Early Detection of Cardiac Damage

  • Giuseppina NovoEmail author
  • Cinzia Nugara
  • Patrizio Lancellotti
Part of the Current Clinical Pathology book series (CCPATH)


Early detection and quantification of cardiac damage in cancer patients are essential to readily intervene with cardioprotective strategies and avoid the need of the discontinuation of antineoplastic treatment.

Many strategies are available to monitor cardiac function during or after chemotherapy including cardiac imaging (echocardiography, nuclear imaging, cardiac magnetic resonance) and measurement of biomarkers (troponin, natriuretic peptides).

Systematic and repeated monitoring of left ventricle ejection fraction (LVEF) remains the most used technique to diagnose cardiotoxicity in clinical practice. Among the new techniques that evaluate cardiac function, GLS derived by 2D-STE is the best validated technique with a considerable amount of evidences supporting its role in the early detection of cardiotoxicity. Regarding CMR, its low availability and the high cost limit its use to particular subsets of patients.

Measuring biomarkers (troponin and NT-proBNP) also appear to be effective in the prediction of cardiotoxicity; their elevations identify high-risk cohort of cancer patients who may benefit from early cardioprotective medication.

A multimodality approach in selected individuals may provide incremental value in predicting cardiotoxicity and prove to be useful in clinical practice; however further studies are needed for wider validation in the clinical setting.


Early detection Cardiotoxicity Echocardiography Biomarkers Multimodality approach Global longitudinal strain 


