頸動(dòng)脈粥樣硬化斑塊無(wú)創(chuàng)性高分辨力磁共振成像研究進(jìn)展

高鵬 楊斌 焦力群 張鴻祺 朱鳳水

·綜述·

頸動(dòng)脈粥樣硬化斑塊無(wú)創(chuàng)性高分辨力磁共振成像研究進(jìn)展

高鵬 楊斌 焦力群 張鴻祺 朱鳳水

頸動(dòng)脈粥樣硬化性狹窄與腦卒中復(fù)發(fā)密切相關(guān)。目前頸動(dòng)脈狹窄的治療方法主要包括藥物治療和外科手術(shù)（頸動(dòng)脈支架成形術(shù)和頸動(dòng)脈內(nèi)膜切除術(shù)）。腦卒中預(yù)防在于識(shí)別頸動(dòng)脈狹窄危險(xiǎn)因素，篩查腦卒中復(fù)發(fā)高?；颊撸瑥亩蛊鋸乃幬镏委熁蛲饪剖中g(shù)中獲益，然而目前僅根據(jù)頸動(dòng)脈狹窄程度制定治療方案，缺乏個(gè)體化治療。近年來(lái)，新型影像學(xué)技術(shù)如無(wú)創(chuàng)性高分辨力磁共振成像（HRMRI）等，可以檢測(cè)出頸動(dòng)脈易損斑塊。與傳統(tǒng)數(shù)字減影血管造影術(shù)測(cè)量的頸動(dòng)脈狹窄程度相比，無(wú)創(chuàng)性HRMRI可以根據(jù)頸動(dòng)脈斑塊特征準(zhǔn)確預(yù)測(cè)同側(cè)腦卒中風(fēng)險(xiǎn)，從而指導(dǎo)個(gè)體化治療。

頸動(dòng)脈狹窄； 動(dòng)脈粥樣硬化； 磁共振成像； 綜述

頸動(dòng)脈狹窄程度和粥樣硬化斑塊穩(wěn)定性均與腦卒中發(fā)生和復(fù)發(fā)密切相關(guān)。目前主要采用數(shù)字減影血管造影術(shù)（DSA）定量檢測(cè)頸動(dòng)脈狹窄程度，而較少關(guān)注頸動(dòng)脈斑塊穩(wěn)定性。近年來(lái)，無(wú)創(chuàng)性高?分辨力磁共振成像（HRMRI）逐漸用于檢測(cè)頸動(dòng)脈斑塊的穩(wěn)定性。與DSA相比，HRMRI具有無(wú)創(chuàng)性、安全、費(fèi)用相對(duì)較低和可重復(fù)性等優(yōu)點(diǎn)，在DSA顯示血管狹窄的同時(shí)，HRMRI可以檢測(cè)斑塊穩(wěn)定性，提供更敏感和客觀信息，具有較高的個(gè)體化預(yù)測(cè)價(jià)值，是一項(xiàng)極具潛力的影像學(xué)技術(shù)。本文擬對(duì)近年HRMRI檢測(cè)頸動(dòng)脈斑塊穩(wěn)定性研究進(jìn)展進(jìn)行綜述。

