冠狀動脈無復流現(xiàn)象的防治

1、冠狀動脈無復流現(xiàn)象的防治,武警部隊心臟研究所武警部隊心血管介入中心 羅建平武警總醫(yī)院心血管內(nèi)科,病人資料,毛某，男性，78歲，糖尿病8年，高血壓病，高脂血癥，吸煙20余年，1年前戒除主因發(fā)作性劍突下疼痛4天，于2007年09月18日由門診以“冠心病 急性心肌梗死”收入科。ECG：V1-V5導聯(lián)ST段抬高>0.2mv。肌鈣蛋白升高。,,CAG,,CAG,球囊擴張前冠脈內(nèi)給予硝酸甘油200ug，欣維寧10ml

2、,,2.5*15mm球囊擴張,球囊擴張后,,植入支架3.0*24mm,植入后造影no-reflow,,先后冠脈給予欣維寧再10ml、硝酸甘油400ug，異搏定400ug后,,近端植入支架3.5*14mm,,植入后造影no-reflow,,再先后冠脈給予欣維寧10ml、硝酸甘油500ug，異搏定600ug后,一、無復流概述,無復流現(xiàn)象(no-reflow)是指閉塞的心外膜冠狀動脈再通后，心肌組織無灌注的現(xiàn)象。冠狀動脈造影表現(xiàn)為血流明顯減慢

3、(血流<=TIMI 2級)，而冠狀動脈無殘余狹窄、夾層、痙攣或血栓形成等機械性梗阻存在。,,研究發(fā)現(xiàn)，無復流是一個隨時間而發(fā)展的過程，而不僅僅是發(fā)生于再灌注當時的急性事件。無復流區(qū)面積隨再灌注時間延長而增加，部分無復流可發(fā)生于再灌注后的24、48小時。另外24小時內(nèi)部分無復流病例在1個月后行心肌聲學造影（MCE）復查時發(fā)生無復流逆轉(zhuǎn)，且心臟功能良好。因此，無復流應(yīng)該是再灌注后的一個動態(tài)過程。,,無復流既可出現(xiàn)在心肌灌注的動物模型上

4、，又可發(fā)生在臨床上AMI再灌注治療(包括溶栓和介人)和擇期的經(jīng)皮冠狀動脈介人治療(PCI)中，是并非少見的緊急并發(fā)癥。Piana等和Abbo等的報道AMI PCI、斑塊旋磨和旋切術(shù)及大隱靜脈橋PCI的無復流發(fā)生率最高，分別達11.5% ，7.7%和4.5%及4%，常規(guī)PCI的發(fā)生率僅1%-2%。,,冠狀動脈無復流可產(chǎn)生嚴重心肌缺血危及患者的生命，甚至發(fā)生心血管崩潰立即致死；而且，無復流是由于組織水平無灌注的結(jié)果，緊急處理甚為棘手；預(yù)后

5、差。Abbo等報道冠狀動脈無復流住院病死率和心肌梗死發(fā)生率分別高達15%和31%，比未發(fā)生無復流的患者高10倍，Ito等也報道AMI無復流者早期心力衰竭更多，恢復期心室擴大和重構(gòu)更明顯。,對無復流現(xiàn)象的認識,從事研究和介人治療的心臟病學家對無復流現(xiàn)象的認識存在差異，前者注重組織灌注水平的無復流，而后者則注重其冠狀動脈造影下的表現(xiàn)。,,2001年Eeckhout和Kern將無復流分為實驗性、心肌梗死再灌注性和血管性無復流三類，分別是指在

6、動物實驗中、AMI在藥物和機械方法使冠狀動脈再通的情況下和常規(guī)PCI中所產(chǎn)生的無復流。Galiuto等又將無復流分為結(jié)構(gòu)性和功能性無復流，前者是由于微血管結(jié)構(gòu)破壞所致，一旦發(fā)生不易改善；而后者微血管結(jié)構(gòu)是完整的，但由于其功能障礙(如痙攣和栓塞)導致無復流，是可改善的無復流。,無復流產(chǎn)生的病理生理機制還不完全清楚，但其結(jié)局是由于微循環(huán)損傷或功能障礙使微血管水平血流受阻所致已被公認。,二、無復流的病理生理機制,可能機制,微血管結(jié)構(gòu)完整性破

