劉永宏 馮丹

(1.樂(lè)山市老年病專科醫(yī)院，四川 樂(lè)山 614000；2.延安大學(xué)醫(yī)學(xué)院，陜西 延安 716000)

流行病學(xué)研究顯示卵圓孔未閉(PFO)在正常成人中的發(fā)病率約為20% ～ 30%[1-2]，而在隱源性腦梗死(CCI)患者中PFO的檢出率卻高達(dá)50% ～ 60%[3-4]。通常因PFO的分流量太小，認(rèn)為其不會(huì)造成嚴(yán)重的臨床后果。近年，由于CCI的患病率逐年上升，PFO的致病作用才越來(lái)越受到廣大專家和學(xué)者的關(guān)注。

在胚胎發(fā)育6～7周時(shí)，心房間隔先后發(fā)出2個(gè)隔，先發(fā)出者稱原發(fā)隔(第一隔)，后發(fā)出者稱繼發(fā)隔(第二隔)，二者在胚胎發(fā)育過(guò)程中未能完全融合，中間遺留下一斜形缺損稱為卵圓孔。胎兒期，卵圓孔作為一個(gè)生理通道使血液從右心房流入左心房，維持胎兒血液循環(huán)。出生以后，肺開(kāi)始有呼吸功能，肺血管阻力降低，從下腔靜脈注入右心房的血液減少，右心房壓力低于左心房，使卵圓孔閉合。正常情況下，卵圓孔在出生后一年閉合，若>3歲的幼兒卵圓孔仍未關(guān)閉，則稱為PFO。Timsit和Breuilly[5]認(rèn)為，經(jīng)現(xiàn)有檢查仍不能解釋患者發(fā)生腦梗死的原因時(shí)，稱之為CCI。當(dāng)腦梗死的病因分型趨向于CCI時(shí),需進(jìn)行常規(guī)以外的深入檢查，如經(jīng)食道超聲心動(dòng)圖、動(dòng)態(tài)心電圖、甚至進(jìn)行病理和基因?qū)W診斷，以尋找PFO、陣發(fā)性心律失常、Fabry病等潛在或明確的病因[6-8]。

1 發(fā)病機(jī)制

PFO作為CCI的致病因素已被證實(shí)[9]，2013年幾個(gè)多中心臨床隨機(jī)對(duì)照研究表明[10-12]，PFO致CCI的發(fā)生機(jī)制主要為反常栓塞(paradoxical embolism，PDE)。即靜脈系統(tǒng)的栓子經(jīng)過(guò)未閉的卵圓孔進(jìn)入動(dòng)脈，從而引起缺血性腦卒中。眾多研究[13-15]提示，PFO的右向左分流(right to left shunt，RLS)是引起CCI的危險(xiǎn)因素，可能與RLS致腦血流自動(dòng)調(diào)節(jié)異常有關(guān)[16-18]。

2 PFO的檢查方法

2.1 經(jīng)胸壁超聲心動(dòng)圖(transthoracic echocardiography，TTE) 常規(guī)TTE可直接了解心臟的解剖結(jié)構(gòu)和血流動(dòng)力學(xué)狀況，但圖像質(zhì)量受多種因素的影響，除與儀器的性能有關(guān)外，還受到患者身體狀況(如肥胖、肺氣腫、胸廓畸形等)的影響，故常規(guī)TTE對(duì)PFO的檢出率較低。TTE結(jié)合聲學(xué)造影(cTTE)可將PFO的檢出率提高至88%，特異性為97%[19]。cTTE的造影劑為8ml生理鹽水、1ml空氣和1ml自體血液混合而成。分別在靜息和做Valsalva動(dòng)作(囑患者深吸氣后緊閉聲門再用力呼氣)狀態(tài)下注射造影劑，造影過(guò)程中均留存動(dòng)態(tài)圖像，造影后逐幀回放并觀察，前三個(gè)心動(dòng)周期內(nèi)左心房?jī)?nèi)出現(xiàn)微氣泡信號(hào)(microbubble，MB)，可診斷為PFO。TTE屬無(wú)創(chuàng)性檢查，因痛苦小可為大多數(shù)人所接受。

