虛擬組織學血管內(nèi)超聲的臨床應用現(xiàn)狀和研究展望

吳小凡 馬長生

近年來,血管內(nèi)超聲(intravascular ultrasound,IVUS)在心血管病學領域得到了廣泛應用。但灰階IVUS表達的僅僅是超聲波的振幅信息而不能反映頻率信息,不能對冠狀動脈斑塊的成分進行有效的評價。虛擬組織學 IVUS(virtual histology IVUS,VH-IVUS)綜合反映了超聲波的振幅和頻率信息,能有效識別富含脂質(zhì)壞死核(necrotic core,NC),從而彌補了灰階IVUS的不足。本文旨在綜述VH-IVUS在心血管疾病尤其介入心臟病學領域的臨床應用和研究熱點。

1.VH-IVUS的基本原理:目前IVUS的頻率范圍在20～45 MHz,軸向分辨率為70～200 μ m,縱向穿透距離達5 mm以上[1-2]。而血液成分在 >40 MHz時才會出現(xiàn)容易混淆血管界面的斑點圖像。因此,灰階IVUS可以準確地顯示血管腔的邊界以及發(fā)現(xiàn)支架內(nèi)的新生內(nèi)膜組織,并對血管腔、外彈力膜的橫截面積和斑塊面積進行定量測定以及對斑塊性質(zhì)做定性分析。但是由于灰階IVUS提供的僅僅是超聲波的振幅信息而不能反映頻率信息,因此灰階IVUS發(fā)現(xiàn)富含脂質(zhì)斑塊的敏感性僅為67%[3]。VH-IVUS綜合反映了超聲波的振幅和頻率信息,其識別富含脂質(zhì)壞死核(necrotic core,NC)的敏感性和特異性提高到91.7%和96.6%[4-5]?；诓±韺φ昭芯?VH-IVUS將冠狀動脈動脈粥樣硬化分為5類:薄帽纖維粥樣硬化(thin-cap fibroatheroma,TCFA),厚帽纖維粥樣硬化(thick-cap fibroatheroma,ThCFA),病理性內(nèi)膜增厚(pathological intimal thickening,PIT),纖維斑塊和纖維鈣化斑塊(圖1)。但是由于“薄帽”的病理學概念是≤65 μ m,而VH-IVUS的軸向分辨率大約為 200 μ m,因此 VHIVUS規(guī)定連續(xù)性NC>10%的斑塊面積,與血管腔中心的角度 >30°,且與血管腔直接接觸時,稱為 TCFA。與 VH-IVUS類似,背向散射IVUS(integrated backscatter IVUS,IB-IVUS)和iMAP也能提供斑塊的組成信息。IB-IVUS在體識別脂質(zhì)池的敏感度和特異度達到90%和92%[6-7],iMAP在豬模型離體識別脂質(zhì)核心的準確性達97%,其在人體識別斑塊成分的準確性還有待進一步研究證實[8]。

但是,VH-IVUS尚不能有效地識別血栓形成,因此,含有血栓的罪犯病變可能被誤判為PIT或纖維斑塊,當TCFA覆蓋血栓時可能被錯誤診斷為ThCFA,從而遺漏易損斑塊[9]。此外,鈣化背后由于超聲波發(fā)生的角度不同以及頻率信號的傳播,80%的興趣區(qū)仍然有超聲信號伴隨著較低的聲噪比,但是20%的興趣區(qū)只有噪音而無超聲信號,這樣就導致鈣化背后的病變可能會錯判為 NC(65%)、纖維組織(18%)或纖維脂肪組織(14%)[10]。

圖1 動脈粥樣硬化斑塊的VH-IVUS分型以及灰階IVUS對照。紅色代表壞死核,白色代表鈣化組織,綠色代表纖維組織,黃綠色代表纖維脂肪組織。依據(jù)各種組織占斑塊的面積百分比可以將動脈粥樣硬化斑塊分為5型,薄帽纖維粥樣硬化(A,a),厚帽纖維粥樣硬化(B,b),病理性內(nèi)膜增厚(C,c),纖維斑塊(D,d),纖維鈣化斑塊(E,e)

2.VH-IVUS與易損斑塊:總的來說,冠狀動脈粥樣硬化斑塊分為2種,即穩(wěn)定性斑塊和不穩(wěn)定性斑塊?；诓±硌芯?前者以小的脂質(zhì)核心覆蓋厚纖維帽為特征,后者表現(xiàn)為大的脂質(zhì)核心覆蓋薄纖維帽,亦稱為“易損斑塊”(vulnerable plaque,VP)。易損斑塊是斑塊破裂繼發(fā)血栓形成導致急性冠脈綜合癥(acute coronary syndromes,ACS),或內(nèi)膜增生致介入術后再狹窄的重要原因之一[11-12]。眾多調(diào)脂試驗顯示較小的斑塊形態(tài)改變可以獲得明顯的ACS事件減少的獲益,而這一獲益得益于斑塊中脂質(zhì)的移除[13-15]。因此,在體評價斑塊性質(zhì)在冠心病的防治鏈中顯得尤為重要。VHIVUS能有效識別冠狀動脈粥樣硬化斑塊的脂質(zhì)核心,因而成為識別易損斑塊和建立斑塊發(fā)生發(fā)展動態(tài)體系的重要手段之一。

