实验犬放射性心脏损伤心肌代谢—灌注显像及超微结构损伤研究

发布时间：2018-06-02 10:18

本文选题：放射性心脏损伤 + PET/CT　；参考：《山西医科大学》2017年博士论文

【摘要】：目的:放射性心脏损伤(Radiation induced heart disease,RIHD)是由胸部肿瘤放疗引起的迟发性不良反应之一,可增加患者心脏病病死率,部分抵消放疗产生的生存受益。近年来RIHD逐渐引起临床关注,目前仍缺乏RIHD特异检查方法及监测指标,本研究拟探讨可早期诊断及监测RIHD的方法。1.构建实验犬放射性心脏损伤模型及无创性评价方法。2.分析~(18)F-FDG PET/CT显像前不同准备方法对Beagle犬心肌~(18)F-FDG生理性摄取的影响,为本实验确定合适实验条件。3.利用~(18)F-FDG PET/CT显像监测实验犬心肌局部照射后代谢改变,同期对照观察心肌超微结构改变,分析照射后心肌代谢变化与病理损伤关系及代谢改变可能发生机制,探讨~(18)F-FDG PET/CT检查在监测RIHD中的潜在价值。4.利用~(13)N-NH_3 PET/CT心肌灌注显像(myocardial perfusion imaging,MPI)监测实验犬心肌局部照射后灌注以及左室功能改变,同期对照观察心肌病理损伤,分析心肌照射后灌注改变与病理损伤关系,以及RIHD的可能发生机制,评估~(13)N-NH_3 PET/CT MPI在监测早期RIHD中的潜在价值。方法:1.取健康成年一岁龄雄性Beagle犬8只,心脏照射前行~(18)F-FDG PET/CT心肌代谢显像,然后行CT模拟定位,勾画心室前壁作为照射靶区,给予20Gy适形放疗(6MV-X线),照射3个月后行同条件下~(18)F-FDG PET/CT心肌代谢显像,观察照射前后心肌代谢变化情况,计算照射区/非照射区的SUV比值(SUVig/SUVnig),发现与照射野一致的代谢增高区视为造模成功;处死动物,大体病理观察照射区与非照射区心脏变化情况,取照射区和非照射区正常心肌作HE染色,光镜观察心肌及血管损伤情况。2.将24只Beagle犬随机分为短时间(12 h)禁食+高糖(SF-GS)组、短时间禁食(SF)组、长时间(18h)禁食(pf)组和短时间禁食+高脂餐(sf-hf)组,每组各6只犬,行18f-fdgpet/ct心肌代谢显像。图像质量分为4个等级:0级为不摄取;1级为轻度(或部分心肌)摄取;2级为心肌摄取且显像基本清晰,但不均匀;3级为心肌完全均匀摄取且显像清晰。在pet/ct融合图上选择左心室为roi并测定suvmax。评价心肌18f-fdg摄取程度,比较各组间心肌18f-fdg图像质量、suvmax及血糖水平(注射显像剂前测定)间的差异。3.将36只beagle犬随机分为对照组(n=18)和照射组(n=18),照射组在图像引导下对实验犬左室前壁行单次20gy照射,而对照组不进行照射。实验犬于照射前1周及照射后3、6、12个月时以12h禁食+高脂餐显像前准备行18f-fdgpet/ct心脏显像检查,并计算照射区/非照射区的suv比值(suvig/suvnig)。完成18f-fdgpet/ct心脏显像检查后在各个时间点分别从两组随机选择6只实验犬,而后处死取离体心脏,进行病理检测观察超微结构改变。4.取36只正常1岁龄雄性beagle犬,按随机数表法将beagle犬完全随机分为对照组(n=18)和照射组(n=18),照射组在图像引导下对实验犬左室前壁行单次20gy照射,而对照组不进行照射。两组实验犬分别于照射前1周及照射后3、6、12个月行13n-nh3pet/ct心肌灌注显像。照射组实验犬在完成13n-nh3pet/ctmpi检查后1周行冠状动脉造影(coronaryangiography,cag)检查。照射后3个月、6个月及12个月分别从两组随机选择6只实验犬,而后处死取离体心脏,进行病理检测。结果:1.根据pet/ct显像及病理结果,8只beagle犬均产生了rihd。与照射前相比,照射后3个月实验犬前壁照射野内心肌代谢均明显增强,代谢增加区域与照射靶区匹配良好。照射3月后处死动物,取心脏肉眼观察8只均可见照射区外表苍白,一只出现心包积液,一只照射区局部心包粘连,横断切开心肌,照射野处质硬,呈灰白瘢痕状,病理观察照射区心肌可见退变,血管肿胀,周围向外渗透,与未照射区有明显差异。2.sf-gs组心肌显像完整均匀(2级2只,3级4只),sf组心肌显像组内差异变化较大,常不均匀(2级4只,1级、3级各1只);pf组(0级3只,1级2只,2级1只)与sf-hf组(0级4只,1级2只)心肌几乎不显影;各组间心肌18f-fdg显像质量分级差异有统计学意义(h=16.83,p0.01)。pf组suvmax(3.01±0.97)与sf-hf组suvmax(2.84±1.15)明显低于sf-gs组(14.76±4.72)与sf组(10.91±2.48)(f=69.84,p0.01)。pf组血糖水平(4.18±0.27)mmol/l与sf-hf组血糖水平(4.25±0.58)mmol/l也明显低于sf-gs组(5.80±0.56)mmol/l与sf组(4.91±0.51)mmol/l(f=13.58,p0.01)。3.照射前对照组及照射组所有实验犬以及照射后3、6、12个月对照组实验犬心肌几乎不显影;与对照组及照射前相比,照射组照射后3个月、6个月及12个月,照射区心肌代谢增加,照射区与非照射区suvig/suvnig比值增高,心肌代谢增高区域均位于照射野内,但是随着时间的延长,心肌代谢增高区域逐渐缩小。电镜检查发现,照射后3个月,照射区心肌超微结构出现损伤,照射后6个月,损伤进一步加重,照射后12个月,出现损伤修复改变。4.与对照组及照射前相比,照射组照射后3个月,照射区心肌血流灌注增加;照射后6个月,照射区血流灌注减低;照射后12个月,照射区灌注缺损。照射前及照射后3个月,对照组及照射组左心室射血分数值(leftventricularejectionfraction,lvef)无统计学差异;照射后6个月,照射组与对照组相比,lvef减低(50.0±8.1%vs.59.3±4.1%,p=0.016);照射后12个月,照射组与对照组相比,lvef明显减低(47.2±6.7%vs.57.4±3.3%,p=0.002)。照射组与对照组在照射前及照射后3、6、12个月冠状动脉造影检查均未见狭窄。照射组照射后3个月未观察到局部室壁运动异常,照射后6个月,左室5/20个节段室壁运动异常,在照射后12个月,左室11/20个节段室壁运动异常,这些室壁运动异常节段位于照射野及其邻近区域。病理学检查发现照射区辐射诱导的心肌退变、微血管损伤及间质纤维化随着时间的延长进行性加重。结论:1.20gy适形照射左室前壁心肌可构建稳定、可靠的rihd模型,18f-fdgpet/ct可用于验证rihd模型是否构建成功。2.pet/ct代谢显像前准备方法不同,心肌显影质量不同,在进行18f-fdgpet/ct检查前,根据检查目的,采用不同准备方法以增强或抑制心肌18f-fdg的生理性摄取,提高图像质量,避免误诊及漏珍。3.18f-fdgpet/ct代谢显像有助于rihd的早期发现与诊断,心肌受照后照射区域fdg摄取异常时,提示有可能发生rihd,应注意密切随访。4.13n-nh3pet/ctmpi能够动态监测rihd早期阶段心肌灌注异常改变及功能异常。在监测及评估RIHD方面,~(13)N-NH_3 PET/CT MPI可能是一个有价值的方法。本课题为国家自然科学基金“实验犬放射性心脏损伤心肌灌注-代谢显像及超微结构细胞损伤研究(编号:81171374)”。
