivors of childhood cancer. Cardiol Res Pract 2012: 713294, 2012.
 3.Armstrong GT, Plana JC, Zhang N, Srivastava D, Green DM, Ness KK, Daniel Donovan F, Metzger ML, Arevalo A, Durand J‐B, Joshi V, Hudson MM, Robison LL, Flamm SD. Screening adult survivors of childhood cancer for cardiomyopathy: Comparison of echocardiography and cardiac magnetic resonance imaging. J Clin Oncol 30: 2876‐2884, 2012.
 4.Arola OJ, Saraste A, Pulkki K, Kallajoki M, Parvinen M, Voipio‐Pulkki LM. Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res 60: 1789‐1792, 2000.
 5.Azarova AM, Lyu YL, Lin C‐P, Tsai Y‐C, Lau JY‐N, Wang JC, Liu LF. Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. Proc Natl Acad Sci U S A 104: 11014‐11019, 2007.
 6.Bellenger NG, Burgess MI, Ray SG, Lahiri A, Coats AJ, Cleland JG, Pennell DJ. Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance; are they interchangeable? Europ Heart J 21: 1387‐1396, 2000.
 7.Berger JM, Gamblin SJ, Harrison SC, Wang JC. Structure and mechanism of DNA topoisomerase II. Nature 379: 225‐232, 1996.
 8.Bernaba BN, Chan JB, Lai CK, Fishbein MC. Pathology of late‐onset anthracycline cardiomyopathy. Cardiovasc Pathol 19: 308‐311, 2010.
 9.Billingham ME, Mason JW, Bristow MR, Daniels JR. Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep 62: 865‐872, 1978.
 10.Bonadonna G, Monfardini S. Cardiac toxicity of daunorubicin. Lancet 1: 837, 1969.
 11.Bosch X, Rovira M, Sitges M, Domènech A, Ortiz‐Pérez JT, de Caralt TM, Morales‐Ruiz M, Perea RJ, Monzó M, Esteve J. Enalapril and carvedilol for preventing chemotherapy‐induced left ventricular systolic dysfunction in patients with malignant hemopathies: The OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol 61: 2355‐2362, 2013.
 12.Bountioukos M, Doorduijn JK, Roelandt JRTC, Vourvouri EC, Bax JJ, Schinkel AFL, Kertai MD, Sonneveld P, Poldermans D. Repetitive dobutamine stress echocardiography for the prediction of anthracycline cardiotoxicity. Eur J Echocardiogr 4: 300‐305, 2003.
 13.Bovelli D, Plataniotis G, Roila F, ESMO Guidelines Working Group. Cardiotoxicity of chemotherapeutic agents and radiotherapy‐related heart disease: ESMO Clinical Practice Guidelines. Ann Oncol 21(Suppl 5): v277‐82, 2010.
 14.Bristow MR, Thompson PD, Martin RP, Mason JW, Billingham ME, Harrison DC. Early anthracycline cardiotoxicity. Am J Med 65: 823‐832, 1978.
 15.Burjonroppa SC, Tong AT, Xiao L‐C, Johnson MM, Yusuf SW, Lenihan DJ. Cancer patients with markedly elevated B‐type natriuretic peptide may not have volume overload. Am J Clin Oncol 30: 287‐293, 2007.
 16.Cadeddu C, Piras A, Mantovani G, Deidda M, Dessì M, Madeddu C, Massa E, Mercuro G. Protective effects of the angiotensin II receptor blocker telmisartan on epirubicin‐induced inflammation, oxidative stress, and early ventricular impairment. Am Heart J 160: 487.e1‐7, 2010.
 17.Cardinale D, Colombo A, Lamantia G, Colombo N, Civelli M, De Giacomi G, Rubino M, Veglia F, Fiorentini C, Cipolla CM. Anthracycline‐induced cardiomyopathy: Clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 55: 213‐220, 2010.
 18.Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, Martinelli G, Veglia F, Fiorentini C, Cipolla CM. Prevention of high‐dose chemotherapy‐induced cardiotoxicity in high‐risk patients by angiotensin‐converting enzyme inhibition. Circulation 114: 2474‐2481, 2006.
 19.Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M, Lamantia G, Civelli M, Peccatori F, Martinelli G, Fiorentini C, Cipolla CM. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high‐dose chemotherapy. Circulation 109: 2749‐2754, 2004.
 20.Cardinale D, Sandri MT, Martinoni A, Borghini E, Civelli M, Lamantia G, Cinieri S, Martinelli G, Fiorentini C, Cipolla CM. Myocardial injury revealed by plasma troponin I in breast cancer treated with high‐dose chemotherapy. Ann Oncol 13: 710‐715, 2002.
 21.Cardinale D, Sandri MT, Martinoni A, Tricca A, Civelli M, Lamantia G, Cinieri S, Martinelli G, Cipolla CM, Fiorentini C. Left ventricular dysfunction predicted by early troponin I release after high‐dose chemotherapy. J Am Coll Cardiol 36: 517‐522, 2000.
 22.Cardinale D, Sandri MT. Role of biomarkers in chemotherapy‐induced cardiotoxicity. Progr Cardiovasc Dis 53: 121‐129, 2010.
 23.Chen B, Zhong L, Roush SF, Pentassuglia L, Peng X, Samaras S, Davidson JM, Sawyer DB, Lim CC. Disruption of a GATA4/Ankrd1 signaling axis in cardiomyocytes leads to sarcomere disarray: Implications for anthracycline cardiomyopathy. PLoS ONE 7: e35743, 2012.
 24.Childrens Oncology Group. Long‐Term Follow‐Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer Survivors. Version 4.0. [2014], accessed on July 2015.
 25.Civelli M, Cardinale D, Martinoni A, Lamantia G, Colombo N, Colombo A, Gandini S, Martinelli G, Fiorentini C, Cipolla CM. Early reduction in left ventricular contractile reserve detected by dobutamine stress echo predicts high‐dose chemotherapy‐induced cardiac toxicity. Intern J Cardiol 111: 120‐126, 2006.
 26.Colucci WS, Kolias TJ, Adams KF, Armstrong WF, Ghali JK, Gottlieb SS, Greenberg B, Klibaner MI, Kukin ML, Sugg JE, REVERT Study Group. Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: The REversal of VEntricular Remodeling with Toprol‐XL (REVERT) trial. Circulation 116: 49‐56, 2007.
 27.Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U, Levine GN, Narula J, Starling RC, Towbin J, Virmani R, American Heart Association, American College of Cardiology, European Society of Cardiology. The role of endomyocardial biopsy in the management of cardiovascular disease: A scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation 116: 2216‐2233, 2007.
 28.D'hooge J, Heimdal A, Jamal F, Kukulski T, Bijnens B, Rademakers F, Hatle L, Suetens P, Sutherland GR. Regional strain and strain rate measurements by cardiac ultrasound: Principles, implementation and limitations. Eur J Echocardiogr 1: 154‐170, 2000.
 29.Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left‐ventricular dysfunction: The CAPRICORN randomised trial. Lancet 357: 1385‐1390, 2001.
 30.Daugaard G, Lassen U, Bie P, Pedersen EB, Jensen KT, Abildgaard U, Hesse B, Kjaer A. Natriuretic peptides in the monitoring of anthracycline induced reduction in left ventricular ejection fraction. Eur J Heart Fail 7: 87‐93, 2005.
