以LDL-C為靶點的降脂治療是ASCVD預防的核心,其受益程度與強化他汀類藥物單藥治療以及與依折麥布和前蛋白轉化酶枯草桿菌蛋白酶9型(PCSK9)抑制劑聯合使LDL-C降低的程度直接相關。降脂治療對冠狀動脈斑塊體積和成分的有益影響被認為是降低心血管風險的關鍵機制。
在過去的幾十年裡,在許多臨床試驗中應用了幾種侵入性和非侵入性成像技術,以評估降脂治療對冠狀動脈斑塊負荷和區域性斑塊特徵的影響。本文總結了既往獲得的關於降脂治療策略對動脈粥樣硬化斑塊消退影響的資料,這些資料主要通過幾種成像方式評估。
斑塊形成是一個複雜的、多因素的、多步驟的過程,通常持續數年或數十年。特別是,在持續暴露於多種致病風險因素(如高血壓、血脂異常、糖尿病和吸菸)導致的內皮功能障礙的情況下,LDL-C等脂蛋白顆粒穿過內皮屏障並留在動脈壁[4-6]。氧化應激誘導的炎性細胞募集促進巨噬細胞對修飾脂蛋白顆粒的攝取,形成了泡沫細胞。充滿脂質的巨噬細胞和平滑肌細胞增殖產生的泡沫細胞的積聚導致纖維帽形成和斑塊生長。炎性細胞浸潤、平滑肌細胞死亡和基質降解導致易損斑塊,斑塊具有薄纖維帽和富含脂質的壞死核心。
動脈粥樣硬化通常被認為是一種慢性進行性疾病,可能因多種缺血事件而變得複雜。動脈粥樣硬化斑塊總負荷的大小可能與迴圈LDL-C和其他含載脂蛋白B(ApoB)的濃度以及接觸這些脂蛋白的總持續時間成正比[2]。斑塊進展分為以下幾個階段:亞臨床動脈粥樣硬化(內膜增厚和內膜脂質條紋)、可能導致血栓形成事件的易損斑塊和鈣化的穩定斑塊。易損斑塊的特徵通常是斑塊負荷增加、正向重塑、薄纖維帽覆蓋的大脂質核心、巨噬細胞積聚和新生血管[7]。
斑塊消退傳統上被定義為冠狀動脈造影管腔直徑的增加,作為斑塊尺寸減小的替代標誌[8]。然而,斑塊成像技術的最新進展不僅可以直接評估動脈粥樣硬化斑塊負荷,還可以評估斑塊成分。除了使用血管內超聲(IVUS)對未來心血管事件進行替代測量的斑塊負荷外,斑塊成分也是斑塊相關缺血性事件的相關決定因素。在這種情況下,斑塊消退可以定義為斑塊形態的有利變化,包括動脈粥樣硬化體積和降低隨後心血管事件風險的成分[9]。在日常實踐中,在強化一級/二級預防後,通常會觀察到斑塊消退,其特徵是斑塊體積減少,從不穩定斑塊變為穩定鈣化斑塊。
斑塊消退的臨床相關性已在之前的薈萃分析中得到解決[10-11]。最近的一項薈萃迴歸分析綜合了23項降脂治療研究,報告了IVUS動脈粥樣硬化體積百分比和臨床結果的變化,表明斑塊消退與心血管事件減少之間存在顯著關聯[12]。在7 407名試驗持續時間為11~104周的患者中,一項調整後的分析顯示平均動脈粥樣硬化體積百分比(PAV)降低1%與主要不良心血管終點(MACE)的機率降低14%相關(調整後的比值比[HR]=0.86)。這些結果表明,PAV的變化可能是心血管事件的替代標誌物,因此可能突出冠狀動脈斑塊時間評估的臨床相關性,以更準確地指導降脂治療的滴定決策。
在之前的臨床研究中,已經使用了幾種侵入性和非侵入性成像方式來評估斑塊負荷和成分。圖1總結了用於評估冠狀動脈斑塊的每種成像模式的特徵。
IVUS成像基於換能器振盪運動產生的超聲波,並利用各種動脈結構的反射差異來生成動脈壁和管腔的橫截面影像。IVUS的解析度為100~150µm,穿透深度為4~8mm。透過檢測管腔和血管輪廓,IVUS可以提供斑塊負荷(斑塊面積=血管面積-管腔面積)。因此,血管內超聲一直是評估動脈粥樣硬化斑塊的主要侵入性方法,目前被認為是斑塊定量的金標準。

圖1.評估冠狀動脈斑塊的影像學特徵。
