This research project aims to identify biomarkers produced when cardiovascular tissue is damaged by ionizing radiation. This study will examine subjects undergoing radiation therapy where their hearts are exposed to ionizing radiation. Non-invasive medical imaging will be used to identify changes in heart tissue that predict later impairment. Prompt identification of damage may allow interventions to prevent progression to cardiac dysfunction. Studying changes to heart tissue that happen during and after radiation therapy would grant insight into the pathophysiology, which may lead to new therapeutic interventions. These results could be correlated with studies performed on animals, or in human cohorts with different types of radiation exposure – such as astronauts.
Research deliverables from this work will help close gaps Degen-2 and -3 as well as feed into countermeasure development and validation in animal studies with space radiation exposures. Results will also drive predictive model development (Degen-5).
If early biomarkers of cardiac injury after radiation exposure can be identified, steps could be taken to prevent progression to irreversible cardiac dysfunction. The results of this study may be correlated with other studies performed in animals or in human cohorts with different types of radiation exposure, such as astronauts during space travel, and the ultimate goal of our work is to develop agents that prevent cardiac toxicity through early detection and intervention. Our overarching hypothesis is that changes in imaging and serum biomarkers will suggest early cardiac injury after radiation exposure and our specific aims are the following:
Aim 1: Assess for cardiac toxicity in cancer patients treated with radiation therapy to the chest. We will assess for cardiac toxicity, looking at a reduction in heart fitness or elevation of damage markers in blood serum.
Aim 2: Assess for an association between 3D imaging findings suggestive of cardiac injury and radiation exposure. We will perform side-by-side comparisons of 3D MRI studies and radiation treatment plans. We will map the relationship between regions of early cardiac injury and radiation dose delivered to these areas. These findings may identify threshold radiation doses for cardiac injury.
Aim 3: Explore the association of radiation exposure with serum biomarker levels. We will collect blood samples from cancer patients receiving standard radiation therapy to the chest and analyse it at different time points for markers of heart tissue damage and inflammation.
Approach : Cancer patients receiving radiation therapy will be enrolled in this study following their written informed consent. Their current cardiovascular health will be evaluated before their radiation treatment, during their final week of treatment, and six months after their treatment. Blood will be collected twice during treatment, and 3, 6, 12, and 24 months after treatment. A history and physical examination will be performed before, twice during treatment, and 3, 6, 12, 18, and 24 months after RT. Subsequently, a cardiac history will be taken in person or by phone annually until study termination, disease progression, or patient death. Immune cells will be separated from the blood samples drawn and counted to note any increase of immune cell populations in the blood, indicating inflammation. They will also be stained to see if they are expressing any markers of inflammation.
Cardiac MRIs will be performed to measure the strength of heart muscle contraction.
Results: Fifteen subjects have been enrolled to the clinical trial to-date. COVID-19 is delaying enrollment and necessary MRI scans. We are working with our clinical team to re-open enrollment as soon as possible. MRI scans scheduled for June are expected to proceed as planned.
Blood Biomarkers: Analysis of blood collected before, during, and after RT has identified p90RSK as a potential early marker of tissue injury from radiation therapy. This marker was significantly elevated in blood collected after radiation exposure as compared to before radiation exposure.
Imaging Biomarkers: Of the 15 subjects currently enrolled, cardiac MRIs were analyzed for 7 subjects. Changes in heart muscle strength were variable across this group. One subject had regions of the heart with impaired strength measurements prior to radiation treatment but had minimal change after radiation treatment, whereas another subject had generally normal functioning heart muscles but had significant decline in heart muscle strength after radiation treatment. Declines like this were seen in two subjects out of the seven who had cardiac MRI before and after radiation treatment.
Discussion: We have enrolled 50% of the total accrual goal, and interesting preliminary data has been found. Despite the delays caused by COVID-19, we anticipate to complete enrollment in the next 12 months, as research operations become fully operational. Further analysis of blood markers, as well as imaging data will be integrated with preliminary results described here.