【摘要】在老齡化社會(huì)背景下,主動(dòng)脈瓣狹窄(AS)作為最常見(jiàn)的瓣膜性心臟病,其發(fā)病率逐年上升,給診斷和治療帶來(lái)了挑戰(zhàn)。AS的主要干預(yù)措施是手術(shù)治療,但有限的數(shù)據(jù)表明,AS患者的治療并不充分。雖然目前還沒(méi)有行之有效的保守治療方法,但各種新的分子靶點(diǎn)和藥物策略正在研究中?,F(xiàn)重點(diǎn)介紹AS的治療進(jìn)展,回顧近年來(lái)AS手術(shù)及保守治療方面的革新,以期為臨床治療決策提供更多的思路。
【關(guān)鍵詞】主動(dòng)脈瓣狹窄;瓣膜置換術(shù);治療
【DOI】10.16806/j.cnki.issn.1004-3934.2024.11.005
Treatment of Aortic Stenosis
YANG Xuemei,ZHANG Dongying
(Department of Cardiology,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400000,China)
【Abstract】In an aging society,the prevalence of aortic stenosis (AS),as the most common valvular heart disease,is steadily rising each year,which brings challenges to diagnosis and therapy.The primary intervention for AS is surgical treatment,but limited data suggest that treatment for patients with AS is not sufficient.While conservative therapies lack definitive evidence,ongoing research into new molecular targets and pharmacological approaches is being investigated.This article explores advancements in the treatment of AS focusing on recent innovations in both surgical and conservative management,in order to provide more insights for clinical treatment decisions.
【Keywords】Aortic stenosis;Valve replacement;Treatment
2019年全球疾病負(fù)擔(dān)研究結(jié)果指出,30年間鈣化性主動(dòng)脈瓣疾病(calcific aortic valve disease,CAVD)患病率逐年穩(wěn)步上升(年齡標(biāo)準(zhǔn)化患病率從約45.5例/10萬(wàn)人上升至約116.3例/10萬(wàn)人)[1]。隨著人口老齡化,未來(lái)幾十年CAVD患病率預(yù)計(jì)至少增加2~3倍。而目前有限的數(shù)據(jù)結(jié)果[2]表明,主動(dòng)脈瓣狹窄(aortic stenosis,AS)作為CAVD最常見(jiàn)的一種類(lèi)型,其患者并未得到充分的治療,仍有超過(guò)一半有癥狀的重度AS患者未接受手術(shù)干預(yù)。因?yàn)榻邮苁中g(shù)治療的患者數(shù)目成倍增長(zhǎng)的同時(shí),達(dá)到手術(shù)指征的患者基數(shù)增長(zhǎng)更快[2]。有嚴(yán)重癥狀A(yù)S患者仍以手術(shù)治療為主但治療不充分,而未達(dá)到手術(shù)指征或不宜行手術(shù)的AS患者尚無(wú)確切治療方法?,F(xiàn)圍繞AS的治療進(jìn)展進(jìn)行敘述,回顧近年來(lái)AS手術(shù)及保守治療方面的革新,對(duì)解答以上問(wèn)題提供有價(jià)值的線索。
