多模态成像无创评价颈动脉斑块易损性：从形态显像到精准诊断引言颈动脉粥样硬化性疾病是缺血性卒中的明确原因之一，引发高达20%的中风或短暂脑缺血发作（Transient Ischemic Attacks，TIA）事件[1]。在有症状的颈动脉病变患者，颈动脉狭窄程度一直是风险分类和拟定治疗策略的主要标准[2]。而在无症状患者，颈动脉狭窄程度的增加未必引起中风风险的相应增加[3]；与之相对，斑块本身“易损”特性使其破裂形成栓子，反而导致了神经症状的出现[4]，甚至引发了几乎一半的中风事件[5]。这不仅符合动脉-动脉栓塞的病理机制，也意味着斑块自身特性在评价中风风险中的重要性。因此，斑块的性质成为继狭窄之外各类影像学检查关注的焦点，也代表更为普遍的动脉粥样硬化表型。 斑块易损性或易损斑指斑块具有易破裂并诱发血栓形成的特性，从而导致不同心脑血管事件[6]。越来越多的证据表明易损斑具有三个明显的组织病理学机制：斑块破裂，斑块腐蚀和钙化结节[7]。斑块易损性在影像学上可表现为斑块溃疡，斑块内出血，薄或破裂的纤维帽，脂质丰富的坏死核，钙化[8]以及炎症反应，包括大量巨噬细胞浸润和新生血管形成[9]。然而，临床发现超声造影（Contrast-Enhanced Ultrasonography，CEUS）显示斑块内丰富的新生血管时，患者可能并无明显症状；反之，当新生血管较少时，也有患者出现急性脑卒中[10]。研究表明核磁成像（Magnetic Resonance Imaging，MRI）显示斑块内脂质坏死核含量与CEUS评估的新生血管数目呈负相关，即新生血管较多时，脂质坏死核含量较低[11]。新生血管多位于溃疡附近[12]，而溃疡常见于脂质斑[13]。MRI证实脂质坏死核高度预示斑块溃疡或纤维帽破裂[14]。多排螺旋CT血管造影（Multidetector Computed Tomography Angiography，MDCTA）发现溃疡对于预测MRI发现斑块内出血有很高的敏感性和特异性[15]。钙化因声影影响常掩盖部分信息，但研究证实其与炎症反应紧密相关[16]，炎症反应又促使新生血管形成，脂质核增大和纤维帽变薄[7]。综上，斑块易损性是多个形态学特性互相影响、互为因果、复合加权的结果，单凭一种特性不能完全决定斑块的易损风险；同样，单凭一种无创影像学检查手段也无法可靠评价斑块易损性并预估中风风险[17]，通过多种影像方法多模态无创呈现颈动脉斑块有助于实现对易损斑的精准诊断。因此，本文将就评价斑块不同易损特性的影像学方法一一论述。 1 斑块内溃疡颈动脉斑块分为表面光滑斑和不规则或溃疡斑[18]，组织学上，溃疡斑指宽度至少为1000 μm的内皮缺损（相当于斑块腐蚀），使斑块的脂质坏死核直接暴露在血液循环中[13]。从影像学角度，不同的观察手段有不同的界定溃疡斑的标准[19]。曾经在已有研究中被广泛使用的超声标准是：① 斑块表面凹陷至少长2 mm，深2 mm；② 二维超声上可以显示境界清晰的后方管壁；③ 彩色多普勒显示凹陷内部血液逆流[5]。然而，后有学者认为该标准在组织学上的敏感性和特异性不高，进而制定新标准：它与凹陷大小无关，而是强调凹陷基底部回声要弱于邻近的斑块表面回声，因为这种弱回声反应了凹陷即溃疡底部附着的血栓等软组织较低的声阻抗[19]。否则，这种斑块表面的凹陷并不真正代表溃疡，而可能只是位于两个相邻斑块之间的简单腔隙，甚至表面覆盖以正常内皮[5]。尽管新标准一定程度提高了US检出溃疡斑的准确率，但由于该标准相对主观，不同观察者之间的一致性受到影响。此外，钙化斑引起的声影限制US对溃疡的判断；镜面伪像造成斑块内出现“血流信号”也会导致假阳性结果[20]。CEUS本质是一种血管造影，内中膜和斑块为低回声，管腔和外膜为高回声[3]，CEUS对斑块外形、轮廓的显示优于传统超声[21]，它以进入斑块内造影剂至少为1 mm×1 mm来判断溃疡斑[22]。研究发现，当CEUS与传统二维和彩色多普勒US结合时，缩小了观察者之间和观察者自身的检测差异，对溃疡斑的敏感性高达87%[22]。3D US改善了对斑块表面的识别能力，它以凹陷容积至少应达到1 mm3作为溃疡标准[23]，溃疡容积大于5 mm3时与中风TIA、心肌梗塞和死亡的发生率密切相关[23]；拥有3个或以上溃疡斑的患者在未来3年更易发生中风甚至死亡[24]。 MDCTA判断溃疡斑的标准为：至少在2个层面上显示造影剂突破血管腔进入斑块，并且长度至少为1 mm[22]。