Mechanism and Prevention of Cardiomyopathy Due to Chemotherapy

  • Rohit Moudgil
  • Edward T. H. Yeh


The emergence of new oncological therapies has seen a great success in attenuating cancer and its metastases. However, the undesirable side-effect of cardiotoxicity has prevented utilization of anticancer therapies to its full potential. This chapter will elucidate some of the mechanisms behind the chemotherapy induced cardiomyopathy and will highlight the potential preventative and therapeutic measures to curb the cardiotoxic effect of anticancer agents. The aim of this chapter is to arm our clinicians with necessary knowledge and guidance as to how to treat chemotherapy related cardiomyopathy in our oncological patients.


Chemotherapy Cardiomyopathy 


  1. 1.
    Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20:1215–21.CrossRefPubMedGoogle Scholar
  2. 2.
    Theodoulou M, Seidman AD. Cardiac effects of adjuvant therapy for early breast cancer. Semin Oncol. 2003;30:730–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol. 2005;23:2900–2.CrossRefPubMedGoogle Scholar
  4. 4.
    Hayek ER, Speakman E, Rehmus E. Acute doxorubicin cardiotoxicity. N Engl J Med. 2005;352:2456–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Bristow MR, Mason JW, Billingham ME, Daniels JR. Doxorubicin cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med. 1978;88:168–75.CrossRefPubMedGoogle Scholar
  6. 6.
    Lenihan DJ. Progression of heart failure from AHA/ACC stage A to stage B or even C: can we all agree we should try to prevent this from happening? J Am Coll Cardiol. 2012;60:2513–4.CrossRefPubMedGoogle Scholar
  7. 7.
    Bristow MR, Thompson PD, Martin RP, Mason JW, Billingham ME, Harrison DC. Early anthracycline cardiotoxicity. Am J Med. 1978;65:823–32.CrossRefPubMedGoogle Scholar
  8. 8.
    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 Zurich, Switzerland, between 1990 and 1996. Ann Oncol. 2001;12:963–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013;14:741–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91:710–7.CrossRefGoogle Scholar
  11. 11.
    Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97:2869–79.CrossRefPubMedGoogle Scholar
  12. 12.
    Nysom K, Holm K, Lipsitz SR, et al. Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol. 1998;16:545–50.CrossRefPubMedGoogle Scholar
  13. 13.
    Vandecruys E, Mondelaers V, De Wolf D, Benoit Y, Suys B. Late cardiotoxicity after low dose of anthracycline therapy for acute lymphoblastic leukemia in childhood. J Cancer Surviv. 2012;6:95–101.CrossRefPubMedGoogle Scholar
  14. 14.
    van der Pal HJ, van Dalen EC, Hauptmann M, et al. Cardiac function in 5-year survivors of childhood cancer: a long-term follow-up study. Arch Intern Med. 2010;170:1247–55.PubMedGoogle Scholar
  15. 15.
    Bodley A, Liu LF, Israel M, et al. DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA. Cancer Res. 1989;49:5969–78.PubMedGoogle Scholar
  16. 16.
    Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med. 2012;18:1639–42.CrossRefPubMedGoogle Scholar
  17. 17.
    L’Ecuyer T, Sanjeev S, Thomas R, et al. DNA damage is an early event in doxorubicin-induced cardiac myocyte death. Am J Physiol Heart Circ Physiol. 2006;291:H1273–80.CrossRefPubMedGoogle Scholar
  18. 18.
    Liu J, Mao W, Ding B, Liang CS. ERKs/p53 signal transduction pathway is involved in doxorubicin-induced apoptosis in H9c2 cells and cardiomyocytes. Am J Physiol Heart Circ Physiol. 2008;295:H1956–65.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hasinoff BB, Herman EH. Dexrazoxane: how it works in cardiac and tumor cells. Is it a prodrug or is it a drug? Cardiovasc Toxicol. 2007;7:140–4.CrossRefPubMedGoogle Scholar
  20. 20.
    Herman EH, el-Hage A, Ferrans VJ. Protective effect of ICRF-187 on doxorubicin-induced cardiac and renal toxicity in spontaneously hypertensive (SHR) and normotensive (WKY) rats. Toxicol Appl Pharmacol. 1988;92:42–53.CrossRefPubMedGoogle Scholar
  21. 21.