7、壞微栓子栓塞白細胞聚集微血管功能完整性損傷，主要是痙攣所致血小板激活氧自由基,可能機制,1 微血管結(jié)構(gòu)完整性破壞電鏡下發(fā)現(xiàn)，無復流區(qū)毛細血管內(nèi)皮腫脹、突出甚至脫落、周邊的壞死心肌壓迫，使毛細血管及內(nèi)皮細胞的完整性遭破壞,,2 微栓子栓塞微栓子栓塞在臨床血管性和心肌梗死再灌注性無復流發(fā)生中起關(guān)鍵作用。主要來源于冠狀動脈不穩(wěn)定病變中的粥樣斑塊碎片(如膽固醇結(jié)晶等)和微血栓，經(jīng)溶栓或PCI時擠壓脫落而致遠端微血管栓塞。近年來，

8、PCI中使用遠端保護裝置，既可回收到血栓和斑塊碎片，也能大大減少無復流發(fā)生。,,3 白細胞聚集無復流區(qū)微血管內(nèi)大量中性粒細胞積聚。無白細胞的血液再灌注可減輕無復流，提示白細胞聚集及其與內(nèi)皮細胞間的相互作用，可能也是產(chǎn)生無復流的機制之一。,缺血再灌注使心臟交感神經(jīng)興奮，由α-受體介導冠狀動脈微小動脈系統(tǒng)彌漫痙攣。缺血再灌注損傷使內(nèi)皮細胞生成NO減少，血管舒張功能減弱，難以拮抗α-受體介導的腎上腺素能血管收縮效應(yīng)。三磷酸腺苷(ATP)

9、敏感的鉀通道(KATP)受抑制致冠狀動脈痙攣。PCI使血栓碎裂和血小板脫顆粒，釋放血栓素A2和5-羥色胺等縮血管因子，引起微血管痙攣。,4 微血管功能完整性損傷。主要是痙攣所致，可能原因為,,5 血小板激活無復流分為由血小板激活造成微血管阻塞的早期階段，及隨后由于中性粒細胞、自由基釋放及細胞水腫造成再灌注損傷的后期階段。缺血再灌注初起，血小板激活可導致微血栓形成，同時脫顆粒釋放血栓素A2和5-羥色胺等縮血管因子，引起微血管痙攣，產(chǎn)

10、生無復流。最近發(fā)現(xiàn)即使在無血栓形成的情況下，血小板的激活仍可造成冠狀動脈無復流。,,6 氧自由基聯(lián)合應(yīng)用超氧化物歧化酶和過氧化氫酶可顯著減輕無復流，提示氧自由基參與了無復流的發(fā)生。在AMI患者的PCI中，發(fā)現(xiàn)冠狀靜脈竇血中氧自由基水平增高。氧自由基直接作用與毛細血管內(nèi)皮和心肌細胞膜的通透性引起水腫，也可通過激活炎性細胞浸潤引起毛細血管壁和心肌細胞水腫最終造成毛細血管機械性的阻塞。,1、臨床癥狀部分病人無癥狀大部分病人出現(xiàn)胸痛（

11、PCI后0-24h）、嚴重者即刻出現(xiàn)心衰、低血壓、心原性休克、甚至死亡。,三、無復流現(xiàn)象的診斷方法,2、心肌標志物升高,AMI患者再灌注治療后，抬高的ST段完全回落或無回落可以作為反映心肌灌注或無復流的替代指標，ST段抬高指數(shù)減少(>=50%)或ST段抬高指數(shù)增加(>=30%)，對判斷微血管灌注或無復流均有較高準確性(81%)。,3、心電圖,,經(jīng)皮冠狀動脈介入治療后原病變部位無夾層、痙攣或阻塞而冠狀動脈血流小于心肌梗死溶栓治

12、療臨床試驗(TIMI)II級或心肌灌注(TMP) 血流分級0-2級，可以判定無復流。對于冠狀動脈血流TIMI III級的病例，一部分表現(xiàn)為緩慢血流，另一部分為快血流，緩慢血流患者經(jīng)超聲、核素檢查后仍可檢出無復流病例，提示TIMI血流分級在判定無復流方面存在局限性。,4、冠狀動脈造影血流分級,在傳統(tǒng)的TIMI血流分級法基礎(chǔ)上用校正的TIMI幀數(shù)來評估微循環(huán)血流。這是一種較精確的識別技術(shù)，較傳統(tǒng)的TIMI分級客觀、定量、可重復、敏感。造影劑