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics 2016. CA Cancer J Clin. 2016;66:7–30.CrossRefGoogle Scholar
  2. 2.
    Thavendiranathan P, Abdel-Qadir H, Fischer HD, Camacho X, Amir E, Austin PC, et al. Breast cancer therapy-related cardiac dysfunction in adult women treated in routine clinical practice: a population-based cohort study. J Clin Oncol. 2016;34(19):2239–46.CrossRefGoogle Scholar
  3. 3.
    Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, 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 J Heart Fail. 2017;19:9–42.CrossRefGoogle Scholar
  4. 4.
    Zito C, Longobardo L, Cadeddu C, Monte I, Novo G, Dell’Oglio S, et al. Cardiovascular imaging in the diagnosis and monitoring of cardiotoxicity: role of echocardiography. J Cardiovasc Med (Hagerstown). 2016;17(Suppl 1):e35–44.CrossRefGoogle Scholar
  5. 5.
    Tan TC, Scherrer-Crosbie M. Assessing the cardiac toxicity of chemotherapeutic agents: role of echocardiography. Curr Cardiovasc Imaging Rep. 2012;5(6):403–9.CrossRefGoogle Scholar
  6. 6.
    Altena R, Perik PJ, van Veldhuisen DJ, de Vries EG, Gietema JA. Cardiovascular toxicity caused by cancer treatment: strategies for early detection. Lancet Oncol. 2009;10:391–9.CrossRefGoogle Scholar
  7. 7.
    Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1–53.CrossRefGoogle Scholar
  8. 8.
    Mulvagh SL, Rakowski H, Vannan MA, Abdelmoneim SS, Becher H, Bierig SM, et al. American Society of Echocardiography consensus statement on the clinical applications of ultrasonic contrast agents in echocardiography. J Am Soc Echocardiogr. 2008;21:1179–201.CrossRefGoogle Scholar
  9. 9.
    Hoffmann R, von Bardeleben S, Kasprzak JD, Borges AC, ten Cate F, Firschke C, et al. Analysis of regional left ventricular function by cineventriculography, cardiac magnetic resonance imaging, and unenhanced and contrast-enhanced echocardiography: a multicenter comparison of methods. J Am Coll Cardiol. 2006;47:121–8.CrossRefGoogle Scholar
  10. 10.
    Walker J, Bhullar N, Fallah-Rad N, Lytwyn M, Golian M, Fang T, et al. Role of three-dimensional echocardiography in breast cancer: comparison with two-dimensional echocardiography, multiple-gated acquisition scans, and cardiac magnetic resonance imaging. J Clin Oncol. 2010;28(21):3429–36.CrossRefGoogle Scholar
  11. 11.
    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. 2013;61(1):77–84.CrossRefGoogle Scholar
  12. 12.
    Monsuez JJ. Detection and prevention of cardiac complications of cancer chemotherapy. Arch Cardiovasc Dis. 2012;105(11):593–604.CrossRefGoogle Scholar
  13. 13.
    Banchs J, Jefferies JL, Plana JC, Hundley WG. Imaging for cardiotoxicity in cancer patients. Tex Heart Inst J. 2011;38:268–9.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Tarr A, Stoebe S. Early detection of cardiotoxicity by 2D and 3D deformation imaging in patients receiving chemotherapy. Echo Res Pract. 2015;2(3):81–8.CrossRefGoogle Scholar
  15. 15.
    Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, 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.CrossRefGoogle Scholar
  16. 16.
    Di Lisi D, Bonura F, Macaione F, Peritore A, Meschisi M, Cuttitta F, et al. Chemotherapy-induced cardiotoxicity: role of the tissue Doppler in the early diagnosis of left ventricular dysfunction. Anti-Cancer Drugs. 2011;22(5):468–72.CrossRefGoogle Scholar
  17. 17.
    Nagy AC, Cserép Z, Tolnay E, Nagykálnai T, Forster T. Early diagnosis of chemotherapy induced cardiomyopathy: a prospective tissue Doppler imaging study. Pathol Oncol Res. 2008;14:69–77.CrossRefGoogle Scholar
  18. 18.
    Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Cohen V, et al. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol. 2011;107:1375–80.CrossRefGoogle Scholar
  19. 19.
    Lancellotti P, Nkomo VT, Badano LP, Bergler-Klein J, Bogaert J, Davin L, European Society of Cardiology Working Groups on Nuclear Cardiology and Cardiac Computed Tomography and Cardiovascular Magnetic Resonance, American Society of Nuclear Cardiology, Society for Cardiovascular Magnetic Resonance, Society of Cardiovascular Computed Tomography, et al. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. Eur Heart J Cardiovasc Imaging. 2013;14:721–40.CrossRefGoogle Scholar
