Cardiac sub-volume targeting demonstrates regional radiosensitivity in the mouse heart

Abstract

Purpose or Objective Radiation induced cardiac toxicity remains one of the most critical dose limiting constraint in radiotherapy and a major cause of mortality amongst cancer survivors. Recent clinical evidence has shown higher doses to the base of the heart are associated with worse overall survival in lung cancer patients receiving curative intent radiotherapy. This work aimed to investigate the impact of subvolume heart irradiation in a mouse model, and to identify critical radiosensitive regions towards developing a mechanistic understanding of regional radiosensitivity. Material and Methods C57BL/6 mice were irradiated with a single fraction of 16 Gy targeted to the base, middle and apex of the heart, with a 3 x 9 mm field and parallel opposed geometry, using a small animal radiotherapy research platform (SARRP, Xstrahl Life Sciences). Cone beam CT and echocardiography were performed at baseline and at 10 week intervals for 50 weeks after treatment. Left ventricle (LV) wall thickness was quantified from M-mode parasternal short-axis scans at the level of the papillary muscles. Fractional shortening (FS) was calculated from the LV end-diastolic and end-systolic diameters, and pulsewave Doppler used to quantify mitral valve (MV) flow, expressed as E/A ratio. Structural and functional parameters were correlated with mean heart dose (MHD) and V5. Results All irradiated mice showed a time dependent increase in LV wall thickness detected as early as 10 weeks following treatment, with the most significant and persistent changes occurring in the base irradiated animals. Similarly, differential effects were observed on cardiac function with base irradiated animals showing the most significant decreases in FS, ejection fraction and E/A ratio compared to control animals at 40 and 50 weeks following irradiation. The observed structural and functional changes did not correlate with MHD and V5 indicating that whole heart dosimetry parameters do not predict physiological changes resulting from irradiation of cardiac subvolumes. Conclusion This is the first report demonstrating structural and functional consequences of subvolume targeting in the mouse heart. Our data are in close agreement with clinical observations indicating the base of the heart as a radiosensitive region and form the basis for further mechanistic investigations.