A Novel Mouse Model of Radiation-Induced Cardiac Injury Reveals Biological and Radiological Biomarkers of Cardiac Dysfunction with Potential Clinical Relevance

Abstract

Purpose: Radiation-induced cardiotoxicity is a significant concern in thoracic oncology patients. However, the basis for this disease pathology is not well-characterized. We developed a novel mouse model of radiation-induced cardiotoxicity to investigate pathophysiologic mechanisms and identify clinically targetable biomarkers of cardiac injury. Experimental Design: Single radiation doses of 20, 40, or 60 Gy were delivered to the cardiac apex of female C57BL/6 mice aged 9-11 weeks, with or without adjacent lung tissue, using conformal radiation therapy (RT). Cardiac tissue was harvested up to 24 weeks post-RT for histologic analysis. Echocardiography and Technetium-99 sestamibi single photon emission computed tomography (SPECT) at 8 and 16 weeks post-RT were implemented to evaluate myocardial function and perfusion. Mouse cardiac tissue and mouse and human plasma were harvested for biochemical studies. Results: Histopathologically, RT resulted in perivascular fibrosis 8 and 24 (p<0.05) weeks post-RT. Apical perfusion deficits on SPECT and systolic and diastolic dysfunction on echocardiography 8 and 16 weeks post-RT were also observed (p<0.05). Irradiated cardiac tissue and plasma showed significant increases in placental growth factor (PlGF), interleukin-6, and tumor necrosis factor-alpha (TNFa) compared to non-radiated matched controls, with greater increases in cardiac cytokine levels when RT involved lung. Human plasma showed increased PlGF (p=0.021) and TNFa (p=0.036) levels post-thoracic RT. Conclusions: We developed and characterized a pathophysiologically relevant mouse model of radiation-induced cardiotoxicity involving in situ irradiation of the cardiac apex. The model can be used to integrate radiomic and biochemical markers of cardiotoxicity to inform early therapeutic intervention and human translational studies.