颈动脉粥样硬化斑块成分的超声、磁共振影像学分析及肥大细胞在粥样硬化斑块中的分布
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摘要
研究背景：颈动脉粥样硬化产生脑缺血症状除了动脉狭窄因素外，动脉硬化斑块的稳定性，也就是斑块的病理成分及病理结构起着更为重要的作用。应用超声及磁共振等无创影像学手段分析动脉粥样硬化的病理成分及病理结构，对颈动脉粥样硬化患者的手术及内科治疗，具有重要临床价值。动脉硬化斑块的稳定性与其细胞成分有关，肥大细胞作为基质中重要的细胞成分，可以释放多种蛋白酶及细胞因子影响基质稳定性。已有实验证明冠状动脉粥样硬化斑块中肥大细胞增多，但颈动脉斑块中肥大细胞的数目及分布情况需要进行研究。
研究目的：1、探讨体内外颈动脉粥样硬化斑块的超声、HRI影像学表现与斑块内病理成分的相关性，并对超声图像进行灰度值量化分析。2、研究两种表型的肥大细胞在颈动脉斑块中的数量及分布情况，评价肥大细胞对斑块稳定性的影响。
研究方法：实验1：颈动脉狭窄患者20例(狭窄度＞70％)，共22侧血管，术前一周内分别行高分辨率超声及高分辨率MRI(应用特制的相控阵线圈)检查斑块形态并记录影像。手术后切除的粥样硬化斑块在体外行超声及MRI检查并记录影像。斑块标本沿与纵轴垂直方向做不同层面病理切片，以颈动脉分叉、血管腔形态及钙化点为参照物，将体内外斑块超声及MRI影像与病理切片相匹配，分析体内外斑块内纤维组织、脂质核、钙化、出血及血栓的超声
解放军总医院军医进修学院 博士学位论文
及MRI影像学表现，并将各种病理成分的超声影像用256级灰度值进行量
化。实验2：32例颈动脉粥样硬化切除标本及10例尸检正常颈动脉标本固定
后包埋切片，相邻切片分别行HE、甲苯胺蓝、抗肥大细胞twtase及chymase
单克隆抗体免疫组化染色、抗T淋巴细胞CD－3及抗巨噬细胞CD－68单克隆
抗体免疫组化染色。观察两种表型的肥大细胞在正常颈动脉内及颈动脉粥样
斑块内的数量及分布，并观察肥大细胞在斑块不同部位脱颗粒情况及其与T
淋巴细胞及巨噬细胞的比例。
研究结果：实验卜 体内斑块中钙化、纤维组织、出血／血栓、脂质的超声影
像灰度值分别为 89士12，53士8，37士6和 39士3，体外斑块中钙化、纤维组
织、出血／血栓、脂质的超声影像灰度值分别为168士＊，136士12，85士12和
89士10，出血／血栓和脂质成分的灰度值差异无显著统计学意义，其他成分之
间灰度值差异均有显著统计学意义。应用特制的相控阵线圈，体内斑块中的
钙化、纤维组织、陈旧出血／血栓、脂质成分在们加权相上分别为低信号、
等信号、等信号、极高信号（相对于肌肉信号而言），在质子相上分别为极
低信号、等信号、高信号、高信号，在TZ加权相上分别为低信号、等信号或
轻度高信号、高信号、高信号。体外斑块MRI检查结果与体内斑块检查结果
相符合。在＊相及质子相上能够很好的分辨钙化及厚的纤维帽，对于部分陈
旧出血／血栓、脂质也能分辨，但对于脂质中混有出血成分的较复杂的斑块，
分辨能力较差。实验2：在正常内膜、斑块帽区、核区、肩区肥大细胞密度
（细胞数／平方毫米）分别为 l．3土 2．3、2．3士2．6、2．二士3．7、6．3士 4．0，
chymase阳性细胞与 tryptase阳性细胞的比值分别为 36％、sl％、47％、
39％，脱颗粒肥大细胞数占肥大细胞总数的比例分别为18％、35％、52％、
65％。斑块肩区肥大细胞密度及脱颗粒细胞比例明显高于其它部位。肥大细
胞与T细胞及巨噬细胞的比例在正常内膜分别为10％和7％，在斑块帽区分别
为12％和7％，在斑块核区分别为6％和5％，在斑块肩区分别为25％和
4
解放军总医院军医进修学院 博士学位论文
14％。光镜下观察肥大细胞也分布于血管外膜、血栓内、钙化周围及新生血
管周围。
研究结论：灰度值分析可以对动脉硬化斑块中不同病理成分的超声影像进行
量化处理，为判定斑块的稳定性提供客观依据。应用特制的相控阵线圈，
Mill可以初步区分斑块成分，可以用来评价斑块的稳定性，并用来观察斑块
的动态变化；肥大细胞参与颈动脉硬化斑块的形成，并通过活化脱颗粒影响
斑块的稳定性。
BACKGROUND-.Besides the degree of stenosis,the stability of carotid plaque is also important in development of clinical events .Plaque contents and structure may play an important role in plaque instability,so using noninvasive ultrasound and MRI to assess the contents of atherosclarotic plaques at the carotid bifurcation has great value.these imaging techniques could be important in evaluating the progression of carotid artery atherosclerosis and its response to pharmacologic and surgical