吳小凡 馬長(zhǎng)生

近年來,血管內(nèi)超聲(intravascular ultrasound,IVUS)在心血管病學(xué)領(lǐng)域得到了廣泛應(yīng)用。但灰階IVUS表達(dá)的僅僅是超聲波的振幅信息而不能反映頻率信息,不能對(duì)冠狀動(dòng)脈斑塊的成分進(jìn)行有效的評(píng)價(jià)。虛擬組織學(xué) 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(shí)別富含脂質(zhì)壞死核(necrotic core,NC),從而彌補(bǔ)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(xué)領(lǐng)域的臨床應(yīng)用和研究熱點(diǎn)。

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(dá)5 mm以上[1-2]。而血液成分在 >40 MHz時(shí)才會(huì)出現(xiàn)容易混淆血管界面的斑點(diǎn)圖像。因此,灰階IVUS可以準(zhǔn)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(duì)血管腔、外彈力膜的橫截面積和斑塊面積進(jìn)行定量測(cè)定以及對(duì)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(shí)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?duì)照研究,VH-IVUS將冠狀動(dòng)脈動(dòng)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(xué)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(shí),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(shí)別脂質(zhì)池的敏感度和特異度達(dá)到90%和92%[6-7],iMAP在豬模型離體識(shí)別脂質(zhì)核心的準(zhǔn)確性達(dá)97%,其在人體識(shí)別斑塊成分的準(zhǔn)確性還有待進(jìn)一步研究證實(shí)[8]。

但是,VH-IVUS尚不能有效地識(shí)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(dāng)TCFA覆蓋血栓時(shí)可能被錯(cuò)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(hào)的傳播,80%的興趣區(qū)仍然有超聲信號(hào)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(hào),這樣就導(dǎo)致鈣化背后的病變可能會(huì)錯(cuò)判為 NC(65%)、纖維組織(18%)或纖維脂肪組織(14%)[10]。

圖1 動(dòng)脈粥樣硬化斑塊的VH-IVUS分型以及灰階IVUS對(duì)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(dòng)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(dòng)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(dǎo)致急性冠脈綜合癥(acute coronary syndromes,ACS),或內(nèi)膜增生致介入術(shù)后再狹窄的重要原因之一[11-12]。眾多調(diào)脂試驗(yàn)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(píng)價(jià)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(shí)別冠狀動(dòng)脈粥樣硬化斑塊的脂質(zhì)核心,因而成為識(shí)別易損斑塊和建立斑塊發(fā)生發(fā)展動(dòng)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(gè)前瞻性評(píng)價(jià)易損斑塊進(jìn)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(shí)別導(dǎo)致未來不良事件的易損斑塊[16]。該研究在美國(guó)和歐洲的40個(gè)中心入選了700例ACS患者,在成功對(duì)罪犯病變置入支架后,對(duì)3支主要冠狀動(dòng)脈進(jìn)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(duì)發(fā)生事件者再次進(jìn)行QCA和IVUS分析和評(píng)價(jià)。PROSPECT研究結(jié)果顯示,VH-IVUS發(fā)現(xiàn)的易損斑塊能夠預(yù)測(cè)未來的不良冠脈事件。對(duì)未置入支架的非罪犯病變的亞組分析揭示導(dǎo)致不良冠狀動(dòng)脈事件的3個(gè)獨(dú)立預(yù)測(cè)因子:TCFA,斑塊負(fù)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(yīng)。TCFA是VH-IVUS診斷的易損斑塊,51.2%的患者含有至少1個(gè)TCFA,48%的事件相關(guān)病變顯示存在 TCFA,16%同時(shí)存在 TCFA和 MLA≤4 mm2,而4.2%同時(shí)存在TCFA,MLA≤4 mm2和斑塊負(fù)荷 >70%。對(duì)冠狀動(dòng)脈斑塊形態(tài)和組成的自然進(jìn)程的VH-IVUS研究顯示,在9個(gè)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(dòng)脈近段且斑塊負(fù)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(duì)于纖維斑塊或纖維鈣化斑塊而言,PIT、TCFA和ThCFA更易于進(jìn)展,表現(xiàn)為斑塊負(fù)荷增大,管腔面積減小[17]。

3.VH-IVUS在介入治療中的應(yīng)用:灰階IVUS在引導(dǎo)經(jīng)皮冠脈介入治療方面已經(jīng)積累了豐富的經(jīng)驗(yàn),包括術(shù)前評(píng)價(jià)病變性質(zhì)、范圍,術(shù)中明確支架直徑、長(zhǎng)度,術(shù)后評(píng)價(jià)支架擴(kuò)張和貼壁以及及時(shí)識(shí)別并發(fā)癥等。VH-IVUS發(fā)展至今,關(guān)于其在介入治療中的應(yīng)用,也積累了一定的經(jīng)驗(yàn),包括對(duì)于易損斑塊的處理、支架長(zhǎng)度的選擇以及病變特點(diǎn)與無復(fù)流之間的關(guān)系以及支架術(shù)后內(nèi)膜覆蓋和再狹窄的評(píng)價(jià)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(gè)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(shí)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(rùn)情況,而后者是斑塊破裂的一個(gè)重要環(huán)節(jié)。同時(shí),大多數(shù)ACS患者含有一個(gè)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(huì)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(kuò)張和支架貼壁的問題。2009年,荷蘭鹿特丹中心的SECRITT I研究進(jìn)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(kuò)張及貼壁良好,且無組織脫垂,6個(gè)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(zhǎng)度的選擇對(duì)于介入治療尤為關(guān)鍵。對(duì)于急性心肌梗死(AMI)患者,冠狀動(dòng)脈造影顯示罪犯病變通常位于血栓負(fù)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(yuǎn)端,因此冠脈造影指導(dǎo)的支架置入往往不能完全覆蓋罪犯病變。來自波蘭的一項(xiàng)針對(duì)40例AMI患者的VH-IVUS研究證實(shí),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(shí)存在于支架近端和遠(yuǎn)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(yuǎn)端,10%同時(shí)存在于支架近端和遠(yuǎn)端。罪犯病變未完全覆蓋對(duì)遠(yuǎn)端栓塞、支架血栓、再狹窄以及病變進(jìn)展等的影響需要進(jìn)一步的大規(guī)模臨床研究加以證實(shí)。