13、到達指定的冠狀動脈遠端所需的血管造影幀數(shù)越多，血流速度越慢，無復流存在的可能越大。,5、校正的心肌梗死溶栓治療臨床試驗幀數(shù)(CTFC),采用多普勒血流導絲，進行血管內(nèi)超聲檢查，測定時相性和平均冠狀動脈血流速度；測定絕對冠狀動脈血流儲備(CFR)指數(shù)，若顯示冠狀動脈血流儲備指數(shù)下降，收縮期順向血流速度下降，異常收縮早期逆向血流，舒張期血流速度迅速下降均提示無復流現(xiàn)象。收縮早期逆向血流是具有敏感性和特異性的評估無復流的指標。,6、冠狀動脈內(nèi)

14、多普勒血流,7、超聲心肌聲學造影(MCE),將聲處理的造影物質(zhì)(如氟丙烷白蛋白)，其中含高能微泡，從冠狀動脈或靜脈途徑注入，然后做心肌超聲檢查，受累區(qū)無復流灌注反應(yīng)或心肌內(nèi)氣泡反常持續(xù)存在提示無復流現(xiàn)象。目前由于聲學造影劑的改進，二次諧波成像技術(shù)的應(yīng)用和心肌聲學造影分析方法的進步，心肌聲學造影被認為是目前評估活體冠狀動脈微循環(huán)異常的最有效方法之一。,8、冠狀動脈內(nèi)壓力測定,應(yīng)用壓力導絲測量靶動脈的壓力階差，并計算心肌血流儲備分數(shù)(FF

15、Rmyo)。當有微循環(huán)病變存在時，血流儲備分數(shù)值會升高，此時還應(yīng)當結(jié)合冠狀動脈內(nèi)血流儲備分數(shù)進行判斷。如果血流儲備分數(shù)值較高而冠狀動脈血流儲備值低，說明有微血管功能障礙存在。,9、其他方法,放射性核素運動心肌灌注顯像、正電子發(fā)射斷層和對比增強磁共振顯像法，都可用于診斷無復流。,四、無復流的危險因素,PCI術(shù)后是否發(fā)生無復流可根據(jù)臨床特點、冠狀動脈造影及冠狀動脈內(nèi)超聲結(jié)果進行初步判斷。研究發(fā)現(xiàn)，SVG PCI時，血栓形成、ACS、退化的

16、靜脈移植物、潰瘍是發(fā)生低或無復流的4個獨立危險因素，發(fā)生SNR的危險分別為：低危(1%-10%) =3個危險因素。,,AMI PCI時，CAG見高負荷的血栓形成是發(fā)生無復流現(xiàn)象的獨立預(yù)測因素，表現(xiàn)為：IRA完全閉塞處呈切面殘端、阻塞近端血栓>5mm、浮動血栓存在、阻塞遠端造影劑持續(xù)淤滯、參考管腔直徑(RLD)>=4mm、II型病變(IRA不完全阻塞性血栓長度超過RLD3倍)。,,IVUS見到的有脂質(zhì)池樣圖象的大血管也處于發(fā)生

17、無復流的高危險。,,相反，早期再灌注=2級、錐形阻塞，為不發(fā)生無復流的獨立預(yù)測因素。,五、無復流的防治,,預(yù)防,藥物遠端保護/血栓抽吸裝置（主要用于橋血管PCI和AMI直接PCI）直接支架植入準分子激光消栓,藥物,PCI術(shù)前或術(shù)中冠狀動脈內(nèi)或外周靜脈給藥 硝酸甘油（Nitroglycerin） 腺苷（Adenosine） 尼可地爾(KATP通道開放劑)（Nicorandil） 維拉帕米（Verapa

18、mil） 地爾硫卓（Diltiazem） GP IIb/IIIa受體拮抗劑（GP IIb/IIIa 　　　　receptor antagonist）等均可減少無復流現(xiàn)象的發(fā)生。,維拉帕米,Early Administration of Intracoronary Verapamil Improves Myocardial Perfusion During Percutaneous Coronary Interventi

19、ons for Acute Myocardial InfarctionAMI 直接PCI前冠脈內(nèi)給予維拉帕米改善心肌灌注,(CHEST 2005; 128:2593–2598),,目的：To evaluate the effects of the administration of intracoronary verapamil before the occurrence of no reflow during direct PCI.