PROSPECT研究(Providing Regional Observations to Study Predictiors of Events in the Coronary Tree:An Imaging Study in Patients with Unstable Atherosclerotic Lesions,PROSPECT)是第一個前瞻性評價易損斑塊進展的多中心臨床研究,旨在采用多種冠脈內(nèi)影像手段尤其是VH-IVUS來早期識別導致未來不良事件的易損斑塊[16]。該研究在美國和歐洲的40個中心入選了700例ACS患者,在成功對罪犯病變置入支架后,對3支主要冠狀動脈進行QCA和IVUS序列分析,所有患者均接受優(yōu)化藥物治療并隨訪3年,對發(fā)生事件者再次進行QCA和IVUS分析和評價。PROSPECT研究結(jié)果顯示,VH-IVUS發(fā)現(xiàn)的易損斑塊能夠預測未來的不良冠脈事件。對未置入支架的非罪犯病變的亞組分析揭示導致不良冠狀動脈事件的3個獨立預測因子:TCFA,斑塊負荷>70%以及最小管腔面積(minimal lumen area,MLA)≤4 mm2,而且這些因子存在累加效應。TCFA是VH-IVUS診斷的易損斑塊,51.2%的患者含有至少1個TCFA,48%的事件相關病變顯示存在 TCFA,16%同時存在 TCFA和 MLA≤4 mm2,而4.2%同時存在TCFA,MLA≤4 mm2和斑塊負荷 >70%。對冠狀動脈斑塊形態(tài)和組成的自然進程的VH-IVUS研究顯示,在9個月的隨訪期間,多數(shù)(3/4)未行支架置入的非罪犯病變的TCFA可以愈合,而部分位于冠狀動脈近段且斑塊負荷較大的TCFA仍未愈合;此外,PIT或ThCFA可發(fā)展為新的TCFA,提示相對于纖維斑塊或纖維鈣化斑塊而言,PIT、TCFA和ThCFA更易于進展,表現(xiàn)為斑塊負荷增大,管腔面積減小[17]。

3.VH-IVUS在介入治療中的應用:灰階IVUS在引導經(jīng)皮冠脈介入治療方面已經(jīng)積累了豐富的經(jīng)驗,包括術前評價病變性質(zhì)、范圍,術中明確支架直徑、長度,術后評價支架擴張和貼壁以及及時識別并發(fā)癥等。VH-IVUS發(fā)展至今,關于其在介入治療中的應用,也積累了一定的經(jīng)驗,包括對于易損斑塊的處理、支架長度的選擇以及病變特點與無復流之間的關系以及支架術后內(nèi)膜覆蓋和再狹窄的評價等。含易損斑塊的臨界病變是否置入支架,是近年來介入治療策略的一個重要挑戰(zhàn)。一方面,易損斑塊容易破裂造成惡性心血管事件,有效的覆蓋可建立易損斑塊與血液的屏障,減少血栓事件的發(fā)生;另一方面,盡管VH-IVUS能有效識別TCFA,但現(xiàn)有的影像手段還不能明確斑塊纖維帽的炎性侵潤情況,而后者是斑塊破裂的一個重要環(huán)節(jié)。同時,大多數(shù)ACS患者含有一個以上的易損斑塊[18],盡管四分之三的易損斑塊可能愈合,但何種易損斑塊不會破裂目前仍不明確。此外,易損斑塊的支架置入尤其需要考慮到組織脫垂、支架擴張和支架貼壁的問題。2009年,荷蘭鹿特丹中心的SECRITT I研究進行了第一例易損斑塊(TCFA)的支架置入,于前降支低壓釋放vProtect自膨脹支架,IVUS和OCT顯示支架擴張及貼壁良好,且無組織脫垂,6個月隨訪顯示TCFA已被增生的血管內(nèi)膜完全覆蓋,且無支架內(nèi)再狹窄[19]

支架大小和長度的選擇對于介入治療尤為關鍵。對于急性心肌梗死(AMI)患者,冠狀動脈造影顯示罪犯病變通常位于血栓負荷最大處,而真正的罪犯病變(culprit of the culprit)常位于造影最狹窄處的近端或遠端,因此冠脈造影指導的支架置入往往不能完全覆蓋罪犯病變。來自波蘭的一項針對40例AMI患者的VH-IVUS研究證實,STEMI有50%的薄帽纖維粥樣硬化(TCFA)未被完全覆蓋,其中35%存在于支架近端,15%同時存在于支架近端和遠端;而NSTEMI有35%的TCFA未被完全覆蓋,20%存在于支架近端,5%存在于支架遠端,10%同時存在于支架近端和遠端。罪犯病變未完全覆蓋對遠端栓塞、支架血栓、再狹窄以及病變進展等的影響需要進一步的大規(guī)模臨床研究加以證實。

