Molecular Mechanisms of Cardiovascular Damage Induced by Anti-HER-2 Therapies

  • Valentina Mercurio
  • Giulio Agnetti
  • Pasquale Pagliaro
  • Carlo G. TocchettiEmail author
Part of the Current Clinical Pathology book series (CCPATH)


In the last two decades, newer biological drugs have been designed in order to “target” specific proteins involved in cancer proliferation and overcome the increased risk of cardiovascular toxicity associated with “broad-spectrum” classic chemotherapeutics. Unfortunately, these proteins are also important for the maintenance of cardiovascular homeostasis. The humanized anti-ErbB2 antibody, trastuzumab, is the prototypical biological drug first introduced in antineoplastic protocols for the treatment of ErbB2+ breast cancer. Indeed, not only is this protein overexpressed in several breast cancers, but also it plays a major role in the cardiovascular system in cell growth, including myocyte growth, and inhibition of apoptosis and can modulate the oxidative damage induced by anthracyclines. Hence, patients treated with trastuzumab developed systolic dysfunction, especially when administered with or shortly after doxorubicin.


Cardiovascular toxicity Anti-ErbB2 drugs Anthracyclines Cardiovascular homeostasis Oxidative stress 



CGT received speaking fees from Alere.


CGT is funded by a Federico II University/Ricerca di Ateneo grant.


