Cardiovascular effects after low-dose exposure and radiotherapy: what research is needed?

The authors of this report met at the Head Quarter of the International Atomic Energy Agency (IAEA) in Vienna, Austria, on 2-4 July 2012, for intensive discussions of an abundance of original publications on new epidemiological studies on cardiovascular effects after low-dose exposure and radiotherapy and radiobiological experiments as well as several comprehensive reviews that were published since the previous meeting by experts sponsored by the IAEA in June 2006. The data necessitated a re-evaluation of the situation with special emphasis on the consequences current experimental and clinical data may have for clinical oncology/radiotherapy and radiobiological research. The authors jointly arrived at the conclusions and recommendations presented here.

An international survey of tissue banking: a preliminary report.

International Atomic Energy Agency is currently carrying out a survey on the tissue banking activities from the tissue banking organisations worldwide. The purpose of the survey is to establish regional and global overview of the current tissue banking activities and practices in order to assist the International Atomic Energy Agency to provide further guidance about the use of radiation technology to sterilise tissues as well as to promote better collaboration between the regional tissue banking associations. The survey is an on-going exercise and the preliminary data is presented here. This exercise is not completed and the authors urge the remaining tissue banks to participate in the survey.

IAEA activities related to radiation biology and health effects of radiation.

The IAEA is involved in capacity building with regard to the radiobiological sciences in its member states through its technical cooperation programme. Research projects/programmes are normally carried out within the framework of coordinated research projects (CRPs). Under this programme, two CRPs have been approved which are relevant to nuclear/radiation accidents: (1) stem cell therapeutics to modify radiation-induced damage to normal tissue, and (2) strengthening biological dosimetry in IAEA member states.

International Conference on Advances in Radiation Oncology (ICARO): outcomes of an IAEA meeting.

The IAEA held the International Conference on Advances in Radiation Oncology (ICARO) in Vienna on 27-29 April 2009. The Conference dealt with the issues and requirements posed by the transition from conventional radiotherapy to advanced modern technologies, including staffing, training, treatment planning and delivery, quality assurance (QA) and the optimal use of available resources. The current role of advanced technologies (defined as 3-dimensional and/or image guided treatment with photons or particles) in current clinical practice and future scenarios were discussed.ICARO was organized by the IAEA at the request of the Member States and co-sponsored and supported by other international organizations to assess advances in technologies in radiation oncology in the face of economic challenges that most countries confront. Participants submitted research contributions, which were reviewed by a scientific committee and presented via 46 lectures and 103 posters. There were 327 participants from 70 Member States as well as participants from industry and government. The ICARO meeting provided an independent forum for the interaction of participants from developed and developing countries on current and developing issues related to radiation oncology.

Residual late radiation damage in mouse stromal tissue assessed by the tumor bed effect.

Irradiation of murine subcutaneous stroma before implantation of tumor cells leads to retarded tumor growth. This effect is called Tumor Bed Effect (TBE) and can be used to assess the sensitivity of stromal tissue to radiation. We tested the ability of stromal tissue to recover from X-ray-induced damage as a function of the time interval between X-irradiation and implantation of tumor cells over a period of 195 days. We also assessed the effects of a second test treatment of X-irradiation before implantation to assess residual damage by the first radiation treatment. The tumor bed effect in C57Bl10xDBA2 mice observed after X-ray treatment and implantation of M8013 cells (from a transplantable mouse mammary carcinoma) declines with the time that elapses between X-rays and implantation. Implantation of tumor cells 195 days after initial irradiation of 10 or 20 Gy resulted in a considerably smaller TBE. The half-time of the decay is estimated as about 50 days. The extent of the recovery was then tested in two-fraction experiments, with radiation fractions separated by intervals of 30 or 180 days. In the experiment with re-irradiation at an interval of 30 days after the first radiation dose of 20 Gy hardly any recovery was observed, whereas at an interval of 180 days a considerable recovery was observed. We presume that the recovery in TBE that was observed a long time after the irradiation results from a proliferative stimulus to endothelial cells which takes place during the post-irradiation period. The proliferative response leads to cell death of the X-ray damaged endothelial cells and thereafter these are replaced by healthy cells.