一、頸動(dòng)脈狹窄相關(guān)臨床試驗(yàn)的缺陷

根據(jù)美國(guó)心臟協(xié)會(huì)（AHA）/美國(guó)卒中協(xié)會(huì)（ASA）指南［1］，頸動(dòng)脈狹窄藥物治療和外科手術(shù)［包括頸動(dòng)脈支架成形術(shù)（CAS）和頸動(dòng)脈內(nèi)膜切除術(shù)（CEA）］的治療決策主要依靠?jī)煞矫妫海?）頸動(dòng)脈狹窄程度，狹窄率＜50%，輕度狹窄；50%～69%，中度狹窄；≥70%，重度狹窄。（2）是否存在臨床癥狀。結(jié)合上述兩方面，近20年涌現(xiàn)出大量頸動(dòng)脈狹窄相關(guān)臨床試驗(yàn)，例如，1991年的北美癥狀性頸動(dòng)脈內(nèi)膜切除術(shù)試驗(yàn)（NASCET）顯示，對(duì)于頸動(dòng)脈狹窄程度＞70%患者，隨訪2年CEA組腦卒中復(fù)發(fā)率為9%，遠(yuǎn)低于單純藥物組的26%［2］。2004年針對(duì)無(wú)癥狀性頸動(dòng)脈狹窄患者的無(wú)癥狀性頸動(dòng)脈外科手術(shù)試驗(yàn)（ACST）顯示，當(dāng)頸動(dòng)脈狹窄程度＞60%時(shí)，隨訪5年CEA組腦卒中復(fù)發(fā)率為6.4%，低于單純藥物組的11.8%；該項(xiàng)研究還顯示，對(duì)于＞75歲的頸動(dòng)脈狹窄程度＞70%患者，隨訪5年腦卒中復(fù)發(fā)率和病死率顯著下降［3］；2010年，ACST試驗(yàn)10年長(zhǎng)期隨訪結(jié)果發(fā)表于Lancet，CEA組腦卒中復(fù)發(fā)率為13.4%，低 于 單 純 藥 物 組 的 17.9%［4］。 Abbott 等［5］和Nicolaides等［6］報(bào)告的無(wú)癥狀性頸動(dòng)脈狹窄患者單純藥物治療后同側(cè)腦卒中年復(fù)發(fā)率為0.6%～1.3%，低于ACST試驗(yàn)的CEA組（5年腦卒中復(fù)發(fā)率為6.4%，腦卒中年復(fù)發(fā)率約1.3%［3］）和無(wú)癥狀性頸動(dòng)脈粥樣硬化研究（ACAS）的CEA組（5年腦卒中復(fù)發(fā)率為5.1%，腦卒中年復(fù)發(fā)率為1.0%［7］）。因此，積極藥物治療仍是頸動(dòng)脈狹窄的主要治療方法，主要表現(xiàn)為：（1）部分高?；颊卟⒉荒軓念i動(dòng)脈支架成形術(shù)和頸動(dòng)脈內(nèi)膜切除術(shù)中獲益。（2）無(wú)論癥狀性（頸動(dòng)脈狹窄程度＜70%）或無(wú)癥狀性頸動(dòng)脈狹窄患者，均無(wú)證據(jù)顯示頸動(dòng)脈支架成形術(shù)和頸動(dòng)脈內(nèi)膜切除術(shù)療效優(yōu)于單純藥物治療［8］。因此，僅根據(jù)頸動(dòng)脈狹窄程度進(jìn)行危險(xiǎn)程度分層是遠(yuǎn)遠(yuǎn)不夠的，準(zhǔn)確評(píng)價(jià)頸動(dòng)脈狹窄程度和檢測(cè)斑塊穩(wěn)定性以預(yù)測(cè)同側(cè)腦卒中風(fēng)險(xiǎn)的個(gè)體化分析具有潛在的臨床價(jià)值。