 31.De Angelis A, Piegari E, Cappetta D, Marino L, Filippelli A, Berrino L, Ferreira‐Martins J, Zheng H, Hosoda T, Rota M, Urbanek K, Kajstura J, Leri A, Rossi F, Anversa P. Anthracycline cardiomyopathy is mediated by depletion of the cardiac stem cell pool and is rescued by restoration of progenitor cell function. Circulation 121: 276‐292, 2010.
 32.Díez J, Querejeta R, López B, González A, Larman M, Martínez Ubago JL. Losartan‐dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 105: 2512‐2517, 2002.
 33.Dodd DA, Atkinson JB, Olson RD, Buck S, Cusack BJ, Fleischer S, Boucek RJ. Doxorubicin cardiomyopathy is associated with a decrease in calcium release channel of the sarcoplasmic reticulum in a chronic rabbit model. J Clin Invest 91: 1697‐1705, 1993.
 34.Dodos F, Halbsguth T, Erdmann E, Hoppe UC. Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline‐induced cardiotoxicity in adults. Clin Res Cardiol 97: 318‐326, 2008.
 35.Doroshow JH, Locker GY, Ifrim I, Myers CE. Prevention of doxorubicin cardiac toxicity in the mouse by N‐acetylcysteine. J Clin Invest 68: 1053‐1064, 1981.
 36.Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: Alterations produced by doxorubicin. J Clin Invest 65: 128‐135, 1980.
 37.Doroshow JH, Tallent C, Schechter JE. Ultrastructural features of Adriamycin‐induced skeletal and cardiac muscle toxicity. Am J Pathol 118: 288‐297, 1985.
 38.Dorup I, Levitt G, Sullivan I, Sorensen K. Prospective longitudinal assessment of late anthracycline cardiotoxicity after childhood cancer: The role of diastolic function. Heart 90: 1214‐1216, 2004.
 39.Drafts BC, Twomley KM, D'Agostino R, Lawrence J, Avis N, Ellis LR, Thohan V, Jordan J, Melin SA, Torti FM, Little WC, Hamilton CA, Hundley WG. Low to moderate dose anthracycline‐based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease. J Am Coll Cardiol Cardiovasc Imaging 6: 877‐885, 2013.
 40.Ewer MS, Ali MK, Mackay B, Wallace S, Valdivieso M, Legha SS, Benjamin RS, Haynie TP. A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin. J Clin Oncol 2: 112‐117, 1984.
 41.Exner DV, Dries DL, Waclawiw MA, Shelton B, Domanski MJ. Beta‐adrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: A post hoc analysis of the Studies of Left Ventricular Dysfunction. J Am Coll Cardiol 33: 916‐923, 1999.
 42.Fallah‐Rad N, Walker JR, Wassef A, Lytwyn M, Bohonis S, Fang T, Tian G, Kirkpatrick IDC, Singal PK, Krahn M, Grenier D, Jassal DS. The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II‐positive breast cancer treated with adjuvant trastuzumab therapy. J Am Coll Cardiol 57: 2263‐2270, 2011.
 43.Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, Kasper EK. Underlying causes and long‐term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 342: 1077‐1084, 2000.
 44.Ferrans VJ. Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treat Rep 62: 955‐961, 1978.
 45.Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase‐5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation 111: 1601‐1610, 2005.
 46.Floyd JD, Nguyen DT, Lobins RL, Bashir Q, Doll DC, Perry MC. Cardiotoxicity of cancer therapy. J Clin Oncol 23: 7685‐7696, 2005.
 47.Francis SA, Cheng S, Arteaga CL, Moslehi J. Heart failure and breast cancer therapies: Moving towards personalized risk assessment. J Am Heart Assoc 3: e000780, 2014.
 48.Friedman MA, Bozdech MJ, Billingham ME, Rider AK. Doxorubicin cardiotoxicity. Serial endomyocardial biopsies and systolic time intervals. JAMA 240: 1603‐1606, 1978.
 49.Friedrich MG, Sechtem U, Schulz‐Menger J, Holmvang G, Alakija P, Cooper LT, White JA, Abdel‐Aty H, Gutberlet M, Prasad S, Aletras A, Laissy J‐P, Paterson I, Filipchuk NG, Kumar A, Pauschinger M, Liu P, International Consensus Group on Cardiovascular Magnetic Resonance in Myocarditis. Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol 53: 1475‐1487, 2009.
 50.Friess GG, Boyd JF, Geer MR, Garcia JC. Effects of first‐dose doxorubicin on cardiac rhythm as evaluated by continuous 24‐hour monitoring. Cancer 56: 2762‐2764, 1985.
 51.Ganz WI, Sridhar KS, Forness TJ. Detection of early anthracycline cardiotoxicity by monitoring the peak filling rate. Am J Clin Oncol 16: 109‐112, 1993.
 52.Gao J, Xiong Y, Ho Y‐S, Liu X, Chua CC, Xu X, Wang H, Hamdy R, Chua BHL. Glutathione peroxidase 1‐deficient mice are more susceptible to doxorubicin‐induced cardiotoxicity. Biochim Biophys Acta 1783: 2020‐2029, 2008.
 53.Gaudin PB, Hruban RH, Beschorner WE, Kasper EK, Olson JL, Baughman KL, Hutchins GM. Myocarditis associated with doxorubicin cardiotoxicity. Am J Clin Pathol 100: 158‐163, 1993.
 54.Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57: 727‐741, 1999.
 55.Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB. Anthracycline cardiotoxicity: From bench to bedside. J Clin Oncol 26: 3777‐3784, 2008.
 56.Giantris A, Abdurrahman L, Hinkle A, Asselin B, Lipshultz SE. Anthracycline‐induced cardiotoxicity in children and young adults. Crit Rev Oncol Hematol 27: 53‐68, 1998.
 57.Goll DE, Thompson VF, Li H, Wei W, Cong J. The calpain system. Physiol Rev 83: 731‐801, 2003.
 58.Gottdiener JS, Mathisen DJ, Borer JS, Bonow RO, Myers CE, Barr LH, Schwartz DE, Bacharach SL, Green MV, Rosenberg SA. Doxorubicin cardiotoxicity: Assessment of late left ventricular dysfunction by radionuclide cineangiography. Ann Intern Med 94: 430‐435, 1981.
 59.Green DM, Grigoriev YA, Nan B, Takashima JR, Norkool PA, D'Angio GJ, Breslow NE. Congestive heart failure after treatment for Wilms” tumor: A report from the National Wilms” Tumor Study group. J Clin Oncol 19: 1926‐1934, 2001.
 60.Grothues F, Smith GC, Moon JCC, Bellenger NG, Collins P, Klein HU, Pennell DJ. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two‐dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol 90: 29‐34, 2002.
 61.Guglin M, Aljayeh M, Saiyad S, Ali R, Curtis AB. Introducing a new entity: Chemotherapy‐induced arrhythmia. Europace 11: 1579‐1586, 2009.
 62.Gulati G, Zhang KW, Scherrer‐Crosbie M, Ky B. Cancer and cardiovascular disease: The use of novel echocardiography measures to predict subsequent cardiotoxicity in breast cancer treated with anthracyclines and trastuzumab. Curr Heart Fail Rep 11: 366‐373, 2014.
