Mitigation of Cardiovascular Damage

Columbia University Health Sciences, New York NY

Investigators

Abstract

PROJECT 3 SUMMARY/ABSTRACT The general population continues to be at risk of exposure to ionizing radiation because of radiological terrorism, including the detonation of improvised nuclear devices (IND) with an increased chance of radiation injuries and cancer. Hence, the development of radiation mitigators is critical to ensure public health. Moreover, minimally invasive biomarkers that predict the development of radiation injuries in particular organ systems may aid in early treatment decisions. Until now, the majority of radiation countermeasures and predictive biomarkers that are under development have been tested in models of exposure to X- or γ-rays delivered by standard pre-clinical irradiators that provide dose rates of a few Gy per minute. In practice, however, the majority of the IND-related radiation dose will be delivered over a time period of less than a millisecond, and a significant component (10 to 50%) of the biological effects on survivors from a ground-burst IND will be from neutrons. It is therefore important to understand whether radiation countermeasures that have been developed and tested in animal models of conventional irradiation are also effective in scenarios of ultra- high dose rates and neutrons with an IND-relevant energy spectrum. Project 3 is aimed at testing predictive biomarkers and interventions in cardiovascular injury from IND-relevant radiation exposures. The project makes use of a WAG/RijCmcr rat model of partial body irradiation with 5% bone marrow shielding that has been characterized to study acute and delayed organ injuries from X-rays. Male and female WAG/RijCmcr rats will be exposed to ultra-high dose rate radiation or IND-neutrons in the P01 Radiation, Animal and Dosimetry Core and transported to the University of Arkansas for Medical Sciences for long-term simvastatin treatment and follow-up to assess cardiac and vascular injuries. In collaboration with Projects 1 and 2, measures of cardiac function and/or specimens of the heart from rats treated with the mitigators MIIST305 and lisinopril will be examined. In addition, cohorts of rats will be exposed to IND-relevant radiation and treated with all three countermeasures (simvastatin, lisinopril and MIIST305) to assess the feasibility of a polypharmacy approach against multi-organ dysfunction. All countermeasures will be combined with an administration of pegylated granulocyte colony stimulating factor, subcutaneous fluids and antibiotics in drinking water as a current standard-of-care. Lastly, the multi-omics based CardioWatch panel consists of 11 proteins, metabolites and lipids that, when upregulated in plasma at 2 weeks to 1 month after irradiation, predicts the development of cardiac radiation fibrosis in animal models of γ- and X-ray exposure. Project 3 will determine whether the CardioWatch panel is functional after IND-relevant radiation exposures. This is a highly translational project that, in synergy with the research cores and other research in this program project will provide data from realistic radiation scenarios due to an IND critical for the clinical implementation of predictive biomarkers and pharmacological countermeasures of cardiovascular radiation injury.