2.2 經(jīng)食道超聲心動(dòng)圖(transesophageal echocardiography，TEE) TEE屬半侵入性檢查(可出現(xiàn)氣管痙攣、心律失常、咽部粘膜損傷等并發(fā)癥)，是將超聲探頭放入患者的食道內(nèi)，因避免了患者身體狀況(如肥胖、肺氣腫、胸廓畸形等)的影響，可以清楚的從心臟的后方觀察其解剖結(jié)構(gòu)，準(zhǔn)確測(cè)量PFO的大小，結(jié)合彩色多普勒顯像技術(shù)可探查異常血流的方向、速度和分布。與cTTE一樣，cTEE(TEE聲學(xué)造影)亦可用于檢測(cè)心房?jī)?nèi)右向左分流情況，對(duì)PFO診斷的靈敏度和特異性可達(dá)100%[20]，長(zhǎng)期以來(lái)，被認(rèn)為是診斷PFO的“金標(biāo)準(zhǔn)”。但由于操作過(guò)程中，患者比較痛苦，不能有效配合行Valsalva動(dòng)作，可出現(xiàn)假陰性的結(jié)果。且有研究認(rèn)為由cTEE檢出的PFO不足以證明其就是CCI的直接病因[21]。

2.3 心腔內(nèi)超聲心動(dòng)圖(intracardiac echocardiography，ICE) ICE是采用導(dǎo)管術(shù)將安裝有微型超聲換能器的心導(dǎo)管經(jīng)血管插入心腔內(nèi)進(jìn)行心臟解剖結(jié)構(gòu)和病理生理功能觀察的技術(shù)[22]。與TEE相比，應(yīng)用ICE將探頭置于房間隔時(shí)可清楚地顯示壁薄弱的卵圓孔部位，同時(shí)可使患者免于食管插管的痛苦。對(duì)診斷結(jié)構(gòu)復(fù)雜的PFO，ICE提高了空間定向，并減少了并發(fā)癥[23]，在定位PFO封堵的位置時(shí)也發(fā)揮了較好的作用[24]。

2.4 經(jīng)顱多普勒超聲(transcranial Doppler，TCD)發(fā)泡實(shí)驗(yàn) TCD是利用多普勒超聲效應(yīng)檢測(cè)顱內(nèi)腦底動(dòng)脈環(huán)上各主要?jiǎng)用}的血流動(dòng)力學(xué)的一項(xiàng)技術(shù)。結(jié)合聲學(xué)造影即TCD發(fā)泡實(shí)驗(yàn)(cTCD)可間接用于檢測(cè)PFO。其原理是有PFO時(shí)，心臟存在RLS的通道，微泡可不經(jīng)過(guò)肺循環(huán)而直接進(jìn)人顱內(nèi)，10 s內(nèi)在大腦中動(dòng)脈檢測(cè)到MB，證明存在PFO[25]。陽(yáng)性患者應(yīng)常規(guī)檢查經(jīng)胸心臟超聲除外合并其他心內(nèi)(如房缺、室缺)或心外分流(肺動(dòng)靜脈畸形)的情況。TCD發(fā)泡實(shí)驗(yàn)配合Valsalva動(dòng)作可以提高陽(yáng)性率，神經(jīng)病學(xué)專家廣泛使用這一方法來(lái)診斷PFO。TCD發(fā)泡實(shí)驗(yàn)診斷PFO的高敏感性與特異性已經(jīng)得到國(guó)內(nèi)外多項(xiàng)研究的證實(shí)[26-28]。對(duì)右向左分流的敏感性為68% ～ 100%，特異性為65% ～ 100%[29-31]。

2.4.1 造影劑的種類 目前較多應(yīng)用于臨床的造影劑有激活生理鹽水(agitated saline solution，AS)，即9ml生理鹽水+1ml空氣；加血激活生理鹽水(agitated saline solution with blood，ASB)，即8ml生理鹽水+1ml空氣+1ml自體血液；碳酸氫鈉與維生素B6溶液(Vitamin B6 and sodium bicarbonate solution，VSBS)，即6ml碳酸氫鈉+4ml維生素B6。眾多研究表明應(yīng)用ASB與AS進(jìn)行cTCD檢查觀察PFO患者RLS時(shí)，可獲得更好的效果[32-34]。國(guó)內(nèi)有研究報(bào)道，ASB組靜息狀態(tài)或Valsalva動(dòng)作后PFO陽(yáng)性率均顯著高于AS組，ASB組靜息狀態(tài)或VM后RLS程度亦顯著高于AS組[35]。其機(jī)制可能與血液可穩(wěn)定微泡本身從而延長(zhǎng)微泡在血液循環(huán)中懸浮的時(shí)間，使更多的微泡通過(guò)PFO。亦有報(bào)道指出，用VSBS行cTCD檢查，對(duì)PFO患者RLS檢測(cè)的敏感性及顯影效果均優(yōu)于AS和ASB[36]。