    Herman EH, Ferrans VJ. Preclinical animal models of cardiac protection from anthracycline-induced cardiotoxicity. Semin Oncol. 1998;25:15–21.PubMedGoogle Scholar
  22. 22.
    Herman EH, Zhang J, Chadwick DP, Ferrans VJ. Comparison of the protective effects of amifostine and dexrazoxane against the toxicity of doxorubicin in spontaneously hypertensive rats. Cancer Chemother Pharmacol. 2000;45:329–34.CrossRefPubMedGoogle Scholar
  23. 23.
    Herman EH, Ferrans VJ. Timing of treatment with ICRF-187 and its effect on chronic doxorubicin cardiotoxicity. Cancer Chemother Pharmacol. 1993;32:445–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Rao VA, Zhang J, Klein SR, et al. The iron chelator Dp44mT inhibits the proliferation of cancer cells but fails to protect from doxorubicin-induced cardiotoxicity in spontaneously hypertensive rats. Cancer Chemother Pharmacol. 2011;68:1125–34.CrossRefPubMedGoogle Scholar
  25. 25.
    Imondi AR. Preclinical models of cardiac protection and testing for effects of dexrazoxane on doxorubicin antitumor effects. Semin Oncol. 1998;25:22–30.PubMedGoogle Scholar
  26. 26.
    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. 1991;324:808–15.CrossRefPubMedGoogle Scholar
  27. 27.
    Marty M, Espie M, Llombart A, et al. Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol. 2006;17:614–22.CrossRefPubMedGoogle Scholar
  28. 28.
    Swain SM, Whaley FS, Gerber MC, et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol. 1997;15:1318–32.CrossRefPubMedGoogle Scholar
  29. 29.
    Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer. 2009;9:338–50.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56:185–229.CrossRefPubMedGoogle Scholar
  31. 31.
    van Dalen EC, van der Pal HJ, Caron HN, Kremer LC. Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline chemotherapy. Cochrane Database Syst Rev. 2009;(4):CD005008.Google Scholar
  32. 32.
    Lipshultz SE, Miller TL, Lipsitz SR, et al. Continuous versus bolus infusion of doxorubicin in children with ALL: long-term cardiac outcomes. Pediatrics. 2012;130:1003–11.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Gupta M, Steinherz PG, Cheung NK, Steinherz L. Late cardiotoxicity after bolus versus infusion anthracycline therapy for childhood cancers. Med Pediatr Oncol. 2003;40:343–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Levitt GA, Dorup I, Sorensen K, Sullivan I. Does anthracycline administration by infusion in children affect late cardiotoxicity? Br J Haematol. 2004;124:463–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Pignata S, Scambia G, Ferrandina G, et al. Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: the MITO-2 randomized phase III trial. J Clin Oncol. 2011;29:3628–35.CrossRefPubMedGoogle Scholar
  36. 36.
    Sharpe M, Easthope SE, Keating GM, Lamb HM. Polyethylene glycol-liposomal doxorubicin: a review of its use in the management of solid and haematological malignancies and AIDS-related Kaposi’s sarcoma. Drugs. 2002;62:2089–126.CrossRefPubMedGoogle Scholar
  37. 37.
    Al-Batran SE, Guntner M, Pauligk C, et al. Anthracycline rechallenge using pegylated liposomal doxorubicin in patients with metastatic breast cancer: a pooled analysis using individual data from four prospective trials. Br J Cancer. 2010;103:1518–23.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Keller AM, Mennel RG, Georgoulias VA, et al. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004;22:3893–901.CrossRefPubMedGoogle Scholar
  39. 39.
    O’Brien ME, Wigler N, Inbar M, et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004;15:440–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Agency EM. Caelyx (doxorubicin hydrochloride in a pegylated liposomal formulation ). 2011.
  41. 41.
    Duggan ST, Keating GM. Pegylated liposomal doxorubicin: a review of its use in metastatic breast cancer, ovarian cancer, multiple myeloma and AIDS-related Kaposi’s sarcoma. Drugs. 2011;71:2531–58.CrossRefPubMedGoogle Scholar
  42. 42.
