Abstract 93: The Radiation Mitigator MMS350 Prevents Bradyarrhythmias in Irradiated Mice

Abstract

Introduction: Radiation exposure is a health hazard and the potential exposure from healthcare and other anthropogenic sources necessitates radioprotective therapy. MMS350, a water soluble oxetanyl sulfoxide, is a radiation mitigator which has protective effects on pulmonary and bone marrow cells following irradiation. We have previously shown that radiation exposure causes cardiac conduction damage including bradyarrhythmia and atrioventricular (AV) block in mice. This study investigates whether MMS350 protects against cardiac conduction damage in C57Bl/6 mice following radiation exposure. Methods: Mice were treated with MMS350 (400 μM) in drinking water ad libitum for 14 days prior to and for 30 days following irradiation, and were injected with MMS350 (20 mg/kg IV) 30 minutes prior to irradiation. Control (n=12) and MMS350-dosed (n=8) mice were total body irradiated (TBI) using a Pantak HF-320 Orthovoltage X-ray machine for a total dose of 6 Gy (1.38 Gy/min). Four-lead ECGs were performed on anesthetized mice at baseline and at day 30; PR, QRS, and QTc (QT normalized to heart rate) intervals were analyzed. Results: TBI control mice had PR (51.2 ± 5.8 vs. 43.4 ± 2.6 ms, P=0.003) and QRS (13.7 ± 0.2 vs. 13.0 ± 0.6 ms, P=0.02) interval prolongation at 30 days compared to baseline, while QTc trended towards a significant lengthening (88.4 ± 6.8 vs. 80.1 ± 10.4 ms, P=0.06). TBI MMS350 mice had no significant PR (46.2 ± 7.8 vs. 42.9 ± 5.1 ms, P=0.41) or QRS (14.0 ± 2.4 vs. 13.7 ± 0.8 ms, P=0.71) interval prolongation at 30 days compared to baseline, while QTc trended towards a significant lengthening (86.1 ± 7.9 vs. 73.0 ± 15.2 ms, P=0.05). New prolonged pauses and/or AV block occurred by day 30 post-irradiation in a third of TBI control mice but not in TBI MMS350 mice. Additionally, compared to baseline, day 6 post- irradiation TBI-only mice lost weight (males: 25.0 ± 1.8 to 24.2 ± 1.6g, P=0.004; females: 21.2 ± 1.0 to 19.2 ± 1.3g, P=0.01) while MMS350-dosed mice did not (males: 25.4 ± 1.7 to 27.8 ± 0.5g, P=0.12); females: 19.3 ± 0.2 to 21.0 ± 1.2g, P=0.08). Conclusion: Our results suggest that MMS350 protects irradiated mice from bradyarrhythmias, cardiac conduction damage, and radiation-associated weight loss. These findings lend further support to MMS350 as a radiation mitigator.