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A novel mouse model of radiation-induced cardiac injury reveals biological and radiological biomarkers of cardiac dysfunction with potential clinical relevance
- Source :
- Clin Cancer Res
- Publication Year :
- 2021
-
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 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Clin Cancer Res
- Accession number :
- edsair.doi.dedup.....5314993bd17076419a6ffea2b5c6ed4b