  1. 1.
    Hurwitz H, Fehrenbacher L. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.CrossRefGoogle Scholar
  2. 2.
    Ewer MS, Gibbs HR, Swafford J, Benjamin RS. Cardiotoxicity in patients receiving trastuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact? Semin Oncol. 1999;26:96–101.PubMedGoogle Scholar
  3. 3.
    Cheng H, Force T. Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ Res. 2010;106:21–34.CrossRefGoogle Scholar
  4. 4.
    Eschenhagen T, Force T, Ewer MS, de Keulenaer GW, Suter TM, Anker SD, et al. Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2011;13:1–10.CrossRefGoogle Scholar
  5. 5.
    Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007;7:332–44.CrossRefGoogle Scholar
  6. 6.
    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.CrossRefGoogle Scholar
  7. 7.
    Mercurio V, Pirozzi F, Lazzarini E, Marone G, Rizzo P, Agnetti G, et al. Models of heart failure based on the cardiotoxicity of anticancer drugs. J Card Fail. 2016;22:449–58.CrossRefGoogle Scholar
  8. 8.
    Tocchetti CG, Ragone G, Coppola C, Rea D, Piscopo G, Scala S, et al. Detection, monitoring, and management of trastuzumab-induced left ventricular dysfunction: an actual challenge. Eur J Heart Fail. 2012;14(2):130–7.CrossRefGoogle Scholar
  9. 9.
    Suter TM, Ewer MS. Cancer drugs and the heart: importance and management. Eur Heart J. 2013;34(15):1102–11.CrossRefGoogle Scholar
  10. 10.
    Ky B, Vejpongsa P, Yeh ET, Force T, Moslehi JJ. Emerging paradigms in cardiomyopathies associated with cancer therapies. Circ Res. 2013;113:754–64. Scholar
  11. 11.
    Tocchetti CG, Cadeddu C, Di Lisi D, Femminò S, Madonna R, Mele D, et al. From molecular mechanisms to clinical management of antineoplastic drug-induced cardiovascular toxicity: a translational overview. Antioxid Redox Signal. 2017; [Epub ahead of print]
  12. 12.
    Odiete O, Hill MF, Sawyer DB. Neuregulin in cardiovascular development and disease. Circ Res. 2012;111:1376–85.CrossRefGoogle Scholar
  13. 13.
    Lim SL, Lam CS, Segers VF, Brutsaert DL, De Keulenaer GW. Cardiac endothelium-myocyte interaction: clinical opportunities for new heart failure therapies regardless of ejection fraction. Eur Heart J. 2015;36:2050–60. Scholar
  14. 14.
    D’Uva G, Aharonov A, Lauriola M, Kain D, Yahalom-Ronen Y, Carvalho S, et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat Cell Biol. 2015;17:627–38.CrossRefGoogle Scholar
  15. 15.
    Gabrielson K, Bedja D, Pin S, Tsao A, Gama L, Yuan B, et al. Heat shock protein 90 and erbB2 in the cardiac response to doxorubicin injury. Cancer Res. 2007;67:1436–41.CrossRefGoogle Scholar
  16. 16.
    De Korte MA, de Vries EG, Lub-de Hooge MN, Jager PL, Gietema JA, van der Graaf WT, et al. 111Indium-trastuzumab visualises myocardial human epidermal growth factor receptor 2 expression shortly after anthracycline treatment but not during heart failure: a clue to uncover the mechanisms of trastuzumab-related cardiotoxicity. Eur J Cancer. 2007;43:2046–51.CrossRefGoogle Scholar
  17. 17.
    Ewer MS, Ewer SM. Troponin I provides insight into cardiotoxicity and the anthracycline-trastuzumab interaction. J Clin Oncol. 2010;28:3901–4.CrossRefGoogle Scholar
  18. 18.
    Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med. 2002;8:459–65.CrossRefGoogle Scholar
  19. 19.
    Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hübner N, et al. Conditional mutation of the ErbB2 (HER-2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci U S A. 2002;99:8880–5.CrossRefGoogle Scholar
  20. 20.
    Belmonte F, Das S, Sysa-Shah P, Sivakumaran V, Stanley B, Guo X, et al. ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity. Am J Physiol Heart Circ Physiol. 2015;309:H1271–80.CrossRefGoogle Scholar
  21. 21.
    Rohrbach S, Niemann B, Silber RE, Holtz J. Neuregulin receptors erbB2 and erbB4 in failing human myocardium—depressed expression and attenuated activation. Basic Res Cardiol. 2005;100:240–9.CrossRefGoogle Scholar
  22. 22.
    Rohrbach S, Yan X, Weinberg EO, Hasan F, Bartunek J, Marchionni MA, et al. Neuregulin in cardiac hypertrophy in rats with aortic stenosis. Differential expression of erbB2 and erbB4 receptors. Circulation. 1999;100:407–12.CrossRefGoogle Scholar
  23. 23.
