Abstract 13201: Sex Difference Following Cardiac-Targeted Irradiation in Mice

Introduction: Acute exposure of the heart to ionizing radiation (IR) can damage myocardium, coronary arteries, valves, and pericardium. Long term sequelae include fibrosis, heart failure, arrhythmias and sudden death. We previously reported a protective effect of the oxetanyl sulfoxide radiation mitigator MMS350 in mice treated acutely with 20 Gy total body IR. Here, we assess the long-term effects of cardiac targeted irradiation (CTI) and MMS350 treatment on cardiac structure and function. Methods: Ten week-old C57BL/6J mice (50% male) were exposed to 20 Gy CTI with (+R+D, n=20) or without (+R-D, n=20) MMS350 using an Xstrahl Small Animal Radiation Research Platform and followed for 9 months (mo); a parallel cohort was not irradiated (-R+D, n=10; -R-D, n=10). MMS350 was given in drinking water (0.087 mg/ml) for 10 days before to 9 mo after CTI with one IV injection (20 mg/kg) 30 minutes prior to CTI. Echocardiography (echo) was performed at baseline, 3, 6 and 9 mo. At euthanasia, heart weight (HW), lung weight (LW), body weight (BW) and histology were assessed. Results: CTI led to radiation dermatitis in 3 female mice requiring euthanasia. MMS350 treatment had no significant effect on any parameters. 9 mo after CTI, HW/BW was increased in male but not female mice, while LW/BW was increased in both sexes (Fig 1A-D). Echo showed a significant increase in EDV with CTI in male (p=0.006) but not female mice (Fig 1E-F), along with a trend towards a decrease in EF in male (79±3 vs 86±2%, p=0.11) but not female mice (85±1 vs 86±1%, p=0.59). Trichrome staining demonstrated fibrosis in both male and female hearts (Fig 1G-N). Conclusions: High dose CTI led to cardiac hypertrophy and ventricular dilation after 9 mo in male but not female mice. Both sexes developed cardiac fibrosis and lung congestion. Thus, sex may influence radiation-induced cardiac pathology through currently unknown mechanisms and may have important implications for radiotherapy of thoracic tumors in humans.