MRI對易損斑塊的臨床研究進展

張兆琪，董 莉，于 薇

心腦血管病是一種常見多發(fā)疾病，據(jù)世界衛(wèi)生組織統(tǒng)計，該疾病已經(jīng)逐漸成為威脅人類生命健康“頭號殺手”。在心腦血管臨床事件中，動脈粥樣硬化斑塊破裂和血栓形成是主要的發(fā)病機制，而斑塊是否破裂取決于斑塊的易損性。由于動脈粥樣硬化斑塊從穩(wěn)定變?yōu)橐讚p的過程涉及到炎癥、免疫、代謝、凝血等多個環(huán)節(jié)，單純顯示動脈管腔或斑塊形態(tài)的診斷技術(shù)已不能滿足臨床的需要。為了判斷斑塊的易損性，需要對斑塊的形態(tài)和功能進行綜合評價。因此，能夠顯示易損斑塊形態(tài)和功能的成像技術(shù)如核磁共振（magnetic resonance imaging，MRI）已成為當前的研究熱點。

MRI血管壁成像結(jié)合黑血及亮血技術(shù)，可以提供血管組織結(jié)構(gòu)、管壁厚度、斑塊成分等信息。這些信息對評價班塊的易損程度非常重要。MRI還可以對斑塊的自然發(fā)展過程、治療干預后療效的評價進行無創(chuàng)的隨訪跟蹤，以指導臨床對動脈粥樣硬化斑塊的轉(zhuǎn)歸有更深層次的理解。

1 斑塊定性、定量研究

動脈粥樣硬化斑塊形成的早期是由于血管內(nèi)皮細胞功能受損，血中低密度脂蛋白顆粒進入血管壁，繼而被巨噬細胞所吞噬形成脂質(zhì)條紋(fatty streak)，血管壁反應性的增厚[1-3]。因此，早期的動脈硬化表現(xiàn)為血管壁增厚。研究證實MR不僅可以清楚地探測血管壁，準確測量血管壁的厚度[4]，而且不同的MR機型、不同掃描、不同閱片者之間都有很好的一致性(可重復性)[5-7]。另外，Underhill等發(fā)現(xiàn)MRI測量管壁與超聲也有很好的一致性(r=0.93，P＜0.001)[8]。

隨著病程的發(fā)展，脂紋表層沉積大量膠原纖維，平滑肌細胞(smooth muscle cell)增生并分泌大量細胞外間質(zhì)(extracellular matrix)，構(gòu)成薄厚不一的纖維帽(fibrous cap)。纖維帽下細胞外脂質(zhì)、富含細胞內(nèi)脂質(zhì)的巨噬細胞和泡沫細胞以及脂紋則構(gòu)成了脂核(lipid core)。脂核進一步發(fā)展可出現(xiàn)壞死(lipid-rich necrotic core)、斑塊內(nèi)微血管出血(intraplaque hemorrhage)、鈣化(calcifi cation)和斑塊內(nèi)微血管化(mircovessels)。

圖1 頸動脈脂質(zhì)斑塊。多種MR加權(quán)圖像示斑塊內(nèi)的脂質(zhì)核在增強T1WI(CE-T1W)為低信號，而在其他加權(quán)像表現(xiàn)為等信號(短箭頭)和完整的纖維帽(長箭頭)。斑塊的邊緣還可見小鈣化(空箭頭)。*代表管腔Fig 1 Atherosclerotic Carotid Artery Lipid-rich Necrotic Core.Multi contrast black and bright blood sequences show a large lipid-rich necrotic core (small arrow) with an intact thick fi brous cap best seen in the post contrast T1 weighted (CE T1W) image (long arrow).Calcifi cation is also visible at the base of the plaque (chevron).Asterisks are placed on the lumen.Reprint from J Cardiovasc Magn Reson.2009;11:53

圖2 頸動脈斑塊內(nèi)出血。多種MR加權(quán)圖像示斑塊內(nèi)出血在TOF和T1WI為高信號，而在其他加權(quán)像表現(xiàn)為等或低信號(箭頭)Fig 2 MRI appearance of plaque hemorrhage in a patient who was scanned prior to carotid endarterectomy. The presence of hemorrhage is indicated by the hyperintense signal seen in the time-of-flight and T1-weighted images (arrows).Reprint from Circulation.2002;106:1368