 63.Hasinoff BB, Patel D, Wu X. The oral iron chelator ICL670A (deferasirox) does not protect myocytes against doxorubicin. Free Radic Biol Med 35: 1469‐1479, 2003.
 64.Hendel RC, Patel MR, Kramer CM, Poon M, Carr JC, Gerstad NA, Gillam LD, Hodgson JM, Kim RJ, Lesser JR, Martin ET, Messer JV, Redberg RF, Rubin GD, Rumsfeld JS, Taylor AJ, Weigold WG, Woodard PK, Brindis RG, Douglas PS, Peterson ED, Wolk MJ, Allen JM, American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group, American College of Radiology, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, American Society of Nuclear Cardiology, North American Society for Cardiac Imaging, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology. ACCF/ACR/SCCT/SCMR/ASNC/NASCI/SCAI/SIR 2006 appropriateness criteria for cardiac computed tomography and cardiac magnetic resonance imaging: A report of the American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group, American College of Radiology, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, American Society of Nuclear Cardiology, North American Society for Cardiac Imaging, Society for Cardiovascular Angiography and Interventions, and Society of Interventional Radiology. J Am Coll Cardiol 48: 1475‐1497, 2006.
 65.Hensley ML, Schuchter LM, Lindley C, Meropol NJ, Cohen GI, Broder G, Gradishar WJ, Green DM, Langdon RJ, Mitchell RB, Negrin R, Szatrowski TP, Thigpen JT, Hoff Von D, Wasserman TH, Winer EP, Pfister DG. American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 17: 3333‐3355, 1999.
 66.Hequet O, Le QH, Moullet I, Pauli E, Salles G, Espinouse D, Dumontet C, Thieblemont C, Arnaud P, Antal D, Bouafia F, Coiffier B. Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults. J Clin Oncol 22: 1864‐1871, 2004.
 67.Ho E, Brown A, Barrett P, Morgan RB, King G, Kennedy MJ, Murphy RT. Subclinical anthracycline‐ and trastuzumab‐induced cardiotoxicity in the long‐term follow‐up of asymptomatic breast cancer survivors: A speckle tracking echocardiographic study. Heart 96: 701‐707, 2010.
 68.Hoff Von DD, Layard MW, Basa P, Davis HL, Hoff Von AL, Rozencweig M, Muggia FM. Risk factors for doxorubicin‐induced congestive heart failure. Ann Intern Med 91: 710‐717, 1979.
 69.Hoff Von DD, Rozencweig M, Layard M, Slavik M, Muggia FM. Daunomycin‐induced cardiotoxicity in children and adults. A review of 110 cases. Am J Med 62: 200‐208, 1977.
 70.Hoffmann R, Bardeleben von S, Cate ten F, Borges AC, Kasprzak J, Firschke C, Lafitte S, Al‐Saadi N, Kuntz‐Hehner S, Engelhardt M, Becher H, Vanoverschelde J‐L. Assessment of systolic left ventricular function: A multi‐centre comparison of cineventriculography, cardiac magnetic resonance imaging, unenhanced and contrast‐enhanced echocardiography. Europ Heart J 26: 607‐616, 2005.
 71.Horacek JM, Pudil R, Jebavy L, Tichy M, Zak P, Maly J. Assessment of anthracycline‐induced cardiotoxicity with biochemical markers. Exp Oncol 29: 309‐313, 2007.
 72.Hotchkiss RS, Strasser A, McDunn JE, Swanson PE. Cell death. N Engl J Med 361: 1570‐1583, 2009.
 73.Huang C, Zhang X, Ramil JM, Rikka S, Kim L, Lee Y, Gude NA, Thistlethwaite PA, Sussman MA, Gottlieb RA, Gustafsson AB. Juvenile exposure to anthracyclines impairs cardiac progenitor cell function and vascularization resulting in greater susceptibility to stress‐induced myocardial injury in adult mice. Circulation 121: 675‐683, 2010.
 74.Hudson MM, Ness KK, Gurney JG, Mulrooney DA, Chemaitilly W, Krull KR, Green DM, Armstrong GT, Nottage KA, Jones KE, Sklar CA, Srivastava DK, Robison LL. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309: 2371‐2381, 2013.
 75.Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B, American College of Cardiology, American Heart Association Task Force on Practice Guidelines, American College of Chest Physicians, International Society for Heart and Lung Transplantation, Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation 112: e154‐235, 2005.
 76.Ichihara S, Yamada Y, Kawai Y, Osawa T, Furuhashi K, Duan Z, Ichihara G. Roles of oxidative stress and Akt signaling in doxorubicin cardiotoxicity. Biochem Biophys Res Commun 359: 27‐33, 2007.
 77.Ichikawa Y, Ghanefar M, Bayeva M, Wu R, Khechaduri A, Naga Prasad SV, Mutharasan RK, Naik TJ, Ardehali H. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J Clin Invest 124: 617‐630, 2014.
 78.Imondi AR, Torre Della P, Mazué G, Sullivan TM, Robbins TL, Hagerman LM, Podestà A, Pinciroli G. Dose‐response relationship of dexrazoxane for prevention of doxorubicin‐induced cardiotoxicity in mice, rats, and dogs. Cancer Res 56: 4200‐4204, 1996.
 79.Izawa H, Murohara T, Nagata K, Isobe S, Asano H, Amano T, Ichihara S, Kato T, Ohshima S, Murase Y, Iino S, Obata K, Noda A, Okumura K, Yokota M. Mineralocorticoid receptor antagonism ameliorates left ventricular diastolic dysfunction and myocardial fibrosis in mildly symptomatic patients with idiopathic dilated cardiomyopathy: A pilot study. Circulation 112: 2940‐2945, 2005.
 80.Jo S‐H, Kim LS, Kim S‐A, Kim H‐S, Han S‐J, Park WJ, Choi YJ. Evaluation of Short‐term use of N‐acetylcysteine as a strategy for prevention of anthracycline‐induced cardiomyopathy: EPOCH trial ‐ A Prospective Randomized Study. Korean Circ J 43: 174‐181, 2013.
 81.Jones LW, Courneya KS, Mackey JR, Muss HB, Pituskin EN, Scott JM, Hornsby WE, Coan AD, Herndon JE, Douglas PS, Haykowsky M. Cardiopulmonary function and age‐related decline across the breast cancer survivorship continuum. J Clin Oncol 30: 2530‐2537, 2012.
 82.Jones LW, Liang Y, Pituskin EN, Battaglini CL, Scott JM, Hornsby WE, Haykowsky M. Effect of exercise training on peak oxygen consumption in patients with cancer: A meta‐analysis. Oncologist 16: 112‐120, 2011.
 83.Jones LW, Watson D, Herndon JE, Eves ND, Haithcock BE, Loewen G, Kohman L. Peak oxygen consumption and long‐term all‐cause mortality in nonsmall cell lung cancer. Cancer 116: 4825‐4832, 2010.
 84.Jong P, Yusuf S, Rousseau MF, Ahn SA, Bangdiwala SI. Effect of enalapril on 12‐year survival and life expectancy in patients with left ventricular systolic dysfunction: A follow‐up study. Lancet 361: 1843‐1848, 2003.
 85.Kalay N, Basar E, Ozdogru I, Er O, Cetinkaya Y, Dogan A, Inanc T, Oguzhan A, Eryol NK, Topsakal R, Ergin A. Protective effects of carvedilol against anthracycline‐induced cardiomyopathy. J Am Coll Cardiol 48: 2258‐2262, 2006.