当以组织学表现作为参考标准时，MDCTA诊断溃疡斑的敏感性明显优于US（93% vs 37%）[13, 25]，这归功于其专业化的三维重建软件，如多平面重建（Multiplanar Reconstruction，MPR）、最大密度投影（Maximum Intensity Projection，MIP）和容积重建（Volume Rendering，VR）。但MDCTA同样受到一些伪像的干扰，比如严重钙化斑引起的光束硬化就会掩盖较小的溃疡[13]。MRI因为良好的观察者之间一致性而常被用于诊断溃疡斑，其特殊的优势在于它可以显示斑块纤维帽的结构——位于明亮的管腔和灰色的斑块之间的黑色区域，当该黑色区域消失时，意味着纤维帽破裂和溃疡形成[26-27]。MRA较单纯MRI轴位图像进一步增加了溃疡探测的敏感性[28]。有研究认为MDCTA诊断斑块溃疡的准确率优于MRA[29]；然而，增强MRA（Contrast Enhanced MRA，CEMRA）在判断斑块性质上更优于MDCTA[30]。 2 斑块内出血和坏死脂质核斑块内出血可因新生血管渗漏而发生在血管壁外膜侧，也可因反复斑块开裂并继发血栓形成而发生在管腔侧[31]。斑块内出血和坏死脂质核在US上均表现为无或低回声，难以区分，且灰阶成像易受主观性影响。尽管有学者认为3D US不仅能提供可靠的斑块容积，也可以提供斑块组成（出血、脂质、钙化、纤维肌性组织）的组织学信息[3]，但还需要更多的研究来验证。MDCTA可以根据CT值的不同，一定程度上区分二者，斑块内出血CT值相对较低，为-17～31 HU[32]，而坏死脂质核CT值为25～32.6 HU[33]。虽然有研究提示CTA与斑块内出血或坏死脂质核的组织学改变有良好的相关性[33-35]，但后两者在CT值上的交叉以及斑块钙化的影响限制了CT在斑块性质分析中的应用。MRI在判断斑块内出血上最有临床价值，根据血栓形成时间长短，斑块内出血可表现为T1W和TOF血管成像的高信号，T2W和质子密度加权序列的低信号（新鲜血栓）；所有增强序列高信号（近期血栓）或低信号（机化的血栓）[17]。然而，因为血栓常位于坏死核内，MRI很难区分斑块内出血和脂质核坏死。T1W常用来确认脂质核的存在，其表现为高信号区域，在不合并斑块内出血时，坏死脂质核的检出率会略有改善[36]。目前，凭借较高的软组织对比度和平面分辨率，MRI是最有潜力的判断斑块成分的影像学手段，但因其费用昂贵、设备要求高（3.0T或7.0T MRI），难以成为常规的风险评估工具。 3 纤维帽薄或裂开的纤维帽与斑块破裂有关。纤维帽的US表现为一个等或高回声的结构，依据GSM（Gray Scale Median）定量检测纤维帽厚度的敏感性和特异性为73%和67%[37]。MDCTA测量的纤维帽厚度与组织学有很好的相关性[38]，裂开的纤维帽被证实与脑血管症状有关[33]。在MRI上，纤维帽呈现为一条游离带，在TOF高信号，在T1W、T2W和质子密度像等信号。当这条带消失时，提示纤维帽破裂或过薄，然而，对后两者的鉴别还是个棘手的问题[17]。 4 钙化钙化曾被认为是动脉粥样硬化斑块稳定性的保护性因素[39]，然而近期研究发现处于不同病理发展阶段的钙化可能代表不同的临床意义和预后[40]。钙化可以出现在动脉粥样硬化发生过程的各个时期，包括内膜增厚的初期，此时是钙化的最早形式，称为微钙化 [40]。微钙化被定义为直径小于50 μm的钙化结节；反之，大于50 μm的钙化结节称为粗大钙化[16]。微钙化或点状、碎片状钙化提示斑块的易损性[6, 40]；而由多个微钙化聚集成的粗大钙化则会稳定斑块[6, 41]。组织学证实，初期或进展活跃的钙化会降低斑块稳定性，而晚期钙化则预示斑块的稳定性[42-43]。因此，有学者认为他汀类药物除有降脂作用外，可以通过加速斑块内形成粗大钙化，达到稳定斑块的效果[44]。此外，钙化强度和位置也与斑块稳定性有关，高密度钙化灶有稳定斑块的倾向[16, 45]，而接近纤维帽或通过纤维帽向管腔突出的钙化结节提示斑块的易损性[10, 46]。 US对斑块内钙化非常敏感，呈现高回声，它可以粗略判断钙化结节所处的斑块内位置，但对于钙化的病理发展、活跃程度等信息无从显示。MRI在观察斑块内钙化上面临一定挑战，钙化组织内水质子的缺乏影响了核磁信号的强度[16]，斑块内钙化表现为低信号，但这与斑块内陈旧出血难以鉴别[47]。