CTA,計算機斷層攝影血管造影;FCT,纖維帽厚度;IVUS,血管內超聲;LCBI,脂質核心負荷指數;NA,不可用;NIRS,近紅外光譜;OCT,光學相干斷層掃描;PAV,動脈粥樣硬化體積百分比;TAV,動脈粥樣硬化總體積。
由於解析度有限,IVUS無法可靠地評估纖維帽厚度和詳細的斑塊成分。之前的一項使用計算機斷層掃描血管造影(CTA)資料的研究報告稱,與動脈粥樣硬化總體積(TAV)和標準化TAV相比,PAV受體表面積的影響較小,可能是量化冠狀動脈粥樣硬化負擔的最佳變數[13]。使用射頻背向散射資料的光譜分析,如虛擬組織學(VH)-IVUS、背向散射積分(IB)-IWUS和iMAP,通過幾種後處理方法評估了斑塊成分。VH-IVUS是以前最常用的斑塊消退評估方法之一,並可提供斑塊成分資訊,包括壞死核心、緻密鈣、纖維和纖維脂肪組織[14]。儘管VH-IVUS衍生的薄帽纖維粥樣斑塊(TCFA)已被用作未來心血管事件的高危特徵[15],但據報道,由於其解析度有限,診斷能力低於光學相干斷層掃描(OCT)[16]。因此,這些模式在當前的日常實踐中已不再使用。
OCT成像使用近紅外光獲得,較IVUS的解析度(10~20μm)高,可提供更詳細的淺表動脈壁微觀結構影像,包括纖維帽厚度、巨噬細胞、潰瘍和血栓。OCT衍生的TCFA是一種易發生急性冠狀動脈事件的高危斑塊特徵,通常定義為纖維帽厚度<65μm[17]。OCT得出的主要結果指標包括最小纖維帽厚度(FCT)、巨噬細胞角和脂質弧。然而,由於組織滲透性低(即最大2mm),OCT不能準確測量斑塊負荷和血管大小,特別是在脂質組織中。近紅外光譜(NIRS)使用背散射光的光譜分析,提供動脈壁中膽固醇含量的資訊。將NIRS與IVUS相結合有助於進行準確和客觀的評估(即減少操作員依賴性)富含脂質的斑塊,管腔和斑塊可見。脂質的量被描述為脂質核心負荷指數(LCBI),透過將黃色畫素的數量除以可用畫素的總數,再乘以1000(範圍從0~1000)來計算[18]。maxLCBI4mm通常用於量化介入靶區內脂質斑塊的最大區域,分為4mm的冠狀動脈段。之前的一項影像學研究報告稱,NIRS衍生的富含脂質的斑塊與IVUS和OCT上的高危斑塊特徵密切相關[19]。
冠狀動脈CTA是一種非侵入性成像技術,可以定量評估冠狀動脈狹窄和斑塊。CTA根據Hounsfield單位將斑塊型別分為低衰減、纖維脂肪、纖維和鈣化斑塊[20]。CTA檢測到的高危斑塊的定性特徵包括低衰減斑塊、陽性重塑、斑點狀鈣化和餐巾環徵[21]。與僅能顯示成像段的冠狀動脈內成像相比,CTA可以提供完整的冠狀動脈樹資訊,包括狹窄、斑塊體積和斑塊成分。最近,CTA已被證明可以顯示冠狀動脈周圍脂肪組織的衰減,這反映了冠狀動脈炎症的程度[22]。CTA的侷限性包括比冠狀動脈內成像和成像偽影更低的解析度,如運動和束硬化,這可能會導致斑塊成分的錯誤分類。
其他非侵入性技術包括心臟磁共振(CMR)和正電子發射斷層掃描(PET)。CMR可以檢測冠狀動脈狹窄並表徵血管壁,包括陽性重塑[23]。然而,由於其有限的空間解析度和耗時的性質,CMR在日常實踐中並不常用於冠狀動脈評估,也沒有研究檢查冠狀動脈斑塊消退。PET可以使用放射性配體(例如18F-氟脫氧葡萄糖[18F-FDG]和18F-氟化鈉)[24]。由於心肌攝取18F-FDG,評估冠狀動脈斑塊炎症的解析度有限。與血管微鈣化結合的新型放射性示蹤劑18F-氟化鈉在識別罪犯病變和易損斑塊方面顯示出良好的診斷能力,尤其是當與CT或CMR結合時[25-26]。
