Systolic versus diastolic cardiac function variables during epirubicin treatment for breast cancer

  • Jon M. Appel
  • Benny V. Jensen
  • Dorte L. Nielsen
  • Marianne Ryberg
  • Bo Zerahn
Original Paper


Anthracyclines are important in the treatment of numerous malignant diseases but the use is limited by a risk of heart failure (CHF). LVEF (left ventricular ejection fraction) measurements by radio-nuclide ventriculography with multiple gated acquisition (MUGA) is often used for cardiac monitoring. However, diastolic variables have been proposed as sensitive supplements. It was hypothesized that a change in diastolic filling variables measured by MUGA could identify individuals after epirubicin treatment (ET) in risk of developing heart failure. A retrospective analysis of registered raw data. Individuals completing high-dose ET for breast cancer were selected from a 2-year period. All had MUGA-scans performed prior to and after ET and were observed clinically for late development of CHF. Eleven of 34 individuals developed CHF. A significant LVEF-reduction was recorded after ET with only minor changes in diastolic parameters. Development of CHF was related to dose, entry-blood pressure and inversely to post-epirubicin LVEF. Risk of CHF was high if LVEF <50% (Hazard ratio 3.31). Epirubicin induces considerable decrease in LVEF and a high risk of CHF. The risk of CHF is significantly higher if LVEF is reduced after ET. Diastolic MUGA-variables seem to add little information to conventional measurements of LVEF.