    Smith DH, Adams JR, Johnston SR, Gordon A, Drummond MF, Bennett CL. A comparative economic analysis of pegylated liposomal doxorubicin versus topotecan in ovarian cancer in the USA and the UK. Ann Oncol. 2002;13:1590–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Creighton AM, Birnie GD. The effect of bisdioxopiperazines on the synthesis of deoxyribonucleic acid, ribonucleic acid and protein in growing mouse-embryo fibroblasts. Biochem J. 1969;114:58P.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    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;67:8839–46.CrossRefPubMedGoogle Scholar
  45. 45.
    Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med. 2004;351:145–53.CrossRefPubMedGoogle Scholar
  46. 46.
    Lipshultz SE, Scully RE, Lipsitz SR, et al. 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. 2010;11:950–61.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Seymour L, Bramwell V, Moran LA. Use of dexrazoxane as a cardioprotectant in patients receiving doxorubicin or epirubicin chemotherapy for the treatment of cancer. The Provincial Systemic Treatment Disease Site Group. Cancer Prev Control. 1999;3:145–59.PubMedGoogle Scholar
  48. 48.
    Speyer JL, Green MD, Zeleniuch-Jacquotte A, et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol. 1992;10:117–27.CrossRefPubMedGoogle Scholar
  49. 49.
    Swain SM, Vici P. The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review. J Cancer Res Clin Oncol. 2004;130:1–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Yu Y, Kalinowski DS, Kovacevic Z, et al. Thiosemicarbazones from the old to new: iron chelators that are more than just ribonucleotide reductase inhibitors. J Med Chem. 2009;52:5271–94.CrossRefPubMedGoogle Scholar
  51. 51.
    van Dalen EC, Caron HN, Dickinson HO, Kremer LC. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev. 2011;(6):CD003917.Google Scholar
  52. 52.
    Schuchter LM, Hensley ML, Meropol NJ, Winer EP, American Society of Clinical Oncology C, Radiotherapy Expert P. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2002;20:2895–903.CrossRefPubMedGoogle Scholar
  53. 53.
    Kalay N, Basar E, Ozdogru I, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol. 2006;48:2258–62.CrossRefPubMedGoogle Scholar
  54. 54.
    Seicean S, Seicean A, Alan N, Plana JC, Budd GT, Marwick TH. Cardioprotective effect of beta-adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: follow-up study of heart failure. Circ Heart Fail. 2013;6:420–6.CrossRefPubMedGoogle Scholar
  55. 55.
    Kaya MG, Ozkan M, Gunebakmaz O, et al. Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. Int J Cardiol. 2013;167:2306–10.CrossRefPubMedGoogle Scholar
  56. 56.
    Bosch X, Rovira M, Sitges M, et al. 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. 2013;61:2355–62.CrossRefPubMedGoogle Scholar
  57. 57.
    Heck SL, Gulati G, Ree AH, et al. Rationale and design of the prevention of cardiac dysfunction during an Adjuvant Breast Cancer Therapy (PRADA) Trial. Cardiology. 2012;123:240–7.CrossRefPubMedGoogle Scholar
  58. 58.
    Gulati G, Heck SL, Ree AH, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J. 2016;37(21):1671–80.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006;114:2474–81.CrossRefPubMedGoogle Scholar
  60. 60.
    Jensen BV, Skovsgaard T, Nielsen SL. Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol. 2002;13:699–709.CrossRefPubMedGoogle Scholar
  61. 61.
    Lipshultz SE, Lipsitz SR, Sallan SE, et al. Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood cancer. J Clin Oncol. 2002;20:4517–22.CrossRefPubMedGoogle Scholar
  62. 62.
    Silber JH, Cnaan A, Clark BJ, et al. Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol. 2004;22:820–8.CrossRefPubMedGoogle Scholar
  63. 63.
    Barry E, Alvarez JA, Scully RE, Miller TL, Lipshultz SE. Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management. Expert Opin Pharmacother. 2007;8:1039–58.CrossRefPubMedGoogle Scholar
  64. 64.