 86.Kalivendi SV, Kotamraju S, Zhao H, Joseph J, Kalyanaraman B. Doxorubicin‐induced apoptosis is associated with increased transcription of endothelial nitric‐oxide synthase. Effect of antiapoptotic antioxidants and calcium. J Biol Chem 276: 47266‐47276, 2001.
 87.Kerr JF, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide‐ranging implications in tissue kinetics. Br J Cancer 26: 239‐257, 1972.
 88.Khiati S, Dalla Rosa I, Sourbier C, Ma X, Rao VA, Neckers LM, Zhang H, Pommier Y. Mitochondrial topoisomerase I (top 1 mt) is a novel limiting factor of Doxorubicin cardiotoxicity. Clin Cancer Res 20: 4873‐4881, 2014.
 89.Kilickap S, Akgul E, Aksoy S, Aytemir K, Barista I. Doxorubicin‐induced second degree and complete atrioventricular block. Europace 7: 227‐230, 2005.
 90.Kleber FX, Niemöller L, Doering W. Impact of converting enzyme inhibition on progression of chronic heart failure: Results of the Munich Mild Heart Failure Trial. Br Heart J 67: 289‐296, 1992.
 91.Knobloch K, Tepe J, Lichtinghagen R, Luck HJ, Vogt PM. Monitoring of cardiotoxicity during immunotherapy with Herceptin using simultaneous continuous wave Doppler depending on N‐terminal pro‐brain natriuretic peptide. Clin Med 7: 88‐9, 2007.
 92.Knobloch K, Tepe J, Rossner D, Lichtinghagen R, Luck HJ, Busch KH, Vogt PM. Combined NT‐pro‐BNP and CW‐Doppler ultrasound cardiac output monitoring (USCOM) in epirubicin and liposomal doxorubicin therapy. Intern J Cardiol 128: 316‐325, 2008.
 93.Køber L, Torp‐Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, Videbaek J, Cole DS, Auclert L, Pauly NC. A clinical trial of the angiotensin‐converting‐enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 333: 1670‐1676, 1995.
 94.Kotamraju S, Chitambar CR, Kalivendi SV, Joseph J, Kalyanaraman B. Transferrin receptor‐dependent iron uptake is responsible for doxorubicin‐mediated apoptosis in endothelial cells: Role of oxidant‐induced iron signaling in apoptosis. J Biol Chem 277: 17179‐17187, 2002.
 95.Kremer LCM, van Dalen EC, Offringa M, Voûte PA. Frequency and risk factors of anthracycline‐induced clinical heart failure in children: A systematic review. Ann Oncol 13: 503‐512, 2002.
 96.Kremer LCM, van der Pal HJH, Offringa M, van Dalen EC, Voûte PA. Frequency and risk factors of subclinical cardiotoxicity after anthracycline therapy in children: A systematic review. Ann Oncol 13: 819‐829, 2002.
 97.Krischer JP, Epstein S, Cuthbertson DD, Goorin AM, Epstein ML, Lipshultz SE. Clinical cardiotoxicity following anthracycline treatment for childhood cancer: The Pediatric Oncology Group experience. J Clin Oncol 15: 1544‐1552, 1997.
 98.Ky B, Putt M, Sawaya H, French B, Januzzi JL, Sebag IA, Plana JC, Cohen V, Banchs J, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer‐Crosbie M. Early increases in multiple biomarkers predict subsequent cardiotoxicity in breast cancer patients treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol 63: 809‐816, 2013.
 99.Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MSJ, Stewart WJ, Chamber Quantification Writing Group, American Society of Echocardiography's Guidelines and Standards Committee, European Association of Echocardiography. Recommendations for chamber quantification: A report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 18: 1440‐1463, 2005.
 100.Lanzarini L, Bossi G, Laudisa ML, Klersy C, Aricò M. Lack of clinically significant cardiac dysfunction during intermediate dobutamine doses in long‐term childhood cancer survivors exposed to anthracyclines. Am Heart J 140: 315‐323, 2000.
 101.Lee BH, Goodenday LS, Muswick GJ, Yasnoff WA, Leighton RF, Skeel RT. Alterations in left ventricular diastolic function with doxorubicin therapy. J Am Coll Cardiol 9: 184‐188, 1987.
 102.Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32: 302‐314, 1973.
 103.Lenneman AJ, Wang L, Wigger M, Frangoul H, Harrell FE, Silverstein C, Sawyer DB, Lenneman CG. Heart transplant survival outcomes for adriamycin‐dilated cardiomyopathy. Am J Cardiol 111: 609‐612, 2013.
 104.Le Winter MM, Granzier H. Cardiac titin: A multifunctional giant. Circulation 121: 2137‐2145, 2010.
 105.Lien Y‐C, Lin S‐M, Nithipongvanitch R, Oberley TD, Noel T, Zhao Q, Daosukho C, St Clair DK. Tumor necrosis factor receptor deficiency exacerbated Adriamycin‐induced cardiomyocytes apoptosis: An insight into the Fas connection. Mol Cancer Ther 5: 261‐269, 2006.
 106.Lightfoot JC, D'Agostino RB, Hamilton CA, Jordan J, Torti FM, Kock ND, Jordan J, Workman S, Hundley WG. Novel approach to early detection of doxorubicin cardiotoxicity by gadolinium‐enhanced cardiovascular magnetic resonance imaging in an experimental model. Circ Cardiovasc Imaging 3: 550‐558, 2010.
 107.Lim CC, Zuppinger C, Guo X, Kuster GM, Helmes M, Eppenberger HM, Suter TM, Liao R, Sawyer DB. Anthracyclines induce calpain‐dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem 279: 8290‐8299, 2004.
 108.Lipshultz SE, Colan SD, Gelber RD, Perez‐Atayde AR, Sallan SE, Sanders SP. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324: 808‐815, 1991.
 109.Lipshultz SE, Colan SD. Cardiovascular trials in long‐term survivors of childhood cancer. J Clin Oncol 22: 769‐773, 2004.
 110.Lipshultz SE, Lipsitz SR, Kutok JL, Miller TL, Colan SD, Neuberg DS, Stevenson KE, Fleming MD, Sallan SE, Franco VI, Henkel JM, Asselin BL, Athale UH, Clavell LA, Michon B, Laverdiere C, Larsen E, Kelly KM, Silverman LB. Impact of hemochromatosis gene mutations on cardiac status in doxorubicin‐treated survivors of childhood high‐risk leukemia. Cancer 119: 3555‐3562, 2013.
 111.Lipshultz SE, Lipsitz SR, Sallan SE, Dalton VM, Mone SM, Gelber RD, Colan SD. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J. Clin. Oncol. 23: 2629‐2636, 2005.
 112.Lipshultz SE, Lipsitz SR, Sallan SE, Simbre VC, Shaikh SL, Mone SM, Gelber RD, Colan SD. Long‐term enalapril therapy for left ventricular dysfunction in doxorubicin‐treated survivors of childhood cancer. J Clin Oncol 20: 4517‐4522, 2002.