Anthracyclines Cardiotoxicity Diastolic function Epirubicin Heart failure 


  1. 1.
    Swain SM, Whaley FS, Ewer MS (2003) Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97(11):2869–2879CrossRefPubMedGoogle Scholar
  2. 2.
    Appel JM, Nielsen D, Zerahn B, Jensen BV, Skagen K (2007) Anthracycline-induced chronic cardiotoxicity and heart failure. Acta Oncol 46(5):576–580CrossRefPubMedGoogle Scholar
  3. 3.
    Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, Muggia FM (1979) Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91(5):710–717Google Scholar
  4. 4.
    Xu MF, Tang PL, Qian ZM, Ashraf M (2001) Effects by doxorubicin on the myocardium are mediated by oxygen free radicals. Life Sci 68(8):889–901CrossRefPubMedGoogle Scholar
  5. 5.
    Escriba PV, Sastre M, Garcia-Sevilla JA (1995) Disruption of cellular signalling pathways by daunomycin through destabilization of non lamellar membrane structures. Proc Natl Acad Sci USA 92(16):7595–7599CrossRefPubMedGoogle Scholar
  6. 6.
    Zhou S, Starkov A, Froberg MK, Leino RL, Wallace KB (2001) Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 61(2):771–777PubMedGoogle Scholar
  7. 7.
    Tokarska-Schlattner M, Zaugg M, Zuppinger C, Wallimann T, Schlattner U (2006) New insights into doxorubicin-induced cardiotoxicity: the critical role of cellular energetics. J Mol Cell Cardiol 41(3):389–405CrossRefPubMedGoogle Scholar
  8. 8.
    Kapelko VI, Williams CP, Gutstein DE, Morgan JP (1996) Abnormal myocardial calcium handling in the early stage of adriamycin cardiomyopathy. Arch Physiol Biochem 104(2):185–191CrossRefPubMedGoogle Scholar
  9. 9.
    Early Breast Cancer Trialists’ Collaborative Group (1998) Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 352(9132):930–942CrossRefGoogle Scholar
  10. 10.
    Henderson IC, Canellos GP (1980) Cancer of the breast: the past decade (second of two parts). N Engl J Med 302(2):78–90PubMedGoogle Scholar
  11. 11.
    Ryberg M, Nielsen D, Skovsgaard T, Hansen J, Jensen BV, Dombernowsky P (1998) Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J Clin Oncol 16(11):3502–3508PubMedGoogle Scholar
  12. 12.
    Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA (1973) A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32(2):302–314CrossRefPubMedGoogle Scholar
  13. 13.
    Ritchie JL, Bateman TM, Bonow RO, Crawford MH, Gibbons RJ, Hall RJ, O’Rourke RA, Parisi AF, Verani MS (1995) Guidelines for clinical use of cardiac radionuclide imaging. Report of the American College of Cardiology/American Heart Association task force on assessment of diagnostic and therapeutic cardiovascular procedures (Committee on Radionuclide Imaging), developed in collaboration with the American Society of Nuclear Cardiology. J Am Coll Cardiol 25(2):521–547CrossRefPubMedGoogle Scholar
  14. 14.
    Steinherz LJ, Graham T, Hurwitz R, Sondheimer HM, Schwartz RG, Shaffer EM, Sandor G, Benson L, Williams R (1992) Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the cardiology committee of the children’s cancer study group. Pediatrics 89(5 Pt 1):942–949PubMedGoogle Scholar
  15. 15.
    Alexander J, Dainiak N, Berger HJ, Goldman L, Johnstone D, Reduto L, Duffy T, Schwartz P, Gottschalk A, Zaret BL (1979) Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med 300(6):278–283PubMedCrossRefGoogle Scholar
  16. 16.
    Belham M, Kruger A, Mepham S, Faganello G, Pritchard C (2007) Monitoring left ventricular function in adults receiving anthracycline-containing chemotherapy. Eur J Heart Fail 9(4):409–414CrossRefPubMedGoogle Scholar
  17. 17.
    Mitani I, Jain D, Joska TM, Burtness B, Zaret BL (2003) Doxorubicin cardiotoxicity: prevention of congestive heart failure with serial cardiac function monitoring with equilibrium radionuclide angiocardiography in the current era. J Nucl Cardiol 10(2):132–139CrossRefPubMedGoogle Scholar
  18. 18.
    Jensen BV, Skovsgaard T, Nielsen SL (2002) Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol 13(5):699–709CrossRefPubMedGoogle Scholar
  19. 19.
    Ganame J, Claus P, Eyskens B, Uyttebroeck A, Renard M, D’hooge J, Gewillig M, Bijnens B, Sutherland GR, Mertens L (2007) Acute cardiac functional and morphological changes after anthracycline infusions in children. Am J Cardiol 99(7):974–977CrossRefPubMedGoogle Scholar
  20. 20.
    Suzuki J, Yanagisawa A, Shigeyama T, Tsubota J, Yasumura T, Shimoyama K, Ishikawa K (1999) Early detection of anthracycline-induced cardiotoxicity by radionuclide angiocardiography. Angiology 50(1):37–45CrossRefPubMedGoogle Scholar
  21. 21.
    Schmitt K, Tulzer G, Merl M, Aichhorn G, Grillenberger A, Wiesinger G, Hofstadler G (1995) Early detection of doxorubicin and daunorubicin cardiotoxicity by echocardiography: diastolic versus systolic parameters. Eur J Pediatr 154(3):201–204CrossRefPubMedGoogle Scholar
  22. 22.
    Nagy AC, Tolnay E, Nagykalnai T, Forster T (2006) Cardiotoxicity of anthracycline in young breast cancer female patients: the possibility of detection of early cardiotoxicity by TDI. Neoplasma 53(6):511–517PubMedGoogle Scholar
  23. 23.
    Lu P (2005) Monitoring cardiac function in patients receiving doxorubicin. Semin Nucl Med 35(3):197–201CrossRefPubMedGoogle Scholar
  24. 24.
    Clements IP, Sinak LJ, Gibbons RJ, Brown ML, O’Connor MK (1990) Determination of diastolic function by radionuclide ventriculography. Mayo Clin Proc 65(7):1007–1019PubMedGoogle Scholar
  25. 25.
    Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML (1991) Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266(12):1672–1677CrossRefPubMedGoogle Scholar
  26. 26.
    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 (2001) Prospective evaluation of early cardiac damage induced by epirubicin-containing adjuvant chemotherapy and loco regional radiotherapy in breast cancer patients. J Clin Oncol 19(10):2746–2753PubMedGoogle Scholar
  27. 27.
    Muntinga HJ, van den Berg F, Knol HR, Niemeyer MG, Blanksma PK, Louwes H, van der Wall EE (1997) Normal values and reproducibility of left ventricular filling parameters by radionuclide angiography. Int J Card Imaging 13(2):165–171 (discussion 173)CrossRefPubMedGoogle Scholar
  28. 28.
    Schulman SP, Lakatta EG, Fleg JL, Lakatta L, Becker LC, Gerstenblith G (1992) Age-related decline in left ventricular filling at rest and exercise. Am J Physiol 263(6 Pt 2):H1932–H1938PubMedGoogle Scholar
  29. 29.
    Kremer LC, van Dalen EC, Offringa M, Ottenkamp J, Voute PA (2001) Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol 19(1):191–196PubMedGoogle Scholar
  30. 30.
    Ryberg M, Nielsen D, Cortese G, Nielsen G, Skovsgaard T, Andersen PK (2008) New insight into epirubicin cardiac toxicity: competing risks analysis of 1097 breast cancer patients. J Natl Cancer Inst 100(15):1058–1067CrossRefPubMedGoogle Scholar
  31. 31.
    Bonow RO (1991) Radionuclide angiographic evaluation of left ventricular diastolic function. Circulation 84(3 Suppl):I208–I215PubMedGoogle Scholar
  32. 32.
    Doyle JJ, Neugut AI, Jacobson JS, Grann VR, Hershman DL (2005) Chemotherapy and cardiotoxicity in older breast cancer patients: a population-based study. J Clin Oncol 23(34):8597–8605CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, B.V. 2009

Authors and Affiliations

  • Jon M. Appel
    • 1
  • Benny V. Jensen
    • 2
  • Dorte L. Nielsen
    • 2
  • Marianne Ryberg
    • 2
  • Bo Zerahn
    • 3
  1. 1.Department of CardiologyHerlev Hospital, University of CopenhagenHerlevDenmark
  2. 2.Department of OncologyHerlev Hospital, University of CopenhagenHerlevDenmark
  3. 3.Department of Nuclear MedicineHerlev Hospital, University of CopenhagenHerlevDenmark

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