1nbsp;手術(shù)治療
1.1"主動(dòng)脈瓣置換術(shù)
主動(dòng)脈瓣置換術(shù)(aortic valve replacement,AVR)是治療AS的主要術(shù)式,分為外科主動(dòng)脈瓣置換術(shù)(surgical aortic valve replacement,SAVR)和經(jīng)導(dǎo)管主動(dòng)脈瓣置換術(shù)(transcatheter aortic valve replacement,TAVR)。SAVR是具有較高手術(shù)風(fēng)險(xiǎn)的開(kāi)胸手術(shù),適用于年輕、相對(duì)健康的患者;TAVR屬于微創(chuàng)介入手術(shù),適用于不宜行SAVR的年老衰弱或存在其他嚴(yán)重健康問(wèn)題的患者。TAVR最初作為SAVR手術(shù)高風(fēng)險(xiǎn)的替代方案,因圍手術(shù)期低風(fēng)險(xiǎn)、恢復(fù)時(shí)間短、微創(chuàng)性,近年來(lái)應(yīng)用漸廣,并逐漸趕超SAVR。
2023年歐洲心臟病學(xué)會(huì)/歐洲心胸外科協(xié)會(huì)(European Society of Cardiology/European Association for Cardio-Thoracic Surgery,ESC/EACTS)指南指出[3],AVR臨床決策時(shí)需考慮患者年齡、臨床狀態(tài)、解剖、患者偏好等多種因素;除風(fēng)險(xiǎn)評(píng)分外,需著重參考心臟瓣膜替代物的耐久性,及患者的預(yù)期壽命等因素。
1.1.1"各類(lèi)手術(shù)風(fēng)險(xiǎn)患者
風(fēng)險(xiǎn)評(píng)分是AS患者術(shù)前檢查的核心考量因素之一[3]。了解SAVR和TAVR兩種術(shù)式在不同風(fēng)險(xiǎn)患者中的作用,對(duì)AS評(píng)估治療有重要價(jià)值。低手術(shù)風(fēng)險(xiǎn)患者,TAVR短期風(fēng)險(xiǎn)更低,長(zhǎng)期隨訪成本更低,且風(fēng)險(xiǎn)無(wú)顯著差異。Ahmad等[4]報(bào)道,低風(fēng)險(xiǎn)患者中TAVR 1年死亡風(fēng)險(xiǎn)(RR=0.67,95%CI 0.47~0.96,P=0.031)、死亡或致殘性卒中發(fā)生率(RR=0.68,95%CI 0.50~0.92,P= 0.014)均低于SAVR。NOTION試驗(yàn)[5]結(jié)果顯示,隨機(jī)接受TAVR或SAVR的低手術(shù)風(fēng)險(xiǎn)AS患者的8年全因死亡率、卒中及心肌梗死估計(jì)風(fēng)險(xiǎn)無(wú)明顯差異。Evolut低風(fēng)險(xiǎn)試驗(yàn)、PARTNER 3試驗(yàn)以及NOTION試驗(yàn)的10年隨訪結(jié)果均得出類(lèi)似結(jié)論[6-8]。另外,Galper團(tuán)隊(duì)[9]從PARTNER 3試驗(yàn)中獲得了一個(gè)有趣的結(jié)論:低手術(shù)風(fēng)險(xiǎn)患者的TAVR長(zhǎng)期成本低于SAVR(TAVR隨訪成本相較SAVR低)。
在中風(fēng)險(xiǎn)及高風(fēng)險(xiǎn)手術(shù)患者中,SAVR與TAVR的短期及長(zhǎng)期死亡及腦卒中風(fēng)險(xiǎn)相似,其余風(fēng)險(xiǎn)各有高低。UK TAVI試驗(yàn)[10]發(fā)現(xiàn)1年隨訪中,TAVR組21例死亡(4.6%),SAVR組30例死亡(6.6%),調(diào)整后的絕對(duì)風(fēng)險(xiǎn)差異為-2.0%(單側(cè) 97.5%CI-∞~1.2%,非劣效性P<0.001)。Ahmad等[4]的薈萃分析研究中也有類(lèi)似的結(jié)果:TAVR與SAVR相比的全因死亡率點(diǎn)估計(jì)HR=1.04(95%CI 0.96~1.13,P=0.34)。為了更清晰地展示數(shù)據(jù)間的比較,以上臨床研究的具體信息見(jiàn)表1。