intervention.The stability of plaque is related to its cellular components too.As the major cellular component of connective tissue,mast cells have the potential to influence the extracellular matrix component of plaque through the production of potent mediators such as proteases and a broad spectrum of multifunctional cytokines.The present of increased numbers of mast cells in coronary plaque has been reported,but there was no any experimental report about the quantity and distribution of mast cell in carotid plaque .
PURPOSE:(1) To correlate ultrasound and MRI imaging of atherosclerotic plaque at the carotid bifurcation with histologic analysis,and perform densitometric analysis of ultrasound images of carotid plaques.(2)To study quantity and distribution of two different phenotype mast cell in atherosclerotic lesions of human carotid arteries,and to evaluate the influence of mast cell on stability of carotid plaque.
METHODS:(1)20 patients(22 lesions) scheduled for carotid endarterectomy were examined by high resolution B-mode ultrasound and high resolution MRI preoperatively,the images of carotid plaque was recorded. The postoperative specimens were also examined by high resolution B-mode ultrasound and high resolution MRI.The transverse pathological sections of plaques were made and were matched with images of ultrasound and MRI,using carotid bifurcation,calcification and the shape of plaque and lumen as the landmark.Performing 256 gray scale ultrasound densitometric analysis of carotid plaque compositions and correlating MRI images of atherosclerotic plaque with histologic findings such as calcium,fibrous tissue,old hemorrage/thrombus and lipid deposits.(2)32 samples of endarterectomy and 10 autopsy normal carotid specimens were fixed and embeded in paraffin,serial sections were stained with hematoxylin-eosin,Toluidine blue stains,monoclonal antibodies against the two major proteases of mast cell(tryptase and chymase) and monoclonal antibodies against CD-3 of T lymphocyte and CD-68 of macrophage. The quantity,distribution and degranule of two different phenotype mast cell in atherosclerotic lesions of human carotid arteries was investigated,and the ratio of mast cell to T lymphocyte and macrophage in atherosclerotic lesions was calculated.
