缺血性卒中：基于磁共振斑塊成像的危險性評估和預(yù)防

孫杰

位于顱內(nèi)外動脈的粥樣硬化斑塊是缺血性卒中最常見的病因之一。近年來隨著生活方式的變化，動脈粥樣硬化危險因素的患病率明顯升高[1-2]。一項(xiàng)在2010年進(jìn)行的全國性流行病學(xué)調(diào)查中，滿足糖尿病或糖尿病前期診斷標(biāo)準(zhǔn)的人群比率分別達(dá)到了11.6%和50.1%[3]。在這樣的背景條件下，診治動脈粥樣硬化，預(yù)防初發(fā)和復(fù)發(fā)缺血性卒中成為了當(dāng)前最為緊迫的臨床和研究工作之一。

包括他汀和阿司匹林在內(nèi)的藥物治療，血管成形及支架植入術(shù)（carotid artery stenting，CAS），以及頸動脈內(nèi)膜剝脫術(shù)（carotid endarterectomy，CEA）等的發(fā)展為降低缺血性卒中的風(fēng)險提供了有效的干預(yù)措施。然而，如何優(yōu)化治療方案，使患者最大程度地從干預(yù)中受益，同時避免不必要的治療風(fēng)險，對患者進(jìn)行缺血性卒中風(fēng)險的個體化評估成為臨床決策過程的關(guān)鍵。血管造影顯示的管腔狹窄程度曾經(jīng)是臨床醫(yī)生認(rèn)識粥樣硬化斑塊的唯一手段，并在一定程度上反映了斑塊的臨床風(fēng)險[4]。例如，在北美癥狀性頸動脈內(nèi)膜剝脫試驗(yàn)（North American Symptomatic Carotid Endarterectomy Trial，NASCET）中，具有輕度狹窄（＜50%）的患者在術(shù)后隨訪期5年內(nèi)的臨床終點(diǎn)并不顯著優(yōu)于單純藥物治療[4]。由于這些歷史性的原因，頸動脈狹窄程度成為指導(dǎo)CEA的主要標(biāo)準(zhǔn)，并延用至今[5]。

然而，大規(guī)模的組織病理研究顯示，斑塊破裂并繼發(fā)血栓是掩藏在管腔狹窄這一現(xiàn)象下，是引起動脈粥樣硬化并發(fā)癥的主要病理生理機(jī)制。Spagnoli等[6]對269例頸動脈斑塊的病理分析顯示，在管腔狹窄程度相同的情況下，74%和缺血性卒中相關(guān)的頸動脈斑塊有明確的炎性纖維帽破裂和新鮮血栓附著，而這些特征僅出現(xiàn)在12%的無癥狀斑塊中。一些在冠狀動脈研究中發(fā)現(xiàn)和定義的高危斑塊特征，如脂質(zhì)壞死核心、纖維帽炎癥細(xì)胞浸潤、表面潰瘍等，不但常見于頸動脈斑塊，且在卒中發(fā)生后的數(shù)月內(nèi)發(fā)生率逐漸減低，這和臨床上卒中復(fù)發(fā)風(fēng)險的變化一致[4，7]。纖維帽破裂誘導(dǎo)動脈血栓，可以逐漸進(jìn)展造成原位栓塞，也有可能脫落引起遠(yuǎn)端栓塞，從而呈現(xiàn)出多樣化的病程。

借助新興的成像手段識別位于顱內(nèi)外動脈的高危粥樣硬化斑塊將推動缺血性卒中臨床干預(yù)策略的重大變革，從而成為近年來研究的重點(diǎn)。由于纖維帽破裂這一過程的生物學(xué)復(fù)雜性，準(zhǔn)確評價斑塊風(fēng)險可能依賴于對包括脂質(zhì)壞死核心、鈣化、斑塊內(nèi)出血（intraplaque hemorrhage，IPH）、炎癥反應(yīng)、新生血管在內(nèi)的諸多組分的有效分析。磁共振成像（magnetic resonance imaging，MRI）具有較好的空間分辨率和軟組織分辨性。磁共振（magnetic resonance，MR）斑塊成像技術(shù)的發(fā)展使臨床醫(yī)生能夠無創(chuàng)地獲取關(guān)于斑塊形態(tài)和組分的豐富信息。越來越多的臨床研究開始使用MR斑塊成像來探討粥樣硬化斑塊和缺血性卒中的關(guān)系。IPH和纖維帽破裂等一些MRI特征的臨床意義逐漸明確。

盡管IPH現(xiàn)象在早期文獻(xiàn)中已有所描述，但由于病理研究的局限性，我們對IPH在斑塊進(jìn)展和臨床事件中所起作用的認(rèn)識一直以來進(jìn)展緩慢[8]。得益于紅細(xì)胞分解代謝的中間產(chǎn)物正鐵血紅蛋白所具有的順磁效應(yīng)，MRI很快成為研究IPH的最有力手段[9-10]。與傳統(tǒng)的組織病理研究相比，MRI檢測IPH避免了樣本來源的局限性，在明確IPH的臨床意義方面提供了令人信服的證據(jù)。多個研究報道，IPH相關(guān)的T1加權(quán)序列高信號在癥狀性斑塊中的出現(xiàn)率顯著高于無癥狀性斑塊，尤其在血管造影僅提示輕度或中度狹窄的情況下[11-12]。這一發(fā)現(xiàn)不僅明確了IPH和缺血性卒中的聯(lián)系，而且提示MRI檢測IPH能夠在一定程度上彌補(bǔ)臨床單純評價管腔狹窄的不足。在以MRI為手段隨訪斑塊變化的研究中，IPH的出現(xiàn)能夠顯著地促進(jìn)斑塊負(fù)荷和脂質(zhì)核心增長，支持其在改變斑塊表型（亞臨床→臨床）上的重要意義[13-15]。