    Sieswerda E, van Dalen EC, Postma A, Cheuk DK, Caron HN, Kremer LC. Medical interventions for treating anthracycline-induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer. Cochrane Database Syst Rev. 2011;(9):CD008011.Google Scholar
  65. 65.
    Cadeddu C, Piras A, Mantovani G, et al. Protective effects of the angiotensin II receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress, and early ventricular impairment. Am Heart J. 2010;160:487.e1–7.CrossRefPubMedGoogle Scholar
  66. 66.
    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;104:2492–8.CrossRefPubMedGoogle Scholar
  67. 67.
    Dessi M, Madeddu C, Piras A, et al. Long-term, up to 18 months, protective effects of the angiotensin II receptor blocker telmisartan on Epirubin-induced inflammation and oxidative stress assessed by serial strain rate. Springplus. 2013;2:198.CrossRefGoogle Scholar
  68. 68.
    Akpek M, Ozdogru I, Sahin O, et al. Protective effects of spironolactone against anthracycline-induced cardiomyopathy. Eur J Heart Fail. 2015;17:81–9.CrossRefPubMedGoogle Scholar
  69. 69.
    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. 2012;60:2384–90.CrossRefPubMedGoogle Scholar
  70. 70.
    Acar Z, Kale A, Turgut M, et al. Efficiency of atorvastatin in the protection of anthracycline-induced cardiomyopathy. J Am Coll Cardiol. 2011;58:988–9.CrossRefPubMedGoogle Scholar
  71. 71.
    Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol. 2010;55:213–20.CrossRefPubMedGoogle Scholar
  72. 72.
    Hassan SB, Banchs J. Monitoring cardiotoxicity with left ventricular ejection fraction; MD Anderson Practices in Onco-Cardiology. 2016 by Department of Cardiology, The University of Texas MD Anderson Cancer Center. ISBN;978-1-944785-94-9.Google Scholar
  73. 73.
    Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37 Suppl 4:S3–8.CrossRefPubMedGoogle Scholar
  74. 74.
    Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–92.CrossRefPubMedGoogle Scholar
  75. 75.
    Chen B, Peng X, Pentassuglia L, Lim CC, Sawyer DB. Molecular and cellular mechanisms of anthracycline cardiotoxicity. Cardiovasc Toxicol. 2007;7:114–21.CrossRefPubMedGoogle Scholar
  76. 76.
    Bird BR, Swain SM. Cardiac toxicity in breast cancer survivors: review of potential cardiac problems. Clin Cancer Res. 2008;14:14–24.CrossRefPubMedGoogle Scholar
  77. 77.
    Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007;357:39–51.CrossRefPubMedGoogle Scholar
  78. 78.
    Yavas O, Yazici M, Eren O, Oyan B. The acute effect of trastuzumab infusion on ECG parameters in metastatic breast cancer patients. Swiss Med Wkly. 2007;137:556–8.PubMedGoogle Scholar
  79. 79.
    Keefe DL. Trastuzumab-associated cardiotoxicity. Cancer. 2002;95:1592–600.CrossRefPubMedGoogle Scholar
  80. 80.
    Perez EA, Rodeheffer R. Clinical cardiac tolerability of trastuzumab. J Clin Oncol. 2004;22:322–9.CrossRefPubMedGoogle Scholar
  81. 81.
    Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol. 2005;23:7820–6.CrossRefPubMedGoogle Scholar
  82. 82.
    de Azambuja E, Bedard PL, Suter T, Piccart-Gebhart M. Cardiac toxicity with anti-HER-2 therapies: what have we learned so far? Target Oncol. 2009;4:77–88.CrossRefPubMedGoogle Scholar
  83. 83.
    Zhao YY, Sawyer DR, Baliga RR, et al. Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem. 1998;273:10261–9.CrossRefPubMedGoogle Scholar
  84. 84.
    Crone SA, Zhao YY, Fan L, et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med. 2002;8:459–65.CrossRefPubMedGoogle Scholar
  85. 85.
    Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009;15:429–40.CrossRefPubMedGoogle Scholar
  86. 86.
    De Keulenaer GW, Doggen K, Lemmens K. The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy. Circ Res. 2010;106:35–46.CrossRefPubMedGoogle Scholar
  87. 87.