許多影像學研究評估了降脂治療對冠狀動脈斑塊的影響,併為降脂治療的心血管益處提供了機制基礎。圖2總結了先前藥理學試驗(他汀類藥物、依折麥布和PCSK9抑制劑)中LDL-C水平與斑塊消退之間的關係。儘管根據研究設計(如基線脂質管理、隨訪時間、患者表現、基線斑塊負荷)和所調查的藥物,各研究之間存在很大差異,但在之前的隨機試驗中,PAV(-5.7%至+0.9%)、TAV(-26.1%至+0.2%)、minFCT(+7.7μm至+110.1μm)和maxLCBI4mm(-149.1至-5.2)的有利變化得到了對照試驗(RCTs)和觀察性研究(圖2)的證實。

圖2冠狀動脈內成像斑塊變數與LDL-C之間的相關性
氣泡圖顯示了PAV(A)的變化、TAV(B)的變化百分比、最小FCT(C)的變化和最大LCBI4mm(D)的變化(y軸),與主要斑塊消退試驗的治療組中達到的LDL-C(x軸)相比(未顯示對照組)。氣泡大小與治療組中的患者數量成正比。FCT,纖維帽厚度;LCBI,脂質核心負荷指數;LDL-C,低密度脂蛋白膽固醇;PAV,動脈粥樣硬化體積百分比;TAV,動脈粥樣硬化總體積。
他汀類藥物透過抑制HMG-CoA還原酶來減少肝臟中的膽固醇合成。細胞內膽固醇的減少促進了肝細胞表面LDL受體的表達,導致血液中LDL-C的攝取增加,LDL和其他含ApoB的脂蛋白(包括富含甘油三酯(TG)的顆粒)的血漿濃度降低。儘管LDL-C的降低程度呈劑量依賴性,且LDL-C降低存在相當大的個體間差異,但他汀類藥物通常會將LDL-C水平降低約30%~50%[27]。
幾項研究調查了他汀類藥物對冠狀動脈斑塊的影響。這些研究大多使用IVUS來評估斑塊負荷的變化,VH-IVUS、OCT和NIRS已被用於評估斑塊成分。斑塊消退的程度與LDL-C降低的程度相關,類似於缺血風險降低與血清LDL-C水平之間的關聯[28]。1997年,Takagi等[29]首次報道了他汀類藥物對冠狀動脈斑塊的有益作用,如IVUS所評估的。與僅接受飲食穩定治療的患者(n=12)相比,接受普伐他汀10 mg治療的患者在36個月時斑塊面積顯著減少(PAV:-7±23 vs +41±23,P<0.0005)。從那時起,進行了很多臨床試驗來探究降脂治療對冠狀動脈斑塊的影響。既往的一些隨機對照試驗顯示,與低強度他汀類藥相比,高強度他汀類藥物可以誘導更大的斑塊體積減少。2004年的REVERSAL試驗報告稱,在654名冠狀動脈疾病(CAD)患者中,阿託伐他汀80mg與普伐他汀40mg相比,在18個月時透過IVUS減少了冠狀動脈粥樣硬化的進展(TAV變化百分比:-0.4% vs +2.7%;P=0.02)[30]。2011年的SATURN試驗在1039名CAD患者中比較了阿託伐他汀80 mg和瑞舒伐他汀40 mg,並報告稱,這兩種方案在24個月時均顯著降低了PAV(-0.99% vs -1.22%,P=0.17)[31]。2009年的急性冠狀動脈綜合徵(ACS)試驗報告稱,在307名ACS患者中,匹伐他汀4 mg和阿託伐他汀20 mg在9個月時同樣導致冠狀動脈斑塊體積顯著下降(TAV:-5.7% vs -6.3%、P=0.5)[32]。2016年橫濱ACS研究調查了4種不同他汀類藥物對118名ACS患者的冠狀動脈斑塊。在10個月時,阿託伐他汀20 mg和匹伐他汀4 mg組的斑塊體積減少幅度大於普伐他汀10 mg和氟伐他汀30 mg組(TAV:-3.6% vs -2.9% vs +1.5% vs +0.4%,P=0.02)[33]。