二、易損斑塊定義

頸動(dòng)脈斑塊性狀的判斷和易損斑塊的辨別，應(yīng)借鑒“冠狀動(dòng)脈易損斑塊”定義?！肮跔顒?dòng)脈易損斑塊”的定義最早由Virmani等［9］于2002年提出，他在尸檢中發(fā)現(xiàn)冠狀動(dòng)脈粥樣硬化斑塊存在較大的富脂壞死核心（LRNC）和菲薄的纖維帽（FC），并確定其與心源性猝死有關(guān)。經(jīng)臨床、病理學(xué)、分子生物學(xué)和影像學(xué)研究，一致認(rèn)為典型易損斑塊的病理學(xué)特征為［7，10］：（1）較大的富脂壞死核心。（2）菲薄的纖維帽。（3）炎癥反應(yīng)，如巨噬細(xì)胞浸潤(rùn)。（4）斑塊裂隙（fissured plaque）。（5）斑塊表面鈣化結(jié)節(jié)。（6）斑塊內(nèi)出血（IPH）。然而，上述“易損斑塊”定義僅限于病理學(xué)層面，實(shí)際工作中難以獲得活體斑塊，因此需要影像學(xué)技術(shù)以實(shí)現(xiàn)體外無(wú)創(chuàng)性斑塊成像。鑒于此，基于MRI的冠狀動(dòng)脈和頸動(dòng)脈易損斑塊成像技術(shù)和影像學(xué)分型應(yīng)運(yùn)而生［11］。1995年，AHA/ASA指南基于尸體解剖提出冠狀動(dòng)脈粥樣硬化斑塊病理學(xué)分型，分為Ⅰ～Ⅷ型［12］，并在此基礎(chǔ)上衍生出基于HRMRI的頸動(dòng)脈易損斑塊影像學(xué)分型，亦分為Ⅰ～Ⅷ型（表1）［13］。

三、頸動(dòng)脈斑塊無(wú)創(chuàng)性HRMRI在預(yù)測(cè)腦卒中風(fēng)險(xiǎn)方面優(yōu)于單純DSA測(cè)量頸動(dòng)脈狹窄程度

1.較大的富脂壞死核心和菲薄的纖維帽顯著增加腦卒中復(fù)發(fā)風(fēng)險(xiǎn) （1）HRMRI可以識(shí)別和定量檢測(cè)頸動(dòng)脈斑塊富脂壞死核心。既往大量研究顯示，富脂壞死核心體積較大和（或）纖維帽菲薄或破裂與近期腦卒中事件、同側(cè)動(dòng)脈?動(dòng)脈栓塞性缺血性卒中事件、頸動(dòng)脈斑塊去穩(wěn)定化、纖維帽破裂、斑塊內(nèi)出 血 和 斑 塊 體 積 擴(kuò) 大 顯 著 相 關(guān)［9，14?18］。 一 項(xiàng) 針 對(duì) 頸動(dòng)脈狹窄程度50%～99%患者的橫斷面臨床研究顯示，HRMRI顯示的同側(cè)短暫性腦缺血發(fā)作（TIA）和（或）腦卒中與較大的富脂壞死核心和（或）菲薄或破裂的纖維帽顯著相關(guān)，而與頸動(dòng)脈狹窄程度無(wú)關(guān)聯(lián)性［14］。（2）富脂壞死核心及其體積可以指導(dǎo)強(qiáng)化調(diào)脂治療，亦可以評(píng)價(jià)調(diào)脂治療效果［19］。Demarco等［14］的研究顯示，盡管頸動(dòng)脈狹窄程度未達(dá)重度狹窄（≤70%），但HRMRI仍顯示易損斑塊，表現(xiàn)為較大的富脂壞死核心合并斑塊內(nèi)出血、菲薄或破裂的纖維帽，考慮為腦卒中高危患者，與近期腦卒中風(fēng)險(xiǎn)具有相關(guān)性；盡管頸動(dòng)脈狹窄程度達(dá)重度狹窄（＞70%），但HRMRI仍顯示穩(wěn)定斑塊，表現(xiàn)為富脂壞死核心體積較小、無(wú)斑塊內(nèi)出血、纖維帽厚重，考慮為無(wú)癥狀性頸動(dòng)脈狹窄。一項(xiàng)納入33例頸動(dòng)脈狹窄患者的前瞻性臨床試驗(yàn)顯示，經(jīng)過(guò)3年強(qiáng)化調(diào)脂治療（阿托伐他汀10～80 mg/d+煙酸緩釋片2 g/d+考來(lái)維侖3.80 g/d），復(fù)查HRMRI顯示富脂壞死核心體積縮小，生物學(xué)時(shí)間效應(yīng)表現(xiàn)為先出現(xiàn)斑塊脂質(zhì)排空，再出現(xiàn)斑塊消融［19］。（3）HRMRI不單純依靠 DSA測(cè)量的頸動(dòng)脈狹窄程度即可定性和定量檢測(cè)頸動(dòng)脈斑塊富脂壞死核心，從而進(jìn)行腦卒中危險(xiǎn)程度分層，篩選出適宜進(jìn)行強(qiáng)化調(diào)脂治療或外科手術(shù)的患者，以及評(píng)價(jià)治療效果。