1.1 脂核和纖維帽

病理學上將斑塊分為穩(wěn)定和不穩(wěn)定斑塊，其中不穩(wěn)定斑塊主要由脂質(zhì)核心與纖維帽組成。有研究表明，當脂質(zhì)成分超過斑塊容積40%時，斑塊易于破裂[9]。研究表明，多種MR加權(quán)成像(T1WI，T2WI/PDWI，TOF)可以顯示脂核(圖1)。與胸鎖乳突肌信號相比，脂核在T1WI和TOF上為等信號，T2WI為低信號。Fabiano等用MR掃描離體斑塊，發(fā)現(xiàn)其敏感性為92%，特異性為74%[10]。在活體，與病理相對照，MR敏感性為92%，特異性為65%[11]。如給予對比劑行增強掃描，可以顯示脂核和纖維帽更多的信息[12-14]。對比劑可使纖維組織的信號提高79.5%，而脂核的信號下降28.6%[12]。強化的纖維帽和未強化的脂核形成了良好的對比，從而更容易勾勒出脂核的邊界而得到準確的定量測量結(jié)果。Wasserman等還發(fā)現(xiàn)與T2WI相比，對比劑增強后T1WI可提升脂核與纖維帽間的對比噪聲比約2倍[13]。Cai等對纖維帽進行了定量分析，發(fā)現(xiàn)MRI與病理有很好的相關(guān)性(最大纖維帽厚度：r=0.78，P＜0.001；長度：r=0.73，P＜0.001；面積：r=0.73，P＜0.001)[14]。

圖3 頸動脈斑塊內(nèi)鈣化。多種MR加權(quán)成像顯示斑塊內(nèi)鈣化在各個權(quán)重圖像均表現(xiàn)為低信號(箭頭)。 *代表管腔Fig 3 Calcification can be found in early atherosclerotic lesions.Black and bright blood multicontrast images show the presence of calcification in the wall of an early lesion of the left common carotid artery (arrow).Asterisks are placed on the lumen.Reprint from J Cardiovasc Magn Reson.2009;11:53

1.2 斑塊內(nèi)微血管出血

斑塊內(nèi)出血來自斑塊內(nèi)未成熟血管的紅細胞滲漏[15]。盡管如何從斑塊內(nèi)出血發(fā)展成斑塊破裂的機制還不十分清楚，但其可加速脂核的形成[16]。由于正鐵血紅蛋白可以不同程度地縮短T1弛豫時間從而在T1加權(quán)像上呈現(xiàn)高信號，因此斑塊內(nèi)出血在MR的信號特征主要取決于血腫內(nèi)正鐵血紅蛋白的期齡。表現(xiàn)為在T1WI和TOF上為高信號，早期的正鐵血紅蛋白在T2WI為低信號，晚期的則為等或高信號(圖2)。此信號特點與病理相對照，敏感性為85%～95%,特異性為70%～77%[17]。Moody等用三維重T1加權(quán)序列(magnetization-prepared rapid acquisition gradientecho，MP-RAGE)觀察出血，其敏感性為84%，特異性為84%[18]。

1.3 鈣化

盡管鈣化經(jīng)常在斑塊內(nèi)出現(xiàn)，但其是否導致斑塊的不穩(wěn)定性尚無定論。一些研究表明出現(xiàn)大量鈣化與增加斑塊破裂的危險性呈正相關(guān)[19-23]，而另一些研究則提示鈣化有助于斑塊的穩(wěn)定性[24-26]。最近，研究者開始提出鈣化出現(xiàn)的位置有可能影響斑塊的穩(wěn)定性。Li等利用生物力學模型研究顯示，如果鈣化出現(xiàn)在薄纖維帽內(nèi)，則纖維帽的最大剪切力相應增加47.5%。相反，如果鈣化出現(xiàn)在脂核或遠離纖維帽的位置，剪切力則沒有增加[27,28]。鈣化在MR的T1WI、T2WI、TOF均表現(xiàn)為低信號(圖3)。Fabiano等報道MR探測鈣化的準確性為98%，特異性為99%。Saam等用MR測量了鈣化的大小，與病理有很好的一致性(r=0.74，P＜0.001)[11]。

