Principal Strain Analysis for Early Detection of Radiation-Induced Cardiotoxicity in a Mouse Model

Purpose: Radiation-induced cardiotoxicity (RIC) is common in patients receiving thoracic radiation and is a major risk factor for morbidity and mortality. The development of novel approaches for early detection and mitigation of RIC remains an acute unmet need. The objective of this study is to develop a mouse model of RIC that recapitulates the progression of cardiac dysfunction seen in patients receiving thoracic radiation and to develop novel cardiac strain markers that exhibit higher sensitivity in detecting subclinical RIC over existing approaches. Methods and Materials: We developed a mouse model of RIC through image guided whole heart irradiation of male C57BL/6J mice using 2 radiation regimens (8 Gy × 5 and 24 Gy × 1). We developed a pipeline for analyzing anatomic and principal strains derived from cardiac magnetic resonance (CMR) imaging obtained at baseline, 3 months, and 6 months following radiation. Results: Both radiation regimens used for whole heart irradiation caused a progressive decline in both anatomic and principal cardiac strains over time. The minimum principal cardiac strain detected a subclinical decline in cardiac contractility at an earlier time point than the traditional anatomic cardiac strains. We also observed asymmetric changes in contractility at the epicardium and endocardium relative to averaged cardiac strain across the full thickness of the left ventricle following cardiac irradiation, further reinforcing the limitations of existing methods, which do not capture the heterogeneity in cardiac strain changes along the transmural axis. Conclusions: We have developed a mouse model of RIC that recapitulates time-dependent deterioration in myocardial contractility noted in patients receiving thoracic radiation. We also developed CMR imaging-derived novel principal strain cardiac markers that detect subclinical deterioration in cardiac contractile function earlier than traditional anatomic cardiac strain markers. If successfully translated into patients, our novel approach of measuring CMR imaging-derived cardiac principal strain analysis may enhance the detection of subclinical RIC in patients receiving thoracic radiation.