[Abstract]:Objective: Radiation induced heart disease (RIHD) is one of the delayed adverse reactions caused by radiotherapy of the chest tumor, which can increase the mortality of the patients with heart disease and partly offset the survival benefit of the radiotherapy. In recent years, RIHD has gradually caused clinical attention. At present, there is still a lack of RIHD specific examination methods and monitoring indicators, this research is still lacking. To explore the method of early diagnosis and monitoring of RIHD.1. construction of experimental dog radioactive heart damage model and noninvasive evaluation method.2. analysis of the effects of different preparation methods before ~ (18) F-FDG PET/CT imaging on the physiological uptake of ~ (18) F-FDG in the myocardium of Beagle dogs, to determine the suitable experimental condition.3. using ~ (18) F-FDG PET/CT monitoring The metabolic changes in the experimental dog myocardium after local irradiation were observed, and the changes of myocardial ultrastructure were observed at the same time. The relationship between myocardial metabolism and pathological injury after irradiation and the possible mechanism of metabolic changes were analyzed. The potential value of ~ (18) F-FDG PET/CT examination in monitoring RIHD using ~ (13) N-NH_3 PET/CT myocardial perfusion imaging (myocardial perfusio) was explored. N imaging, MPI) monitoring the perfusion and left ventricular function changes after local irradiation of myocardium in the experimental dogs. The pathological injury of myocardium was observed at the same time. The relationship between perfusion change and pathological injury after myocardial irradiation, and the possible mechanism of RIHD were analyzed, and the potential value of ~ (13) N-NH_3 PET/CT MPI in early monitoring of early RIHD was evaluated. Method: 1. to take healthy adult one. 8 years old male Beagle dogs were treated with ~ (18) F-FDG PET/CT myocardial metabolism imaging before heart irradiation, then CT simulated location was performed and the anterior wall of the ventricle was used as the target area of the irradiated target. 20Gy conformal radiotherapy (6MV- X ray) was given. After 3 months of irradiation, the myocardial metabolic changes of ~ (18) F-FDG PET/CT were observed under the same condition, and the changes of myocardial metabolism before and after irradiation were observed and the irradiated area was calculated. The SUV ratio (SUVig/SUVnig) of the non irradiated area was found to be a successful model in the irradiated field. The animals were killed and the heart changes in the irradiated and non irradiated areas were observed by general pathology. The normal myocardium in the irradiated and non irradiated areas was stained with HE, and the damage of the cardiac muscle and blood vessels by the light microscope was divided into 24 Beagle dogs randomly. Short time (12 h) fasting + high sugar (SF-GS) group, short time fasting (SF) group, long time (PF) group and short time fasting + high fat meal (sf-hf) group, each group of 6 dogs, 18f-fdgpet/ct myocardial metabolism imaging. The image quality is divided into 4 grades: 0 level is not intake; 1 is mild (or partial myocardial) intake; 2 level of myocardial uptake and imaging basic Clear, but not uniform; the 3 level was the complete and uniform uptake of the myocardium and the imaging was clear. On the pet/ct fusion map, the left ventricle was selected as ROI and the 18F-FDG uptake of the myocardium was measured by suvmax.. The myocardial 18F-FDG image quality was compared, and the difference.3. between the SUVmax and the blood glucose level (before the injection of the injection imaging agent) was divided into 36 beagle dogs randomly into the control group. N=18) and irradiation group (n=18), the irradiated group irradiated the