NOTE: End date changed to 8/22/2023 per NSSC information (Ed., 2/7/23)

NOTE: End date changed to 8/22/2022 per NSSC information (Ed., 10/14/21)

NOTE: Period of performance is now 8/23/2018-8/22/2021 per NSSC information since now the project goes through NSSC (Ed., 5/29/19)

Within the “Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure and Secondary Spaceflight Stressors,” the gaps Degen-2 and -3 involve identification of adverse outcome pathways, progression rates and latency periods, and early surrogate markers for radiation-induced cardiovascular disease. To date, no tasks have included human radiotherapy cohorts to assess those parameters and identify biomarkers. The proposed work will acquire data on cardiovascular impairments and associated biomarkers observed in patients undergoing cardiac exposure to ionizing radiation with emphasis on non-invasive imaging modalities to quantify predictive changes linked to late impairment. Prompt identification of damage may enable interventions to prevent progression to cardiac dysfunction. Furthermore, study of cardiac changes that occur during and soon after radiotherapy would grant insight into the pathophysiology, which may lead to novel therapeutic interventions. The results may then be correlated with other studies performed in 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). Specific Aims for the work include: 1) Assess for cardiac toxicity in patients treated with radiotherapy to the chest. 2) Assess for an association between 3D imaging findings suggestive of cardiac injury and radiation dosimetry. 3) Explore the association of radiation exposure with serum biomarker levels.

Research Deliverables

1. Evaluation of MRI as noninvasive imaging modality for detection of early indicators of cardiotoxicity following radiotherapy, compared with electrocardiograms.

2. Evaluation of serum markers and other cardiovascular parameters for detection of early indicators of cardiotoxicity following radiotherapy.

This study aims to identify early markers of cardiac injury after radiation exposure, at a time when 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.

To date, 30 patients are enrolled in protocol PA16-0971 with at least baseline and end of treatment imaging.

Serum Biomarkers: see FY22 report.

Correlation of Imaging and Blood Biomarkers: Of the 22 patients with baseline and matching post-radiation Cardiac MRI (CMR) data, we have not had a clinically actionable cardiovascular event; some patients had global longitudinal strain (GLS) declines on CMR of 2-5% range at the end of radiation or at first follow-up. However, what was especially significant is the number of dysfunctional GLS segments >10 in a significant proportion of patients. On the Chi-square test, these changes were not significantly correlated with the P90RSK changes seen.

Despite some setbacks due to the pandemic, we have completed the accrual to the trial. Some deviation includes only enrolling 5 hematologic patients since the doses for these patients are generally very low, so it was difficult to accrue enough patients with heart doses that exceed 6 Gy. For a subset of patients, GLS declines were seen, whereas it is preserved in the majority of patients. Long-term follow-up with repeat scans will be needed to determine if the changes will continue to manifest or worsen. We will need additional follow-up on patients to determine if any of the imaging or blood biomarker changes correlate with clinical manifestation of cardiovascular disease as a result of radiation injury. We will need 6 months imaging studies for another 7 patients. Further analysis of cytokines and cardiac enzymes, as well as imaging data, will be integrated with preliminary results described here.

NOTE: End date changed to 8/22/2022 per NSSC information (Ed., 10/14/21)

NOTE: Period of performance is now 8/23/2018-8/22/2021 per NSSC information since now the project goes through NSSC (Ed., 5/29/19)

Within the “Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure and Secondary Spaceflight Stressors,” the gaps Degen-2 and -3 involve identification of adverse outcome pathways, progression rates and latency periods, and early surrogate markers for radiation-induced cardiovascular disease. To date, no tasks have included human radiotherapy cohorts to assess those parameters and identify biomarkers. The proposed work will acquire data on cardiovascular impairments and associated biomarkers observed in patients undergoing cardiac exposure to ionizing radiation with emphasis on non-invasive imaging modalities to quantify predictive changes linked to late impairment. Prompt identification of damage may enable interventions to prevent progression to cardiac dysfunction. Furthermore, study of cardiac changes that occur during and soon after radiotherapy would grant insight into the pathophysiology, which may lead to novel therapeutic interventions. The results may then be correlated with other studies performed in 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). Specific Aims for the work include: 1) Assess for cardiac toxicity in patients treated with radiotherapy to the chest. 2) Assess for an association between 3D imaging findings suggestive of cardiac injury and radiation dosimetry. 3) Explore the association of radiation exposure with serum biomarker levels.

Research Deliverables

1. Evaluation of MRI as noninvasive imaging modality for detection of early indicators of cardiotoxicity following radiotherapy, compared with electrocardiograms.

2. Evaluation of serum markers and other cardiovascular parameters for detection of early indicators of cardiotoxicity following radiotherapy.

This study aims to identify early markers of cardiac injury after radiation exposure, at a time when 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.

