Author + information
- Aarti Asnani,
- Xu Shi,
- Laurie Farrell,
- Robert Tainsh,
- Sara Vandenwijngaert,
- Kai-Hung Cheng,
- Emmanuel Buys,
- Robert Gerszten and
- Marielle Scherrer-Crosbie
Background: Anthracyclines are effective chemotherapeutic agents, but their use is limited by cardiotoxicity that can lead to heart failure. The purpose of this study was to identify metabolic changes associated with anthracycline cardiotoxicity in mice and to validate these findings in patients.
Methods: C57BL/6J mice were treated with doxorubicin (DOX) 4 mg/kg or saline intraperitoneally each week for 5 weeks, after which hearts were isolated for analysis. A targeted mass spectrometry-based platform was used to measure 66 metabolites. Mean metabolite levels were compared using Student's t-test followed by correction for multiple hypotheses using the Benjamini-Hochberg (BH) method. Findings in mice were validated in 38 women with breast cancer treated with anthracycline-based chemotherapy, 19 of whom developed cardiotoxicity. Plasma was collected at baseline, at the completion of anthracycline therapy (3 months), and at 6 months. The Mann-Whitney U test was used to compare median percent change in metabolites over time in cardiotoxicity and control patients.
Results: Citrate levels were lower in hearts isolated from DOX-treated compared to vehicle-treated mice (ratio 0.74, p = 0.003). Similar trends were observed for the downstream Krebs cycle intermediates α-ketoglutarate and succinate. In patients, changes in citrate correlated with the development of cardiotoxicity. Patients with cardiotoxicity had decreased citrate levels compared to baseline (median change −3.2% at 3 months and −6.5% at 6 months), whereas patients without cardiotoxicity had increased citrate levels (median change 10.2% at 3 months and 12.9% at 6 months; p = 0.008 at 3 months and 0.007 at 6 months for cardiotoxicity versus control patients). We noted similar changes in aconitate, an intermediate in the isomerization of citrate to isocitrate. Importantly, these changes were apparent in human plasma prior to the development of left ventricular dysfunction on echocardiography.
Conclusions: Mice treated with DOX exhibited altered citrate metabolism in the heart that was mirrored in humans who developed cardiotoxicity. Restoration of these metabolites may be protective in patients treated with anthracyclines.
Room 144 A
Saturday, March 18, 2017, 9:04 a.m.-9:14 a.m.
Session Title: Highlighted Original Research: Heart Failure and Cardiomyopathies and the Year in Review
Abstract Category: 12. Heart Failure and Cardiomyopathies: Basic
Presentation Number: 902-12
- 2017 American College of Cardiology Foundation