趙宇心，任建麗*，王志剛

(1.重慶醫(yī)科大學(xué)附屬第二醫(yī)院超聲科，重慶 400010；2.重慶醫(yī)科大學(xué)超聲影像學(xué)研究所 超聲分子影像重慶市重點(diǎn)實(shí)驗(yàn)室，重慶 400010)

化療相關(guān)心臟毒性指在化療藥物使用過程中或使用后化療藥物損傷心肌細(xì)胞導(dǎo)致的心臟或循環(huán)系統(tǒng)功能紊亂。具有心臟毒性的化療藥物主要包括以表柔比星為代表的蒽環(huán)類藥物和以曲妥珠單抗為代表的靶向治療藥物。蒽環(huán)類藥物致心臟毒性多與劑量呈正相關(guān)，多不可逆，主要表現(xiàn)為心功能進(jìn)行性障礙，部分患者后期可出現(xiàn)嚴(yán)重心力衰竭甚至死亡[1-2]；靶向治療藥物多與劑量無(wú)相關(guān)性，常可逆，主要表現(xiàn)為無(wú)癥狀的左心室射血分?jǐn)?shù)(left ventricular ejection fraction, LVEF)減低，較少出現(xiàn)心力衰竭[3]。兩類藥物致心臟毒性均主要表現(xiàn)為心功能不全，而超聲心動(dòng)圖及其新技術(shù)主要通過觀察心臟收縮和舒張功能來(lái)評(píng)估心臟毒性。本文就超聲心動(dòng)圖及其新技術(shù)評(píng)估化療相關(guān)心臟毒性的研究進(jìn)展進(jìn)行綜述。

1 超聲心動(dòng)圖評(píng)估化療相關(guān)心室收縮功能紊亂

1.1 常規(guī)超聲心動(dòng)圖 LVEF是常規(guī)超聲心動(dòng)圖評(píng)估左心室收縮功能最常用的指標(biāo)，LVEF減低與心力衰竭相關(guān)。常規(guī)超聲心動(dòng)圖可識(shí)別治療過程中LVEF的最小降低值約為10%[4]。根據(jù)美國(guó)超聲心動(dòng)圖協(xié)會(huì)(American Society of Echocardiography, ASE)和歐洲心血管成像協(xié)會(huì)(European Association of Cardiovascular Imaging, EACI)專家共識(shí)，使用致心臟毒性的化療藥物后，LVEF至少降低10%是診斷化療相關(guān)心臟毒性的截?cái)嘀礫5]。無(wú)癥狀患者LVEF降低<10%～20%時(shí)，超聲心動(dòng)圖檢測(cè)亞臨床、局部左心室收縮功能紊亂并不敏感。常規(guī)超聲心動(dòng)圖主要通過三尖瓣環(huán)收縮期峰值位移(tricuspid annular plane systolic excusion, TAPSE)和右心室面積應(yīng)變率(fractional area change, FAC)評(píng)估化療后右心室收縮功能。Boczar等[6-7]研究證實(shí)，使用蒽環(huán)類藥物后，超聲心動(dòng)圖可檢測(cè)到右心室FAC、TAPSE降低(P<0.01)，但右心室收縮功能受損對(duì)心臟毒性的診斷及預(yù)測(cè)價(jià)值尚需進(jìn)一步研究。

1.2 組織多普勒成像(tissue Doppler imaging, TDI) TDI采用多普勒原理測(cè)量心肌位移、運(yùn)動(dòng)速度和時(shí)間，可定量評(píng)估心肌局部和整體運(yùn)動(dòng)功能，且不受心臟幾何形態(tài)及心率等影響。TDI評(píng)價(jià)心室收縮功能的主要指標(biāo)包括心肌收縮期峰值速度(peak systolic velocity, s')和心肌做功指數(shù)(myocardial performance index, MPI)。有學(xué)者[8]采用TDI評(píng)估使用蒽環(huán)類藥物化療后無(wú)心力衰竭癥狀患者(病例組)的左心室功能，發(fā)現(xiàn)病例組左心室前壁各節(jié)段s'均顯著低于健康對(duì)照組(P<0.05)，而2組間LVEF差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。Abdar Esfahani等[9]也發(fā)現(xiàn)使用蒽環(huán)類藥物化療的乳腺癌患者右心室游離壁s'較治療前顯著減低。有學(xué)者[9-10]采用TDI評(píng)估在使用蒽環(huán)類藥物化療過程中患者心室整體功能，發(fā)現(xiàn)左、右心室MPI較治療前增高，而LVEF較治療前無(wú)明顯改變，提示TDI較常規(guī)超聲心動(dòng)圖可更敏感、早期地檢出化療后左、右心室局部或整體收縮功能降低。由于TDI具有角度依賴性，致其準(zhǔn)確率和可重復(fù)性降低，且關(guān)于其預(yù)測(cè)及診斷心臟毒性的指標(biāo)和截?cái)嘀档难芯枯^少見，針對(duì)上述問題仍需進(jìn)一步研究。