盡管個別研究顯示纖維組織或纖維脂肪組織與支架術后無復流有關[20-21],但目前大多數(shù)的VH-IVUS研究顯示NC與支架術后遠端微栓塞致無復流有關[22-25]?；译AIVUS發(fā)現(xiàn)的超聲衰減斑塊富含微鈣化和膽固醇結(jié)晶,可廣泛見于急性心肌梗死(40% ～70%)而極少見于穩(wěn)定性心絞痛患者[26-27]。與VH-IVUS的比較分析發(fā)現(xiàn),超聲衰減斑塊含有大量的NC,并與纖維粥樣硬化有關[28]。而臨床研究進一步證實,超聲衰減斑塊支架術后無復流/慢血流明顯增多,與斑塊在支架擴張過程中釋放大量微栓塞物質(zhì)損傷心肌有關[27,29-30]。與此一致,IB-IVUS研究顯示脂質(zhì)體積占斑塊體積百分比越大,支架術后心肌酶譜升高越顯著[31],光學相干斷層造影(optical coherent tomography,OCT)研究顯示斑塊脂質(zhì)大小(脂質(zhì)弓)與ACS患者介入術后無復流有關[32],近紅外波譜分光鏡(near-infrared spectroscopy,NIS)研究也顯示斑塊脂質(zhì)大小與介入術后無復流有關[33]。因此介入術前對斑塊成分進行評價及早發(fā)現(xiàn)富含脂質(zhì)斑塊,對介入策略和防治無復流具有重要的臨床意義。介入術后支架小梁在VH-IVUS往往顯示為白色的鈣化環(huán)繞紅色的NC,因此基線IVUS影像是VH-IVUS評價術后內(nèi)膜覆蓋的重要參考。Leiden MISSION研究顯示,支架置入術后9個月,雷帕霉素藥物洗脫支架的新生內(nèi)膜體積明顯小于金屬裸支架[34]。與之一致,支架置入后10個月的VH-IVUS隨訪研究顯示,金屬裸支架置入后由于內(nèi)膜覆蓋致使通過支架小梁接觸管腔的NC明顯減少(75%到19%,P<0.001),而藥物支架置入后,保護性的內(nèi)膜增生受到抑制,導致接觸管腔的NC減少不明顯(76%到61%,P=0.036),這種情況在參考節(jié)段也同樣存在,提示在易損斑塊置入藥物支架由于內(nèi)膜增生受到抑制,斑塊的不穩(wěn)定性可能長期存在[35]。對不同隨訪時期的再狹窄病例的新生內(nèi)膜的VH-IVUS研究表明,隨著隨訪時間的延長,NC和鈣化組織占新生內(nèi)膜的百分比成上升趨勢,但是新生內(nèi)膜組成成分的驗證性研究還有待進一步的病例組織學對照研究加以證實。

4.新近研究熱點:由于VH-IVUS能有效評價斑塊性質(zhì),因此越來越廣泛地應用于冠心病的基礎和臨床研究中。近年來的研究主要集中在以下幾個方面:(1)結(jié)合流行病學和病理學研究識別高危冠心病患者;(2)評價藥物對動脈粥樣硬化斑塊的治療效果;(3)評價支架置入的安全性和有效性;(4)預測遠期不良事件。

全球IVUS注冊研究顯示,VH-TCFA與Framingham危險分數(shù)相關,Framingham風險≥20%者,TCFA發(fā)生率高達21.4%,而Framingham風險<10%者,TCFA發(fā)生率下降一半,約11.3%[36]。糖尿病患者冠狀動脈病變形態(tài)學研究顯示,與非糖尿病患者相比,糖尿病患者冠狀動脈粥樣硬化斑塊含有豐富的壞死核成分[37]。另一項VH-IVUS注冊研究也證實了這一點,即糖尿病患者冠狀動脈粥樣硬化斑塊壞死核體積百分比明顯高于非糖尿病患者[38]。VH-IVUS能有效識別斑塊性質(zhì),近年來越來越多地應用于評價藥物對動脈粥樣硬化斑塊的治療效果。對急性冠脈綜合征患者應用脂蛋白相關磷脂酶A2(Lp-PLA2)Darapladib治療的對照研究顯示,與安慰劑比較,Darapladib能明顯降低患者冠狀動脈粥樣硬化斑塊的壞死核體積(-0.5±13.9)mm3比(4.5±17.9)mm3,P=0.012[39]。無復流是冠狀動脈支架術最嚴重的并發(fā)癥之一,VH-IVUS研究證實,富含壞死核心的斑塊與支架術后無復流密切相關[22-25]。此外,PROSPECT研究證實VHIVUS發(fā)現(xiàn)的易損斑塊能夠預測未來的不良冠脈事件[16]。

隨著VH-IVUS技術的不斷完善,其對斑塊組成的識別功能將會越來越廣泛地應用于心腦血管疾病領域,包括對支架術后再狹窄、新生內(nèi)膜組成,以及針對新藥對斑塊影響的在體動態(tài)評價等。

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