綜上,低手術(shù)風(fēng)險(xiǎn)患者可適當(dāng)放寬TAVR指征,中高手術(shù)風(fēng)險(xiǎn)患者則需臨床醫(yī)師根據(jù)患者情況選擇個(gè)性化術(shù)式??蓞⒖甲钚翬SC/EACTS指南建議:尚無(wú)最佳的年齡界值,但二葉式主動(dòng)脈瓣、存在經(jīng)股入路禁忌、同期需行心臟血運(yùn)重建術(shù)或二尖瓣手術(shù)的患者首選SAVR,而瓷化主動(dòng)脈患者可優(yōu)先考慮TAVR;另再尋求患者預(yù)期壽命與心臟瓣膜替代物耐久性之間的平衡,同時(shí)結(jié)合患者偏好進(jìn)行決策[1]。
1.1.2"低流量低梯度主動(dòng)脈瓣狹窄患者
低流量低梯度主動(dòng)脈瓣狹窄(low-flow low-gradient aortic stenosis,LFLG-AS)患者的圍手術(shù)期風(fēng)險(xiǎn)大、預(yù)后差,治療策略需更加個(gè)性化。目前研究[11-12]證實(shí)早期AVR能使所有亞類(lèi)LFLG-AS患者獲得重大的生存獲益,但術(shù)式選擇上仍存在爭(zhēng)議。TOPAS多中心隊(duì)列研究[11]發(fā)現(xiàn)其治療加權(quán)逆概率模型中,經(jīng)股動(dòng)脈TAVR優(yōu)于SAVR(HR=0.28,95%CI 0.11~0.72,P=0.008)。但Ueyama等[12]的研究結(jié)論有所不同:在不同類(lèi)型LFLG-AS患者中,SAVR與TAVR的全因死亡率無(wú)顯著差異。雖然目前有限的研究數(shù)據(jù)提示TAVR在LFLG-AS患者中的潛在優(yōu)勢(shì),但尚不能說(shuō)明TAVR優(yōu)于SAVR,需進(jìn)一步的高質(zhì)量研究證據(jù)支撐TAVR在LFLG-AS中適應(yīng)證的擴(kuò)展。
1.1.3"無(wú)癥狀嚴(yán)重AS患者
最新ESC/EACTS指南建議對(duì)無(wú)癥狀嚴(yán)重AS患者采取長(zhǎng)期隨訪策略,但研究表明盡早手術(shù)干預(yù)更有利于無(wú)癥狀嚴(yán)重AS患者的預(yù)后。RECOVERY試驗(yàn)[13]首次證明早期SAVR手術(shù)能使無(wú)癥狀嚴(yán)重AS患者獲得更好的生存效益(HR=0.09,95%CI 0.01~0.67,P=0.003)。AVATAR試驗(yàn)[14]納入了左室射血分?jǐn)?shù)的考量,也得出了類(lèi)似的結(jié)論:在意向治療分析中,早期AVR組患者的主要復(fù)合終點(diǎn)(全因死亡、急性心肌梗死、卒中或因心力衰竭而意外住院)發(fā)生率顯著低于保守治療組患者(HR=0.46,95%CI 0.23~0.90,P=0.02)。
最近,Javadikasgari團(tuán)隊(duì)[15]研究無(wú)癥狀嚴(yán)重AS且左室射血分?jǐn)?shù)≥50%患者隊(duì)列時(shí)發(fā)現(xiàn),SAVR可帶來(lái)生存獲益并改善左心室肥厚,但術(shù)前已有左心室肥厚會(huì)導(dǎo)致患者生存效益受損(HR=2.32,95%CI 1.02~5.27,P=0.045)。前述研究證實(shí)了對(duì)無(wú)癥狀嚴(yán)重AS患者早期干預(yù),預(yù)后更佳。臨床醫(yī)師可對(duì)有手術(shù)條件者進(jìn)行相對(duì)積極處理,尤其是預(yù)期壽命較長(zhǎng)的患者。
目前大部分研究都是基于SAVR展開(kāi),TAVR作為具有強(qiáng)大臨床潛力的術(shù)式,尚缺少其在無(wú)癥狀嚴(yán)重AS患者中的證據(jù)。暫未發(fā)布結(jié)果的EARLY TAVR試驗(yàn)(NCT03042104)以及正在進(jìn)行的EASY-AS試驗(yàn)(NCT04204915)和EVOLVED試驗(yàn)(NCT03094143),可能在未來(lái)可提供更高質(zhì)量的研究證據(jù),以指導(dǎo)臨床決策。