2.斑塊內(nèi)出血可以顯著增加腦卒中復(fù)發(fā)風(fēng)險(xiǎn)

（1）斑塊內(nèi)出血發(fā)生機(jī)制是頸動(dòng)脈斑塊內(nèi)富脂壞死核心的紅細(xì)胞滲出和鐵離子沉積。上述兩個(gè)過(guò)程促進(jìn)炎癥反應(yīng)，導(dǎo)致斑塊去穩(wěn)定化［10，20］。一項(xiàng)前瞻性臨床試驗(yàn)顯示，頸動(dòng)脈斑塊內(nèi)出血與斑塊進(jìn)展相關(guān)［21］。既往由于臨床檢查方法有限，不能動(dòng)態(tài)觀察斑塊內(nèi)出血的發(fā)生與發(fā)展過(guò)程；現(xiàn)有的無(wú)創(chuàng)性頸動(dòng)脈斑塊成像技術(shù)可以同時(shí)觀察斑塊進(jìn)展和頸動(dòng)脈粥樣硬化自然病程。（2）斑塊內(nèi)出血與斑塊體積擴(kuò)大和同側(cè)動(dòng)脈?動(dòng)脈栓塞性缺血性卒中事件相關(guān)。Takaya等［17］納入98例無(wú)癥狀性中至重度頸動(dòng)脈狹窄患者，HRMRI顯示43例（43.88%）存在斑塊內(nèi)出血，經(jīng)過(guò)38.20個(gè)月隨訪，6例（6.12%）發(fā)生同側(cè)缺血性卒中且均存在斑塊內(nèi)出血。Altaf等［22］納入64例癥狀性頸動(dòng)脈狹窄患者（狹窄程度30%～69%），39例（60.94%）基線HRMRI顯示存在斑塊內(nèi)出血，經(jīng)28個(gè)月隨訪，14例（21.88%）發(fā)生同側(cè)缺血性卒中，其中13例（20.31%）存在斑塊內(nèi)出血。Meta分析顯示，基線HRMRI顯示存在斑塊內(nèi)出血的頸動(dòng)脈狹窄患者發(fā)生同側(cè)腦卒中風(fēng)險(xiǎn)是無(wú)斑塊內(nèi)出血患者的 5.60 倍［23］。

表1 基于HRMRI的頸動(dòng)脈易損斑塊影像學(xué)分型［13］Table 1. Conventional and modified classification of carotid vulnerable plaque based on HRMRI［13］

3.頸動(dòng)脈斑塊性狀的性別差異及其與同側(cè)腦卒中風(fēng)險(xiǎn)的關(guān)系 Ota等［24］納入131例頸動(dòng)脈狹窄患者（狹窄程度≥50%），男性不穩(wěn)定型斑塊特征高于女性，表現(xiàn)為男性頸動(dòng)脈斑塊富脂壞死核心、纖維帽菲薄或破裂、斑塊內(nèi)出血發(fā)生率均高于女性，男性易損斑塊發(fā)生率亦高于女性，可以部分解釋頸動(dòng)脈內(nèi)膜切除術(shù)在預(yù)防男性無(wú)癥狀性頸動(dòng)脈狹窄相關(guān)腦卒中方面優(yōu)于女性。另一項(xiàng)研究顯示，頸動(dòng)脈斑塊性狀的性別差異不僅限于中至重度頸動(dòng)脈狹窄患者，亦存在于輕度頸動(dòng)脈狹窄患者（狹窄程度＜50%）［25］。因此，頸動(dòng)脈狹窄的治療策略應(yīng)同時(shí)考慮易損斑塊特征和性別因素。