他汀類藥物對斑塊組成的影響已在幾項使用VH-IVUS、IB-IVUS,OCT和NIRS的研究中進行了評估。VH-和IB-IVUS研究通常表明斑塊穩定,包括纖維和鈣化斑塊體積增加,壞死核心和非鈣化斑塊體積減少。在OCT試驗中,2014年EASY-FIT試驗調查了70名不穩定型心絞痛患者中阿託伐他汀20 mg與阿託伐他汀5 mg對斑塊穩定的影響。在1年時,阿託伐他汀20 mg顯著提高了最小FCT(+73μm vs +19μm,P=0.002),降低了脂質弧度(-50°vs -10°,P<0.001)[34]。2018年的IBIS-4觀察性研究表明,在103名ST段抬高型心肌梗死(STEMI)患者中,瑞舒伐他汀40 mg在1年內顯著增加了最小FCT(+24μm),減少了巨噬細胞弧(-3°)。使用近紅外光譜黃色試驗表明,與標準治療組相比,瑞舒伐他汀40 mg組在7周時最大LCBI4mm顯著降低(-149 vs +2.4,P=0.01)[36]。幾項CTA研究表明,他汀類降脂治療可以減輕斑塊體積進展[37-39]。2018年的PARADIGM研究調查了他汀類藥物對1255名無冠心病(CAD)病史患者的冠狀動脈斑塊的影響。與他汀類藥物患者的病變相比,他汀類藥物服用患者的總體PAV進展速度較慢(每年1.76%±2.40% vs每年2.04%±2.37%,P=0.002),但鈣化PAV進展更快(每年1.27%±1.54% vs 每年0.98%±1.27%,P<0.001)[38]。
依折麥布可抑制腸道對膳食和膽汁膽固醇的攝取,而不影響脂溶性營養素的吸收,從而減少輸送到肝臟的膽固醇量。由於膽固醇輸送減少,肝細胞表面LDL受體表達上調,導致血液中LDL-C的清除率增加。當新增到正在進行的他汀類藥物治療中時,依折麥布在有或沒有CAD的血脂異常患者中可將LDL-C水平額外降低21%~27%[27]。
幾項使用IVUS的隨機試驗評估了除他汀類藥物外,依折麥布10mg對冠狀動脈斑塊消退的益處,並一致顯示斑塊消退(PAV變化)範圍為-0.4%~-2.9%。2012年的HEAVEN試驗表明[40],在89名CAD穩定的患者中,與標準治療(即單獨使用他汀類藥物)相比,依折麥布10mg和阿託伐他汀80mg在1年時顯著降低了PAV(-0.4% vs +1.4,P=0.014)。Masuda等[41]在2015年證明,依折麥布聯合瑞舒伐他汀5 mg在6個月時顯著降低了TAV(-13.2% vs -3.1%; P=0.05)與單獨使用瑞舒伐他汀5mg治療51名CAD穩定的患者相比。2015年的PRECISE-IVUS同樣顯示,在202名接受經皮冠狀動脈介入治療(PCI)的患者中,與單獨使用阿託伐他汀相比,阿託伐他汀聯合依折麥布可使斑塊明顯消退(PAV變化:-1.4% vs -0.3%,P=0.001)[42]。其他試驗,包括ZEUS(2014)[43]和OCTIVUS(2016)[44]試驗以及Hibi等[45](2018)和Oh等[46](2021)的研究,顯示依折麥布聯合他汀類藥物治療的患者斑塊消退程度在數值上比單獨使用他汀類藥物的患者更大;然而,這些差異在統計學上並不顯著。使用VH-IVUS [40-44]、IB-IVUS[45]和NIRS-IVUS[46]評估依折麥布與他汀類藥物治療對斑塊組成的影響,但治療組之間沒有觀察到顯著差異。
2017年的ZIPANGU研究報告稱,在131名穩定型CAD患者中,聯合治療組(阿託伐他汀10~20mg加依折麥布)和單藥治療組(阿伐他汀10~20mg)的血管鏡黃色等級(等級越高,表明脂質越多)顯著降低,但治療組之間沒有顯著差異[47]。PCSK9抑制劑血漿中PCSK9濃度或功能的增加透過促進溶酶體分解代謝來降低LDL受體表達,導致血漿LDL濃度增加。