20、50 patients ready to undergo direct PCI within 12 h from the onset of AMIIntracoronary verapamil was administered immediately prior to balloon inflationHad not received intracoronary calcium-channel blockers were enro

21、lled as control subjects.,(CHEST 2005; 128:2593–2598),(CHEST 2005; 128:2593–2598),,TMPG ：TIMI myocardial perfusion grade,,尼可地爾,Effects of Intravenous Nicorandil Before Reperfusion for Acute Myocardial Infarction in Patie

22、nts With Stress HyperglycemiaAMI并應(yīng)激性高血糖病人再灌注治療前靜脈注射尼可地爾的療效,Diabetes Care 29:202–206, 2006,,METHODS：This study consisted of 158 consecutive first AMI patients with stress hyperglycemia who underwent PCI within 24 h from

23、the onset. They were randomly assigned to receive 12 mg of nicorandil (n=81) or a placebo (n =77) intravenously just before reperfusion. Stress hyperglycemia was defined as a blood glucose level 10 mmol/l (180 mg/dl).,D

24、iabetes Care 29:202–206, 2006,,（P=0.032）,（P=0.027）,（P=0.032）,Diabetes Care 29:202–206, 2006,尼可地爾不同給藥途徑的療效,Impact of Nicorandil to Prevent Reperfusion Injury in Patients With Acute Myocardial InfarctionSigmart Multicente

25、r Angioplasty Revascularization Trial (SMART),Circ J 2006; 70: 1099 – 1104),90 個AMI起病6小時內(nèi)的住院病人，PCI前TIMI血流0-1級。隨機分為A、B、C 3組 ，A組：尼可地爾 0.5 mg/次，PCI前和后1-2次冠脈注射 (總量原則上1-2 mg)。B組：將尼可地爾配成1 mg/ml. 先靜脈推注4 mg，然后6ml/h靜脈輸注，加上A組方案

26、冠脈內(nèi)給藥。C組：無藥組,Circ J 2006; 70: 1099 – 1104),Circ J 2006; 70: 1099 – 1104),Fig 1. Primary endpoint. *p<0.05,Circ J 2006; 70: 1099 – 1104),,The effect of tirofiban and clopidogrel pretreatment on outcome of old saphenou

27、s vein graft stenting in patients with acute coronary syndromes.替羅非班和氯吡格雷對靜脈橋血管并ACS患者的影響,Tohoku-J-Exp-Med. 2005 May; 206(1),,A total of 47 patients, who had lesions in saphenous vein grafts and acute coronary syndrome

28、randomized to treated group (n = 24), who received Tirofiban and clopidogrel for 48 hours before the interventionand untreated group (n = 23), who did not receive Tirofiban and clopidogrel. In the untreated groupthe in

29、tervention was performed just after the coronary angiography.,,The rate of no-reflow or slow-flow phenomenon was significantly lower in treated group (one patient vs 9 patients, p = 0.004).,,During short-term follow-up,

30、there were no acute myocardial infarction, coronary bypass surgery or death in both groups. There was no major bleeding. Minor bleeding was more frequent in treated group, but it did not achieve statistical significance

31、 (3 vs 1; p = 0.322).,遠端保護裝置,遠端保護/血栓抽吸裝置可以分為4大類,1、Guardwire Plus System為代表的遠端球囊阻塞/血栓抽吸裝置2、X-Sizer為代表的機械血栓抽吸裝置3、Filterwire EX為代表的遠端濾過血栓抽吸裝置4、Diver CE為代表的單純血栓抽吸導管,,,,,Guardwire System.遠端球囊阻塞/血栓抽吸裝置,SAFER,the first mul

