Effects of low-to-moderate doses of X-rays on the cardiac rhythm via the sympathetic nervous system in female mice

Abstract

Radiotherapy is one of the common therapeutic approaches in the treatment of breast cancer, with the heart inevitably being exposed to ionizing radiation which may cause late cardiac pathologies. Our recent study revealed that right atrium irradiation of right-sided breast cancer patients is associated with the development of cardiac diseases such as heart failure, arrhythmias, and conduction disorders. The aim of this project is to examine the effect of low to moderate doses of X-rays on the development of late cardiac pathologies. We specifically studied the alterations in the cardiac sympathetic nervous system which is located in potentially arrhythmogenic structures of the sinoatrial and atrioventricular nodes. Female C57Bl/6J mice were exposed to X-rays irradiation targeted to top, bottom or whole heart, such that different cardiac nodes were exposed. To examine the presence of a threshold in a dose-response for cardiac rhythm pathology, as assessed by ultrasound examinations, mice were exposed to doses ranging from 0.25 to 2 Gy. Molecular and cellular mechanisms involved in these cardiac disorders at early (24-hours) and late (60-weeks) time points post-irradiation were studied. At the functional level, our Doppler echography data show the presence of an alteration of cardiac function with the occurrence of arrhythmic events at 60-weeks post-irradiation in all irradiated animals, specifically in top heart irradiation. To confirm these results, we will also use transesophageal atrial stimulation (10 Hz during 3 sec) to assess supraventricular arrhythmias. At the molecular level, we focused on proteins involved in cardiac conduction system and in sympathetic innervation patterning 24-hours post-irradiation. Our Western Blot results show a significant increase of Connexin 40 (P = 0.02), Connexin 43 (P = 0.02), Tyrosine Hydroxylase (P = 0.04), and b3-Tubulin (P = 0.03) protein levels in whole heart irradiated animals. Altogether, our preliminary results showed modifications of cardiac function 60-weeks post-irradiation with the development of cardiac rhythm disorders and molecular alterations of cardiac conduction and sympathetic nervous system already present 24-hours post-irradiation.