1.4 斑塊內(nèi)微血管化形成

圖4 頸動脈粥樣硬化評分系統(tǒng)。對管壁小于2 mm的患者給予1分(低風險)，對管壁大于2 mm的患者進行進一步評估，已是否出現(xiàn)脂質(zhì)核為界，無脂質(zhì)核者給予1分，有脂質(zhì)核者給予2分(中風險)或以上。根據(jù)脂質(zhì)核的大小，將患者分為中風險(2分，脂質(zhì)核≤20%)，中高風險(3分，脂質(zhì)核＞20%但≤40%)，和高風險(4分，脂質(zhì)核＞40%)。經(jīng)作者同意摘自參考文獻52(Am J Neuroradiol.2010; 31(6): 1068-1075)Fig 4 Flow diagram of CAS.Subjects with a maximum wall thickness ＞2 mm require additional evaluation.Further categorization of lesions can be determined by the size of the maximum percentage LRNC.CAS 1 is determined as maximum wall thickness ＜2 mm (low-risk).CAS 2 is determined as maximum percentage LRNC ≤20% (intermediate risk).CAS 3 is determined as maximum percentage LRNC ＞20% and ≤40% (intermediate-high risk).CAS 4 is determined as maximum percentage LRNC ＞40%(high risk).Reprint from Am J Neuroradiol.2010;31:1068

細胞內(nèi)微血管化的形成一方面是供給斑塊營養(yǎng)的來源，另一方面也是傳導、運輸炎性細胞、炎性因子的渠道。在頸動脈粥樣硬化進展過程中，炎性反應的特征表現(xiàn)為內(nèi)皮細胞通透性增加、巨噬細胞浸潤、血管壁缺氧和血管外膜層滋養(yǎng)血管增生。浸潤的巨噬細胞吞噬脂質(zhì)，發(fā)生凋亡，使粥樣斑塊中心壞死不斷進展增大。 Moreno等發(fā)現(xiàn)微血管的數(shù)目不僅和炎性細胞的數(shù)量相關(guān)，也和斑塊破裂有關(guān)[29]。Mofidi也發(fā)現(xiàn)微血管的數(shù)目和斑塊內(nèi)出血相關(guān)[30]。目前有兩種MR技術(shù)探測斑塊內(nèi)微血管化。一種是利用動態(tài)增強(dynamic contrast enhanced MRI，DCE-MRI)技術(shù)。這種技術(shù)最初被應用于腫瘤微血管化的研究。在斑塊內(nèi)部，利用這種技術(shù)同樣可以觀察微血管的數(shù)目和通透性[31,32]。有研究證實，分數(shù)血漿容量(fractional plasma volume，Vp)與微血管的面積相關(guān)[33]，而對比劑的轉(zhuǎn)移常數(shù)(transfer constant，Ktrans)與微血管的通透性相關(guān)[31]。另一種MR技術(shù)是應用超順磁性氧化鐵顆粒(ultrasmall superparamagnetic iron oxide，USPIO)。USPIO顆粒可以通過受損的內(nèi)皮細胞進入斑塊內(nèi)，并被巨噬細胞所吞噬，表現(xiàn)為信號缺失。Trivedi等發(fā)現(xiàn)這種局部信號的缺失出現(xiàn)在75%的易損斑塊中，而只有7%在穩(wěn)定斑塊中[34]。

2 MR對斑塊的進展與轉(zhuǎn)歸的隨訪

2.1 回顧性研究

一些回顧性研究探討了腦卒中、短暫性腦缺血發(fā)作和斑塊破裂的關(guān)系。Saam等報道患者的神經(jīng)癥狀和斑塊破裂具有相關(guān)性。在有癥狀組斑塊破裂的發(fā)生率為78%，而在無癥狀組斑塊破裂的發(fā)生率只有30%(P=0.007)[35]。Sadat等則發(fā)現(xiàn)斑塊破裂出現(xiàn)在急性癥狀組約50%，35%在近期癥狀組，在無癥狀組沒有發(fā)生斑塊破裂[36]。另一些研究探討了其他斑塊特征和癥狀的關(guān)系。Murphy等發(fā)現(xiàn)斑塊內(nèi)出血與癥狀相關(guān)。Howarth等發(fā)現(xiàn)斑塊內(nèi)炎癥與癥狀也相關(guān)，有癥狀的斑塊內(nèi)存在更多的炎癥跡象[37]。

2.2 前瞻性研究

斑塊內(nèi)成分是否可以成為預測心腦血管事件的指標已逐漸成為研究的焦點。在一項154名患者隨訪38個月的研究中，Takaya等提示出現(xiàn)薄/破裂的纖維帽，斑塊內(nèi)出血，大的脂核可預示今后臨床癥狀的出現(xiàn)[38]。同樣，Altaf等也證實斑塊內(nèi)出血可以預測兩年內(nèi)心腦血管事件的發(fā)生(hazard ratio＝9.8，P=0.03)[39]。

