Vascular Damage in the Aorta of Wild-Type Mice Exposed to Ionizing Radiation: Sparing and Enhancing Effects of Dose Protraction

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Abstract

During medical (therapeutic or diagnostic) procedures or in other settings, the circulatory system receives ionizing radiation at various dose rates. Here, we analyzed prelesional changes in the circulatory system of wild-type mice at six months after starting acute, intermittent, or continuous irradiation with 5 Gy of photons. Independent of irradiation regimens, irradiation had little impact on left ventricular function, heart weight, and kidney weight. In the aorta, a single acute exposure delivered in 10 minutes led to structural disorganizations and detachment of the aortic endothelium, and intima-media thickening. These morphological changes were accompanied by increases in markers for profibrosis (TGF-β1), fibrosis (collagen fibers), proinflammation (TNF-α), and macrophages (F4/80 and CD68), with concurrent decreases in markers for cell adhesion (CD31 and VE-cadherin) and vascular functionality (eNOS) in the aortic endothelium. Compared with acute exposure, the magnitude of such aortic changes was overall greater when the same dose was delivered in 25 fractions spread over 6 weeks, smaller in 100 fractions over 5 months, and much smaller in chronic exposure over 5 months. These findings suggest that dose protraction alters vascular damage in the aorta, but in a way that is not a simple function of dose rate.

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ICRP publication 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs--threshold doses for tissue reactions in a radiation protection context.

R Shore, C Muirhead, Maria Aleman … (2012)

This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further. Copyright © 2012. Published by Elsevier Ltd.

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Shumin Gao, David H. Ho, Dorothy Vatner … (2011)

Murine models have been utilized with increasing frequency mainly due to availability of genetically engineered models. With advancement in high spatial and temporal resolution, echocardiography is used extensively for the evaluation of cardiovascular function in murine models of cardiovascular disease. This review summarizes the general applications and methods involved in echocardiography used to study mouse models for cardiovascular research, based on 20 years of experience in our laboratory. The goal of this article is to provide a practical guide to the use of echo techniques in mice to evaluate cardiac systolic and diastolic function.

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Radiation and circulatory disease.

Mark Little (2016)

Exposure to therapeutic doses of ionizing radiation is associated with damage to the heart and coronary arteries. However, only recently have studies with high-quality individual dosimetry data allowed this risk to be quantified while also adjusting for concomitant chemotherapy, and medical and lifestyle risk factors. At lower levels of exposure the evidence is less clear. In this article I review radiation-associated risks of circulatory disease in groups treated with radiotherapy for malignant and non-malignant disease, and in occupationally- or environmentally-exposed groups receiving rather lower levels of radiation dose, also for medical diagnostic purposes. Results of a meta-analysis suggest that excess relative risks per unit dose for various types of heart disease do not exhibit statistically significant (p>0.2) heterogeneity between studies. Although there are no marked discrepancies between risks derived from the high-dose therapeutic and medical diagnostic studies and from the moderate/low dose occupational and environmental studies, at least for ischemic heart disease and stroke there are indications of larger risks per unit dose for lower dose rate and fractionated exposures. Risks for stroke and other types of circulatory disease are significantly more variable (p<0.0001), possibly resulting from confounding and effect-modification by well known (but unobserved) risk factors. Adjustment for any of mean dose, dose fractionation or age at exposure results in the residual heterogeneity for cerebrovascular disease becoming non-significant. The review provides strong evidence in support of a causal association between both low and high dose radiation exposure and most types of circulatory disease.