X-ray imaging and the skin: radiation biology, patient dosimetry and observed effects.

A wide variety of radiation-induced deterministic skin effects have been observed after X-ray guided interventions ranging from mild effects, such as transient erythema or temporary epilation, to severe effects, such as desquamation and necrosis. Radiation biologists have identified, in addition to absorbed dose to the skin, other factors that strongly influence the type and severity of a skin reaction, including exposure-related factors (dose rate, fractionation, the size of the exposed area and its site), biological factors (age, oxygen status, capillary density, hormonal status and genetic factors) and ethnic differences. A peak entrance skin dose of 2 Gy is an arbitrary, but pragmatic, threshold for radiation-induced skin effects after X-ray guided interventions. Transient skin injury originating in the epidermis is not expected in the average patient population at peak entrance skin doses up to 6 Gy. Serious skin effects are not likely to occur in clinical practice when optimised X-ray equipment is used in combination with good techniques for fluoroscopy and imaging. However, this might not be true for patients with biological factors that are associated with an increased sensitivity for radiation-induced skin reactions.

Influence of mast cells on structural and functional manifestations of radiation-induced heart disease.

Radiation-induced heart disease (RIHD), characterized by accelerated atherosclerosis and adverse tissue remodeling, is a serious sequelae after radiotherapy of thoracic and chest wall tumors. Adverse cardiac remodeling in RIHD and other cardiac disorders is frequently accompanied by mast cell hyperplasia, suggesting that mast cells may affect the development of cardiac fibrosis. This study used a mast cell-deficient rat model to define the role of mast cells in RIHD. Mast cell-deficient rats (Ws/Ws) and mast cell-competent littermate controls (+/+) were exposed to 18 Gy localized single-dose irradiation of the heart. Six months after irradiation, cardiac function was examined by echocardiography and Langendorff-perfused isolated heart preparation, whereas structural changes were assessed using quantitative histology and immunohistochemical analysis. Mast cell-deficient rats exhibited more severe postradiation changes than mast cell-competent littermates. Hence, mast cell-deficient rats exhibited a greater upward/leftward shift in the left ventricular (LV) diastolic pressure-volume relationship (P = 0.001), a greater reduction in in vivo LV diastolic area (from 0.50 +/- 0.024 cm in age-matched controls to 0.24 +/- 0.032 cm after irradiation; P = 0.006), and a greater increase in LV posterior wall thickness (from 0.13 +/- 0.003 cm in age-matched controls to 0.15 +/- 0.003 cm after irradiation; P = 0.04). Structural analysis revealed more pronounced postradiation accumulation of interstitial collagen III but less myocardial degeneration in hearts from mast cell-deficient rats. These data show that the absence of mast cells accelerates the development of functional changes in the irradiated heart, particularly diastolic dysfunction, and suggest that, in contrast to what has been the prevailing assumption, the role of mast cells in RIHD is predominantly protective.

Microarray analysis of gene expression profiles of cardiac myocytes and fibroblasts after mechanical stress, ionising or ultraviolet radiation.