To date, 38 patients have been identified and consented to the protocol PA16-0971 with at least one baseline imaging. However, only 24 patients have been considered evaluable if more than one imaging has been acquired. Due to the COVID-19 pandemic, the 7 months from March to October 2020 enrollment was halted and a number of post-scans and follow-ups were canceled; and patients withdrew from study due to the need for travel. Study fully reopened in October.

Serum Biomarkers: Blood samples collected before, during and at the end of radiotherapy (RT) were processed for 17 patients. The p90RSK activity after H2O2 stimulation was significantly higher (p=0.0015) in the post-RT group, compared with both pre-RT and mid-RT groups. No significant difference was found among pre-RT and mid-RT groups and no significant difference was detected in basal p90RSK activity. Our preliminary results suggest that peripheral blood mononuclear cells (PBMCs) p90RSK is a potential early marker of endothelial injury from radiation therapy.

Correlation of Imaging and Blood Biomarkers: Of the 24 patients registered to the study, baseline and matching post-radiation Cardiac MRI (CMR) data were collected for 22 patients. No statistical correlations were identified between p90RSK activation and any of the Echo and CMR parameters.

DISCUSSION:

Despite some setbacks due to the pandemic, we are near target accrual to this study. We still need to enlist 8 more lymphoma patients but have completed accrual to the thoracic cancer cohorts. We are actively working with the lymphoma department to fulfill the accrual goal of 30 evaluable patients across primary tumor diagnoses. Due to the COVID-19 delays in patient accrual, we are submitting for a no-cost extension and adjustment in timelines to complete the target patient enrollment and data collection.

For a subset of patients, global longitudinal strain (GLS) declines were seen, whereas it is preserved in the majority of patients. Long-term follow-up with repeat scans will be needed to determine if the changes will continue to manifest or worsen. We will need additional follow-up on patients to determine if any of the imaging or blood biomarker changes correlate with clinical manifestation of cardiovascular disease as a result of radiation injury. Further analysis of cytokines and cardiac enzymes, as well as imaging data, will be integrated with preliminary results described here.

NOTE: Period of performance is now 8/23/2018-8/22/2021 per NSSC information since now the project goes through NSSC (Ed., 5/29/19)

Within the “Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure and Secondary Spaceflight Stressors,” the gaps Degen-2 and -3 involve identification of adverse outcome pathways, progression rates and latency periods, and early surrogate markers for radiation-induced cardiovascular disease. To date, no tasks have included human radiotherapy cohorts to assess those parameters and identify biomarkers. The proposed work will acquire data on cardiovascular impairments and associated biomarkers observed in patients undergoing cardiac exposure to ionizing radiation with emphasis on non-invasive imaging modalities to quantify predictive changes linked to late impairment. Prompt identification of damage may enable interventions to prevent progression to cardiac dysfunction. Furthermore, study of cardiac changes that occur during and soon after radiotherapy would grant insight into the pathophysiology, which may lead to novel therapeutic interventions. The results may then be correlated with other studies performed in 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). Specific Aims for the work include: 1) Assess for cardiac toxicity in patients treated with radiotherapy to the chest. 2) Assess for an association between 3D imaging findings suggestive of cardiac injury and radiation dosimetry. 3) Explore the association of radiation exposure with serum biomarker levels.

Research Deliverables

1. Evaluation of MRI as noninvasive imaging modality for detection of early indicators of cardiotoxicity following radiotherapy, compared with electrocardiograms.

2. Evaluation of serum markers and other cardiovascular parameters for detection of early indicators of cardiotoxicity following radiotherapy.

This study aims to identify early markers of cardiac injury after radiation exposure, at a time when 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.

To date, 24 patients have been identified and enrolled in protocol PA16-0971 with at least one baseline imaging. However, only 22 patients have been considered evaluable if more than one imaging has been acquired. Due to COVID-19 pandemic in the 7 months from March to October 2020 enrollment was halted and a number of post-scans and follow-ups were canceled and patients withdrew from study due to the need for travel. Study fully reopened in October.

Comparing the cardiovascular parameters using the 3 different devices (cardiac MRI (CMR), cardiac Echo, and Fully Integrate Toilet (FIT) seat)), we compared the robustness of data collection on these three different modalities. We found that the left ventricular end diastolic volume and the left ventricular end systolic volume correlate comparing CMR and Echocardiogram. Furthermore, comparing FIT with CMR and Echo measurements, we find the strongest correlation between FIT and Echo measurements in stroke volume (SV) measurements but not with CMR. Serum Biomarkers: Blood samples collected before, during, and at the end of RT were processed for 17 patients. The levels after H2O2 stimulation of p90RSK activity as a percentage of CD14+ PBMCs from pre-RT, mid-radiation treatment (2-3 weeks), and end of RT (3 months) were determined using the ratio between phosphorylated p90RSK and total p90RSK, detected by flow cytometry. p90RSK activity after H2O2 stimulation was significantly higher (p=0.0015) in the post-RT group compared with both pre-RT and mid-RT groups. No significant difference was found among pre-RT and mid-RT groups and no significant difference was detected in basal p90RSK activity. Our preliminary results suggest that PBMCs p90RSK is a potential early marker of endothelial injury from radiation therapy.

