本文選題：放射性心臟損傷 + PET/CT　； 參考：《山西醫(yī)科大學》2017年博士論文

【摘要】：目的:放射性心臟損傷(Radiation induced heart disease,RIHD)是由胸部腫瘤放療引起的遲發(fā)性不良反應之一,可增加患者心臟病病死率,部分抵消放療產(chǎn)生的生存受益。近年來RIHD逐漸引起臨床關注,目前仍缺乏RIHD特異檢查方法及監(jiān)測指標,本研究擬探討可早期診斷及監(jiān)測RIHD的方法。1.構建實驗犬放射性心臟損傷模型及無創(chuàng)性評價方法。2.分析~(18)F-FDG PET/CT顯像前不同準備方法對Beagle犬心肌~(18)F-FDG生理性攝取的影響,為本實驗確定合適實驗條件。3.利用~(18)F-FDG PET/CT顯像監(jiān)測實驗犬心肌局部照射后代謝改變,同期對照觀察心肌超微結構改變,分析照射后心肌代謝變化與病理損傷關系及代謝改變可能發(fā)生機制,探討~(18)F-FDG PET/CT檢查在監(jiān)測RIHD中的潛在價值。4.利用~(13)N-NH_3 PET/CT心肌灌注顯像(myocardial perfusion imaging,MPI)監(jiān)測實驗犬心肌局部照射后灌注以及左室功能改變,同期對照觀察心肌病理損傷,分析心肌照射后灌注改變與病理損傷關系,以及RIHD的可能發(fā)生機制,評估~(13)N-NH_3 PET/CT MPI在監(jiān)測早期RIHD中的潛在價值。方法:1.取健康成年一歲齡雄性Beagle犬8只,心臟照射前行~(18)F-FDG PET/CT心肌代謝顯像,然后行CT模擬定位,勾畫心室前壁作為照射靶區(qū),給予20Gy適形放療(6MV-X線),照射3個月后行同條件下~(18)F-FDG PET/CT心肌代謝顯像,觀察照射前后心肌代謝變化情況,計算照射區(qū)/非照射區(qū)的SUV比值(SUVig/SUVnig),發(fā)現(xiàn)與照射野一致的代謝增高區(qū)視為造模成功;處死動物,大體病理觀察照射區(qū)與非照射區(qū)心臟變化情況,取照射區(qū)和非照射區(qū)正常心肌作HE染色,光鏡觀察心肌及血管損傷情況。2.將24只Beagle犬隨機分為短時間(12 h)禁食+高糖(SF-GS)組、短時間禁食(SF)組、長時間(18h)禁食(pf)組和短時間禁食+高脂餐(sf-hf)組,每組各6只犬,行18f-fdgpet/ct心肌代謝顯像。圖像質量分為4個等級:0級為不攝取;1級為輕度(或部分心肌)攝取;2級為心肌攝取且顯像基本清晰,但不均勻;3級為心肌完全均勻攝取且顯像清晰。在pet/ct融合圖上選擇左心室為roi并測定suvmax。評價心肌18f-fdg攝取程度,比較各組間心肌18f-fdg圖像質量、suvmax及血糖水平(注射顯像劑前測定)間的差異。3.將36只beagle犬隨機分為對照組(n=18)和照射組(n=18),照射組在圖像引導下對實驗犬左室前壁行單次20gy照射,而對照組不進行照射。實驗犬于照射前1周及照射后3、6、12個月時以12h禁食+高脂餐顯像前準備行18f-fdgpet/ct心臟顯像檢查,并計算照射區(qū)/非照射區(qū)的suv比值(suvig/suvnig)。完成18f-fdgpet/ct心臟顯像檢查后在各個時間點分別從兩組隨機選擇6只實驗犬,而后處死取離體心臟,進行病理檢測觀察超微結構改變。4.取36只正常1歲齡雄性beagle犬,按隨機數(shù)表法將beagle犬完全隨機分為對照組(n=18)和照射組(n=18),照射組在圖像引導下對實驗犬左室前壁行單次20gy照射,而對照組不進行照射。兩組實驗犬分別于照射前1周及照射后3、6、12個月行13n-nh3pet/ct心肌灌注顯像。照射組實驗犬在完成13n-nh3pet/ctmpi檢查后1周行冠狀動脈造影(coronaryangiography,cag)檢查。照射后3個月、6個月及12個月分別從兩組隨機選擇6只實驗犬,而后處死取離體心臟,進行病理檢測。結果:1.根據(jù)pet/ct顯像及病理結果,8只beagle犬均產(chǎn)生了rihd。與照射前相比,照射后3個月實驗犬前壁照射野內心肌代謝均明顯增強,代謝增加區(qū)域與照射靶區(qū)匹配良好。