1.3 負(fù)荷超聲心動(dòng)圖(stress echocardiography, SE) SE通過運(yùn)動(dòng)、藥物負(fù)荷等來(lái)評(píng)估亞臨床心功能損傷和心臟儲(chǔ)備功能。Ryerson等[11]研究發(fā)現(xiàn)，采用運(yùn)動(dòng)SE無(wú)法檢測(cè)惡性腫瘤患兒使用蒽環(huán)類藥物化療后的亞臨床心臟功能損傷，但證實(shí)心臟儲(chǔ)備功能在化療早期并未明顯受損。Yildirim等[12]采用多巴酚丁胺SE評(píng)估接受蒽環(huán)類藥物治療患者(病例組)的亞臨床心臟毒性，發(fā)現(xiàn)注射多巴酚丁胺后病例組左心室后壁增厚率、收縮末室壁張力、二尖瓣血流加速時(shí)間顯著低于對(duì)照組，提示上述指標(biāo)對(duì)亞臨床心臟毒性具有診斷價(jià)值。SE的局限性為部分患者無(wú)法承受藥物或運(yùn)動(dòng)負(fù)荷，其結(jié)果的主觀性及觀察者間差異較大。

1.4 斑點(diǎn)追蹤成像(speckle tracking imaging, STI) STI通過斑點(diǎn)追蹤技術(shù)逐幀追蹤心肌聲學(xué)斑點(diǎn)，并獲得其運(yùn)動(dòng)軌跡，從而評(píng)估心肌運(yùn)動(dòng)功能，其優(yōu)點(diǎn)為無(wú)角度依賴性，可更客觀、準(zhǔn)確地定量評(píng)估心肌運(yùn)動(dòng)。STI主要包括二維斑點(diǎn)追蹤成像(two-dimensional speckle tracking imaging, 2D-STI)及三維斑點(diǎn)追蹤成像(three-dimensional speckle tracking imaging, 3D-STI)。2D-STI評(píng)估左心室收縮功能的主要指標(biāo)包括整體縱向應(yīng)變(global longitudinal strain, GLS)、整體徑向應(yīng)變(global radial strain, GRS)及整體圓周應(yīng)變(global circumferential strain, GCS)。有學(xué)者[13]采用2D-STI測(cè)量發(fā)現(xiàn)，患者使用蒽環(huán)類藥物后早期左心室GLS、GRS及GCS較治療前顯著減低，而LVEF較治療前無(wú)明顯變化。Yu等[14]研究發(fā)現(xiàn)GLS較LVEF可更敏感地檢出亞臨床左心室收縮功能障礙。Negishi等[15]發(fā)現(xiàn)，GLS在化療過程中較化療前降低11%是心臟毒性的最強(qiáng)預(yù)測(cè)因子，當(dāng)GLS較治療前降低>15%時(shí)提示左心室收縮功能異常；而Charbonnel等[16]則發(fā)現(xiàn)，當(dāng)無(wú)法與化療前GLS值對(duì)比時(shí)，接受低劑量(150 mg/m2)蒽環(huán)類藥物的患者GLS值>-17.45%是后期出現(xiàn)心臟毒性的獨(dú)立預(yù)測(cè)因子。2D-STI評(píng)估右心室收縮功能的主要指標(biāo)為右心室游離壁縱向應(yīng)變(right ventricular longitudinal strain_free wall, RVLS_FW)。Chang等[17]發(fā)現(xiàn)RVLS_FW較FAC、右心室MPI、三尖瓣環(huán)s'等指標(biāo)可更敏感地檢測(cè)到化療早期患者的右心室收縮功能降低，該研究還表明RVLS_FW于化療早期降低對(duì)于右心衰竭的發(fā)生具有預(yù)測(cè)價(jià)值。

3D-STI在2D-STI的基礎(chǔ)上增加了整體面積應(yīng)變(global area strain, GAS)，可同時(shí)顯示心室所有節(jié)段的三維運(yùn)動(dòng)和形變，較2D-STI更快速獲得應(yīng)變數(shù)據(jù)。有研究[18-19]證實(shí)3D-STI可較好地評(píng)估原發(fā)性高血壓、系統(tǒng)性紅斑狼瘡等患者早期相關(guān)左心室收縮功能減低。目前采用3D-STI評(píng)估化療相關(guān)心臟毒性的研究較少見。Morno等[20]采用3D-STI測(cè)得使用蒽環(huán)類化療藥物患者的3D-GLS、3D-GRS及3D-GCS較治療前顯著減低，LVEF較治療前無(wú)明顯改變，且3D-GLS是預(yù)測(cè)后期蒽環(huán)類藥物相關(guān)心臟毒性的唯一獨(dú)立因子。Toro-Salazar等[21]采用3D-STI評(píng)估使用蒽環(huán)類藥物后患者的心臟收縮功能，發(fā)現(xiàn)截?cái)嘀禐?17.5%時(shí)，3D-GLS可敏感地識(shí)別被CMR診斷為亞臨床心臟收縮功能損傷者。Santoro等[22]采用3D-STI與2D-STI評(píng)估使用蒽環(huán)類藥物后患者的心臟功能，發(fā)現(xiàn)2D-GLS、3D-GLS、3D-GRS、3D-GCS及3D-GAS均較治療前顯著減低。3D-STI易受左乳切除術(shù)、胸壁放療及假體植入等因素的影響，其可操作性低于2D-STI，應(yīng)用受限。

