Changes in Citric Acid Cycle and Nucleoside Metabolism Are Associated with Anthracycline Cardiotoxicity in Patients with Breast Cancer

  • Aarti AsnaniEmail author
  • Xu Shi
  • Laurie Farrell
  • Rahul Lall
  • Igal A. Sebag
  • Juan Carlos Plana
  • Robert E. Gerszten
  • Marielle Scherrer-Crosbie
Original Article
Part of the following topical collections:
  1. Special Issue: Cardiovascular Function and Cancer Treatment


Anthracyclines and HER2-targeted antibodies are very effective for the treatment of breast cancer, but their use is limited by cardiotoxicity. In this nested case-control study, we assessed the role of intermediary metabolism in 38 women with breast cancer treated with anthracyclines and trastuzumab. Using targeted mass spectrometry to measure 71 metabolites in the plasma, we identified changes in citric acid and aconitic acid that differentiated patients who developed cardiotoxicity from those who did not. In patients with cardiotoxicity, the magnitude of change in citric acid at three months correlated with the change in left ventricular ejection fraction (LVEF) and absolute LVEF at nine months. Patients with cardiotoxicity also demonstrated more pronounced changes in purine and pyrimidine metabolism. Early metabolic changes may therefore provide insight into the mechanisms associated with the development of chemotherapy-associated cardiotoxicity.


Anthracyclines Breast cancer Cardiotoxicity Chemotherapy Citric acid Heart failure HER2 Metabolism 



Angiotensin converting enzyme


Body mass index


Citric acid cycle




Diastolic blood pressure


Liquid chromatography mass spectrometry


Left ventricular ejection fraction


Systolic blood pressure



AA was supported by a Scholar Award from the Sarnoff Cardiovascular Research Foundation (Great Falls, VA). The project was supported by an investigator-initiated grant from Susan G. Komen (Dallas, TX) and a SPARK grant initiated by Massachusetts General Hospital (Boston, MA), both to MSC.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human Subjects/Informed Consent Statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation at Massachusetts General Hospital, MD Anderson Cancer Center, and McGill University and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.


