Elsevier

Radiotherapy and Oncology

Volume 152, November 2020, Pages 133-145
Radiotherapy and Oncology

Original Article
Plasma metabolite biomarkers predictive of radiation induced cardiotoxicity

https://doi.org/10.1016/j.radonc.2020.04.018Get rights and content

Highlights

  • Metabolomics biomarkers predictive of Radiation-induced heart disease (RIHD).

  • Use of rat model and patient plasma to assess overlap in radiation response.

  • Predictive biomarkers of adverse cardiac function outcomes in esophageal cancer.

Abstract

Purpose

Although advancements in cancer treatments using radiation therapy (RT) have led to improved outcomes, radiation-induced heart disease (RIHD) remains a significant source of morbidity and mortality in survivors of cancers in the chest. Currently, there are no diagnostic tests in clinical use due to a lack of understanding of the natural history and mechanisms of RIHD development. Few studies have examined the utility of using metabolomics to prospectively identify cancer survivors who are at risk of developing cardiotoxicity.

Methods

We analyzed plasma and left ventricle heart tissue samples collected from a cohort of male Sprague Dawley (SD) rats that were either sham irradiated or received fractionated doses (9 Gy per day × 5 days) of targeted X-ray radiation to the heart. Metabolomic and lipidomic analyses were utilized as a correlative approach for delineation of novel biomarkers associated with radiation-induced cardiac toxicity. Additionally, we used high-resolution mass spectrometry to examine the metabolomic profiles of plasma samples obtained from patients receiving high dose thoracic RT for esophageal cancer.

Results

Metabolic alterations in the rat model and patient plasma profiles, showed commonalities of radiation response that included steroid hormone biosynthesis and vitamin E metabolism. Alterations in patient plasma profiles were used to develop classification algorithms predictive of patients at risk of developing RIHD.

Conclusion

Herein, we report the feasibility of developing a metabolomics-based biomarker panel that is associated with adverse outcomes of cardiac function in patients who received RT for the treatment of esophageal cancer.

Section snippets

Animal irradiation and sample collection

Rat local heart irradiation was performed as described previously [9]. In short, male SD rats were obtained from Charles River Laboratories and maintained on a 12:12 light-to-dark cycle with free access to food and water. At a weight of 250–290 g (about 9 weeks of age), rats received local heart irradiation using an image-guided X-ray machine (Small Animal Conformal RT Device, SACRTD). Rats were anesthetized with 3% isoflurane and placed vertically in a cylindrical Plexiglas holder that was cut

Results

Exposure to ionizing radiation causes long-term changes in metabolic profiles of rat heart and plasma. We have previously reported on radiation-induced alterations in mitochondria in the heart of adult male SD rats, either after a single dose of X-rays to the heart [5] or after five once-a-day fractions of 9 Gy (5 × 9 Gy) [9]. At 6 months after 5 × 9 Gy local heart irradiation, small but statistically significant changes in cardiac function and a small increase in cardiac collagen deposition

Discussion

Exposure of the heart to radiation leads to significant morbidity and mortality in survivors of cancer. The risk of cardiac events increases in a dose-dependent manner [21]. Elevated risk begins within the first few years and continues for decades after RT [22]. Current practices for diagnosis and prediction of patients at risk for RT related cardiac events are not yet developed. Commonly available testing such as echocardiogram and nuclear medicine studies are not used routinely and do not

Acknowledgments

This work was supported by CCSG Developmental funding LCCC-AWD413088, Georgetown University, Washington DC, United States to KU and AKC and 1U01AI133561-01 funding from, National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID), Bethesda, Maryland, United States to MB and AKC. The authors would like to acknowledge the Metabolomics Shared Resource in Georgetown University (Washington, DC, USA) which is partially supported by NIH/NCI/CCSG grant P30-CA051008,

Author contributions

Study design: KU, MBS, AKC. Performance of the study: CY, AB, EAB, VS. Metabolomic Data acquisition and analysis: MJ, YL, MG. Drafting of the manuscript: AKC, KU, YL, MBS. All authors have read and approved the final version of the submitted manuscript.

Competing interests

The author(s) declare no competing interests.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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