 113.Lipshultz SE, Miller TL, Scully RE, Lipsitz SR, Rifai N, Silverman LB, Colan SD, Neuberg DS, Dahlberg SE, Henkel JM, Asselin BL, Athale UH, Clavell LA, Laverdiere C, Michon B, Schorin MA, Sallan SE. Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high‐risk acute lymphoblastic leukemia: Associations with long‐term echocardiographic outcomes. J Clin Oncol 30: 1042‐1049, 2012.
 114.Lipshultz SE, Rifai N, Dalton VM, Levy DE, Silverman LB, Lipsitz SR, Colan SD, Asselin BL, Barr RD, Clavell LA, Hurwitz CA, Moghrabi A, Samson Y, Schorin MA, Gelber RD, Sallan SE. The effect of dexrazoxane on myocardial injury in doxorubicin‐treated children with acute lymphoblastic leukemia. N Engl J Med 351: 145‐153, 2004.
 115.Lipshultz SE, Rifai N, Sallan SE, Lipsitz SR, Dalton V, Sacks DB, Ottlinger ME. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 96: 2641‐2648, 1997.
 116.Lipshultz SE, Scully RE, Lipsitz SR, Sallan SE, Silverman LB, Miller TL, Barry EV, Asselin BL, Athale U, Clavell LA, Larsen E, Moghrabi A, Samson Y, Michon B, Schorin MA, Cohen HJ, Neuberg DS, Orav EJ, Colan SD. Assessment of dexrazoxane as a cardioprotectant in doxorubicin‐treated children with high‐risk acute lymphoblastic leukaemia: Long‐term follow‐up of a prospective, randomised, multicentre trial. Lancet Oncol 11: 950‐961, 2010.
 117.Liu L, Zhang X, Qian B, Min X, Gao X, Li C, Cheng Y, Huang J. Over‐expression of heat shock protein 27 attenuates doxorubicin‐induced cardiac dysfunction in mice. Eur J Heart Fail 9: 762‐769, 2007.
 118.Marchandise B, Schroeder E, Bosly A, Doyen C, Weynants P, Kremer R, Pouleur H. Early detection of doxorubicin cardiotoxicity: Interest of Doppler echocardiographic analysis of left ventricular filling dynamics. Am Heart J 118: 92‐98, 1989.
 119.Mason JW, Bristow MR, Billingham ME, Daniels JR. Invasive and noninvasive methods of assessing adriamycin cardiotoxic effects in man: Superiority of histopathologic assessment using endomyocardial biopsy. Cancer Treat Rep 62: 857‐864, 1978.
 120.Mathé G, Hayat M, Schwarzenberg L, Amiel JL, Schneider M, Cattan A, Schlumberger JR, Jasmin C. Acute lymphoblastic leukaemia treated with a combination of prednisone, vincristine, and rubidomycin. Value of pathogen‐free rooms. Lancet 2: 380‐382, 1967.
 121.McKillop JH, Bristow MR, Goris ML, Billingham ME, Bockemuehl K. Sensitivity and specificity of radionuclide ejection fractions in doxorubicin cardiotoxicity. Am Heart J 106: 1048‐1056, 1983.
 122.Meinardi MT, van der Graaf WT, van Veldhuisen DJ, Gietema JA, de Vries EG, Sleijfer DT. Detection of anthracycline‐induced cardiotoxicity. Cancer Treat Rev 25: 237‐247, 1999.
 123.Meinardi MT, van Veldhuisen DJ, Gietema JA, Dolsma WV, Boomsma F, van den Berg MP, Volkers C, Haaksma J, de Vries EG, Sleijfer DT, van der Graaf WT. Prospective evaluation of early cardiac damage induced by epirubicin‐containing adjuvant chemotherapy and locoregional radiotherapy in breast cancer patients. J Clin Oncol 19: 2746‐2753, 2001.
 124.Midtgaard J, Christensen JF, Tolver A, Jones LW, Uth J, Rasmussen B, Tang L, Adamsen L, Rørth M. Efficacy of multimodal exercise‐based rehabilitation on physical activity, cardiorespiratory fitness, and patient‐reported outcomes in cancer survivors: A randomized, controlled trial. Ann Oncol 24: 2267‐2273, 2013.
 125.Miranda CJ, Makui H, Soares RJ, Bilodeau M, Mui J, Vali H, Bertrand R, Andrews NC, Santos MM. Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin. Blood 102: 2574‐2580, 2003.
 126.Møgelvang J, Stokholm KH, Saunamäki K, Reimer A, Stubgaard M, Thomsen C, Fritz‐Hansen P, Henriksen O. Assessment of left ventricular volumes by magnetic resonance in comparison with radionuclide angiography, contrast angiography and echocardiography. Europ Heart J 13: 1677‐1683, 1992.
 127.Moghrabi A, Levy DE, Asselin B, Barr R, Clavell L, Hurwitz C, Samson Y, Schorin M, Dalton VK, Lipshultz SE, Neuberg DS, Gelber RD, Cohen HJ, Sallan SE, Silverman LB. Results of the Dana‐Farber Cancer Institute ALL Consortium Protocol 95‐01 for children with acute lymphoblastic leukemia. Blood 109: 896‐904, 2007.
 128.Monsuez J‐J, Charniot J‐C, Vignat N, Artigou J‐Y. Cardiac side‐effects of cancer chemotherapy. Intern J Cardiol 144: 3‐15, 2010.
 129.Mor‐Avi V, Lang RM, Badano LP, Belohlavek M, Cardim NM, Derumeaux G, Galderisi M, Marwick T, Nagueh SF, Sengupta PP, Sicari R, Smiseth OA, Smulevitz B, Takeuchi M, Thomas JD, Vannan M, Voigt J‐U, Zamorano JL. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. J Am Soc Echocardiogr 24: 277‐313, 2011.
 130.Muindi JR, Sinha BK, Gianni L, Myers CE. Hydroxyl radical production and DNA damage induced by anthracycline‐iron complex. FEBS Lett 172: 226‐230, 1984.
 131.Mulrooney DA, Yeazel MW, Kawashima T, Mertens AC, Mitby P, Stovall M, Donaldson SS, Green DM, Sklar CA, Robison LL, Leisenring WM. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: Retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 339: b4606, 2009.
 132.Myers CE, McGuire WP, Liss RH, Ifrim I, Grotzinger K, Young RC. Adriamycin: The role of lipid peroxidation in cardiac toxicity and tumor response. Science 197: 165‐167, 1977.
 133.Naik MM, Diamond GA, Pai T, Soffer A, Siegel RJ. Correspondence of left ventricular ejection fraction determinations from two‐dimensional echocardiography, radionuclide angiography and contrast cineangiography. J Am Coll Cardiol 25: 937‐942, 1995.
 134.Nakamae H, Tsumura K, Terada Y, Nakane T, Nakamae M, Ohta K, Yamane T, Hino M. Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Cancer 104: 2492‐2498, 2005.
 135.Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA. Apoptosis in myocytes in end‐stage heart failure. N Engl J Med 335: 1182‐1189, 1996.
 136.Negishi K, Negishi T, Haluska BA, Hare JL, Plana JC, Marwick TH. Use of speckle strain to assess left ventricular responses to cardiotoxic chemotherapy and cardioprotection. Eur Heart J Cardiovasc Imaging 15: 324‐331, 2014.
 137.Negishi K, Negishi T, Hare JL, Haluska BA, Plana JC, Marwick TH. Independent and incremental value of deformation indices for prediction of trastuzumab‐induced cardiotoxicity. J Am Soc Echocardiogr 26: 493‐498, 2013.
