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Epidemiological studies have revealed a potential of low doses (< 500mGy) of gamma-radiation to induce cardiac pathologies, such as circulatory disease and ischemia. Involvement of Arrythmias in this pathological context is less clear. Indeed the development of arrythmia is reported in some but not all epidemiological studies (internal 137-Cesium (137Cs) exposure). The controversies can be attributed to the lack of understanding of the underlying mechanisms involved. Arrhythmias may be caused by an imbalance between stimulation of the sympathetic nervous system and inhibition by the parasympathetic. The objective of this project is to identify the signalling pathways involved in cardiac pathologies after exposure and over time. The study hypothesis would be that exposure to low doses of gamma-radiation induces tissue and nerve remodelling in the heart. We exposed C57Bl/6J male mice to whole-body single external doses ranging from 50 to 2000mGy from a 137Cs gamma-radiation source. Two post-exposure time points were studied (4 hours and 3 months). The heart function was monitored by Doppler ultrasound examination. Signalling pathways were examined by measuring levels of proteins involved in various cardiac functions by Western blotting and Sirius red staining of histological sections. In all, 4 hours after exposure, Western blot analysis showed a significant decrease in the expression of proteins involved in the conduction of cardiac nerve influx (Connexins 43 at 100 and 250mGy; P -value < 0.05) and in the synthesis of catecholamines (Tyrosine Hydroxylase at 50 and 250mGy; P -value < 0.05). These decreases may be responsible for heart contraction problems. Conversely, at 3 months post-exposure, we observed a significant increase in the levels of these same proteins of interest (Connexins 43 and Synapsin at 500 and 2000mGy; P -value < 0.05) which could induce long-term arrhythmia. These protein expression changes were observed only in the atrium and right ventricle. In addition, we observed interstitial fibrosis in the hearts of the mice exposed to the same doses (P -value < 0.05). Lastly, we observed a significant increase in the percentage of muscularized pulmonary arterioles (at 500mGy; P -value < 0.05), indicating the development of pulmonary hypertension. In summary, our results suggest that a single external exposure to a low dose of gamma rays can induce long-term functional alteration in the heart and that a potential dose threshold for such effect is below 500mGy. [ABSTRACT FROM AUTHOR]

Abstract: After normal tissue exposure to radiation therapy, late side effects can occur and may reduce patients’ quality of life due to their progressive nature. Late toxicities occurrence is the main limiting factor of radiotherapy. Various biological disorders related to irradiation are involved in the development of late toxicities including fibrosis. The present review will focus on the recent physiopathological and molecular mechanisms described to be involved in the development of late radio-induced toxicities, that provide therapeutic perspective for pharmacomodulation. [Copyright &y& Elsevier]