1.2"Ross手術(shù)
Ross手術(shù)又稱(chēng)為自體肺動(dòng)脈瓣移植術(shù),其將患者自身肺動(dòng)脈瓣移植到主動(dòng)脈瓣部位,避免了諸多人工瓣膜的弊端。與老年患者相比,年輕患者對(duì)主動(dòng)脈瓣替代物耐用性以及遠(yuǎn)期預(yù)后的要求更高。AVR受限于其不可忽視的缺點(diǎn)——生物瓣耐用性有限,機(jī)械瓣需長(zhǎng)期抗凝治療。盡管Ross手術(shù)在材質(zhì)上優(yōu)于AVR手術(shù),但其仍不被推薦首選于年輕AS患者。多項(xiàng)觀察性研究發(fā)現(xiàn),年輕(18~60歲)AS患者的Ross手術(shù)具有良好的安全性及術(shù)后長(zhǎng)期生存率,且避免了瓣膜相關(guān)不良事件[16-17],但其再次手術(shù)風(fēng)險(xiǎn)較AVR高[16,18]。另外,ESC/EACTS指南[3]認(rèn)為Ross手術(shù)研究證據(jù)尚不充分。Ross手術(shù)對(duì)外科手術(shù)醫(yī)生技術(shù)、術(shù)后管理要求極高,苛刻的實(shí)施條件并不能滿足大部分患者需求。
1.3"Ozaki手術(shù)
Ozaki手術(shù)也稱(chēng)尾崎手術(shù),其使用患者自身組織(心包)構(gòu)建新的主動(dòng)脈瓣,減少了機(jī)械瓣使用可能帶來(lái)的排異反應(yīng)和其他并發(fā)癥的風(fēng)險(xiǎn),相對(duì)生物瓣也更加耐用。但Ozaki手術(shù)相關(guān)研究尚處于較早期階段,并不推薦首選于AS患者。Ozaki手術(shù)已在一些研究和案例中顯示出良好的結(jié)果[19-20],但相較于傳統(tǒng)手術(shù),其開(kāi)展相對(duì)較少且局限,臨床數(shù)據(jù)和長(zhǎng)期隨訪結(jié)果也較少,缺乏高質(zhì)量的研究評(píng)估其安全性及遠(yuǎn)期預(yù)后。另外,Ozaki手術(shù)與Ross手術(shù)有著類(lèi)似嚴(yán)苛的實(shí)施條件,Ozaki手術(shù)并不適用于大部分患者。
1.4"球囊主動(dòng)脈瓣成形術(shù)
球囊主動(dòng)脈瓣成形術(shù)(balloon aortic valvuloplasty,BAV)作為一種介入性治療手段,通常用于無(wú)法手術(shù)且需臨時(shí)緩解癥狀的患者。但作為一種過(guò)渡療法,BAV并不優(yōu)于直接手術(shù)治療。Toutouzas等[21]指出嚴(yán)重AS患者的BAV預(yù)處理相較直接TAVR并無(wú)顯著優(yōu)勢(shì)(log-rank P分別為0.49和0.54)。另有研究[22]報(bào)道,相較直接TAVR,緊急BAV后擇期TAVR的院內(nèi)及圍手術(shù)期不良反應(yīng)增加。BAV作為過(guò)渡療法可能延遲AVR治療,增加潛在手術(shù)風(fēng)險(xiǎn)以及影響預(yù)后[22-23]。若不能尋找新的應(yīng)用方向,BAV未來(lái)可能面臨淘汰。
2"無(wú)創(chuàng)超聲治療
Cardiawave公司的Valvosoft設(shè)備是用于治療鈣化性主動(dòng)脈瓣狹窄(calcific aortic stenosis,CAS)的一種無(wú)創(chuàng)超聲治療(non-invasive ultrasound therapy,NIUT)醫(yī)療設(shè)備,其通過(guò)提供極其精確和聚焦的超聲波束以軟化瓣膜組織、恢復(fù)瓣葉活動(dòng)性,并改善血流動(dòng)力學(xué)相關(guān)參數(shù),以改善主動(dòng)脈瓣相關(guān)的整體臨床狀態(tài)。
