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

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Abstract

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.

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Abbreviations

ACE:

Angiotensin converting enzyme

BMI:

Body mass index

CAC:

Citric acid cycle

CV:

Cardiovascular

DBP:

Diastolic blood pressure

LC-MS:

Liquid chromatography mass spectrometry

LVEF:

Left ventricular ejection fraction

SBP:

Systolic blood pressure

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Funding

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.

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Authors and Affiliations

  1. CardioVascular Institute, Center for Life Sciences, Beth Israel Deaconess Medical Center and Harvard Medical School, 3 Blackfan Circle, 9th Floor, Boston, MA, 02115, USA

    Aarti Asnani, Xu Shi, Laurie Farrell, Rahul Lall, Robert E. Gerszten & Marielle Scherrer-Crosbie

  2. Cardiovascular Research Center and Corrigan Minehan Heart Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Aarti Asnani, Xu Shi, Laurie Farrell, Robert E. Gerszten & Marielle Scherrer-Crosbie

  3. Sir Mortimer B. Davis-Jewish General Hospital and McGill University, Montreal, CA, USA

    Igal A. Sebag

  4. MD Anderson Cancer Center, Houston, TX, USA

    Juan Carlos Plana

  5. Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Marielle Scherrer-Crosbie

Authors
  1. Aarti Asnani
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  2. Xu Shi
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  3. Laurie Farrell
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  4. Rahul Lall
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  5. Igal A. Sebag
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  7. Robert E. Gerszten
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Correspondence to Aarti Asnani.

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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.

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Associate Editor Ana Barac oversaw the review of this article

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Asnani, A., Shi, X., Farrell, L. et al. Changes in Citric Acid Cycle and Nucleoside Metabolism Are Associated with Anthracycline Cardiotoxicity in Patients with Breast Cancer. J. of Cardiovasc. Trans. Res. 13, 349–356 (2020). https://doi.org/10.1007/s12265-019-09897-y

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  • DOI: https://doi.org/10.1007/s12265-019-09897-y

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