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

Abstract

Background and purpose: Radiation-induced cardiac toxicity (RICT) remains one of the most critical dose limiting constraints in radiotherapy. Recent studies have shown higher doses to the base of the heart are associated with worse overall survival in lung cancer patients receiving radiotherapy. This work aimed to investigate the impact of sub-volume heart irradiation in a mouse model using small animal image-guided radiotherapy.Materials and Methods: C57BL/6 mice were irradiated with a single fraction of 16 Gy to the base, middle or apex of the heart using a small animal radiotherapy research platform. Cone beam CT and echocardiography were performed at baseline and at 10 week intervals until 50 weeks post-treatment. Structural and functional parameters were correlated with mean heart dose (MHD) and volume of heart receiving 5 Gy (V5).Results: All irradiated mice showed a time dependent increase in left ventricle wall thickness in diastole of ~0.2 mm detected at 10 weeks post-treatment, with the most significant and persistent changes occurring in the heart base-irradiated animals. Similarly, statistically different functional effects (p<0.01) were observed in base-irradiated animals which showed the most significant decreases compared to controls. The observed functional changes did not correlate with MHD and V5 (R 2 <0.1), indicating that whole heart dosimetry parameters do not predict physiological changes resulting from cardiac sub-volume irradiation.Conclusions: This is the first report demonstrating the structural and functional consequences of sub-volume targeting in the mouse heart and reverse translates clinical observations indicating the heart base as a critical radiosensitive region.

Murine models of radiation cardiotoxicity: A systematic review and recommendations for future studies

“…Given the size-related technical challenges of atrial research in mouse models, it is possible that alternative larger animal species will may be more applicable for investigations of regional radiosensitivity in the heart. Moreover, there is a pressing need to study the atria and ANP because the biological mechanism for the recently proposed base-mediated cardiac radiosensitivity is as yet undetermined [138][139][140].…”

Regional Responses in Radiation-Induced Normal Tissue Damage

“…Since precise irradiation of specific structures of the heart is challenging in small animal models, only few preclinical studies on the sensitivity of cardiac substructures are available [140]. A recent study by Ghita et al showed that the basal parts of the heart are more sensitive to irradiation [141] (Figure 2b). Mean heart dose was not found to be a reliable predictor of functional changes after irradiation of cardiac sub-volumes in a mouse model.…”

“…The observation of more pronounced effects after irradiation of the base of the heart indicated the presence of sensitive substructures in this part. These could potentially be related to the presence of the aortic and mitral valves, the pulmonary and coronary arteries, and the superior vena cava [141].…”

Leveraging Radiobiology for Arrhythmia Management: A New Treatment Paradigm?

“…Additional studies have also shown that the incidence of cardiac complications, such as pericardial effusions and ischaemic events, can correlate with whole heart or cardiac substructure doses [47,49]. Specifically, recent results in both human and animal studies have suggested that radiation doses between 8.5 and 16 Gy delivered to the base of the ventricles was associated with poorer outcomes [51,52] and altered ventricular function [53].…”