BACKGROUND: During excessive pressure or volume overload, cardiac cells are subjected to increased mechanical stress (MS). We set out to investigate how the stress response of cardiac cells to MS can be compared to genotoxic stresses induced by DNA damaging agents. We chose for this purpose to use ionising radiation (IR), which during mediastinal radiotherapy can result in cardiac tissue remodelling and diminished heart function, and ultraviolet radiation (UV) that in contrast to IR induces high concentrations of DNA replication- and transcription-blocking lesions. RESULTS: Cultures enriched for neonatal rat cardiac myocytes (CM) or fibroblasts were subjected to any one of the three stressors. Affymetrix microarrays, analysed with Linear Modelling on Probe Level, were used to determine gene expression patterns at 24 hours after (the start of) treatment. The numbers of differentially expressed genes after UV were considerably higher than after IR or MS. Remarkably, after all three stressors the predominant gene expression response in CM-enriched fractions was up-regulation, while in fibroblasts genes were more frequently down-regulated. To investigate the activation or repression of specific cellular pathways, genes present on the array were assigned to 25 groups, based on their biological function. As an example, in the group of cholesterol biosynthesis a significant proportion of genes was up-regulated in CM-enriched fractions after MS, but down-regulated after IR or UV. CONCLUSION: Gene expression responses after the types of cellular stress investigated (MS, IR or UV) have a high stressor and cell type specificity.

Increased deposition of von Willebrand factor in the rat heart after local ionizing irradiation.

BACKGROUND AND PURPOSE: Von Willebrand factor (vWf), a glycoprotein involved in blood coagulation, is synthesized by endothelial cells. Increased amounts of vWf in blood plasma or tissue samples are indicative of damaged endothelium. In the present study, mRNA expression and localization of vWf were determined in irradiated rat heart tissue. MATERIAL AND METHODS: Sprague-Dawley rats received local heart irradiation with a single dose of 0, 15, or 20 Gy. Hearts were dissected at different time points (up to 16 months) after irradiation. In a second experiment, rats were injected with the radioprotector amifostine (160 mg/kg, i. p.) 15-20 min before irradiation and sacrificed after 6 months. Immunohistochemistry was performed using a polyclonal anti-vWf antibody. Serial sections were subjected to a general rat endothelial cell immunostaining (RECA-1) or a collagen staining (picrosirius red). mRNA expression was determined by using PCR. RESULTS: In control tissue, all endothelial cells lining the lumen of the endocardium and coronary arteries, but not capillary endothelial cells, were stained for vWf. 1 month after irradiation with both 15 and 20 Gy, myocardial capillaries became immunoreactive. From 3 months onward, staining was observed also within the extracellular matrix (ECM) of fibrotic areas. At mRNA level, no changes in vWf could be observed at all time points after irradiation, suggesting that vWf deposition was not due to increased biosynthesis of the protein. In sections of amifostine-treated rat hearts, vWf staining was increased to a lesser extent. CONCLUSION: These dose- and time-dependent increases in deposition of vWf indicate the presence of damaged endothelium in the irradiated rat heart. These increases in vWf accumulation precede development of fibrosis in the subendocardial layer and myocardium of the left ventricles, right ventricles, and atria.

Effects of amifostine on radiation-induced cardiac damage.

The purpose of this study was to investigate whether administration of amifostine prior to irradiation could reduce radiation damage of the rat heart. Female Spraque-Dawley rats were randomized to receive single-dose irradiation (0-22.5 Gy) locally to the heart. Fifteen to twenty minutes before radiation exposure, the animals received either intraperitoneally administered amifostine (160 mg/kg) or buffered saline solution. At 6 months post-irradiation, cardiac function was assessed by the in vitro working rat heart preparation. The severity of interstitial and/or perivascular fibrosis in different anatomical regions of the rat heart was assessed using a semi-quantitative scoring system. Radiation exposure to doses > or = 20 Gy markedly reduced coronary flow, aortic flow and cardiac output. Administration of amifostine prior to radiotherapy afforded protection against these effects and normal cardiac output was maintained, even after 22.5 Gy. A small, non-significant, reduction in histological damage (i.e. perivascular fibrosis and interstitial fibrosis) was also apparent in animals treated with amifostine. There was a clear protective effect of amifostine on the severity and extent of macroscopic damage in lung tissue included in the cardiac irradiation field. The findings of this study suggest that a single dose of amifostine administered prior to irradiation is effective in reducing cardiac damage.