| Objective:1. Focal increased 18F-FDG uptake in the irradiation field is sometimes seen in patients with thoracic tumors after radiotherapy. However, the value of 18F-FDG PET for the diagnosis of radiation induced heart disease(RIHD) has not been fully explored. We aimed to determine the efficacy of 18F-FDG PET/CT in the detection of RIHD in beagles by comparing two pre-scan preparation protocols as well as to determine the correlation between abnormal myocardial FDG uptake and pathological findings.2. To investigate the impact of connective tissue growth factor(CTGF) on radiation induced heart disease.3. Accumulating evidence has revealed that mature dendrite cells(DCs)play critical roles in the differentiation of effector T cells into CD4+ T cells, which effectively participate in the onset of acute coronary syndrome(ACS). IFN regulatory factor(IRF)-1 has been shown to be involved in various immune processes. The aim of the study was to investigate the expression of IRF-1 in dendritic cells and explore the possible role of IRF-1 in DCs in the pathogenesis of ACS.Methods:1. The anterior myocardium of 12 beagles received intensity modulated radiotherapy locally with a single X-ray dose of 20 Gy. Echocardiography and 18F-FDG cardiac PET/CT were performed at baseline and 3 months after radiation. The left ventricular function parameters were obtained by echocardiography before and after irradiation. Twelve beagles underwent two different preparation protocols before being subjected to PET/CT: 12 h of fasting(12H-F), 12 h of fasting followed by a high-fat diet(F-HFD). The qualities of dogs′ myocardial 18F-FDG uptake imaging before RT were classified into four grades based on the visual interpretation by two experienced physicians on 18F-FDG PET/CT images: grade 0, myocardial FDG was not visualized; grade 1, faint or partial visualization of the myocardial FDG uptake; grade2, distinct visualization of myocardial FDG uptake; grade 3, strong and complete visualization of myocardial FDG uptake. The maximal standardized uptake values(SUVmax) of the left ventricular myocardium before radiation was measured. Regions of interest(ROIs) were drawn on the irradiation and the non-irradiation fields to obtain their maximal standardized uptake values(SUVmax). Then the ratio of the irradiation field to the non-irradiation field SUV(irradiation to non-irradiation ratio, INR) was then computed. Histopathological changes were identified by light and electron microscopy.2. A total of 18 Sprague Dawley(SD) rats were randomly divided into three groups(1 control group, 2 irradiation groups: 3 months after radiation, 6 months after radiation). 12 rats received radiotherapy locally with a single X-ray dose of 20 Gy. Biodistribution studies with technetium(99m Tc) sestamibi were performed 3 and 6 months after irradiation. The percent radioactivity(%ID/g) was calculated for each heart. All the rats were sacrificed and the hearts were harvested. The m RNA and protein of CTGF and FN in myocardium were detected by RT-PCR and Western Blotting. The pathology of heart were evaluated with HE, electron microscopy and 0.1% Sirius-picric staining,3. Patients with clinical presentation of chest pain(CPS), stable angina(SA), unstable angina(UA) and acute myocardial infarction(AMI) were enrolled in this study. Dendritic cells were enriched. The CD80, CD83-positive DC cells were detected by Flow cytometry. The expression of IRF-1 in DCs was analyzed by real-time PCR and western-blot method. The concentrations of IL- 6, IL-12p70, TNF-α, and IL-10 were detected by ELISA. The correlation between IRF-1 and cytokines were analyzed by Pearson correlation analysis.Results:1. No difference of cardiac function between baseline and 3months after radiation. Physiology myocardial FDG uptake was distinct visualized and not even under 12H-F protocol(4 for grade 2, 1 for grade 1, 1 for grade 3), however, myocardial FDG uptake was hardly visualized under F-HFD protocol(3 for grade 0, 1 for grade 1, 1 for grade 2). The SUVmax in 12h-F preparation protocol was lower than those in F-HFD protocol prior to radiation(SUVmax 2.84±1.15 vs. 10.91±2.48 P<0.05). Using the 12H-F protocol, the average INRs were 1.18±0.10 and 1.41±0.18 before and after irradiation, respectively(P=0.021). Using the F-HFD protocol, the average INRs were 0.99±0.15 and 2.54±0.43, respectively(P<0.001). By visual analysis, a high FDG uptake in the irradiation field was detected in 33.3%(4/12) of samples using the 12H-F protocol and 83.3%(10/12) of samples using the F-HFD protocol(P=0.031). The pathology of the irradiated myocardium showed obvious perivascular fibrosis and changes in mitochondrial vacuoles.2. Six months after irradiation, a significant drop of myocardial uptake was observed(P<0.01). The severity and extent of myocardial injury has became more evident at the end of six month. At ultrastructural level, prominent changes have been observed in the capillary endothelial and myocardial cells. The m RNA and protein expression of CTGF and FN increased markedly in 6 and 3 months after irradiation compared to the control group(P<0.01). The expression of CTGF m RNA and protein was positively correlated to the proportion of collagen fibers in the rats’ hearts after irradiation.3. The results demonstrated that positive of CD80, CD83 DCs was significantly high and the expression of IRF-1 in DCs was significantly increased in patients with ACS. The expression of IRF-1 were positively correlated with IL-6, IL-12p70, TNF-α and negatively correlated with IL-10.Conclusions:1. F-HFD may be an effective and low-cost method to inhibit physiological myocardial 18F-FDG uptake. High FDG uptake in an irradiated field may be related with RIHD resulting from microvascular damage and mitochondrial injury. An F-HFD preparation protocol used before obtaining PET/CT can improve the sensitivity of the detection of RIHD.2. This study demonstrated that radiation induces myocardial damage because of the direct effects of irradiation on the endothelial cells of microvascular tissue, causing myocardial ischemia, and ultimately leading to progressive myocardial fibrosis. Perfusion decreased was observed in months after irradiation. Therefore, myocardial perfusion imaging is an important noninvasive technique for follow-up RIHD. This study also indicated that CTGF take a key role in the development and progress of radiation induced heart disease.3. The present data demonstrate that IRF-1 might effectively induce the maturation of monocyte-derived DCs and promote the inflammatory response in atherosclerosis and ACS. |
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