Abstract 3659: Early in vivo detection of radiation-induced cardiotoxicity
Authors: Sharma Jayesh , Zhang Elizabeth , Wang Xuliang , Ma Junjie , Chen Jun , Schiattarella Gabriele , Hill Joseph , Park Jaemo , Malloy Craig , Zaha Vlad , Alluri Prasanna 
Published: June 2022

Abstract
Background: Radiation-Induced Heart Disease (RIHD) is a major source of morbidity and mortality in patients receiving thoracic radiation, which is a common treatment for malignancies like lung cancer. There is currently no standardized program for follow-up of RIHD in cancer survivors. Therefore, there is an acute need for developing detection of RIHD at a stage that offers potential for early intervention and reversibility.
The gold standard for detection of global cardiac dysfunction is echocardiography. However, this current paradigm detects cardiac changes in metrics such as Left Ventricular Ejection Fraction (LVEF), which are relatively late manifestations in the pathology of cardiotoxicity, decreasing the possibility of reversing such damage. We sought to assess radiation-induced changes significantly earlier than the current standard of care by measuring the efficiency of the tricarboxylic acid cycle in cardiac mitochondria; we hypothesized that radiation leads to impaired mitochondrial function, causing increased conversion of pyruvate to lactate in the cytosol and decreased conversion in the mitochondria. In order to non-invasively measure this impairment, we utilized Magnetic Resonance Spectroscopy (MRS) to track the fate of hyperpolarized (HP) C-13 pyruvate.
Methods: Sprague-Dawley rats underwent baseline and post treatment echocardiography and HP C-13 pyruvate MRS at multiple timepoints. Half of the animals underwent image-guided cardiac radiation with cone-beam CT, to a total dose of 40 Gy in 5 fractions, a paradigm similar to a common dose given to lung cancer patients.
Results: In the cardiac radiation group, C-13 pyruvate MRS demonstrated a statistically significant decrease in cardiac function (determined by bicarbonate-to-lactate ratio in myocardial mitochondria) compared to pre-radiation baseline (p=0.02, one-tailed paired t-test) as early as 1 week post treatment. No significant decrease in this ratio was observed in the non-irradiated, age matched controls (p=0.95). Comparatively, no significant changes in LVEF or global longitudinal strain were observed in either the cardiac irradiation or control group of rats until 2 months post treatment.
Conclusion: Radiation-induced myocardial mitochondrial dysfunction is an early event that can be characterized and detected in vivo by hyperpolarized C-13 pyruvate MRS within 1 week after radiation prior to onset of echocardiographic changes. For the first time, we have demonstrated feasibility of employing HP C-13 pyruvate MRS for detecting radiation-induced myocardial mitochondrial metabolic changes in a pre-clinical rat model. This technology has the potential to serve as a platform for building radiation-focused cardio-oncology programs for early detection and mitigation of radiation-induced cardiac injury in hundreds of thousands of patients receiving thoracic radiation annually.
Citation Format: Jayesh Sharma, Elizabeth Zhang, Xuliang Wang, Junjie Ma, Jun Chen, Gabriele Schiattarella, Joseph Hill, Jaemo Park, Craig Malloy, Vlad Zaha, Prasanna Alluri. Early in vivo detection of radiation-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3659.