left ventricle anterior wall of the experimental dog under the guidance of the single 20GY, and the control group did not irradiate. The experimental dogs were prepared by 18f-fdgpet/ct cardiac imaging before 1 weeks of irradiation and 3,6,12 months after irradiation, and the SUV ratio (suvig/su) in the irradiated area / non irradiation area (suvig/su) was calculated. Vnig). After completing the 18f-fdgpet/ct cardiac imaging examination, 6 experimental dogs were randomly selected from two groups at each time point, then the isolated heart was executed, and the ultrastructural changes were observed to observe the ultrastructural changes in 36 normal 1 year old male beagle dogs, and the Beagle dogs were randomly divided into the control group (n=18) and the irradiation group (n=18) according to the random number table method. In the irradiation group, the left ventricle anterior wall of the experimental dog was irradiated with single 20GY, while the control group did not irradiate. The two groups of experimental dogs were performed 13n-nh3pet/ct myocardial perfusion imaging for 1 weeks before irradiation and 3,6,12 months after irradiation. The experimental dogs were performed coronary angiography (coronaryangiography, CAG) at 1 weeks after the completion of the 13n-nh3pet/ctmpi examination. After 3 months, 6 months and 12 months after irradiation, 6 experimental dogs were randomly selected from two groups, then the isolated heart was killed and pathological examination was performed. Results: 1. according to pet/ct imaging and pathological results, 8 beagle dogs produced rihd. compared with pre irradiation, and 3 months after irradiation, the metabolism of inner muscle metabolism in the canine anterior wall irradiated field was significantly enhanced. Metabolism was significantly enhanced. The region was matched well with the radiation target area. After March, the animals were killed, and all the animals were killed after March. In the eyes of the heart, 8 eyes were observed to be pale, a pericardial effusion, a local pericardial adhesion in a irradiated area, a transverse incision of the myocardium, and a hard, gray and white scar in the field. There was significant difference between the.2.sf-gs group and the unirradiated area (grade 2, 2, 3 and 4). The difference in myocardial imaging group in group SF was very different, and was often uneven (2 level 4, 1, 3 each), and group pf (0 3, 1 2 only, 2 grade only) myocardium almost did not show; 18F-FDG imaging quality in group sf-hf There were statistical significance (h=16.83, P0.01).Pf group SUVmax (3.01 + 0.97) and sf-hf group SUVmax (2.84 + 1.15) significantly lower than group sf-gs (14.76 + 4.72) and SF group (10.91 + 2.48) (f=69.84, P0.01).Pf group blood glucose level (4.18 + 0.27) mmol/l and blood glucose level (4.25 + 0.58) After exposure to mmol/l (f=13.58, P0.01).3., all the experimental dogs in the control group and the irradiated group and the control group of the irradiated group were almost undeveloped. Compared with the control group and before the irradiation, the irradiated group irradiated the myocardium for 3 months, 6 months and 12 months after irradiation, and the ratio of the suvig/suvnig ratio in the irradiated area to the non irradiated area was higher than that of the control group and the irradiated group, and the ratio of the myocardium to the irradiated area was higher than that of the non irradiated area, and the ratio of the myocardium to the irradiated area was higher than that of the control group and