主要使用針對PCSK9的人源化單克隆抗體開發了治療策略,該抗體特異性結合PCSK9以抑制其對LDL受體的影響,導致LDL-C降低高達60%。英克司蘭(Inclisiran)是一種新型的基於小干擾RNA的療法,可抑制PCSK9的合成,使LDL-C降低高達50%[27];然而,目前關於其對斑塊消退影響的證據僅限於抗人PCSK9單克隆抗體。2016年的GLAGOV試驗透過IVUS 48評估了依洛尤單抗(evolocumab)和他汀類藥物對冠狀動脈斑塊的影響。在968名接受冠狀動脈造影的患者中,與安慰劑組相比,依洛尤單抗組在76周時的PAV顯著降低(-0.95% vs +0.05%,P<0.01)。2019年的ODYSSEY J-IVUS試驗使用IVUS評估了206名近期ACS患者服用75 mg阿利西尤單抗對冠狀動脈斑塊的影響。36周時,阿利西尤單抗組和標準治療組的標準化TAV變化百分比沒有顯著差異(-4.8% vs -3.1%,P=0.23)。2022年的PACMANAMI試驗使用NIRS-IVUS和OCT[50]和其他多效性效應[51-53]。在300名AMI患者中研究了在他汀類藥物治療中新增阿利西尤單抗對冠狀動脈粥樣硬化的影響。1年時,阿利西尤單抗導致的斑塊體積減少較安慰劑更大(PAV變化:-2.13%vs -0.92%,P<0.001)。此外,阿利西尤單抗對斑塊成分有良好的影響(近紅外光譜顯示最大LCBI4mm:-79.42 vs -37.60,P=0.006,OCT顯示最小FCT:62.67μm vs 33.19μm,P<0.001)[54]。
PACMAN-AMI研究的一項子研究報告稱,阿利西尤單抗治療和較高的基線最大LCBI4mm是“三重逆轉”的獨立預測因素(即PAV減少、最大LCBI4mm減少和最小FCT增加),這與MACE風險降低有關[55]。同樣,2022年的HUYGENS試驗報告稱,在161名非STEMI患者中,依洛尤單抗在1年時較安慰劑導致最小FCT增加更多(+42.7 vs +21.5μm,P=0.015)。
眾所周知,高TG水平(>150mg/dL)是潛在的CVD危險因素,但目前的指南建議,只有當TG>200 mg/dL且僅透過生活方式措施無法充分降低時,才考慮在高危患者中使用藥物降低TG水平[27]。幾項研究使用IVUS、OCT和CTA研究了二十碳五烯酸(EPA)對冠狀動脈斑塊的影響,結果喜憂參半。2017年的CHERRY研究報告稱,在193名接受PCI的患者中,與單獨使用匹伐他汀4mg相比,匹伐他汀4 mg和EPA 1800 mg/天的組合在8個月時顯著降低了IB-IVUS引起的TAV。2020年的EVAPORATE試驗表明,在18個月時,二十碳五烯酸乙酯(icosapent ethyl,IPE)4 g/天組的CTA斑塊體積變化百分比較安慰劑組(-9%比+11%,P=0.0019)顯著降低。然而,需要仔細考慮IPE組的高基線斑塊體積和使用礦物油作為安慰劑,這對炎症和脂質狀況有不利影響[58]。另外兩項使用IB-IVUS(Niki等[59],2016)和CTA(Alfaddagh等[60],2017)的隨機對照試驗顯示,斑塊體積的變化沒有顯著差異。Nishio等[61]在2014年報告稱,在30名接受PCI的患者中,與單獨使用瑞舒伐他汀相比,在9個月時,在瑞舒伐他丁中新增EPA 1800 mg/天顯著增加了OCT的FCT(+54.8μm vs +23.5μm,P<0.001),而Kita等[62]在2020年報告說,除他汀類藥物治療外,EPA或EPA+二十二碳六烯酸(DHA)治療並沒有顯著增加FCT。