四、展望

1.頸動(dòng)脈斑塊HRMRI技術(shù) 未來(lái)頸動(dòng)脈斑塊HRMRI技術(shù)有待改進(jìn)和提高成像質(zhì)量、縮短成像時(shí)間。2013年出現(xiàn)的非對(duì)比血管造影和出血成像（SNAP），將檢查時(shí)間縮短至4～5分鐘，可以檢測(cè)到斑塊內(nèi)出血［26］。2012年出現(xiàn)的多對(duì)比三維梯度回波序列，可以提高成像質(zhì)量，提供良好的信噪比（SNR）［27］。共識(shí)普遍認(rèn)為，綜合 3 項(xiàng) HRMRI序列（如SNAP、3D?T1WI和增強(qiáng)3D?T1WI）掃描4分鐘，即可獲得頸動(dòng)脈易損斑塊的所有特征，包括富脂壞死核心、纖維帽和斑塊內(nèi)出血。若這一技術(shù)實(shí)現(xiàn)，快速多對(duì)比頸動(dòng)脈斑塊成像可以列入常規(guī)影像學(xué)檢查。此外，提高成像質(zhì)量還有賴(lài)于專(zhuān)用的頸動(dòng)脈斑塊線圈。第1代4通道線圈通常置于頸部中間，可以提供高信噪比圖像，掃描范圍覆蓋10～12 cm區(qū)域；第2代頸部線圈采用高密度設(shè)計(jì)（6～8通道線圈），全面提高信噪比，亦可以增加掃描范圍（覆蓋16～18 cm區(qū)域），第1和2代線圈均已通過(guò)美國(guó)食品與藥品管理局（FDA）審批，并已廣泛應(yīng)用于臨床；第3代線圈為頸部高度集成線圈，系神經(jīng)血管專(zhuān)用，掃描范圍下至主動(dòng)脈弓，上至Willis環(huán)和腦組織。如果將第3代線圈與新研發(fā)的HRMRI序列相結(jié)合，可以在45分鐘內(nèi)完成主動(dòng)脈弓、頸動(dòng)脈、腦組織和Willis環(huán)成像，極大地?cái)U(kuò)展頸動(dòng)脈斑塊成像的臨床應(yīng)用。目前，HRMRI技術(shù)自動(dòng)識(shí)別頸動(dòng)脈斑塊成分的可行性已經(jīng)完成［28］，有助于臨床醫(yī)師對(duì)頸動(dòng)脈斑塊的認(rèn)識(shí)和理解。

2.頸動(dòng)脈斑塊HRMRI的前瞻性多中心研究未來(lái)研究最核心的問(wèn)題在于，頸動(dòng)脈斑塊HRMRI能否替代傳統(tǒng)DSA測(cè)量的頸動(dòng)脈狹窄程度以指導(dǎo)臨床決策、改進(jìn)治療效果。可以設(shè)想，頸動(dòng)脈易損斑塊HRMRI可以同時(shí)指導(dǎo)藥物治療和外科手術(shù)。（1）HRMRI可以檢出頸動(dòng)脈易損斑塊的富脂壞死核心，從而指導(dǎo)臨床醫(yī)師進(jìn)行積極藥物治療；此外，還可以根據(jù)頸動(dòng)脈斑塊HRMRI設(shè)計(jì)前瞻性多中心隨機(jī)對(duì)照臨床試驗(yàn)，將存在富脂壞死核心的頸動(dòng)脈狹窄患者隨機(jī)分為標(biāo)準(zhǔn)藥物治療組和積極藥物治療組，除將短暫性腦缺血發(fā)作和（或）腦卒中作為終點(diǎn)事件外，也將富脂壞死核心體積變化作為終點(diǎn)事件或頸動(dòng)脈粥樣硬化療效判定指標(biāo)。（2）對(duì)于近期發(fā)生癥狀性頸動(dòng)脈狹窄的患者，HRMRI可以進(jìn)行腦卒中危險(xiǎn)程度分層，篩選出適宜早期外科手術(shù)（頸動(dòng)脈支架成形術(shù)或頸動(dòng)脈內(nèi)膜切除術(shù)）的患者。由此可見(jiàn)，即使輕至中度頸動(dòng)脈狹窄患者，如果HRMRI檢出斑塊內(nèi)出血，同側(cè)短暫性腦缺血發(fā)作和（或）腦卒中風(fēng)險(xiǎn)明顯增加；早期外科手術(shù)（頸動(dòng)脈支架成形術(shù)或頸動(dòng)脈內(nèi)膜切除術(shù)）可以有效預(yù)防腦卒中復(fù)發(fā)，尚待前瞻性多中心隨機(jī)對(duì)照臨床試驗(yàn)的驗(yàn)證。