  20. 20.
    Maisch B, Seferović PM, Ristić AD, Erbel R, Rienmüller R, Adler Y, et al. Guidelines on the diagnosis and management of pericardial diseases executive summary; The Task force on the diagnosis and management of pericardial diseases of the European society of cardiology. Eur Heart J. 2004;25:587–610.CrossRefGoogle Scholar
  21. 21.
    Cameli M, Mondillo S, Galderisi M, Mandoli GE, Ballo P, Nistri S, et al. Speckle tracking echocardiography: a practical guide. G Ital Cardiol (Rome). 2017;18(4):253–69.Google Scholar
  22. 22.
    Migrino RQ, Aggarwal D, Konorev E, Brahmbhatt T, Bright M, Kalyanaraman B. Early detection of doxorubicin cardiomyopathy using two-dimensional strain echocardiography. Ultrasound Med Biol. 2008;34:208–14.CrossRefGoogle Scholar
  23. 23.
    Cheung YF, Hong WJ, Chan GC, Wong SJ, Ha SY. Left ventricular myocardial deformation and mechanical dyssynchrony in children with normal ventricular shortening fraction after anthracycline therapy. Heart. 2010;96:1137–41.CrossRefGoogle Scholar
  24. 24.
    Bi X, Deng Y, Zeng F, Zhu Y, Wu Y, Zhao C, et al. Evaluation of epirubicin-induced cardiotoxicity by two-dimensional strain echocardiography in breast cancer patients. J Huazhong Univ Sci Technolog Med Sci. 2009;29:391–4.CrossRefGoogle Scholar
  25. 25.
    Ho E, Brown A, Barrett P, Morgan RB, King G, Kennedy MJ, et al. Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study. Heart. 2010;96:701–7.CrossRefGoogle Scholar
  26. 26.
    Kang Y, Cheng L, Li L, Chen H, Sun M, Wei Z, et al. Early detection of anthracycline-induced cardiotoxicity using two dimensional speckle tracking echocardiography. Cardiol J. 2013;20:592–9.CrossRefGoogle Scholar
  27. 27.
    Stoodley PW, Richards DA, Hui R, Boyd A, Harnett PR, Meikle SR, et al. Two-dimensional myocardial strain imaging detects changes in left ventricular systolic function immediately after anthracycline chemotherapy. Eur J Echocardiogr. 2011;12:945–52.CrossRefGoogle Scholar
  28. 28.
    Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Tan TC, et al. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging. 2012;5:596–603.CrossRefGoogle Scholar
  29. 29.
    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. 2013;26:493–8.CrossRefGoogle Scholar
  30. 30.
    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. 2014;15(3):324–31.CrossRefGoogle Scholar
  31. 31.
    Pizzino F, Vizzari G, Qamar R, Bomzer C, Carerj S, Zito C, et al. Multimodality imaging in cardiooncology. J Oncol. 2015;2015:263950.CrossRefGoogle Scholar
  32. 32.
    Yu HK, Yu W, Cheuk DK, Wong SJ, Chan GC, Cheung YF. New three-dimensional speckle-tracking echocardiography identifies global impairment of left ventricular mechanics with a high sensitivity in childhood cancer survivors. J Am Soc Echocardiogr. 2013;26(8):846–52.CrossRefGoogle Scholar
  33. 33.
    Mornoş C, Manolis AJ, Cozma D. The value of left ventricular global longitudinal strain assessed by three-dimensional strain imaging in the early detection of anthracycline-mediated cardiotoxicity. Hell J Cardiol. 2014;55(3):235–44.Google Scholar
  34. 34.
    Gottdiener JS, Mathisen DJ, Borer JS, Bonow RO, Myers CE, Barr LH, et al. Doxorubicin cardiotoxicity: assessment of late left ventricular dysfunction by radionuclide cineangiography. Ann Intern Med. 1981;94:430–5.CrossRefGoogle Scholar
  35. 35.
    Takuma S, Ota T, Muro T, Hozumi T, Sciacca R, Di Tullio MR, et al. Assessment of left ventricular function by real-time 3-dimensional echocardiography compared with conventional noninvasive methods. J Am Soc Echocardiogr. 2001;14(4):275–84.CrossRefGoogle Scholar
  36. 36.
    Pepe A, Pizzino F, Gargiulo P, Perrone-Filardi P, Cadeddu C, Mele D, et al. Cardiovascular imaging in the diagnosis and monitoring of cardiotoxicity: cardiovascular magnetic resonance and nuclear cardiology. J Cardiovasc Med (Hagerstown). 2016;17(Suppl 1):e45–54.CrossRefGoogle Scholar
  37. 37.
    Goenka AH, Flamm SD. Cardiac magnetic resonance imaging for the investigation of cardiovascular disorders. Part 1: current applications. Tex Heart Inst J. 2014;41:7–20.CrossRefGoogle Scholar