NIUT在AS患者中可行且相對(duì)安全,具有優(yōu)于傳統(tǒng)手術(shù)的無(wú)負(fù)性腦損害(包括短暫性腦缺血發(fā)作或卒中、認(rèn)知功能下降等)特點(diǎn)。Messas等[24]首次將Valvosoft設(shè)備用于無(wú)癥狀嚴(yán)重AS患者,隨訪1月,10例患者中無(wú)死亡、心肌梗死、腦卒中或短暫性腦缺血發(fā)作事件報(bào)告,無(wú)明顯認(rèn)知功能受損及新發(fā)或惡化的主動(dòng)脈瓣反流情況發(fā)生;另外,這些患者治療后1個(gè)月的主動(dòng)脈瓣口面積增加16.4%,平均壓力梯度下降12.5%。該團(tuán)隊(duì)還通過(guò)完善術(shù)前及術(shù)后頭顱磁共振檢查以評(píng)估NIUT有無(wú)引起急性腦缺血變化,研究結(jié)果顯示NIUT未對(duì)大腦產(chǎn)生負(fù)性影響[25]。Messas等[26]最新研究進(jìn)一步證實(shí)了NIUT的有效性及安全性,隨訪6個(gè)月,患者平均主動(dòng)脈瓣面積增加10%[從基線時(shí)的0.58 cm2增加到隨訪時(shí)的0.64 cm2(P=0.008 8)],平均壓力梯度從41.9 mmHg(1 mmHg=0.133 3 kPa)下降到38.8 mmHg(P=0.024),總生存率為72.5%(95%CI 56.0~83.7)(無(wú)手術(shù)相關(guān)死亡),患者臨床狀態(tài)較大改善(96%患者紐約心功能分級(jí)改善或穩(wěn)定)。
NIUT的有效性及安全性已得到初步證實(shí),在AS缺少藥物治療的當(dāng)下是極具潛力的治療措施,未來(lái)可能是AS患者的重要備選或輔助治療方案。但NIUT作為近年來(lái)的新興技術(shù),其相關(guān)研究較少,有待更多高質(zhì)量臨床研究證據(jù)支持。可持續(xù)關(guān)注目前尚未發(fā)布最終試驗(yàn)結(jié)果的NIUT相關(guān)研究(NCT04665596和NCT05235568)。
3"藥物治療
AS手術(shù)治療技術(shù)日趨成熟,但AS患者仍未得到充分治療。藥物治療AS是非常具有前景的研究領(lǐng)域。
3.1"降脂治療
降脂治療具有較大的AS治療潛力,但缺少研究證據(jù)支持。早期研究已證實(shí)了低密度脂蛋白膽固醇與脂蛋白a在CAS中的因果作用,但低密度脂蛋白膽固醇相關(guān)研究未能獲得積極結(jié)果。近年來(lái)針對(duì)脂蛋白a的藥物研究已取得階段性成果[27-28],已有研究[29]發(fā)現(xiàn)前蛋白轉(zhuǎn)化酶枯草溶菌素9(proprotein convertase subtilisin/kexin type 9,PCSK9)抑制劑類(lèi)藥物可減少冠心病患者AS發(fā)生率,只是尚未在AS患者中驗(yàn)證其有效性。PCSK9抑制劑延緩AS作用的臨床試驗(yàn)(NCT03051360和NCT04968509)還未發(fā)布研究結(jié)果。
3.2"靶向NO途徑
血管中NO在維持瓣膜小葉平衡中起著重要作用,其可通過(guò)Notch1信號(hào)傳導(dǎo)影響瓣膜纖維化和鈣化。NO信號(hào)傳導(dǎo)途徑的靶向治療研究潛力巨大,已在基礎(chǔ)實(shí)驗(yàn)中初見(jiàn)成效,相應(yīng)臨床試驗(yàn)也已在開(kāi)展中。ataciguat(一種氧化可溶性鳥(niǎo)苷酸環(huán)化酶激活劑)可減緩小鼠主動(dòng)脈瓣鈣化的進(jìn)展[30],二肽基肽酶-4抑制劑也被發(fā)現(xiàn)與糖尿病患者AS進(jìn)展緩慢相關(guān)[31]。在此基礎(chǔ)上,Jordan團(tuán)隊(duì)設(shè)計(jì)了一項(xiàng)隨機(jī)對(duì)照試驗(yàn)以評(píng)估ataciguat在CAS患者中延緩瓣膜鈣化進(jìn)展的作用(NCT02481258),Dong-AST公司也開(kāi)展了一項(xiàng)多中心隨機(jī)臨床試驗(yàn),旨在評(píng)估DA-1229(依格列汀)在CAS患者中的療效及安全性(NCT04055883)。
3.3"調(diào)控鈣磷代謝