照射3月后處死動物,取心臟肉眼觀察8只均可見照射區(qū)外表蒼白,一只出現(xiàn)心包積液,一只照射區(qū)局部心包粘連,橫斷切開心肌,照射野處質硬,呈灰白瘢痕狀,病理觀察照射區(qū)心肌可見退變,血管腫脹,周圍向外滲透,與未照射區(qū)有明顯差異。2.sf-gs組心肌顯像完整均勻(2級2只,3級4只),sf組心肌顯像組內差異變化較大,常不均勻(2級4只,1級、3級各1只);pf組(0級3只,1級2只,2級1只)與sf-hf組(0級4只,1級2只)心肌幾乎不顯影;各組間心肌18f-fdg顯像質量分級差異有統(tǒng)計學意義(h=16.83,p0.01)。pf組suvmax(3.01±0.97)與sf-hf組suvmax(2.84±1.15)明顯低于sf-gs組(14.76±4.72)與sf組(10.91±2.48)(f=69.84,p0.01)。pf組血糖水平(4.18±0.27)mmol/l與sf-hf組血糖水平(4.25±0.58)mmol/l也明顯低于sf-gs組(5.80±0.56)mmol/l與sf組(4.91±0.51)mmol/l(f=13.58,p0.01)。3.照射前對照組及照射組所有實驗犬以及照射后3、6、12個月對照組實驗犬心肌幾乎不顯影;與對照組及照射前相比,照射組照射后3個月、6個月及12個月,照射區(qū)心肌代謝增加,照射區(qū)與非照射區(qū)suvig/suvnig比值增高,心肌代謝增高區(qū)域均位于照射野內,但是隨著時間的延長,心肌代謝增高區(qū)域逐漸縮小。電鏡檢查發(fā)現(xiàn),照射后3個月,照射區(qū)心肌超微結構出現(xiàn)損傷,照射后6個月,損傷進一步加重,照射后12個月,出現(xiàn)損傷修復改變。4.與對照組及照射前相比,照射組照射后3個月,照射區(qū)心肌血流灌注增加;照射后6個月,照射區(qū)血流灌注減低;照射后12個月,照射區(qū)灌注缺損。照射前及照射后3個月,對照組及照射組左心室射血分數(shù)值(leftventricularejectionfraction,lvef)無統(tǒng)計學差異;照射后6個月,照射組與對照組相比,lvef減低(50.0±8.1%vs.59.3±4.1%,p=0.016);照射后12個月,照射組與對照組相比,lvef明顯減低(47.2±6.7%vs.57.4±3.3%,p=0.002)。照射組與對照組在照射前及照射后3、6、12個月冠狀動脈造影檢查均未見狹窄。照射組照射后3個月未觀察到局部室壁運動異常,照射后6個月,左室5/20個節(jié)段室壁運動異常,在照射后12個月,左室11/20個節(jié)段室壁運動異常,這些室壁運動異常節(jié)段位于照射野及其鄰近區(qū)域。病理學檢查發(fā)現(xiàn)照射區(qū)輻射誘導的心肌退變、微血管損傷及間質纖維化隨著時間的延長進行性加重。結論:1.20gy適形照射左室前壁心肌可構建穩(wěn)定、可靠的rihd模型,18f-fdgpet/ct可用于驗證rihd模型是否構建成功。2.pet/ct代謝顯像前準備方法不同,心肌顯影質量不同,在進行18f-fdgpet/ct檢查前,根據(jù)檢查目的,采用不同準備方法以增強或抑制心肌18f-fdg的生理性攝取,提高圖像質量,避免誤診及漏珍。3.18f-fdgpet/ct代謝顯像有助于rihd的早期發(fā)現(xiàn)與診斷,心肌受照后照射區(qū)域fdg攝取異常時,提示有可能發(fā)生rihd,應注意密切隨訪。4.13n-nh3pet/ctmpi能夠動態(tài)監(jiān)測rihd早期階段心肌灌注異常改變及功能異常。在監(jiān)測及評估RIHD方面,~(13)N-NH_3 PET/CT MPI可能是一個有價值的方法。本課題為國家自然科學基金“實驗犬放射性心臟損傷心肌灌注-代謝顯像及超微結構細胞損傷研究(編號: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)".
【學位授予單位】：山西醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R730.55

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