2.4.2 影響右向左分流的因素 許多日常活動(dòng)，如負(fù)重、嘆氣、大笑、咳嗽、潛水、用力排便，劇烈運(yùn)動(dòng)、蹲起動(dòng)作等均可導(dǎo)致RLS[37-38]。體位對(duì)cTCD檢測(cè)右向左分流亦有影響，有研究表明正常呼吸時(shí)仰臥位敏感性最低，右側(cè)臥位較高，以坐位結(jié)合Valsalva動(dòng)作檢出率最高[39-40]。而研究結(jié)果表明左側(cè)臥位高于右側(cè)臥位及仰臥位[41-42]。但左側(cè)臥位與直立坐位無(wú)顯著差異。

2.4.3 陽(yáng)性結(jié)果的判斷 目前較新的分級(jí)方法有6級(jí)分級(jí)法[43]，0級(jí)(無(wú)心臟RLS，即0個(gè)MB)、1級(jí)(輕度心臟RLS，行Valsalva動(dòng)作后采集到1～20個(gè)MB)，2級(jí)(中度心臟RLS，行Valsalva動(dòng)作后采集到>20個(gè)MB，非雨簾狀)、3級(jí)(中度心臟RLS，行Valsalva動(dòng)作后采集到雨簾狀MB)、4級(jí)(持續(xù)輕/中度心臟RLS，靜息狀態(tài)下<10個(gè)MB，行Valsalva動(dòng)作后采集到雨簾狀MB)、5級(jí)(持續(xù)重度心臟RLS，靜息狀態(tài)下采集到雨簾狀MB)；4分法[44](0 MB、1～10個(gè)MB、10～30個(gè)MB但未形成雨簾、雨簾)及3分法[45](0 MB、1～10個(gè)MB、>10個(gè)MB)等。

3 PFO的治療

3.1 藥物治療 PFO的藥物治療包括抗凝和抗血小板治療，一項(xiàng)臨床隨機(jī)對(duì)照試驗(yàn)認(rèn)為兩者治療PFO患者缺血性卒中復(fù)發(fā)率無(wú)顯著差異性[46]，任何藥物治療對(duì)其防治均無(wú)效[47]。2014年美國(guó)卒中協(xié)會(huì)二級(jí)預(yù)防指南[48]指出：目前尚無(wú)足夠證據(jù)支持PFO患者抗凝治療等效或優(yōu)于抗血小板治療，缺血性卒中伴PFO未進(jìn)行抗凝治療的患者，建議進(jìn)行抗血小板治療(I類，B級(jí))；缺血性卒中伴PFO及深靜脈血栓的患者，建議進(jìn)行抗凝治療(I類，A級(jí))。近年也有學(xué)者提出[49-50]，安全、有效的新型口服抗凝劑可能成為PFO患者的更佳治療方法。

3.2 介入治療 國(guó)內(nèi)有學(xué)者對(duì)26例缺血性腦卒中患者進(jìn)行介入封堵治療，24例封堵成功，術(shù)后隨訪6個(gè)月至1年，復(fù)查TTE及cTCD均無(wú)右向左分流，所有患者均未發(fā)生缺血性腦卒中[51]。陳林坤等[52]對(duì)國(guó)外3項(xiàng)隨機(jī)對(duì)照試驗(yàn)的2303名CCI患者進(jìn)行方法學(xué)質(zhì)量評(píng)價(jià)，結(jié)果表明，目前尚無(wú)足夠證據(jù)證明卵圓孔封堵術(shù)在預(yù)防CCI患者復(fù)發(fā)方面優(yōu)于藥物治療，且兩種療法安全性相當(dāng)。Messe SR[53]基于對(duì)3項(xiàng)隨機(jī)對(duì)照試驗(yàn)的分析，不推薦經(jīng)皮封堵術(shù)用于治療PFO。

4 小結(jié)

自CCI概念被提出以來(lái)，我們致力于尋找CCI的病因、發(fā)病機(jī)制、檢測(cè)手段及治療方法，在此基礎(chǔ)上獲得二級(jí)預(yù)防的有效證據(jù)，以提高患者生存質(zhì)量，減輕家庭和社會(huì)負(fù)擔(dān)。PFO可能是中青年缺血性卒中的危險(xiǎn)因素之一，PFO致缺血性卒中的發(fā)病機(jī)制可能與右向左分流的嚴(yán)重程度有關(guān)，但其確切機(jī)制仍未完全明了，需要進(jìn)一步臨床研究觀察，為預(yù)防和治療缺血性卒中提供理論依據(jù)。

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