Mitigation of Radiation-induced Cardiotoxicity by Subcutaneous "Protective Wounding"

Recent advances in dose-delivery techniques have led to a reduction in normal tissue complications in radiotherapy patients. However, significant early and late cardiovascular (CV) effects may result when the heart is included in the radiation field and exposed to doses commonly used to treat several types of malignancies, or during total-body irradiation (TBI) prior to hematopoietic stem cell transplantation. Moreover, a radiological or nuclear (RAD/NUC) incident in which thousands of people are exposed to potentially lethal doses of ionizing radiation could result in the development of delayed effects of acute radiation exposure (DEARE) in survivors; several life-threatening cardiac DEARE-related pathologies would be observed months to years after TBI doses that trigger the hematopoietic acute radiation syndrome (H-ARS). While mitigators are available to treat acute symptoms in individuals that received radiation doses high enough to trigger the H-ARS, there are no drugs or strategies for mitigating early or late cardiovascular effects in radiotherapy patients, or late cardiac pathologies that would subsequently manifest in H-ARS survivors; while some drugs have shown promise, toxicity, limited efficacy or logistical issues regarding administration precludes their clinical use. Thus, there is great interest in the development of mitigators of cardiovascular dysfunction. We previously identified a novel non-pharmacological strategy that is effective in mitigating the lethal effects of TBI in mice when administered after exposure. Our approach involved the creation of a small subcutaneous (SC) incision postirradiation. We found that subcutaneous wounding several minutes after a high-dose TBI greatly protected against lethality, and that mitigation of the resulting H-ARS was likely mediated by enhanced recovery of hematopoiesis. We refer to this approach as "protective wounding." We now show that a subcutaneous cut preserves cardiac function, specifically, pumping capacity as measured by the Langendorff technique, in mice when assessed 30 days after a single dose or fractionated TBI. For example, left ventricular developed pressure (LVDP) at end diastolic pressure (EDP) 30-39 was 22.5% greater in mice that received a cut after a TBI dose of 6.5 Gy, compared to sham-cut mice. We propose that "protective wounding" may be used as a novel model for interrogating the proteins and pathways involved in reducing cardiotoxicity after irradiation and ultimately guiding development of pharmacological mitigators of cardiotoxicity in radiotherapy patients or victims of RAD/NUC incidents.