RESULTS:(l)Ultrasonic density measurement of calcium,fibrous tissue,hemorrage/thrombus and lipid deposits was 89 +12, 53 + 8, 37 + 6 and 39 + 3 respectively in vivo. Ultrasonic density measurement of calcium,fibrous tissue,hemorrage/thrombus and lipid deposits was 168
?1, 136 + 12, 85 + 12 and 89 + 10 respectively in vitro.There were significant statistics difference of density measurement between different components except between hemorrage/thrombus and lipid deposits.In vivo relative signal intensities of calcium,fibrous tissue,old hemorrage/thrombus and lipid deposits were low,equal,equal and very high respectively on T1W MR image(relative to signal intensity of muscle). In vivo relative signal intensities of calcmm,fibrous tissue,old hemorrage/thrombus and lipid deposits were very low,equal,high and high respectively on PDW MR image. In vivo relative signal intensities of calcium,fibrous tissue,old hemorrage/thrombus and lipid deposits were low,equal or slight high,high and high respectively on T2W MR image. Signal intensities of plaque contents in vivo were corelated to signal intensities ex vivo.Calcium and thick fibrous cap were identified very well on T1W and PDW images, hemorrage/thrombus and lipid deposits also could be identified,but it was diffi
研究目的：1、探讨体内外颈动脉粥样硬化斑块的超声、HRI影像学表现与斑块内病理成分的相关性，并对超声图像进行灰度值量化分析。2、研究两种表型的肥大细胞在颈动脉斑块中的数量及分布情况，评价肥大细胞对斑块稳定性的影响。
研究方法：实验1：颈动脉狭窄患者20例(狭窄度＞70％)，共22侧血管，术前一周内分别行高分辨率超声及高分辨率MRI(应用特制的相控阵线圈)检查斑块形态并记录影像。手术后切除的粥样硬化斑块在体外行超声及MRI检查并记录影像。斑块标本沿与纵轴垂直方向做不同层面病理切片，以颈动脉分叉、血管腔形态及钙化点为参照物，将体内外斑块超声及MRI影像与病理切片相匹配，分析体内外斑块内纤维组织、脂质核、钙化、出血及血栓的超声
解放军总医院军医进修学院 博士学位论文
及MRI影像学表现，并将各种病理成分的超声影像用256级灰度值进行量
化。实验2：32例颈动脉粥样硬化切除标本及10例尸检正常颈动脉标本固定
后包埋切片，相邻切片分别行HE、甲苯胺蓝、抗肥大细胞twtase及chymase
单克隆抗体免疫组化染色、抗T淋巴细胞CD－3及抗巨噬细胞CD－68单克隆
抗体免疫组化染色。观察两种表型的肥大细胞在正常颈动脉内及颈动脉粥样
斑块内的数量及分布，并观察肥大细胞在斑块不同部位脱颗粒情况及其与T
淋巴细胞及巨噬细胞的比例。
研究结果：实验卜 体内斑块中钙化、纤维组织、出血／血栓、脂质的超声影
像灰度值分别为 89士12，53士8，37士6和 39士3，体外斑块中钙化、纤维组
织、出血／血栓、脂质的超声影像灰度值分别为168士＊，136士12，85士12和
89士10，出血／血栓和脂质成分的灰度值差异无显著统计学意义，其他成分之
间灰度值差异均有显著统计学意义。应用特制的相控阵线圈，体内斑块中的
钙化、纤维组织、陈旧出血／血栓、脂质成分在们加权相上分别为低信号、
等信号、等信号、极高信号（相对于肌肉信号而言），在质子相上分别为极
低信号、等信号、高信号、高信号，在TZ加权相上分别为低信号、等信号或
轻度高信号、高信号、高信号。体外斑块MRI检查结果与体内斑块检查结果
相符合。在＊相及质子相上能够很好的分辨钙化及厚的纤维帽，对于部分陈
旧出血／血栓、脂质也能分辨，但对于脂质中混有出血成分的较复杂的斑块，
分辨能力较差。实验2：在正常内膜、斑块帽区、核区、肩区肥大细胞密度
（细胞数／平方毫米）分别为 l．3土 2．3、2．3士2．6、2．二士3．7、6．3士 4．0，
chymase阳性细胞与 tryptase阳性细胞的比值分别为 36％、sl％、47％、
39％，脱颗粒肥大细胞数占肥大细胞总数的比例分别为18％、35％、52％、
65％。斑块肩区肥大细胞密度及脱颗粒细胞比例明显高于其它部位。肥大细
胞与T细胞及巨噬细胞的比例在正常内膜分别为10％和7％，在斑块帽区分别
为12％和7％，在斑块核区分别为6％和5％，在斑块肩区分别为25％和
4
解放军总医院军医进修学院 博士学位论文
14％。光镜下观察肥大细胞也分布于血管外膜、血栓内、钙化周围及新生血
管周围。
研究结论：灰度值分析可以对动脉硬化斑块中不同病理成分的超声影像进行
量化处理，为判定斑块的稳定性提供客观依据。应用特制的相控阵线圈，
Mill可以初步区分斑块成分，可以用来评价斑块的稳定性，并用来观察斑块
的动态变化；肥大细胞参与颈动脉硬化斑块的形成，并通过活化脱颗粒影响
斑块的稳定性。
BACKGROUND-.Besides the degree of stenosis,the stability of carotid plaque is also important in development of clinical events .Plaque contents and structure may play an important role in plaque instability,so using noninvasive ultrasound and MRI to assess the contents of atherosclarotic plaques at the carotid bifurcation has great value.these imaging techniques could be important in evaluating the progression of carotid artery atherosclerosis and its response to pharmacologic and surgical intervention.The stability of plaque is related to its cellular components too.As the major cellular component of connective tissue,mast cells have the potential to influence the extracellular matrix component of plaque through the production of potent mediators such as proteases and a broad spectrum of multifunctional cytokines.The present of increased numbers of mast cells in coronary plaque has been reported,but there was no any experimental report about the quantity and distribution of mast cell in carotid plaque .