    Badache A, Hynes NE. A new therapeutic antibody masks ErbB2 to its partners. Cancer Cell. 2004;5:299–301.CrossRefPubMedGoogle Scholar
  88. 88.
    Cameron DA, Stein S. Drug Insight: intracellular inhibitors of HER2—clinical development of lapatinib in breast cancer. Nat Clin Pract Oncol. 2008;5:512–20.CrossRefPubMedGoogle Scholar
  89. 89.
    Rusnak DW, Lackey K, Affleck K, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther. 2001;1:85–94.PubMedGoogle Scholar
  90. 90.
    Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002;21:6255–63.CrossRefPubMedGoogle Scholar
  91. 91.
    Cardinale D, Colombo A, Torrisi R, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol. 2010;28:3910–6.CrossRefPubMedGoogle Scholar
  92. 92.
    Jones AL, Barlow M, Barrett-Lee PJ, et al. Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring. Br J Cancer. 2009;100:684–92.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Rock CL, Flatt SW, Newman V, et al. Factors associated with weight gain in women after diagnosis of breast cancer. Women’s Healthy Eating and Living Study Group. J Am Diet Assoc. 1999;99:1212–21.CrossRefPubMedGoogle Scholar
  94. 94.
    Koelwyn GJ, Khouri M, Mackey JR, Douglas PS, Jones LW. Running on empty: cardiovascular reserve capacity and late effects of therapy in cancer survivorship. J Clin Oncol. 2012;30:4458–61.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Irwin ML, Crumley D, McTiernan A, et al. Physical activity levels before and after a diagnosis of breast carcinoma: the Health, Eating, Activity, and Lifestyle (HEAL) study. Cancer. 2003;97:1746–57.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Gulati M, Pandey DK, Arnsdorf MF, et al. Exercise capacity and the risk of death in women: the St James Women Take Heart Project. Circulation. 2003;108:1554–9.CrossRefPubMedGoogle Scholar
  97. 97.
    Giallauria F, Fattirolli F, Tramarin R, et al. Clinical characteristics and course of patients with diabetes entering cardiac rehabilitation. Diabetes Res Clin Pract. 2015;107:267–72.CrossRefPubMedGoogle Scholar
  98. 98.
    Giallauria F, Maresca L, Vitelli A, et al. Exercise training improves heart rate recovery in women with breast cancer. Springplus. 2015;4:388.CrossRefGoogle Scholar
  99. 99.
    Mishra SI, Scherer RW, Snyder C, Geigle PM, Berlanstein DR, Topaloglu O. Exercise interventions on health-related quality of life for people with cancer during active treatment. Cochrane Database Syst Rev. 2012;(8):CD008465.Google Scholar
  100. 100.
    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:vii155–66.PubMedGoogle Scholar
  101. 101.
    Lang RM, Bierig M, Devereux RB, et al. 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. 2005;18:1440–63.CrossRefPubMedGoogle Scholar
  102. 102.
    Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;(4):CD006243.Google Scholar
  103. 103.
    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. Eur Heart J Cardiovasc Imaging. 2014;15:1063–93.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Virani SA, Dent S, Brezden-Masley C, et al. Canadian Cardiovascular Society Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy. Can J Cardiol. 2016;32:831–41.CrossRefPubMedGoogle Scholar
  105. 105.
    Zamorano JL, Lancellotti P, Rodriguez Munoz 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;37:2768–801.CrossRefPubMedGoogle Scholar
  106. 106.
    Vaz-Luis I, Keating NL, Lin NU, Lii H, Winer EP, Freedman RA. Duration and toxicity of adjuvant trastuzumab in older patients with early-stage breast cancer: a population-based study. J Clin Oncol. 2014;32:927–34.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Yeboah J, Rodriguez CJ, Stacey B, et al. Prognosis of individuals with asymptomatic left ventricular systolic dysfunction in the multi-ethnic study of atherosclerosis (MESA). Circulation. 2012;126:2713–9.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of CardiologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Professor of Medicine, Department of Cardiovascular MedicineUniversity of Missouri, Hospital DriveColumbiaUSA

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