A novel mouse model of radiation-induced cardiac injury reveals biological and radiological biomarkers of cardiac dysfunction with potential clinical relevance
Autor: | Anastasia Velalopoulou, Denisa Goia, Constantinos Koumenis, Scott D. Metzler, Bonnie Ky, Ioannis I. Verginadis, Susan Mazzoni, Steven J. Feigenberg, Paco E Bravo, Harris Avgousti, Swapnil V. Shewale, Khayrullo Shoniyozov, Alexandra D. Dreyfuss |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Cancer Research
Pathology medicine.medical_specialty Lung Neoplasms medicine.medical_treatment Disease 030204 cardiovascular system & hematology Single-photon emission computed tomography Article 03 medical and health sciences Mice 0302 clinical medicine Thoracic Oncology medicine Animals Humans Clinical significance Tomography Emission-Computed Single-Photon Cardiotoxicity medicine.diagnostic_test business.industry Myocardium Dose-Response Relationship Radiation Heart Fibrosis Pathophysiology Radiation therapy Radiation Injuries Experimental Oncology Echocardiography 030220 oncology & carcinogenesis Female business Perfusion Biomarkers |
Zdroj: | Clin Cancer Res |
Popis: | 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 ages 9–11 weeks, with or without adjacent lung tissue, using conformal radiotherapy. Cardiac tissue was harvested up to 24 weeks post-radiotherapy for histologic analysis. Echocardiography and Technetium-99m sestamibi single photon emission computed tomography (SPECT) at 8 and 16 weeks post-radiotherapy were implemented to evaluate myocardial function and perfusion. Mouse cardiac tissue and mouse and human plasma were harvested for biochemical studies. Results: Histopathologically, radiotherapy resulted in perivascular fibrosis 8 and 24 (P < 0.05) weeks post-radiotherapy. Apical perfusion deficits on SPECT and systolic and diastolic dysfunction on echocardiography 8 and 16 weeks post-radiotherapy were also observed (P < 0.05). Irradiated cardiac tissue and plasma showed significant increases in placental growth factor (PlGF), IL6, and TNFα compared with nonradiated matched controls, with greater increases in cardiac cytokine levels when radiotherapy involved lung. Human plasma showed increased PlGF (P = 0.021) and TNFα (P = 0.036) levels after thoracic radiotherapy. PlGF levels demonstrated a strong correlation (r = 0.89, P = 0.0001) with mean heart dose. 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. |
Databáze: | OpenAIRE |
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