PURPOSE:(1) To correlate ultrasound and MRI imaging of atherosclerotic plaque at the carotid bifurcation with histologic analysis,and perform densitometric analysis of ultrasound images of carotid plaques.(2)To study quantity and distribution of two different phenotype mast cell in atherosclerotic lesions of human carotid arteries,and to evaluate the influence of mast cell on stability of carotid plaque.
METHODS:(1)20 patients(22 lesions) scheduled for carotid endarterectomy were examined by high resolution B-mode ultrasound and high resolution MRI preoperatively,the images of carotid plaque was recorded. The postoperative specimens were also examined by high resolution B-mode ultrasound and high resolution MRI.The transverse pathological sections of plaques were made and were matched with images of ultrasound and MRI,using carotid bifurcation,calcification and the shape of plaque and lumen as the landmark.Performing 256 gray scale ultrasound densitometric analysis of carotid plaque compositions and correlating MRI images of atherosclerotic plaque with histologic findings such as calcium,fibrous tissue,old hemorrage/thrombus and lipid deposits.(2)32 samples of endarterectomy and 10 autopsy normal carotid specimens were fixed and embeded in paraffin,serial sections were stained with hematoxylin-eosin,Toluidine blue stains,monoclonal antibodies against the two major proteases of mast cell(tryptase and chymase) and monoclonal antibodies against CD-3 of T lymphocyte and CD-68 of macrophage. The quantity,distribution and degranule of two different phenotype mast cell in atherosclerotic lesions of human carotid arteries was investigated,and the ratio of mast cell to T lymphocyte and macrophage in atherosclerotic lesions was calculated.
RESULTS:(l)Ultrasonic density measurement of calcium,fibrous tissue,hemorrage/thrombus and lipid deposits was 89 +12, 53 + 8, 37 + 6 and 39 + 3 respectively in vivo. Ultrasonic density measurement of calcium,fibrous tissue,hemorrage/thrombus and lipid deposits was 168
?1, 136 + 12, 85 + 12 and 89 + 10 respectively in vitro.There were significant statistics difference of density measurement between different components except between hemorrage/thrombus and lipid deposits.In vivo relative signal intensities of calcium,fibrous tissue,old hemorrage/thrombus and lipid deposits were low,equal,equal and very high respectively on T1W MR image(relative to signal intensity of muscle). In vivo relative signal intensities of calcmm,fibrous tissue,old hemorrage/thrombus and lipid deposits were very low,equal,high and high respectively on PDW MR image. In vivo relative signal intensities of calcium,fibrous tissue,old hemorrage/thrombus and lipid deposits were low,equal or slight high,high and high respectively on T2W MR image. Signal intensities of plaque contents in vivo were corelated to signal intensities ex vivo.Calcium and thick fibrous cap were identified very well on T1W and PDW images, hemorrage/thrombus and lipid deposits also could be identified,but it was diffi