纖維帽破裂也許是提示斑塊和下游卒中相關(guān)的最直接的影像學(xué)證據(jù)。隱源性卒中在臨床并不少見，提示檢測纖維帽完整性在明確病因和開展針對性二級預(yù)防上具有潛在意義[16]。結(jié)合多個序列，特別是時間飛躍（time of flight，TOF）、T2加權(quán)和增強(qiáng)T1加權(quán)序列對顯示纖維帽的完整性具有良好的敏感性和特異性[17]。包含這些序列的多重對比MRI是目前顯示纖維帽狀態(tài)、診斷復(fù)雜斑塊的標(biāo)準(zhǔn)MRI技術(shù)[18]。在多項(xiàng)回顧性研究中，近期發(fā)生過臨床事件的斑塊出現(xiàn)纖維帽破裂的比率顯著高于無癥狀斑塊[19-21]。Parmar等[22]在卒中急性期進(jìn)行MR斑塊成像研究，初步顯示了MRI檢測纖維帽狀態(tài)或復(fù)雜斑塊在病因診斷上的作用。

MRI顯示的斑塊易損性特征和缺血性卒中的關(guān)系已經(jīng)十分明確，然而，用這些成像信息判斷患者預(yù)后，包括新發(fā)腦缺血事件、新發(fā)腦梗死灶和大腦認(rèn)知功能變化的臨床研究尚處在早期（表1）。Takaya等[23]對154例頸動脈中度狹窄（50%～79%）的無癥狀患者進(jìn)行隨訪，首次報道了IPH、纖維帽完整性及脂質(zhì)核心大小等多個頸動脈斑塊MRI測量指標(biāo)和新發(fā)腦缺血事件風(fēng)險的相關(guān)性。Kwee等[24]的研究進(jìn)一步說明斑塊特征和腦缺血事件的病理生理聯(lián)系具有普遍適用性，在頸動脈30%～69%狹窄的癥狀性患者中同樣能夠預(yù)測新發(fā)腦缺血事件的風(fēng)險。Altaf和Singh等[25-26]的研究證實(shí)了IPH在頸動脈中度狹窄的患者群體中預(yù)測初發(fā)或復(fù)發(fā)腦缺血事件的價值。這些單中心研究初步顯示了MRI在評價斑塊危險性方面的良好的前景，但由于樣本量小和研究群體的差異，無法對某一斑塊特征的臨床預(yù)測價值給出較為準(zhǔn)確的估計[23-32]。最近，Saam等[33]對以往研究IPH預(yù)測新發(fā)腦缺血事件的文獻(xiàn)進(jìn)行了及時的薈萃分析。IPH使患者發(fā)生腦缺血事件的風(fēng)險增大約5倍，在癥狀性患者中預(yù)測復(fù)發(fā)腦缺血事件的風(fēng)險比更是達(dá)到了11.7。因此，MRI檢測IPH很有可能率先在指導(dǎo)臨床決策方面起到重要作用。值得注意的是，關(guān)于MR斑塊成像信息預(yù)測新發(fā)腦缺血事件的薈萃分析今年以來被多次報道，顯示了臨床研究者對這一主題的關(guān)注[27，33-34]。

表1 利用MR斑塊成像信息預(yù)測新發(fā)腦缺血事件的文獻(xiàn)匯總

針對顱內(nèi)動脈粥樣硬化斑塊的MRI研究仍然處在早期。由于缺少病理標(biāo)本對比，MR顱內(nèi)斑塊成像的圖像分析多借鑒頸動脈成像的經(jīng)驗(yàn)。Li等[35]對比MR顱內(nèi)斑塊成像和磁共振血管造影（magnetic resonance angiography，MRA）的數(shù)據(jù)提示，作為目前臨床常規(guī)檢測手段的MRA并不能準(zhǔn)確反映斑塊負(fù)荷。Ma等[36]首先對基底動脈斑塊的正性重構(gòu)（positive remodeling）程度進(jìn)行了定量的描述。斑塊成分方面，Xu等[37]發(fā)現(xiàn)IPH現(xiàn)象也存在于大腦中動脈斑塊，并和臨床表現(xiàn)相關(guān)。

目前來看，MR斑塊成像在臨床研究中的應(yīng)用豐富了我們對粥樣硬化性缺血性卒中的病理生理機(jī)制的認(rèn)識，也在小樣本的前瞻性研究中初步顯現(xiàn)了它在臨床診斷和預(yù)后判斷上的潛在價值?；贛RI的多中心大樣本的斑塊自然史研究，以及用斑塊信息（而非管腔狹窄程度）指導(dǎo)干預(yù)的臨床試驗(yàn)，仍然是MR斑塊成像技術(shù)最終轉(zhuǎn)化到臨床實(shí)踐中的關(guān)鍵步驟。與此同時，新的MRI技術(shù)仍然不斷涌現(xiàn)和完善，一方面使得具有針對性的斑塊成分成像更簡單快捷并易于臨床應(yīng)用[38]，另一方面在持續(xù)探索斑塊功能層面提供有益的信息[39]?；贛R斑塊成像的個體化危險性評估將在預(yù)防缺血性卒中上發(fā)揮重要的作用。

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