迄今為止,還沒有關於貝特類藥物對冠狀動脈斑塊消退影響的研究報告。目前,一項隨機試驗正在進行中,該試驗調查了培馬貝特對CAD和空腹TG水平升高患者的冠狀動脈斑塊和腎功能的影響(PEMA-CORE研究)。
多項研究一致報告稱,糖尿病的存在與降脂治療使冠狀動脈斑塊消退遲鈍有關[67-68]。之前對5項隨機對照試驗(包括2237名接受連續IVUS成像以評估幾種藥物對冠狀動脈斑塊進展影響的患者)的薈萃分析表明,糖尿病患者的斑塊進展比非糖尿病患者更大(PAV:+0.6% vs +0.05%,P=0.0001,TAV:-0.6% vs -2.7%,P=0.03)[63]。糖尿病的存在可能會減弱降脂治療對斑塊消退的影響。
脂蛋白(a)(Lp[a])對斑塊消退的影響存在爭議。YOKOHAMA-ACS研究的一個子分析報告稱,與Lp(a)≤20mg/dl的患者相比,Lp(a)>20mg/dl患者的斑塊消退減弱(PAV:+2.5% vs -6.8%,p=0.02)[68],而SATURN研究的一個子分析表明,Lp(a)水平與PAV的變化無關[69]。
幾種成像技術已應用於臨床試驗,以確定降脂治療對冠狀動脈斑塊負荷和成分的影響。儘管IVUS是評估斑塊負荷最廣泛使用的方法,但其他侵入性方法,如OCT和近紅外光譜,可以提供斑塊易損性的相關資料,而CTA可以非侵入性地檢測斑塊體積和特徵。大量證據支援他汀類藥物單獨或與依折麥布和PCSK9抑制劑聯合降低LDL-C持續改善斑塊負荷和有利的形態學變化的觀點。未來的研究應側重於新的治療方案對新興治療靶點的影響,包括Lp(a)、TG和炎症對冠狀動脈斑塊的影響,儘管需要明確的臨床終點試驗來確認臨床療效和潛在的不良反應。此外,鑑於斑塊消退與心血管事件減少之間的因果關係,直接進行斑塊成像以監測動脈粥樣硬化斑塊體積和成分的時間變化可能在指導一級和二級預防的治療決策方面發揮一定的作用。常規斑塊成像指導下的最佳藥物治療是否真的能改善臨床結果,仍需進一步研究證實。
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專家簡介

鄭剛 教授
•現任泰達國際心血管病醫院特聘專家,濟興醫院副院長
•中國高血壓聯盟理事,中國心力衰竭學會委員,中國老年醫學會高血壓分會天津工作組副組長、中國醫療保健國際交流促進會高血壓分會委員。天津醫學會心血管病專業委員會委員,天津醫學會老年病專業委員會常委。天津市醫師協會高血壓專業委員會常委,天津市醫師協會老年病專業委員會委員,天津市醫師協會心力衰竭專業委員,天津市醫師協會心血管內科醫師分會雙心專業委員會委員。天津市心臟學會理事、天津市心律學會第一屆委員會委員,天津市房顫中心聯盟常委。天津市醫藥學專家協會第一屆心血管專業委員會委員,天津市藥理學會臨床心血管藥理專業委員會常委。天津市中西醫結合學會心血管疾病專業委員會常委
•《中華老年心腦血管病雜誌》編委,《中華臨床 醫師雜誌》(電子版)特邀審稿專家,《中華診斷學電子雜誌》審稿專家,《華夏醫學》雜誌副主編,《中國心血管雜誌》常務編委,《中國心血管病研究》雜誌第四屆編委,《世界臨床藥物》雜誌編委、《醫學綜述》雜誌會編委、《中國醫藥導報》雜誌編委、《中國現代醫生》雜誌編委、《心血管外科雜誌(電子版)》審稿專家
•本人在專業期刊和心血管網發表文章948篇其中第一作者759篇,參加著書11部