綜上所述，腦卒中預(yù)防的關(guān)鍵在于早期識(shí)別危險(xiǎn)因素。過(guò)去幾十年，全世界在危險(xiǎn)因素控制方面取得長(zhǎng)足進(jìn)步，如高血壓、冠心病、糖尿病、高脂血癥等均得到有效控制。未來(lái)腦卒中預(yù)防的重點(diǎn)在于識(shí)別個(gè)體化危險(xiǎn)因素。國(guó)際上多個(gè)單中心臨床試驗(yàn)業(yè)已證實(shí)基于HRMRI的頸動(dòng)脈易損斑塊成像技術(shù)較傳統(tǒng)的頸動(dòng)脈超聲或DSA能夠更準(zhǔn)確預(yù)測(cè)腦卒中復(fù)發(fā)風(fēng)險(xiǎn)［17，29?30］。我們也寄希望于國(guó)際上的前瞻性臨床試驗(yàn)以驗(yàn)證頸動(dòng)脈易損斑塊與同側(cè)動(dòng)脈?動(dòng)脈栓塞性缺血性卒中事件的相關(guān)性。未來(lái)有望根據(jù)頸動(dòng)脈易損斑塊的HRMRI，提供個(gè)體化藥物治療和外科手術(shù)方案。

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Research progress of noninvasive high?resolution magnetic resonance imaging in carotid atherosclerotic plaque

GAO Peng,YANG Bin,JIAO Li?qun,ZHANG Hong?qi,ZHU Feng?shui

Department of Neurosurgery,Xuanwu Hospital,Capital Medical University,Beijing 100053,China

Carotid atherosclerotic stenosis is closely related to recurrent ischemic stroke.Currently,therapies for carotid artery stenosis are mainly intensive medication or surgery,including carotid artery stenting(CAS)and carotid endarterectomy(CEA).The prevention of stroke lies in identifying risk factors for carotid artery stenosis,screening patients with high risk of recurrent stroke,so as to benefit from medication or surgery.However,therapeutic schedule is formulated only according to the degrees of carotid artery stenosis,and there lacks of individualized treatment. Recently,new imaging modalities,such as noninvasive high?resolution MRI(HRMRI)could detect the vulnerability of carotid atherosclerotic plaque.Compared with the degree of carotid artery stenosis measured by conventional DSA,noninvasive HRMRI can precisely predict the risk of ipsilateral stroke according to plaque morphology,so as to guide individualized treatment.

Carotid stenosis; Atherosclerosis; Magnetic resonance imaging; Review

ZHU Feng?shui(Email:zhufengshui@sina.com)

This study was supported by the NationalKey Research and DevelopmentProgram (No.2016YFC1301700)and Beijing Municipal Scientific and Technological New Star Plan Program (No.2010B052).

10.3969/j.issn.1672?6731.2017.05.012

國(guó)家重點(diǎn)研發(fā)計(jì)劃項(xiàng)目（項(xiàng)目編號(hào)：2016YFC1301700）；北京市科技新星計(jì)劃項(xiàng)目（項(xiàng)目編號(hào)：2010B052）

100053 北京，首都醫(yī)科大學(xué)宣武醫(yī)院神經(jīng)外科

朱鳳水（Email：zhufengshui@sina.com）

2017?05?02）