1.5 實(shí)時(shí)三維超聲心動(dòng)圖(real-time three-dimensional echocardiography, RT-3DE) RT-3DE不依賴特定的幾何假設(shè)，可實(shí)時(shí)全容積采集和同步顯示心臟的動(dòng)態(tài)立體三維圖像，從而準(zhǔn)確、快速測(cè)量心室容積和功能，同時(shí)具備操作簡(jiǎn)便、無(wú)創(chuàng)等優(yōu)點(diǎn)。有研究[4]發(fā)現(xiàn)，采用RT-3DE測(cè)量的LVEF結(jié)果較常規(guī)超聲心動(dòng)圖及左心室聲學(xué)造影更具有可重復(fù)性，更有利于評(píng)估心臟毒性的漸進(jìn)式發(fā)展。但Armstrong等[23]對(duì)比研究發(fā)現(xiàn)，由于LVEF評(píng)估收縮功能的自身局限性，3D-LVEF評(píng)估亞臨床心臟收縮功能紊亂的敏感度仍低于2D-GLS。目前采用RT-3DE評(píng)估化療后右心室收縮功能的研究較少見，但Li等[24]發(fā)現(xiàn)采用RT-3DE可較準(zhǔn)確地評(píng)估肺動(dòng)脈高壓患者的右心室容積和功能，且測(cè)量結(jié)果與CMR具有較好的相關(guān)性。將RT-3DE用于評(píng)估化療后右心室收縮功能可能具有一定價(jià)值，尚需進(jìn)一步研究。

2 超聲心動(dòng)圖對(duì)化療相關(guān)心室舒張功能紊亂的評(píng)估

常規(guī)超聲心動(dòng)圖主要通過二、三尖瓣口血流頻譜E峰與A峰比值(E/A)、等容舒張時(shí)間(isovolumic relaxation time, IVRT)等來(lái)評(píng)估心室舒張功能。 Abdar Esfahani等[9,25]研究發(fā)現(xiàn)使用蒽環(huán)類藥物后二、三尖瓣口E/A降低及左心室IVRT延長(zhǎng)，提示左、右心室舒張功能受損。由于E/A、IVRT等易受年齡、化療過程中容量負(fù)荷增加等因素的影響，故ASE和EACI指南建議超聲心動(dòng)圖可聯(lián)合TDI技術(shù)評(píng)估左、右心室舒張功能[26-27]。TDI技術(shù)評(píng)估心室舒張功能的指標(biāo)主要有心肌舒張?jiān)缙诜逯邓俣?early diastolic velocity, e')、心肌舒張晚期峰值速度(late diastolic velocity, a')及脈沖多普勒瓣口血流頻譜E峰與瓣環(huán)e'比值(E/e')。Zidan等[28]采用TDI測(cè)得使用蒽環(huán)類藥物化療后患者存在左心室舒張功能受損，而Agha等[29]發(fā)現(xiàn)患者亦存在右心室舒張功能受損。在化療后心室舒張與收縮功能關(guān)系的研究中，Honda等[30]采用TDI評(píng)估使用靶向藥物化療患者的心室舒張與收縮功能，發(fā)現(xiàn)化療早期心室舒張功能紊亂并不能較好地預(yù)測(cè)化療后期的收縮功能紊亂；但Boyd等[31]采用2D-STI評(píng)估使用蒽環(huán)類藥物后患者的舒張功能，發(fā)現(xiàn)舒張?jiān)缙趹?yīng)變率較治療前降低，且其降低可預(yù)測(cè)后期GLS降低。上述研究均證實(shí)化療過程中存在心室舒張功能受損，且其發(fā)生常先于收縮功能受損，但關(guān)于早期舒張功能受損是否可預(yù)測(cè)心室收縮功能受損目前尚無(wú)統(tǒng)一結(jié)論，有待進(jìn)一步研究。

3 小結(jié)

由于自身的局限性，常規(guī)超聲心動(dòng)圖、SE及RT-3DE無(wú)法較敏感地檢測(cè)使用致心臟毒性化療藥物后亞臨床的心臟功能紊亂。TDI可較敏感、早期地檢出化療藥物相關(guān)的亞臨床心臟功能損傷，但具有角度依賴性。STI技術(shù)可更準(zhǔn)確、敏感地評(píng)估化療后左、右心室收縮功能，且其中2D-STI有望成為檢測(cè)并預(yù)測(cè)心臟毒性的新手段。

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