引文
1．于普林。老年流行病学。北京；中国科技出版社。2000，8，第一版：142-143。
2．宋继谒。病理学。北京；科学出版社。1999，1，第一版：154-156。
3. Ross R.The pathogenesis of atherosclerosis:a perspective for the 1990s.Nature,1993,362:801.
4. Meredith IT.Role of impaired endothelium-dependent vasodipation in ischemic manifestations of coronary artery disease. Circulation,1993,87(Suppl V):V56.
5. Hass WK,Fields WB,North RR,et al.Joint study of extracranial arterial occlusion:Ⅱarteriography,technique,sites and complications.JAMA,1968,203:961-968.
6. Feldmann E,Daneault N,Kwan E,et al.Chinese-white differences in the distribution of occlusive cerebrovascular disease.Neurology,1990,40:154 1-1545.
7. Jeng JS,Chung MY,Yip PK,et al.Extracranial carotid atherosclerosis and vascular risk factors in different types of ischemic stroke in Taiwan.Stroke,1994,25:1989-1993.
8. Wong KS,Huang YN,Gao S,et al.Intracranial stenosis in Chinese patients with acute stroke.Neurology,1998,50:812-813.
9. Toshiyuki U,Masayasu T,Takatoshi H,et al.Asymptomatic occlusive lesion of carotid and intracranial arteries in Japanese patients with ischemic cerebrovascular disease.Stroke,1996,27:393-397.
10．丁建平，华扬，王拥军等。急性缺血性脑血管病患者脑动脉粥样硬化的分布。中国医学影像技术，2001，17(1)：29-31。
11. Cave EM,Pugh ND,Wilson RJ,et al.Carotid artery duplex scanning:Does plaque echogenicity correlate with patient symptoms?Eur J Vasc Endovasc Surg,1995,10:77-81.
12. Holdworth RJ,Mc Collum RT,Bryce JS,et al.Symptoms,stenosis and carotid plaque morphology relevant?Eur J Vasc Endovasc Surg,1995,9:80-85.
13. Wang YQ,Guo DQ,Fu WG.Is there any relation between ischemic cerebrovascular disease and extracranial internal carotid stenosis?Chin Med J,1998,111(6):510-513.
14． Geroulakos G,Hobson RW,Nicolaides A.Ultrasonographic carotid plaque morphology in predicting stroke risk.Br J Surg, 1996,83:582-587．
15． Carpenter JP,Texa FJ,Dains JT,et al.Determination of duplex ultrasound criteria appropriate to the North American Symptomatic Carotid Endarterectomy Trial.Stroke, 1996,27:695-699．
16． Langsfeld M,Lusby RJ.Amaurosis fugax:the importance of carotid plaque morphology.Aust N Z J Ophthalomal,1988,16:275-280．
17． Johnson JM,Kennelly MM,Decesare D,et al.Nature history of asymptomatic carotid plaque.Arch Surg,1995,120:1010-1012．
18． Urbani MP,Picano E,Parenti G,et al.In vivo radiofrequency-based ultrasonic tissue characterization of the artherosclerotic plaque. Stroke, 1993,24:1507-1512．
19． el-Barghouty N,Geroulakos G,Nicolaides A,et al.Computer-assisted carotid plaque characterization.Eur J Vasc Endovasc Surg,1995,9:389-393．
20． Mazzone AM,Urbani MP,Picano E,et al.In vivo ultrasonic parametric imaging of carotid atherosclerosis plaque by videodensitometric technique.Angiology,1995,46:663-672．
21． Vadim YB,Roger EK,Mmarjorie F,et al.Ultrasound densitometric analysis of carotid plaque composition.Stroke,1996,27(12) :2173-2177．
22 周康荣,陈祖望,体部磁共振成像.上海医科大学出版社,中国.上海.2000年.第一版,p658．
23． Hatsukami TS,Ross R,Polissar NL,et al.Visualization of fibrous cap thickness and rupture in human atherosclerotic carotid plaque in vivo with high resolution magnetic resonance imaging.Circulation,2000;102(9) :959-964．