    Uray IP, Connelly JH, Thoma’zy V, Shipley GL, Vaughn WK, Frazier OH, et al. Left ventricular unloading alters receptor tyrosine kinase expression in the failing human heart. J Heart Lung Transplant. 2002;21:771–82.CrossRefGoogle Scholar
  24. 24.
    Doggen K, Ray L, Mathieu M, Mc Entee K, Lemmens K, De Keulenaer GW. Ventricular ErbB2/ErbB4 activation and downstream signaling in pacing-induced heart failure. J Mol Cell Cardiol. 2009;46:33–8.CrossRefGoogle Scholar
  25. 25.
    Jeon TJ, Lee JD, Ha JW, Yang WI, Cho SH. Evaluation of cardiac adrenergic neuronal damage in rats with doxorubicin-induced cardiomyopathy using iodine-131 MIBG autoradiography and PGP 9.5 immunohistochemistry. Eur J Nucl Med. 2000;27:686–93.CrossRefGoogle Scholar
  26. 26.
    Nousiainen T, Vanninen E, Jantunen E, Remes J, Ritanen E, Vuolteenaho O, et al. Neuroendocrine changes during the evolution of doxorubicin-induced left ventricular dysfunction in adult lymphoma patients. Clin Sci (Lond). 2001;101:601–7.CrossRefGoogle Scholar
  27. 27.
    Sysa-Shah P, Tocchetti CG, Gupta M, Rainer PP, Shen X, Kang BH, et al. Bidirectional cross-regulation betweenErbB2 and b-adrenergic signalling pathways. Cardiovasc Res. 2016;109:358–73.CrossRefGoogle Scholar
  28. 28.
    Sandoo A, Kitas G, Carmichael A. Endothelial dysfunction as a determinant of trastuzumab mediated cardiotoxicity in patients with breast cancer. Anticancer Res. 2014;1152:1147–51.Google Scholar
  29. 29.
    Zeglinski M, Ludke A, Jassal DS, Singal PK. Trastuzumab-induced cardiac dysfunction: a ‘dual-hit’. Exp Clin Cardiol. 2011;16(3):70–4.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Lemmens K, Segers VF, Demolder M, , De Keulenaer GW. Role of neuregulin-1/ErbB2 signaling in endothelium-cardiomyocyte cross-talk. J Biol Chem 2006;281:19469–19477.CrossRefGoogle Scholar
  31. 31.
    Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM. Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1 and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation. 2002;105:1551–4.CrossRefGoogle Scholar
  32. 32.
    Lemmens K, Doggen K, De Keulenaer GW. Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation. 2007;116:954–60. Scholar
  33. 33.
    Pugatsch T, Abedat S, Lotan C, Beeri R. Anti-erbB2 treatment induces cardiotoxicity by interfering with cell survival pathways. Breast Cancer Res. 2006;8(4):R35.CrossRefGoogle Scholar
  34. 34.
    Albini A, Cesana E, Donatelli F, Cammarota R, Bucci EO, Baravelli M, et al. Cardio-oncology in targeting the HER receptor family: the puzzle of different cardiotoxicities of HER2 inhibitors. Futur Cardiol. 2011;7:693–704.CrossRefGoogle Scholar
  35. 35.
    Hervent AS, De Keulenaer GW. Molecular mechanisms of cardiotoxicity induced by ErbB receptor inhibitor cancer therapeutics. Int J Mol Sci. 2012;13(10):12268–86.CrossRefGoogle Scholar
  36. 36.
    Geisberg CA, Wang G, Safa RN, Smith HM, Anderson B, Peng XY, et al. Circulating neuregulin-1β levels vary according to the angiographic severity of coronary artery disease and ischemia. Coron Artery Dis. 2011;22:577–82. Scholar
  37. 37.
    Hedhli N, Huang Q, Kalinowski A, Palmeri M, Hu X, Russell RR, et al. Endothelium-derived neuregulin protects the heart against ischemic injury. Circulation. 2011;123:2254–62. Scholar
  38. 38.
    Gui C, Zhu L, Hu M, Lei L, Long Q. Neuregulin-1/ErbB signaling is impaired in the rat model of diabetic cardiomyopathy. Cardiovasc Pathol. 2012;21:414–20. Scholar
  39. 39.
    Jay SM, Murthy AC, Hawkins JF, Wortzel JR, Steinhauser ML, Alvarez LM, et al. An engineered bivalent neuregulin protects against doxorubicin-induced cardiotoxicity with reduced proneoplastic potential. Circulation. 2013;128:152–61. Scholar
  40. 40.
    Herrmann J, Yang EH, Iliescu CA, Cilingiroglu M, Charitakis K, Hakeem A, et al. Vascular toxicities of cancer therapies: the old and the new – an evolving avenue. Circulation. 2016;133(13):1272–89.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Valentina Mercurio
    • 1
  • Giulio Agnetti
    • 2
    • 3
  • Pasquale Pagliaro
    • 4
  • Carlo G. Tocchetti
    • 5
    Email author
  1. 1.Division of Pulmonary and Critical Care MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.DIBINEMUniversity of BolognaBolognaItaly
  4. 4.Clinical and Biological SciencesAOU San Luigi GonzagaOrbassanoItaly
  5. 5.Department of Translational Medical SciencesFederico II UniversityNaplesItaly

Personalised recommendations