CTA被普遍认为在探测动脉钙化的敏感性上胜于MRI，表现为斑块内某一位置的高密度结构，并且MDCTA能对钙化程度进行可靠的量化，反映钙化强度的高低，研究证实较低密度的钙化恰与较多神经症状的发生相关[48]。然而，CT仅是检测粗大钙化的良好方法，对于高易损风险的微钙化应用有限，也无法提供钙化发展过程的生物学信息[16]。PET-CT提供了分子显像的可能，因18F-sodium fluoride（18F-NaF）渗透进粗大钙化结节的能力有限，其作为示踪剂高度集中在微钙化区域；而该区域也被证实是处于钙化的初期[48-49]，进一步验证了此类斑块内钙化的易损性。 5 斑块内新生血管和炎症动脉粥样硬化是动脉管壁的慢性进展性炎性疾病，使管壁局部增厚，这种炎症使外膜滋养血管穿过外膜、中膜，生长进入内膜，即所谓斑块内新生血管[50]。CEUS对新生血管的识别具有堪比CT和MRI的准确性[50-51]。CEUS使斑块内的新生血管不同程度增强，停止注射造影剂后，某些斑块内增强还会持续一段时间（超过6 min），即所谓“晚期增强”[3]。其原理在于微泡被单核细胞吞噬并粘附于炎性内皮，使其在斑块局部保留一段时间，由此提示具有“晚期增强”现象的斑块富含更多的炎性细胞，斑块更易破裂，“晚期增强”也成为斑块易损性的标记[52]。据此衍生出一系列超声靶向分子成像研究，将斑块局部特定病变（新生血管或炎症）的特异性配体或抗体连于超声微泡表面，构建靶向微泡，以其作为易损斑的分子探针，进行分子水平的超声显影。比如靶向炎症的P-选择素和血管细胞粘附因子-1、靶向新生血管的血管内皮细胞生长因子1等[53]。CEUS的局限性在于剂量依赖性和非线性传播伪像，即颈动脉后壁（位于远场）外膜假性增强[54-55]；此外严重钙化斑的声影也会影响CEUS的效果[56]。 新生血管在CTA上表现为从动脉管腔进入管壁滋养血管内的少量造影剂，管壁的CT值与滋养血管的空间分布呈正比[57]；然而，因动脉搏动或其他生理活动产生的动作伪像限制了其在新生血管检查中的应用[58]。动态增强MRI（Dynamic Contrast Enhanced MRI，DCE-MRI）可以实现对斑块内新生血管的评估，它依靠Ktrans等动力学参数反映造影剂在血管腔与血管外膜间的转运情况[59]，然而其局限性也与Ktrans有关，Ktrans评估只在管壁厚度达到或超过2 mm时才是准确的[60]，此外其费用昂贵、费时较长。因此，CTA和MRI均不适合成为大规模筛查斑块内新生血管的主要手段[50]。近年来，PET-CT已被用来观察斑块形态与斑块内炎症的联系，研究通过斑块对18F-FDG的摄取反映炎症高低，高炎性反应关联低密度斑块[61]；进一步，应用99Tcm-Duramycin和99Tc-RGD分别作为靶向凋亡和新生血管的分子探针，应用PET-CT进行动脉易损斑块的分子显像[62]，判断其易损性。 6 机械因素对斑块易损性的影响除了斑块的结构成分外，作用于斑块的生物力学因素也会增加斑块破裂的风险。生物力学因素包括血流动力学对斑块的影响和斑块本身的机械粘弹性。超声或核磁弹性或应变成像的发展使观察和量化斑块在内、外力作用下的组织形变成为可能[3]。研究发现回声较低的斑块呈现更高、更大的应变率[3]。CEUS显示有较多新生血管的斑块弹性更高、分布更不均[63]。因此，低回声和高弹性的结合预示不稳定斑。类似的，MRI也证实高应变率与不稳定斑密切相关[64]。 综上所述，各种无创影像学手段的发展，提供了从斑块形态到炎性代谢乃至机械形变的各类信息，但目前单凭一种检查手段尚无法可靠评价斑块易损性，通过多模态成像从不同角度显示斑块特征，有助于全面、客观评价斑块构成和生物学特性，达到对斑块易损性的精准评估，从而预估中风的风险并指导预防和治疗。 [1] Fairhead JF,Rothwell PM.The need for urgency in identi fication and treatment of symptomatic carotid stenosis is already established[J].Cerebrovasc 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Multimodality Non-Invasive Imaging of Carotid Plaque Vulnerability: From Morphology Character to Precision Diagnosis |