 138.Negoro S, Oh H, Tone E, Kunisada K, Fujio Y, Walsh K, Kishimoto T, Yamauchi‐Takihara K. Glycoprotein 130 regulates cardiac myocyte survival in doxorubicin‐induced apoptosis through phosphatidylinositol 3‐kinase/Akt phosphorylation and Bcl‐xL/caspase‐3 interaction. Circulation 103: 555‐561, 2001.
 139.Neilan TG, Blake SL, Ichinose F, Raher MJ, Buys ES, Jassal DS, Furutani E, Perez‐Sanz TM, Graveline A, Janssens SP, Picard MH, Scherrer‐Crosbie M, Bloch KD. Disruption of nitric oxide synthase 3 protects against the cardiac injury, dysfunction, and mortality induced by doxorubicin. Circulation 116: 506‐514, 2007.
 140.Neilan TG, Coelho‐Filho OR, Pena‐Herrera D, Shah RV, Jerosch‐Herold M, Francis SA, Moslehi J, Kwong RY. Left ventricular mass in patients with a cardiomyopathy after treatment with anthracyclines. Am J Cardiol. 110: 1679‐1686, 2012.
 141.Neilan TG, Coelho‐Filho OR, Shah RV, Abbasi SA, Heydari B, Watanabe E, Chen Y, Mandry D, Pierre‐Mongeon F, Blankstein R, Kwong RY, Jerosch‐Herold M. Myocardial extracellular volume fraction from T1 measurements in healthy volunteers and mice: Relationship to aging and cardiac dimensions. J Am Coll Cardiol Cardiovasc Imaging 6: 672‐683, 2013.
 142.Neilan TG, Coelho‐Filho OR, Shah RV, Feng JH, Pena‐Herrera D, Mandry D, Pierre‐Mongeon F, Heydari B, Francis SA, Moslehi J, Kwong RY, Jerosch‐Herold M. Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline‐based chemotherapy. Am J Cardiol 111: 717‐722, 2013.
 143.Neilan TG, Doherty GA, Chen G, Deflandre C, McAllister H, Butler RK, McClelland SE, Kay E, Ballou LR, Fitzgerald DJ. Disruption of COX‐2 modulates gene expression and the cardiac injury response to doxorubicin. Am J Physiol Heart Circ Physiol 291: H532‐6, 2006.
 144.Neilan TG, Jassal DS, Scully MF, Chen G, Deflandre C, McAllister H, Kay E, Austin SC, Halpern EF, Harmey JH, Fitzgerald DJ. Iloprost attenuates doxorubicin‐induced cardiac injury in a murine model without compromising tumour suppression. Europ Heart J 27: 1251‐1256, 2006.
 145.Neilan TG. Tissue Doppler imaging predicts left ventricular dysfunction and mortality in a murine model of cardiac injury. Europ Heart J 27: 1868‐1875, 2006.
 146.Nisticò C, Bria E, Cuppone F, Carpino A, Ferretti G, Vitelli G, Sperduti I, Calabretta F, Toglia G, Tomao S, Cognetti F, Terzoli E. Troponin‐T and myoglobin plus echocardiographic evaluation for monitoring early cardiotoxicity of weekly epirubicin‐paclitaxel in metastatic breast cancer patients. Anticancer Drugs 18: 227‐232, 2007.
 147.Nousiainen T, Jantunen E, Vanninen E, Remes J, Vuolteenaho O, Hartikainen J. Natriuretic peptides as markers of cardiotoxicity during doxorubicin treatment for non‐Hodgkin's lymphoma. Eur J Haematol 62: 135‐141, 1999.
 148.Nozaki N, Shishido T, Takeishi Y, Kubota I. Modulation of doxorubicin‐induced cardiac dysfunction in toll‐like receptor‐2‐knockout mice. Circulation 110: 2869‐2874, 2004.
 149.Okumura H, Iuchi K, Yoshida T, Nakamura S, Takeshima M, Takamatsu H, Ikeno A, Usuda K, Ishikawa T, Ohtake S, Matsuda T. Brain natriuretic peptide is a predictor of anthracycline‐induced cardiotoxicity. Acta Haematol 104: 158‐163, 2000.
 150.Ondrias K, Borgatta L, Kim DH, Ehrlich BE. Biphasic effects of doxorubicin on the calcium release channel from sarcoplasmic reticulum of cardiac muscle. Circ Res 67: 1167‐1174, 1990.
 151.Otterstad JE, Froeland G, St John Sutton M, Holme I. Accuracy and reproducibility of biplane two‐dimensional echocardiographic measurements of left ventricular dimensions and function. Europ Heart J 18: 507‐513, 1997.
 152.Pennell DJ. Cardiovascular magnetic resonance. Circulation 121: 692‐705, 2010.
 153.Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 327: 669‐677, 1992.
 154.Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer‐Crosbie M, Ganame J, Sebag IA, Agler DA, Badano LP, Banchs J, Cardinale D, Carver J, Cerqueira M, DeCara JM, Edvardsen T, Flamm SD, Force T, Griffin BP, Jerusalem G, Liu JE, Magalhães A, Marwick T, Sanchez LY, Sicari R, Villarraga HR, Lancellotti P. 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 27: 911‐939, 2014.
 155.Porter TR, Kaminksy W, Mayer JM. Preparation, structural characterization and thermochemistry of an isolable 4‐aryl phenoxyl radical. J Org Chem 79(20): 9451‐9454, 2014.
 156.Rahman AM, Yusuf SW, Ewer MS. Anthracycline‐induced cardiotoxicity and the cardiac‐sparing effect of liposomal formulation. Int J Nanomed 2: 567‐583, 2007.
 157.Raj S, Franco VI, Lipshultz SE. Anthracycline‐induced cardiotoxicity: A review of pathophysiology, diagnosis, and treatment. Curr Treat Options Cardiovasc Med 16: 315, 2014.
 158.Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C, Hartwiger S, Biedert S, Schaub N, Buerge C, Potocki M, Noveanu M, Breidthardt T, Twerenbold R, Winkler K, Bingisser R, Mueller C. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 361: 858‐867, 2009.
 159.Riad A, Bien S, Westermann D, Becher PM, Loya K, Landmesser U, Kroemer HK, Schultheiss HP, Tschöpe C. Pretreatment with statin attenuates the cardiotoxicity of Doxorubicin in mice. Cancer Res 69: 695‐699, 2009.
 160.Rickard J, Kumbhani DJ, Baranowski B, Martin DO, Tang WH, Wilkoff BL. Usefulness of cardiac resynchronization therapy in patients with Adriamycin‐induced cardiomyopathy. Am J Cardiol 105: 522‐526, 2010.
 161.Ritchie JL, Bateman TM, Bonow RO, Crawford MH, Gibbons RJ, Hall RJ, O'Rourke RA, Parisi AF, Verani MS. Guidelines for clinical use of cardiac radionuclide imaging. A report of the American Heart Association/American College of Cardiology Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures, Committee on Radionuclide Imaging, developed in collaboration with the American Society of Nuclear Cardiology. Circulation 91: 1278‐1303, 1995.