24． Yuan C,Muracami JW,Hayes CE,et al.Phased-array magnetic resonance imaging of the carotid artery bifurcation:preliminary results in healthy volunteers and a patient with atherosclerotic disease.JMRI, 1995,5:561-565．
25． Winn WB,Schmiedl UP,Reichenbach DD,et al.Detection and characterization of atherosclerotic fibrous caps with T2 weighted MR.AJNR Am J Neuroradiol,1998,19(1) : 129-134．
26． Skinner MP,Yuan C,Mitsumori L,et al.Serial magnetic resonance imaging of experimental atherosclerosis detects lesions,fine stmctures,progression,and complications in vivo.Nature Med, 1995,1:69-73．
27． Chun Y,Kirk WB,Llewellyn HS,et al.Measurement of atherosclerotic carotid plaque size in vivo using high resolution magnetic resonance imaging.Circulation, 1998,98:2666-2671．
28． Shaoxiong Z,Thomas SH,Nayak L,et al.Comparison of carotid vessel wall area measurements using three different contrast-weighted black blood MR imaging techniques. JMRI,2001,19:795-802．
2．宋继谒。病理学。北京；科学出版社。1999，1，第一版：154-156。
3. Ross R.The pathogenesis of atherosclerosis:a perspective for the 1990s.Nature,1993,362:801.
4. Meredith IT.Role of impaired endothelium-dependent vasodipation in ischemic manifestations of coronary artery disease. Circulation,1993,87(Suppl V):V56.
5. Hass WK,Fields WB,North RR,et al.Joint study of extracranial arterial occlusion:Ⅱarteriography,technique,sites and complications.JAMA,1968,203:961-968.
6. Feldmann E,Daneault N,Kwan E,et al.Chinese-white differences in the distribution of occlusive cerebrovascular disease.Neurology,1990,40:154 1-1545.
7. Jeng JS,Chung MY,Yip PK,et al.Extracranial carotid atherosclerosis and vascular risk factors in different types of ischemic stroke in Taiwan.Stroke,1994,25:1989-1993.
8. Wong KS,Huang YN,Gao S,et al.Intracranial stenosis in Chinese patients with acute stroke.Neurology,1998,50:812-813.
9. Toshiyuki U,Masayasu T,Takatoshi H,et al.Asymptomatic occlusive lesion of carotid and intracranial arteries in Japanese patients with ischemic cerebrovascular disease.Stroke,1996,27:393-397.
10．丁建平，华扬，王拥军等。急性缺血性脑血管病患者脑动脉粥样硬化的分布。中国医学影像技术，2001，17(1)：29-31。
11. Cave EM,Pugh ND,Wilson RJ,et al.Carotid artery duplex scanning:Does plaque echogenicity correlate with patient symptoms?Eur J Vasc Endovasc Surg,1995,10:77-81.
12. Holdworth RJ,Mc Collum RT,Bryce JS,et al.Symptoms,stenosis and carotid plaque morphology relevant?Eur J Vasc Endovasc Surg,1995,9:80-85.
13. Wang YQ,Guo DQ,Fu WG.Is there any relation between ischemic cerebrovascular disease and extracranial internal carotid stenosis?Chin Med J,1998,111(6):510-513.
14． Geroulakos G,Hobson RW,Nicolaides A.Ultrasonographic carotid plaque morphology in predicting stroke risk.Br J Surg, 1996,83:582-587．
15． Carpenter JP,Texa FJ,Dains JT,et al.Determination of duplex ultrasound criteria appropriate to the North American Symptomatic Carotid Endarterectomy Trial.Stroke, 1996,27:695-699．
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