  1. 1.
    Cardinale, D., Colombo, A., Bacchiani, G., Tedeschi, I., Meroni, C. A., Veglia, F., et al. (2015). Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation, 131(22), 1981–1988. Scholar
  2. 2.
    Limat, S., Demesmay, K., Voillat, L., Bernard, Y., Deconinck, E., Brion, A., et al. (2003). Early cardiotoxicity of the CHOP regimen in aggressive non-Hodgkin’s lymphoma. Annals of Oncology, 14(2), 277–281.CrossRefGoogle Scholar
  3. 3.
    Tan, T. C., Neilan, T. G., Francis, S., Plana, J. C., & Scherrer-Crosbie, M. (2015). Anthracycline-induced cardiomyopathy in adults. Comprehensive Physiology, 5(3), 1517–1540. Scholar
  4. 4.
    Bowles, E. J., Wellman, R., Feigelson, H. S., Onitilo, A. A., Freedman, A. N., Delate, T., et al. (2012). Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: A retrospective cohort study. Journal of the National Cancer Institute, 104(17), 1293–1305. Scholar
  5. 5.
    Octavia, Y., Tocchetti, C. G., Gabrielson, K. L., Janssens, S., Crijns, H. J., & Moens, A. L. (2012). Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies. Journal of Molecular and Cellular Cardiology, 52(6), 1213–1225. Scholar
  6. 6.
    Ichikawa, Y., Ghanefar, M., Bayeva, M., Wu, R., Khechaduri, A., Naga Prasad, S. V., et al. (2014). Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. The Journal of Clinical Investigation, 124(2), 617–630. Scholar
  7. 7.
    Zhang, S., Liu, X., Bawa-Khalfe, T., Lu, L. S., Lyu, Y. L., Liu, L. F., et al. (2012). Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nature Medicine, 18(11), 1639–1642. Scholar
  8. 8.
    Li, D. L., Wang, Z. V., Ding, G., Tan, W., Luo, X., Criollo, A., et al. (2016). Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation, 133(17), 1668–1687. Scholar
  9. 9.
    Finkelman, B. S., Putt, M., Wang, T., Wang, L., Narayan, H., Domchek, S., et al. (2017). Arginine-nitric oxide metabolites and cardiac dysfunction in patients with breast cancer. Journal of the American College of Cardiology, 70(2), 152–162. Scholar
  10. 10.
    Ky, B., Putt, M., Sawaya, H., French, B., Januzzi, J. L., Jr., Sebag, I. A., et al. (2014). Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. Journal of the American College of Cardiology, 63(8), 809–816. Scholar
  11. 11.
    Thompson Legault, J., Strittmatter, L., Tardif, J., Sharma, R., Tremblay-Vaillancourt, V., Aubut, C., et al. (2015). A metabolic signature of mitochondrial dysfunction revealed through a monogenic form of Leigh syndrome. Cell Reports, 13(5), 981–989. Scholar
  12. 12.
    Roberts, L. D., Bostrom, P., O'Sullivan, J. F., Schinzel, R. T., Lewis, G. D., Dejam, A., et al. (2014). beta-Aminoisobutyric acid induces browning of white fat and hepatic beta-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metabolism, 19(1), 96–108. Scholar
  13. 13.
    Zhou, S., Starkov, A., Froberg, M. K., Leino, R. L., & Wallace, K. B. (2001). Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Research, 61(2), 771–777.Google Scholar
  14. 14.
    Sawaya, H., Sebag, I. A., Plana, J. C., Januzzi, J. L., Ky, B., Tan, T. C., et al. (2012). Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circulation Cardiovascular Imaging, 5(5), 596–603. Scholar
  15. 15.
    Plana, J. C., Galderisi, M., Barac, A., Ewer, M. S., Ky, B., Scherrer-Crosbie, M., et al. (2014). 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. European Heart Journal Cardiovascular Imaging, 15(10), 1063–1093. Scholar
  16. 16.
    Danz, E. D., Skramsted, J., Henry, N., Bennett, J. A., & Keller, R. S. (2009). Resveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway. Free Radical Biology & Medicine, 46(12), 1589–1597. Scholar
  17. 17.
    Jirkovsky, E., Popelova, O., Krivakova-Stankova, P., Vavrova, A., Hroch, M., Haskova, P., et al. (2012). Chronic anthracycline cardiotoxicity: Molecular and functional analysis with focus on nuclear factor erythroid 2-related factor 2 and mitochondrial biogenesis pathways. The Journal of Pharmacology and Experimental Therapeutics, 343(2), 468–478. Scholar
  18. 18.
    Guo, J., Guo, Q., Fang, H., Lei, L., Zhang, T., Zhao, J., et al. (2014). Cardioprotection against doxorubicin by metallothionein is associated with preservation of mitochondrial biogenesis involving PGC-1alpha pathway. European Journal of Pharmacology, 737, 117–124. Scholar
  19. 19.
    Doenst, T., Nguyen, T. D., & Abel, E. D. (2013). Cardiac metabolism in heart failure: Implications beyond ATP production. Circulation Research, 113(6), 709–724. Scholar
  20. 20.
    Czibik, G., Steeples, V., Yavari, A., & Ashrafian, H. (2014). Citric acid cycle intermediates in cardioprotection. Circulation. Cardiovascular Genetics, 7(5), 711–719. Scholar
  21. 21.
    Stewart, D. J., Grewaal, D., Green, R. M., Mikhael, N., Goel, R., Montpetit, V. A., et al. (1993). Concentrations of doxorubicin and its metabolites in human autopsy heart and other tissues. Anticancer Research, 13(6A), 1945–1952.Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.CardioVascular Institute, Center for Life SciencesBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA
  2. 2.Cardiovascular Research Center and Corrigan Minehan Heart CenterMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  3. 3.Sir Mortimer B. Davis-Jewish General Hospital and McGill UniversityMontrealUSA
  4. 4.MD Anderson Cancer CenterHoustonUSA
  5. 5.Perelman Center for Advanced MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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