鈣磷代謝是調(diào)節(jié)血管和瓣膜鈣化的關(guān)鍵因素。Raggi團(tuán)隊(duì)[32]發(fā)現(xiàn)SNF472(靜脈用肌醇六磷酸鹽)顯著減緩了慢性腎臟疾病患者主動(dòng)脈瓣鈣化的進(jìn)展。但進(jìn)一步的藥物研究未能取得預(yù)期的結(jié)果。Pawade團(tuán)隊(duì)[33]的雙盲隨機(jī)對(duì)照試驗(yàn)中,與安慰劑組相比,地諾單抗(一種核因子κB受體激活蛋白配體抑制劑,核因子κB受體激活蛋白配體參與調(diào)節(jié)骨轉(zhuǎn)換和瓣膜鈣化)或阿侖膦酸(一種雙膦酸鹽)組CAS患者的1年主動(dòng)脈瓣鈣化評(píng)分變化無(wú)明顯差異,其平均壓力梯度或主動(dòng)脈瓣面積也無(wú)組間差異。通過(guò)調(diào)節(jié)鈣磷代謝以延緩瓣膜病變暫不可行,仍需探索替代途徑和機(jī)制。
3.4"抑制腎素-血管緊張素-醛固酮系統(tǒng)
既往研究[34]顯示血管緊張素轉(zhuǎn)換酶2活性水平與AS患者的瓣膜鈣化增加相關(guān)。另有研究[35]發(fā)現(xiàn)腎素-血管緊張素-醛固酮系統(tǒng)抑制劑可改善TAVR術(shù)后AS患者的預(yù)后。但是否對(duì)AS發(fā)揮直接作用尚缺乏臨床研究證據(jù)。旨在評(píng)估血管緊張素Ⅱ受體阻滯劑減緩AS瓣膜狹窄進(jìn)展功效的ARBAS隨機(jī)對(duì)照試驗(yàn)(NCT04913870)正在進(jìn)行中。評(píng)估非馬沙坦對(duì)AS患者的安全性和有效性的ALFA試驗(yàn)(NCT01589380)也暫未發(fā)布研究結(jié)果。
3.5"補(bǔ)充維生素K
維生素K可防止血管鈣化,還可輔助基質(zhì)Gla蛋白(體內(nèi)起到抑制心血管鈣化的作用)發(fā)揮完整生理活性作用。但目前證據(jù)暫不支持補(bǔ)充維生素K可延緩AS進(jìn)展。一項(xiàng)隨機(jī)對(duì)照試驗(yàn)[36]發(fā)現(xiàn)補(bǔ)充維生素K可減緩主動(dòng)脈瓣鈣化進(jìn)展,但基于此試驗(yàn)的進(jìn)一步研究未能驗(yàn)證補(bǔ)充維生素K對(duì)AS的積極作用[37]。適量維生素K攝入可減少心血管疾病的風(fēng)險(xiǎn),但是否改善CAS尚不能明確。
3.6"其他
近年來(lái)科研人員發(fā)現(xiàn)了許多有潛力的蛋白組學(xué)或代謝組學(xué)靶點(diǎn),如PI3K/Akt信號(hào)通路、半乳糖凝集素-3、MFSD5跨膜運(yùn)輸?shù)鞍椎?sup>[38-40]。這些靶點(diǎn)在基礎(chǔ)實(shí)驗(yàn)中被發(fā)現(xiàn)與主動(dòng)脈瓣鈣化進(jìn)程相關(guān)。另外,基因組學(xué)研究也發(fā)現(xiàn)AS與鈣化、脂質(zhì)代謝、肥胖、血壓和炎癥具有遺傳相關(guān)性[41],探索出了AS潛在基因靶點(diǎn),也為AS治療提供了更多的研究思路,目前已開(kāi)展了秋水仙堿抗炎治療與AS的研究(NCT05162742)。表2列出了各類(lèi)AS藥物治療的臨床研究。
4"展望
目前AS仍以手術(shù)治療為主且術(shù)式選擇豐富,TAVR有著巨大的治療潛力,未來(lái)可能應(yīng)用于更多類(lèi)型AS患者。對(duì)未達(dá)到手術(shù)指征或不宜行手術(shù)治療的AS患者,NIUT在未來(lái)或可成為治療首選,并且有望應(yīng)用于門(mén)診患者。目前尚無(wú)療效確切的藥物可用于AS患者,但諸多有潛力的藥物正在臨床研究中,未來(lái)或可打破無(wú)藥可用的局面。
當(dāng)前AS治療手段趨于單一且適用范圍窄,尚有許多AS患者未能及時(shí)得到有效干預(yù)。在積極發(fā)展和打磨手術(shù)技術(shù)的同時(shí),研究并實(shí)踐出有效的全面治療AS的方法極其重要,也是當(dāng)下醫(yī)療背景下迫在眉睫的需求。
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收稿日期:2024-07-10