  38. 38.
    Neilan TG, Coelho-Filho OR, Pena-Herrera D, Shah RV, Jerosch-Herold M, Francis SA, et al. Left ventricular mass in patients with a cardiomyopathy after treatment with anthracyclines. Am J Cardiol. 2012;110:1679–86.CrossRefGoogle Scholar
  39. 39.
    Mewton N, Opdahl A, Choi EY, Almeida AL, Kawel N, Wu CO, et al. Left ventricular global function index by magnetic resonance imaging–a novel marker for assessment of cardiac performance for the prediction of cardiovascular events: the multi-ethnic study of atherosclerosis. Hypertension. 2013;61:770–8.CrossRefGoogle Scholar
  40. 40.
    Drafts BC, Twomley KM, D’Agostino R Jr, Lawrence J, Avis N, Ellis LR, et al. Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease. JACC Cardiovasc Imaging. 2013;6:877–85.CrossRefGoogle Scholar
  41. 41.
    Grover S, Leong DP, Chakrabarty A, Joerg L, Kotasek D, Cheong K, et al. Left and right ventricular effects of anthracycline and trastuzumab chemotherapy: a prospective study using novel cardiac imaging and biochemical markers. Int J Cardiol. 2013;168:5465–7.CrossRefGoogle Scholar
  42. 42.
    Jordan JH, D’Agostino RB Jr, Hamilton CA, Vasu S, Hall ME, Kitzman DW, et al. Longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of cardiotoxic chemotherapies using T1-weighted and T2-weighted cardiovascular magnetic resonance. Circ Cardiovasc Imaging. 2014;7:872–9.CrossRefGoogle Scholar
  43. 43.
    Fallah-Rad N, Walker JR, Wassef A, Lytwyn M, Bohonis S, Fang T, et al. 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. 2011;57:2263–70.CrossRefGoogle Scholar
  44. 44.
    Fallah-Rad N, Lytwyn M, Fang T, Kirkpatrick I, Jassal DS. Delayed contrast enhancement cardiac magnetic resonance imaging in trastuzumab induced cardiomyopathy. J Cardiovasc Magn Reson. 2008;10:5.CrossRefGoogle Scholar
  45. 45.
    Wadhwa D, Fallah-Rad N, Grenier D, Krahn M, Fang T, Ahmadie R, et al. Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study. Breast Cancer Res Treat. 2009;117:357–64.CrossRefGoogle Scholar
  46. 46.
    Toro-Salazar OH, Gillan E, O’Loughlin MT, Burke GS, Ferranti J, Stainsby J, et al. Occult cardiotoxicity in childhood cancer survivors exposed to anthracycline therapy. Circ Cardiovasc Imaging. 2013;6:873–80.CrossRefGoogle Scholar
  47. 47.
    Tham EB, Haykowsky MJ, Chow K, Spavor M, Kaneko S, Khoo NS, et al. Diffuse myocardial fibrosis by T1-mapping in children with subclinical anthracycline cardiotoxicity: relationship to exercise capacity, cumulative dose and remodeling. J Cardiovasc Magn Reson. 2013;15:48.CrossRefGoogle Scholar
  48. 48.
    Neilan TG, Coelho-Filho OR, Shah RV, Feng JH, Pena-Herrera D, Mandry D, et al. Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline-based chemotherapy. Am J Cardiol. 2013;111:717–22.CrossRefGoogle Scholar
  49. 49.
    Novo G, Cadeddu C, Sucato V, Pagliaro P, Romano S, Tocchetti CG, et al. Role of biomarkers in monitoring antiblastic cardiotoxicity. J Cardiovasc Med (Hagerstown). 2016;17(Suppl 1 Special issue on Cardiotoxicity from Antiblastic Drugs and Cardioprotection):e27–34.CrossRefGoogle Scholar
  50. 50.
    Cardinale D, Sandri MT, Martinoni A, Tricca A, Civelli M, Lamantia G, et al. Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol. 2000;36(2):517–22.CrossRefGoogle Scholar
  51. 51.
    Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M, Lamantia G, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004;109:2749–54.CrossRefGoogle Scholar
  52. 52.
    Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli M, Salvatici M, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol. 2010;28:3910–6.CrossRefGoogle Scholar
  53. 53.
    Ky B, Putt M, Sawaya H, French B, Januzzi JL Jr, Sebag IA, et al. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol. 2014;63:809–16.CrossRefGoogle Scholar
  54. 54.
    Feola M, Garrone O, Occelli M, Francini A, Biggi A, Visconti G, et al. Cardiotoxicity after anthracycline chemotherapy in breast carcinoma: effects on left ventricular ejection fraction, troponin I and brain natriuretic peptide. Int J Cardiol. 2011;148:194–8.CrossRefGoogle Scholar