盡管個(gè)別研究顯示纖維組織或纖維脂肪組織與支架術(shù)后無復(fù)流有關(guān)[20-21],但目前大多數(shù)的VH-IVUS研究顯示NC與支架術(shù)后遠(yuǎn)端微栓塞致無復(fù)流有關(guān)[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(guān)[28]。而臨床研究進(jìn)一步證實(shí),超聲衰減斑塊支架術(shù)后無復(fù)流/慢血流明顯增多,與斑塊在支架擴(kuò)張過程中釋放大量微栓塞物質(zhì)損傷心肌有關(guān)[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(shù)后心肌酶譜升高越顯著[31],光學(xué)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(shù)后無復(fù)流有關(guān)[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(shù)后無復(fù)流有關(guān)[33]。因此介入術(shù)前對(duì)斑塊成分進(jìn)行評(píng)價(jià)及早發(fā)現(xiàn)富含脂質(zhì)斑塊,對(duì)介入策略和防治無復(fù)流具有重要的臨床意義。介入術(shù)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(píng)價(jià)術(shù)后內(nèi)膜覆蓋的重要參考。Leiden MISSION研究顯示,支架置入術(shù)后9個(gè)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(gè)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(hù)性的內(nèi)膜增生受到抑制,導(dǎo)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(zhǎng)期存在[35]。對(duì)不同隨訪時(shí)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(shí)間的延長(zhǎng),NC和鈣化組織占新生內(nèi)膜的百分比成上升趨勢(shì),但是新生內(nèi)膜組成成分的驗(yàn)證性研究還有待進(jìn)一步的病例組織學(xué)對(duì)照研究加以證實(shí)。

4.新近研究熱點(diǎn):由于VH-IVUS能有效評(píng)價(jià)斑塊性質(zhì),因此越來越廣泛地應(yīng)用于冠心病的基礎(chǔ)和臨床研究中。近年來的研究主要集中在以下幾個(gè)方面:(1)結(jié)合流行病學(xué)和病理學(xué)研究識(shí)別高危冠心病患者;(2)評(píng)價(jià)藥物對(duì)動(dòng)脈粥樣硬化斑塊的治療效果;(3)評(píng)價(jià)支架置入的安全性和有效性;(4)預(yù)測(cè)遠(yuǎn)期不良事件。

全球IVUS注冊(cè)研究顯示,VH-TCFA與Framingham危險(xiǎn)分?jǐn)?shù)相關(guān),Framingham風(fēng)險(xiǎn)≥20%者,TCFA發(fā)生率高達(dá)21.4%,而Framingham風(fēng)險(xiǎn)<10%者,TCFA發(fā)生率下降一半,約11.3%[36]。糖尿病患者冠狀動(dòng)脈病變形態(tài)學(xué)研究顯示,與非糖尿病患者相比,糖尿病患者冠狀動(dòng)脈粥樣硬化斑塊含有豐富的壞死核成分[37]。另一項(xiàng)VH-IVUS注冊(cè)研究也證實(shí)了這一點(diǎn),即糖尿病患者冠狀動(dòng)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(shí)別斑塊性質(zhì),近年來越來越多地應(yīng)用于評(píng)價(jià)藥物對(duì)動(dòng)脈粥樣硬化斑塊的治療效果。對(duì)急性冠脈綜合征患者應(yīng)用脂蛋白相關(guān)磷脂酶A2(Lp-PLA2)Darapladib治療的對(duì)照研究顯示,與安慰劑比較,Darapladib能明顯降低患者冠狀動(dòng)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(fù)流是冠狀動(dòng)脈支架術(shù)最嚴(yán)重的并發(fā)癥之一,VH-IVUS研究證實(shí),富含壞死核心的斑塊與支架術(shù)后無復(fù)流密切相關(guān)[22-25]。此外,PROSPECT研究證實(shí)VHIVUS發(fā)現(xiàn)的易損斑塊能夠預(yù)測(cè)未來的不良冠脈事件[16]。

隨著VH-IVUS技術(shù)的不斷完善,其對(duì)斑塊組成的識(shí)別功能將會(huì)越來越廣泛地應(yīng)用于心腦血管疾病領(lǐng)域,包括對(duì)支架術(shù)后再狹窄、新生內(nèi)膜組成,以及針對(duì)新藥對(duì)斑塊影響的在體動(dòng)態(tài)評(píng)價(jià)等。

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