Abstract 3584: Early and non-invasive detection of radiation-induced cardiotoxicity in pre-clinical and clinical models
Authors: Higgins Taylor-Jade , Sharma Jayesh , Zhang-Velten Elizabeth R. , Elliott Sarah , Ma Junjie , Chen Jun , Schiattarella Gabriele , Vidal Chantal , Jiang Nan , Daou Daniel , Hill Joseph , Gillette Thomas , Malloy Craig , Zaha Vlad , Park Jae Mo , Alluri Prasanna 
Published: June 2023

Abstract
Background: Nearly half of all patients receive radiation therapy as a component of their cancer care. Despite the efficacy of radiation therapy as a cancer treatment, cardiotoxicity is a major concern in patients receiving chest radiotherapy. There are currently no standardized approaches for early detection of radiation-induced cardiotoxicity as a stage that offers potential for early intervention. In this study, we employ hyperpolarized 13C- pyruvate magnetic resonance spectroscopy to non-invasively characterize early metabolic changes in the heart in response to radiation.
Methods: We established a pre-clinical model of radiation induced heart disease (RIHD) by performing whole heart irradiation (8Gy x 5) in rats. Echocardiography was used characterize mechanical changes in the heart following radiation. To non-invasively detect myocardial mitochondrial dysfunction following cardiac irradiation in vivo, we employed hyperpolarized 13C- pyruvate magnetic resonance spectroscopy (MRS) to track the fate of pyruvate, an intermediate of glucose metabolism, as it is metabolized in the heart. Hyperpolarized 13C- pyruvate MRS was also employed in a patient who received thoracic radiation for treatment of thymoma to non-invasively study changes in glucose metabolism in response to radiation.
Results: We identified evidence of early cardiac mitochondrial dysfunction prior to onset of mechanical changes in the heart. Following cardiac irradiation, due to mitochondrial dysfunction, pyruvate was preferentially metabolized to lactate in the cytoplasm (as opposed to bicarbonate in the mitochondria in non-irradiated hearts). The ratio of products of 13C- pyruvate metabolism in the mitochondria and cytoplasm as ascertained by hyperpolarized 13C- pyruvate MRS served as a biomarker for metabolic dysfunction in the heart both in a pre-clinical rat model and in a patient who received thoracic radiation.
Conclusions: We have developed a non-invasive approach for detection of cardiac mitochondrial dysfunction, which may serve as a biomarker for early detection of radiation-induced cardiotoxicity, and shown feasibility in a human patient. Clinical adoption of this approach may enable early identification of patients who are at high risk for future cardiac complications and may benefit from mitigation strategies.
Citation Format: Taylor-Jade Higgins, Jayesh Sharma, Elizabeth R. Zhang-Velten, Sarah Elliott, Junjie Ma, Jun Chen, Gabriele Schiattarella, Chantal Vidal, Nan Jiang, Daniel Daou, Joseph Hill, Thomas Gillette, Craig Malloy, Vlad Zaha, Jae Mo Park, Prasanna Alluri. Early and non-invasive detection of radiation-induced cardiotoxicity in pre-clinical and clinical models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3584.