Abstract 14676: Susceptibility to Cardiac-Targeted Irradiation in Wild-Type and Nos1 Haploinsufficient Mice

Abstract

Introduction: Cardiac irradiation causes heart failure and arrhythmias. We reported that cardiac-targeted irradiation (CTI) led to cardiac dilation with increased end diastolic volume (EDV) by echocardiogram (echo) after 9 months in wild-type C57Bl6/J (WT) male (M) but not female (F) mice. Both sexes developed cardiac fibrosis and evidence of lung congestion, and the radiation mitigator MMS350 did not protect either sex. Here, we studied the effect of CTI on Nitric Oxide Synthase 1 haploinsufficient (Nos +/- ) mice treated with/without MMS350. Methods: 10 week-old Nos +/- and WT mice were exposed to 20 Gy CTI (R) with or without MMS350 (D) and followed for 9 months (Nos +/- : +R+D, n = 9M, 6F; +R-D, n = 6M, 7F; WT: +R+D, n = 12M, 14F; +R-D, n = 13M, 14F), with parallel unirradiated controls (Nos +/- : -R+D, n = 8M, 6F; -R-D, n = 10M, 7F; WT: -R+D, n = 8M, 12F; -R-D, n = 7M, 8F)). Echos and EKGs were performed at baseline and every 3 months. Heart weight (HW), lung weight (LW), and body weight (BW) were measured. Results: Unlike irradiated male WT mice where EDV was increased (p=0.001), EDV was smaller in male (p=0.04) and EF was decreased in both male (p=0.01) and female (p=0.05) Nos +/- irradiated mice compared to unirradiated controls, independent of MMS350 treatment (Figure). In addition, the PR interval was shorter in irradiated Nos +/- male (p=0.008) and female (p=0.003) mice compared to unirradiated controls. HW/BW was not significantly changed in any group, while LW/BW was significantly increased only in WT male (p=0.04) and female (p=0.001) irradiated mice. Conclusions: In long term follow-up of CTI-treated mice, Nos1 deficiency prevents sex-specific cardiac dilation in males, promotes left ventricular systolic dysfunction and alters cardiac conduction system properties. Further investigation into the role of nitric oxide in radiation-induced cardiac damage and the mechanisms underlying sex differences in the response to radiation are warranted.