before the irradiation. The ratio of the heart to the irradiated area was higher than that of the non irradiated area, and the ratio of the heart to the irradiated area was higher than that of the non irradiated area before the irradiation. The region of increased muscle metabolism was located in the radiation field, but with the time prolonged, the area of myocardial metabolism increased gradually. It was found that the ultrastructure of the myocardium in the irradiated area was damaged at 3 months after irradiation, and the damage was further aggravated in 6 months after irradiation, and the damage repair changes of.4. were compared with the control group and before the irradiation, after 12 months of irradiation. The blood flow perfusion in the irradiated area was increased at 3 months after irradiation, and the blood flow perfusion in the irradiated area decreased at 6 months after irradiation, and the defect was perfused in the irradiated area for 12 months after irradiation. The left ventricular ejection fraction (leftventricularejectionfraction, LVEF) in the control group and the irradiated group had no statistical difference before and after irradiation, and the irradiated group had no statistical difference for 6 months after irradiation. Compared with the control group, LVEF decreased (50 + 8.1%vs.59.3 + 4.1%, p=0.016), and 12 months after irradiation, compared with the control group, the LVEF decreased significantly (47.2 + 6.7%vs.57.4 + 3.3%, p=0.002). There was no stenosis in the irradiation group and the control group at the coronary angiography before and after irradiation, and the group was not observed for 3 months after irradiation. The movement of the ventricular wall was abnormal and the left ventricular wall movement was abnormal at 6 months after irradiation. At 12 months after irradiation, the ventricular wall movement in the left ventricular 11/20 segment was abnormal. The abnormal segments of the ventricular wall were located in the irradiated field and its adjacent area. The pathological examination found the radiated myocardium degeneration, microvascular injury and interstitial fibrosis in the irradiated area. Conclusion: 1.20gy conformal irradiation of the left ventricle anterior wall can construct a stable, reliable RIHD model. 18f-fdgpet/ct can be used to verify whether the RIHD model has been constructed successfully before.2.pet/ct metabolism imaging, and the quality of the myocardium is different. Before the 18f-fdgpet/ct examination, the purpose of the examination is to use the different methods. Preparation methods to enhance or inhibit the physiological uptake of 18F-FDG in the myocardium, improve the image quality, avoid misdiagnosis and leakage of.3.18f-fdgpet/ct metabolism imaging can help the early detection and diagnosis of RIHD. When the FDG uptake in the irradiated area after the myocardial exposure is abnormal, it is possible to occur RIHD. Attention should be paid to the close follow-up of.4.13n-nh3pet/ctmpi to monitor r dynamically. The abnormal changes of myocardial perfusion and dysfunction at the early stage of IHD. ~ (13) N-NH_3 PET/CT MPI may be a valuable method for monitoring and evaluating RIHD. The subject is the National Natural Science Foundation of National Natural Science "experimental dog radioactivity cardiac perfusion metabolic imaging and ultrastructural cell damage study (No. 81171374)".
【学位授予单位】：山西医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R730.55

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