2.3 斑塊自然進展

在一項對中國人斑塊和美國人斑塊的研究中，Saam等發(fā)現(xiàn)中國人頸總動脈脂核明顯大于美國人的脂核(頸總動脈：52.5 vs 37.5 mm2，P= 0.007；脂核：13.6 vs 7.8 mm2，P=0.002)[40]。Tayaka等發(fā)現(xiàn)斑塊內(nèi)出血可加速脂核的生長。與沒有出血的斑塊相比，18個月內(nèi)有出血的脂核生長明顯加快(28.4% vs-5.2%，P=0.001)[38]。而且，如果在基線出現(xiàn)斑塊內(nèi)出血，則18個月內(nèi)再次出現(xiàn)出血的機會明顯增高(43% vs 0%，P=0.006)。另一項研究還證實斑塊負荷也逐年增長。平均管壁面積每年以2.2%的速度增長(P=0.001)[41]。這些都證明MR不僅可以觀察斑塊的自然進展，還能夠?qū)Π邏K內(nèi)成分間的相互作用予以揭示。

2.4 斑塊治療的療效監(jiān)測

多中心長期隨訪臨床實驗表明，使用他汀類藥物調(diào)脂治療(statin therapy)可以減少臨床事件的發(fā)生[42-44]。一些MR研究證實調(diào)脂治療可以減輕斑塊的負荷[45,46]，還可以減小脂核容積。美國兩項臨床研究均發(fā)現(xiàn)，通過調(diào)脂治療，斑塊內(nèi)脂核體積明顯縮小[47,48]。值得一提的是，如果斑塊內(nèi)有出血，調(diào)脂治療也許對脂核的改變沒有幫助[49]。也有一些研究著重調(diào)查調(diào)脂治療對炎性反應的干預。在一項美國臨床研究中，經(jīng)過一年的調(diào)脂治療，DCE-MRI顯示斑塊內(nèi)的炎癥細胞明顯下降(P＝0.02)[50]。在ATHEROMA研究中，USPIO顯示的炎癥也有明顯的減低(6個星期：P＝0.003，12個星期：P＜0.0001)[51]。

3 MRI對危險分層標準制定的指導意義

對斑塊危險進行評分，尤其是應用MRI這一理念可以對臨床管理動脈粥樣硬化的策略有所指導。Underhill等提出的CAS評分系統(tǒng)就是用MRI對易損斑塊進行危險分層的很好的探索[52]。此研究為多中心、大規(guī)模臨床研究，盡管是回顧性研究，仍然開啟了評分系統(tǒng)的大門，為今后前瞻性研究奠定了基礎(chǔ)。通過研究，他們發(fā)現(xiàn)如果斑塊負荷小于2 mm，則認為是低風險斑塊；超過2 mm，但脂核占斑塊小于20%，也為低風險斑塊；如斑塊負荷超過2 mm，脂核占20%～40%，為中風險斑塊，大于40%的情況下則為高危斑塊(圖4)。盡管此評分是提示斑塊內(nèi)出血和纖維帽的破裂，但由于這兩種斑塊的特征與心腦血管事件有著緊密的聯(lián)系，所以此評分系統(tǒng)仍有一定的價值。如果今后的研究把對斑塊評分與事件直接聯(lián)系起來，將更有說服力。

4 討論

一系列研究已表明血管壁MR成像可以觀察斑塊的成分和轉(zhuǎn)歸，這將為臨床提供一種除狹窄之外的新的評判指標，對那些狹窄程度還不是很重的高危患者提供更多的診斷信息。今后，我們需要更大規(guī)模的多中心研究來證實血管壁MR成像在診斷動脈粥樣硬化疾病的重要價值。

另外，隨著分子對比劑的發(fā)展，在今后的十年里此項技術(shù)還將會有長足的發(fā)展。盡管還存在技術(shù)上的挑戰(zhàn)，如搏動偽影、空間分辨率不足等問題，研究的最終的目標是將此技術(shù)推廣到其他血管床，例如股動脈，甚至冠狀動脈。

總之，血管壁MR成像在早期、中晚期動脈粥樣性斑塊病變中均能提供有價值的影像學信息，能夠幫助我們進一步理解、跟蹤觀察動脈粥樣硬化疾病的發(fā)展過程和藥物治療的療效。相信隨著研究的進展和技術(shù)的進步，這種無創(chuàng)手段最終將在臨床擁有廣泛的應用前景。

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