 162.Romano S, Fratini S, Ricevuto E, Procaccini V, Stifano G, Mancini M, Di Mauro M, Ficorella C, Penco M. Serial measurements of NT‐proBNP are predictive of not‐high‐dose anthracycline cardiotoxicity in breast cancer patients. Br J Cancer 105: 1663‐1668, 2011.
 163.Romond EH, Jeong J‐H, Rastogi P, Swain SM, Geyer CE, Ewer MS, Rathi V, Fehrenbacher L, Brufsky A, Azar CA, Flynn PJ, Zapas JL, Polikoff J, Gross HM, Biggs DD, Atkins JN, Tan‐Chiu E, Zheng P, Yothers G, Mamounas EP, Wolmark N. 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 30: 3792‐3799, 2012.
 164.Saeki K, Obi I, Ogiku N, Shigekawa M, Imagawa T, Matsumoto T. Doxorubicin directly binds to the cardiac‐type ryanodine receptor. Life Sci 70: 2377‐2389, 2002.
 165.Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Cohen V, Gosavi S, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer‐Crosbie M. Early detection and prediction of cardiotoxicity in chemotherapy‐treated patients. Am J Cardiol 107: 1375‐1380, 2011.
 166.Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Tan TC, Cohen V, Banchs J, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer‐Crosbie M. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes and trastuzumab. Circ Cardiovasc Imaging 5: 596‐603, 2012.
 167.Sawyer DB. Anthracyclines and heart failure. N Engl J Med 368: 1154‐1156, 2013.
 168.Schwartz RG, McKenzie WB, Alexander J, Sager P, D'Souza A, Manatunga A, Schwartz PE, Berger HJ, Setaro J, Surkin L. Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven‐year experience using serial radionuclide angiocardiography. Am J Med 82: 1109‐1118, 1987.
 169.Seicean S, Seicean A, Plana JC, Budd GT, Marwick TH. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: An observational clinical cohort study. J Am Coll Cardiol 60: 2384‐2390, 2012.
 170.Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20: 1215‐1221, 2002.
 171.Shan Y‐X, Liu T‐J, Su H‐F, Samsamshariat A, Mestril R, Wang PH. Hsp10 and Hsp60 modulate Bcl‐2 family and mitochondria apoptosis signaling induced by doxorubicin in cardiac muscle cells. J Mol Cell Cardiol 35: 1135‐1143, 2003.
 172.Shioji K, Kishimoto C, Nakamura H, Masutani H, Yuan Z, Oka S‐I, Yodoi J. Overexpression of thioredoxin‐1 in transgenic mice attenuates adriamycin‐induced cardiotoxicity. Circulation 106: 1403‐1409, 2002.
 173.Silber JH, Cnaan A, Clark BJ, Paridon SM, Chin AJ, Rychik J, Hogarty AN, Cohen MI, Barber G, Rutkowski M, Kimball TR, Delaat C, Steinherz LJ, Zhao H. Enalapril to prevent cardiac function decline in long‐term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol 22: 820‐828, 2004.
 174.Singal PK, Iliskovic N. Doxorubicin‐induced cardiomyopathy. N Engl J Med 339: 900‐905, 1998.
 175.Skovgaard D, Hasbak P, Kjaer A. BNP predicts chemotherapy‐related cardiotoxicity and death: Comparison with gated equilibrium radionuclide ventriculography. PLoS ONE 9: e96736, 2014.
 176.Smith LA, Cornelius VR, Plummer CJ, Levitt G, Verrill M, Canney P, Jones A. Cardiotoxicity of anthracycline agents for the treatment of cancer: Systematic review and meta‐analysis of randomised controlled trials. BMC Cancer 10: 337, 2010.
 177.Steinberg JS, Cohen AJ, Wasserman AG, Cohen P, Ross AM. Acute arrhythmogenicity of doxorubicin administration. Cancer 60: 1213‐1218, 1987.
 178.Steinherz LJ, Graham T, Hurwitz R, Sondheimer HM, Schwartz RG, Shaffer EM, Sandor G, Benson L, Williams R. Guidelines for cardiac monitoring of children during and after anthracycline therapy: Report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics 89: 942‐949, 1992.
 179.Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266: 1672‐1677, 1991.
 180.Stoddard MF, Seeger J, Liddell NE, Hadley TJ, Sullivan DM, Kupersmith J. Prolongation of isovolumetric relaxation time as assessed by Doppler echocardiography predicts doxorubicin‐induced systolic dysfunction in humans. J Am Coll Cardiol 20: 62‐69, 1992.
 181.Suzuki G, Morita H, Mishima T, Sharov VG, Todor A, Tanhehco EJ, Rudolph AE, McMahon EG, Goldstein S, Sabbah HN. Effects of long‐term monotherapy with eplerenone, a novel aldosterone blocker, on progression of left ventricular dysfunction and remodeling in dogs with heart failure. Circulation 106: 2967‐2972, 2002.
 182.Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer 97: 2869‐2879, 2003.
 183.Swain SM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D, Jones SE, Wadler S, Desai A, Vogel C, Speyer J, Mittelman A, Reddy S, Pendergrass K, Velez‐Garcia E, Ewer MS, Bianchine JR, Gams RA. Cardioprotection with dexrazoxane for doxorubicin‐containing therapy in advanced breast cancer. J Clin Oncol 15: 1318‐1332, 1997.
 184.Tallaj JA, Franco V, Rayburn BK, Pinderski L, Benza RL, Pamboukian S, Foley B, Bourge RC. Response of doxorubicin‐induced cardiomyopathy to the current management strategy of heart failure. J Heart Lung Transplant 24: 2196‐2201, 2005.
 185.Tan TC, Scherrer‐Crosbie M. Assessing the cardiac toxicity of chemotherapeutic agents: Role of echocardiography. Curr Cardiovasc Imaging Rep 5: 403‐409, 2012.
 186.Tan TC, Scherrer‐Crosbie M. Cardiac complications of chemotherapy: Role of imaging. Curr Treat Options Cardiovasc Med 16: 296‐305, 2014.
 187.Tan‐Chiu E, Yothers G, Romond E, Geyer CE, Ewer M, Keefe D, Shannon RP, Swain SM, Brown A, Fehrenbacher L, Vogel VG, Seay TE, Rastogi P, Mamounas EP, Wolmark N, Bryant J. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node‐positive, human epidermal growth factor receptor 2‐overexpressing breast cancer: NSABP B‐31. J Clin Oncol 23: 7811‐7819, 2005.
 188.Tassan‐Mangina S, Codorean D, Metivier M, Costa B, Himberlin C, Jouannaud C, Blaise AM, Elaerts J, Nazeyrollas P. Tissue Doppler imaging and conventional echocardiography after anthracycline treatment in adults: Early and late alterations of left ventricular function during a prospective study. Eur J Echocardiogr 7: 141‐146, 2006.
 189.Thavendiranathan P, Grant AD, Negishi T, Plana JC, Popović ZB, Marwick TH. Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: Application to patients undergoing cancer chemotherapy. J Am Coll Cardiol 61: 77‐84, 2013.
 190.Thavendiranathan P, Poulin F, Lim K‐D, Plana JC, Woo A, Marwick TH. 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 63: 2751‐2768, 2014.
 191.Toyoda E, Kagaya S, Cowell IG, Kurosawa A, Kamoshita K, Nishikawa K, Iiizumi S, Koyama H, Austin CA, Adachi N. NK314, a topoisomerase II inhibitor that specifically targets the alpha isoform. J Biol Chem 283: 23711‐23720, 2008.