  55. 55.
    Suzuki T, Hayashi D, Yamazaki T, Mizuno T, Kanda Y, Komuro I, et al. Elevated B-type natriuretic peptide levels after anthracycline administration. Am Heart J. 1998;136:362–3.CrossRefGoogle Scholar
  56. 56.
    Sandri MT, Salvatici M, Cardinale D, Zorzino L, Passerini R, Lentati P, et al. N-terminal pro-B-type natriuretic peptide after high-dose chemotherapy: a marker predictive of cardiac dysfunction? Clin Chem. 2005;51:1405–10.CrossRefGoogle Scholar
  57. 57.
    Romano S, Fratini S, Ricevuto E, Procaccini V, Stifano G, Mancini M, et al. Serial measurements of NT-proBNP are predictive of not high-dose anthracycline cardiotoxicity in breast cancer patients. Br J Cancer. 2011;105:1663–8.CrossRefGoogle Scholar
  58. 58.
    Lagoa R, Gañán C, López-Sánchez C, García-Martínez V, Gutierrez-Merino C. The decrease of NAD(P)H:quinone oxidoreductase 1 activity and increase of ROS production by NADPH oxidases are early biomarkers in doxorubicin cardiotoxicity. Biomarkers. 2014;19:142–53.CrossRefGoogle Scholar
  59. 59.
    El Ghandour AH, El Sorady M, Azab S, El Rahman M. Human heart-type fatty acid-binding protein as an early diagnostic marker of doxorubicin cardiac toxicity. Hematol Rev. 2009;1:29–32.Google Scholar
  60. 60.
    Horacek JM, Tichy M, Pudil R, Jebavy L. Glycogen phosphorylase BB could be a new circulating biomarker for detection of anthracycline cardiotoxicity. Ann Oncol. 2008;19:1656–7.CrossRefGoogle Scholar
  61. 61.
    Horie T, Ono K, Nishi H, Nagao K, Kinoshita M, Watanabe S, et al. Acute doxorubicin cardiotoxicity is associated with miR-146a-induced inhibition of the neuregulin-ErbB pathway. Cardiovasc Res. 2010;87:656–64.CrossRefGoogle Scholar
  62. 62.
    Levis EB, Binkley BF, Shapiro CL. Cardiotoxic effects of anthracycline-based therapy: what is the evidence and what are the potential harms? Lancet Oncol. 2017;18:e445–56.CrossRefGoogle Scholar
  63. 63.
    Pistillucci G, Ciorra AA, Sciacca V, Raponi M, Rossi R, Veltri E. [Troponin I and B-type Natriuretic Peptide (BNP) as biomarkers for the prediction of cardiotoxicity in patients with breast cancer treated with adjuvant anthracyclines and trastuzumab]. Clin Ter. 2015;166:e67–71. [Article in Italian.]Google Scholar
  64. 64.
    Meinardi MT, van Veldhuisen DJ, Gietema JA, Dolsma WV, Boomsma F, van den Berg MP, et al. Prospective evaluation of early cardiac damage induced by epirubicin-containing adjuvant chemotherapy and locoregional radiotherapy in breast cancer patients. J Clin Oncol. 2001;19:2746–53.CrossRefGoogle Scholar
  65. 65.
    Lee HS, Son CB, Shin SH, Kim YS. Clinical correlation between brain natriutetic peptide and anthracyclin-induced cardiac toxicity. Cancer Res Treat. 2008;40:121–6.CrossRefGoogle Scholar
  66. 66.
    Urun Y, Utkan G, Yalcin B, Akbulut H, Onur H, Oztuna DG, et al. The role of cardiac biomarkers as predictors of trastuzumab cardiotoxicity in patients with breast cancer. Exp Oncol. 2015;37:53–7.PubMedGoogle Scholar
  67. 67.
    Yu AF, Ky B. Roadmap for biomarkers of cancer therapy cardiotoxicity. Heart. 2016;102(6):425–30.CrossRefGoogle Scholar
  68. 68.
    Moonen M, Oury C, Lancellotti P. Cardiac imaging: multimodality advances and surveillance strategies in detection of cardiotoxicity. Curr Oncol Rep. 2017;19:63.CrossRefGoogle Scholar
  69. 69.
    Putt M, Hahn VS, Januzzi JL, Sawaya H, Sebag IA, Plana JC, et al. Longitudinal changes in multiple biomarkers are associated with cardiotoxicity in breast cancer patients treated with doxorubicin, taxanes, and trastuzumab. Clin Chem. 2015;61(9):1164–72.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Giuseppina Novo
    • 1
    Email author
  • Cinzia Nugara
    • 2
    • 3
  • Patrizio Lancellotti
    • 4
  1. 1.Division of Cardiology, Biomedical Department of Internal Medicine and Specialities (DIBIMIS), University of PalermoPalermoItaly
  2. 2.Biomedical Department of Internal Medicine and Specialities (DIBIMIS), University of PalermoPalermoItaly
  3. 3.IRCCS Bonino PulejoMessinaItaly
  4. 4.University of Liège HospitalLiegeBelgium

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