缺血性卒中：基于磁共振斑塊成像的危險性評估和預防

孫杰

位于顱內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]。一項在2010年進行的全國性流行病學調查中，滿足糖尿病或糖尿病前期診斷標準的人群比率分別達到了11.6%和50.1%[3]。在這樣的背景條件下，診治動脈粥樣硬化，預防初發和復發缺血性卒中成為了當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的藥物治療，血管成形及支架植入術（carotid artery stenting，CAS），以及頸動脈內膜剝脫術（carotid endarterectomy，CEA）等的發展為降低缺血性卒中的風險提供了有效的干預措施。然而，如何優化治療方案，使患者最大程度地從干預中受益，同時避免不必要的治療風險，對患者進行缺血性卒中風險的個體化評估成為臨床決策過程的關鍵。血管造影顯示的管腔狹窄程度曾經是臨床醫生認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險[4]。例如，在北美癥狀性頸動脈內膜剝脫試驗（North American Symptomatic Carotid Endarterectomy Trial，NASCET）中，具有輕度狹窄（＜50%）的患者在術后隨訪期5年內的臨床終點并不顯著優于單純藥物治療[4]。由于這些歷史性的原因，頸動脈狹窄程度成為指導CEA的主要標準，并延用至今[5]。

然而，大規模的組織病理研究顯示，斑塊破裂并繼發血栓是掩藏在管腔狹窄這一現象下，是引起動脈粥樣硬化并發癥的主要病理生理機制。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，而這些特征僅出現在12%的無癥狀斑塊中。一些在冠狀動脈研究中發現和定義的高危斑塊特征，如脂質壞死核心、纖維帽炎癥細胞浸潤、表面潰瘍等，不但常見于頸動脈斑塊，且在卒中發生后的數月內發生率逐漸減低，這和臨床上卒中復發風險的變化一致[4，7]。纖維帽破裂誘導動脈血栓，可以逐漸進展造成原位栓塞，也有可能脫落引起遠端栓塞，從而呈現出多樣化的病程。

借助新興的成像手段識別位于顱內外動脈的高危粥樣硬化斑塊將推動缺血性卒中臨床干預策略的重大變革，從而成為近年來研究的重點。由于纖維帽破裂這一過程的生物學復雜性，準確評價斑塊風險可能依賴于對包括脂質壞死核心、鈣化、斑塊內出血（intraplaque hemorrhage，IPH）、炎癥反應、新生血管在內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）斑塊成像技術的發展使臨床醫生能夠無創地獲取關于斑塊形態和組分的豐富信息。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現象在早期文獻中已有所描述，但由于病理研究的局限性，我們對IPH在斑塊進展和臨床事件中所起作用的認識一直以來進展緩慢[8]。得益于紅細胞分解代謝的中間產物正鐵血紅蛋白所具有的順磁效應，MRI很快成為研究IPH的最有力手段[9-10]。與傳統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。多個研究報道，IPH相關的T1加權序列高信號在癥狀性斑塊中的出現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]。這一發現不僅明確了IPH和缺血性卒中的聯系，而且提示MRI檢測IPH能夠在一定程度上彌補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的出現能夠顯著地促進斑塊負荷和脂質核心增長，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的最直接的影像學證據。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防上具有潛在意義[16]。結合多個序列，特別是時間飛躍（time of flight，TOF）、T2加權和增強T1加權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、診斷復雜斑塊的標準MRI技術[18]。在多項回顧性研究中，近期發生過臨床事件的斑塊出現纖維帽破裂的比率顯著高于無癥狀斑塊[19-21]。Parmar等[22]在卒中急性期進行MR斑塊成像研究，初步顯示了MRI檢測纖維帽狀態或復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系已經十分明確，然而，用這些成像信息判斷患者預后，包括新發腦缺血事件、新發腦梗死灶和大腦認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%）的無癥狀患者進行隨訪，首次報道了IPH、纖維帽完整性及脂質核心大小等多個頸動脈斑塊MRI測量指標和新發腦缺血事件風險的相關性。Kwee等[24]的研究進一步說明斑塊特征和腦缺血事件的病理生理聯系具有普遍適用性，在頸動脈30%～69%狹窄的癥狀性患者中同樣能夠預測新發腦缺血事件的風險。Altaf和Singh等[25-26]的研究證實了IPH在頸動脈中度狹窄的患者群體中預測初發或復發腦缺血事件的價值。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測價值給出較為準確的估計[23-32]。最近，Saam等[33]對以往研究IPH預測新發腦缺血事件的文獻進行了及時的薈萃分析。IPH使患者發生腦缺血事件的風險增大約5倍，在癥狀性患者中預測復發腦缺血事件的風險比更是達到了11.7。因此，MRI檢測IPH很有可能率先在指導臨床決策方面起到重要作用。值得注意的是，關于MR斑塊成像信息預測新發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注[27，33-34]。

表1 利用MR斑塊成像信息預測新發腦缺血事件的文獻匯總

針對顱內動脈粥樣硬化斑塊的MRI研究仍然處在早期。由于缺少病理標本對比，MR顱內斑塊成像的圖像分析多借鑒頸動脈成像的經驗。Li等[35]對比MR顱內斑塊成像和磁共振血管造影（magnetic resonance angiography，MRA）的數據提示，作為目前臨床常規檢測手段的MRA并不能準確反映斑塊負荷。Ma等[36]首先對基底動脈斑塊的正性重構（positive remodeling）程度進行了定量的描述。斑塊成分方面，Xu等[37]發現IPH現象也存在于大腦中動脈斑塊，并和臨床表現相關。

目前來看，MR斑塊成像在臨床研究中的應用豐富了我們對粥樣硬化性缺血性卒中的病理生理機制的認識，也在小樣本的前瞻性研究中初步顯現了它在臨床診斷和預后判斷上的潛在價值。基于MRI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）指導干預的臨床試驗，仍然是MR斑塊成像技術最終轉化到臨床實踐中的關鍵步驟。與此同時，新的MRI技術仍然不斷涌現和完善，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用[38]，另一方面在持續探索斑塊功能層面提供有益的信息[39]。基于MR斑塊成像的個體化危險性評估將在預防缺血性卒中上發揮重要的作用。

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