 192.Tukenova M, Guibout C, Oberlin O, Doyon F, Mousannif A, Haddy N, Guérin S, Pacquement H, Aouba A, Hawkins M, Winter D, Bourhis J, Lefkopoulos D, Diallo I, de Vathaire F. Role of cancer treatment in long‐term overall and cardiovascular mortality after childhood cancer. J Clin Oncol 28: 1308‐1315, 2010.
 193.Ueno M, Kakinuma Y, Yuhki K‐I, Murakoshi N, Iemitsu M, Miyauchi T, Yamaguchi I. Doxorubicin induces apoptosis by activation of caspase‐3 in cultured cardiomyocytes in vitro and rat cardiac ventricles in vivo. J Pharmacol Sci 101: 151‐158, 2006.
 194.Unverferth DV, Fetters JK, Unverferth BJ, Leier CV, Magorien RD, Arn AR, Baker PB. Human myocardial histologic characteristics in congestive heart failure. Circulation 68: 1194‐1200, 1983.
 195.van Dalen EC, Caron HN, Dickinson HO, Kremer LC. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev CD003917, 2011.
 196.van Dalen EC, van den Brug M, Caron HN, Kremer LCM. Anthracycline‐induced cardiotoxicity: Comparison of recommendations for monitoring cardiac function during therapy in paediatric oncology trials. Eur. J. Cancer 42: 3199‐3205, 2006.
 197.van Dalen EC, van der Pal HJH, Kok WEM, Caron HN, Kremer LCM. Clinical heart failure in a cohort of children treated with anthracyclines: A long‐term follow‐up study. Eur J Cancer 42: 3191‐3198, 2006.
 198.Vantrimpont P, Rouleau JL, Wun CC, Ciampi A, Klein M, Sussex B, Arnold JM, Moyé L, Pfeffer M. Additive beneficial effects of beta‐blockers to angiotensin‐converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators. J Am Coll Cardiol 29: 229‐236, 1997.
 199.Vásquez‐Vivar J, Martasek P, Hogg N, Masters BS, Pritchard KA, Kalyanaraman B. Endothelial nitric oxide synthase‐dependent superoxide generation from adriamycin. Biochemistry 36: 11293‐11297, 1997.
 200.Vedam K, Nishijima Y, Druhan LJ, Khan M, Moldovan NI, Zweier JL, Ilangovan G. Role of heat shock factor‐1 activation in the doxorubicin‐induced heart failure in mice. Am J Physiol Heart Circ Physiol 298: H1832‐41, 2010.
 201.Venkatakrishnan CD, Tewari AK, Moldovan L, Cardounel AJ, Zweier JL, Kuppusamy P, Ilangovan G. Heat shock protects cardiac cells from doxorubicin‐induced toxicity by activating p38 MAPK and phosphorylation of small heat shock protein 27. Am J Physiol Heart Circ Physiol 291: H2680‐91, 2006.
 202.Visscher H, Ross CJD, Rassekh SR, Barhdadi A, Dube MP, Al‐Saloos H, Sandor GS, Caron HN, van Dalen EC, Kremer LC, van der Pal HJ, Brown AMK, Rogers PC, Phillips MS, Rieder MJ, Carleton BC, Hayden MR, Canadian Pharmacogenomics Network for Drug Safety Consortium. Pharmacogenomic Prediction of Anthracycline‐Induced Cardiotoxicity in Children. J Clin Oncol 30: 1422‐1428, 2012.
 203.Vogelsang TW, Jensen RJ, Hesse B, Kjaer A. BNP cannot replace gated equilibrium radionuclide ventriculography in monitoring of anthracycline‐induced cardiotoxity. Intern J Cardiol 124: 193‐197, 2008.
 204.Volkova M, Russell R. Anthracycline cardiotoxicity: Prevalence, pathogenesis and treatment. Curr Cardiol Rev 7: 214‐220, 2011.
 205.Wang JC. DNA topoisomerases. New break for archaeal enzyme. Nature 386: 329‐331, 1997.
 206.Wang JC. Cellular roles of DNA topoisomerases: A molecular perspective. Nat Rev Mol Cell Biol 3: 430‐440, 2002.
 207.Wassmuth R, Lentzsch S, Erdbruegger U, Schulz‐Menger J, Doerken B, Dietz R, Friedrich MG. Subclinical cardiotoxic effects of anthracyclines as assessed by magnetic resonance imaging‐a pilot study. Am Heart J 141: 1007‐1013, 2001.
 208.Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin‐angiotensin‐aldosterone system. Circulation 83: 1849‐1865, 1991.
 209.Wojnowski L, Kulle B, Schirmer M, Schlüter G, Schmidt A, Rosenberger A, Vonhof S, Bickeböller H, Toliat MR, Suk E‐K, Tzvetkov M, Kruger A, Seifert S, Kloess M, Hahn H, Loeffler M, Nürnberg P, Pfreundschuh M, Trümper L, Brockmöller J, Hasenfuss G. NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin‐induced cardiotoxicity. Circulation 112: 3754‐3762, 2005.
 210.Wong FL, Bhatia S, Landier W, Francisco L, Leisenring W, Hudson MM, Armstrong GT, Mertens A, Stovall M, Robison LL, Lyman GH, Lipshultz SE, Armenian SH. Cost‐effectiveness of the children's oncology group long‐term follow‐up screening guidelines for childhood cancer survivors at risk for treatment‐related heart failure. Ann Intern Med 160: 672‐683, 2014.
 211.Wouters KA, Kremer LCM, Miller TL, Herman EH, Lipshultz SE. Protecting against anthracycline‐induced myocardial damage: A review of the most promising strategies. Br J Haematol 131: 561‐578, 2005.
 212.Wu C‐C, Li T‐K, Farh L, Lin L‐Y, Lin T‐S, Yu Y‐J, Yen T‐J, Chiang C‐W, Chan N‐L. Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Science 333: 459‐462, 2011.
 213.Yahalom J, Portlock CS. Long‐term cardiac and pulmonary complications of cancer therapy. Heart Failure Clinics 7: 403‐411, 2011.
 214.Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJV, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WHW, Tsai EJ, Wilkoff BL, American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 128(16): e240–327, 2013.
 215.Yeh ETH, Bickford CL. Cardiovascular complications of cancer therapy: Incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 53: 2231‐2247, 2009.
 216.Yeh JM, Nohria A, Diller L. Routine echocardiography screening for asymptomatic left ventricular dysfunction in childhood cancer survivors: A model‐based estimation of the clinical and economic effects. Ann Intern Med 160: 661, 2014.
 217.Zhang S, Liu X, Bawa‐Khalfe T, Lu L‐S, Lyu YL, Liu LF, Yeh ETH. Identification of the molecular basis of doxorubicin‐induced cardiotoxicity. Nat Med 18: 1639‐1642, 2012.
 218.Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigattors. N Engl J Med 327: 685‐691, 1992.

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Timothy C. Tan, Tomas G. Neilan, Sanjeev Francis, Juan Carlos Plana, Marielle Scherrer‐Crosbie. Anthracycline‐Induced Cardiomyopathy in Adults. Compr Physiol 2015, 5: 1517-1540. doi: 10.1002/cphy.c140059