Correlation of Imaging and Blood Biomarkers: Of the 24 patients registered to the study, baseline and matching post-radiation CMR data were collected for 22 patients. While in the short follow up for these patients, we have not had a clinically actionable cardiovascular event, some patients had Global Longitudinal Strain (GLS) declines on CMR of 2-5% range at the end of radiation or at first follow up. However, what was especially significant is the number of dysfunctional GLS segments >10 in a significant proportion of patients. On Chi-square test, these changes were not significantly correlated with the P90RSK changes seen. What we found significantly positively correlated was between activated P90RSK levels in the peripheral blood cells and the left ventricular end diastolic volume measured on CMR at the end of treatment (R2=0.376, p=0.045).

DISCUSSION:

Despite some setbacks due to the pandemic, we are near accrual to this study. We still need to enlist 8 more lymphoma patients but have completed accrual to the thoracic cancer cohorts. We are currently working with the lymphoma department to determine if this is something they would accrue to or that we will expand the patients to incorporate additional thoracic cancer patients in order to fulfill the accrual goal of 30 evaluable patients. For a subset of patients, GLS declines were seen, whereas it is preserved in the majority of patients. Long term follow-up with repeat scans will be needed to determine if the changes will continue to manifest or worsen. We will need additional follow up on patients to determine if any of the imaging or blood biomarker changes correlate with clinical manifestation of cardiovascular disease as a result of radiation injury. Further analysis of cytokines and cardiac enzymes, as well as imaging date will be integrated with preliminary results described here.

Within the “Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure and Secondary Spaceflight Stressors,” the gaps Degen-2 and -3 involve identification of adverse outcome pathways, progression rates and latency periods, and early surrogate markers for radiation-induced cardiovascular disease. To date, no tasks have included human radiotherapy cohorts to assess those parameters and identify biomarkers. The proposed work will acquire data on cardiovascular impairments and associated biomarkers observed in patients undergoing cardiac exposure to ionizing radiation with emphasis on non-invasive imaging modalities to quantify predictive changes linked to late impairment. Prompt identification of damage may enable interventions to prevent progression to cardiac dysfunction. Furthermore, study of cardiac changes that occur during and soon after radiotherapy would grant insight into the pathophysiology, which may lead to novel therapeutic interventions. The results may then be correlated with other studies performed in 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). Specific Aims for the work include: 1) Assess for cardiac toxicity in patients treated with radiotherapy to the chest. 2) Assess for an association between 3D imaging findings suggestive of cardiac injury and radiation dosimetry. 3) Explore the association of radiation exposure with serum biomarker levels.

Research Deliverables

1. Evaluation of MRI as noninvasive imaging modality for detection of early indicators of cardiotoxicity following radiotherapy, compared with electrocardiograms.

2. Evaluation of serum markers and other cardiovascular parameters for detection of early indicators of cardiotoxicity following radiotherapy.

This study aims to identify early markers of cardiac injury after radiation exposure, at a time when 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.

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.

Within the “Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure and Secondary Spaceflight Stressors,” the gaps Degen-2 and -3 involve identification of adverse outcome pathways, progression rates and latency periods, and early surrogate markers for radiation-induced cardiovascular disease. To date, no tasks have included human radiotherapy cohorts to assess those parameters and identify biomarkers. The proposed work will acquire data on cardiovascular impairments and associated biomarkers observed in patients undergoing cardiac exposure to ionizing radiation with emphasis on non-invasive imaging modalities to quantify predictive changes linked to late impairment. Prompt identification of damage may enable interventions to prevent progression to cardiac dysfunction. Furthermore, study of cardiac changes that occur during and soon after radiotherapy would grant insight into the pathophysiology, which may lead to novel therapeutic interventions. The results may then be correlated with other studies performed in 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). Specific Aims for the work include: 1) Assess for cardiac toxicity in patients treated with radiotherapy to the chest. 2) Assess for an association between 3D imaging findings suggestive of cardiac injury and radiation dosimetry. 3) Explore the association of radiation exposure with serum biomarker levels.

Research Deliverables

1. Evaluation of MRI as noninvasive imaging modality for detection of early indicators of cardiotoxicity following radiotherapy, compared with electrocardiograms.

2. Evaluation of serum markers and other cardiovascular parameters for detection of early indicators of cardiotoxicity following radiotherapy.