32、ticenter randomized trial共納入801 名大隱靜脈橋血管直徑狹窄>50%并為心絞痛罪犯血管的患者，隨機分為PCI術(shù)中使用 Guardwire Plus 的遠端球囊阻塞/血栓抽吸裝置組（N=406 ）和傳統(tǒng)0.014 inch導絲組 （N=395 ） 主要終點：30天內(nèi)死亡、心肌梗死、急診搭橋或靶病變再血管成形術(shù)的聯(lián)合終點。,Circulation. 2002;105:1285-1290.),,Circu

33、lation. 2002;105:1285-1290.),( P=0.004),（P=0.008),（P=0.02),,The Distal Protection During Primary Percutaneous Coronary Intervention Alleviates the Adverse Effects of Large Thrombus Burden on Myocardial Reperfusion遠端保護對大

34、血栓負荷直接PCI心肌再灌注的影響,Circ J 2006; 70: 232 – 238,,88 consecutive patients undergoing DP during primary PCI within 24 h from the onset of AMI were enrolled in the study (DP group).81 consecutive patients undergoing primary P

35、CI without using the DP device for AMI during the preceding 1 year (control group).,Circ J 2006; 70: 232 – 238,,The GuardWire Plus (Medtronic ) consists of a 0.014-inch guidewire incorporating a central inflation lumen t

36、o which an elastomeric balloon (3.0–6.0 mm in diameter),Circ J 2006; 70: 232 – 238,Circ J 2006; 70: 232 – 238,,,Circ J 2006; 70: 232 – 238,,,Circ J 2006; 70: 232 – 238,,Limitations of using a GuardWire temporary occlusio

37、n and aspiration system in patients with acute myocardial infarction: multicenter investigation of coronary artery protection with a distal occlusion device in acute myocardial infarction (MICADO).,J-Invasive-Cardiol. 20

38、07 Mar; 19(3): 132-8,MICADO,The study was conducted as a prospective， randomized，multicenter trial. This study evaluated the efficacy of distal protection with the GuardWire distal protection device in PCI at the time o

39、f AMI revascularization.Patients with AMI within 24 hours from onset were randomized into either PCI combined with a GuardWire，or PCI without distal protection.The primary endpoints were TIMI perfusion grade (TMP) and

40、no incidence of reflow. Secondary endpoints were major cardiac events (MACE) during 6-month follow up.,J-Invasive-Cardiol. 2007 Mar; 19(3): 132-8,,J-Invasive-Cardiol. 2007 Mar; 19(3): 132-8,（p = 0.054）,MACE was observed

41、 in similar incidences between the two groups after 6-month follow up,X-Sizer機械血栓抽吸裝置,Incidence, predictors, and outcomes of device failure of X-sizer thrombectomy: Real-world experience of 200 cases in 5 years,Am Heart

42、J 2007;153:14.e13-14.e19.,Am Heart J 2007;153:14.e13-14.e19.,Am Heart J 2007;153:14.e13-14.e19.,,,Am Heart J 2007;153:14.e13-14.e19.,直接支架植入,A Randomized Comparison of Direct Stenting With Conventional Stent Implantation

43、in Selected Patients With Acute Myocardial InfarctionAMI直接支架植入和傳統(tǒng)支架植入的隨機對照研究,J Am Coll Cardiol 2002;39:15–21,,randomized, single-center trial206 were allocated to direct stent implantation (n=102) or stent implantation

44、 after balloon pre-dilation (n=104),J Am Coll Cardiol 2002;39:15–21,,,,J Am Coll Cardiol 2002;39:15–21,,J Am Coll Cardiol 2002;39:15–21,兩組住院期間的臨床結(jié)果,準分子激光消栓,Excimer laser thrombus elimination for prevention of distal embo

45、lization and no-reflow in patients with acute ST elevation myocardial infarction Results from the randomized Laser AMI study27 consecutive patients with ST-segment elevation AMI (aged 57.8±9.2 years) were randomiz

46、ed either to balloon angioplasty and stent implantation alone (n=13) or adjunct ELCA (n=14).,International Journal of Cardiology 116 (2007) 20–26,ELCA was feasible and safe in all cases. No procedure-associated complicat

47、ions were observed.,International Journal of Cardiology 116 (2007) 20–26,P>0.05,International Journal of Cardiology 116 (2007) 20–26,International Journal of Cardiology 116 (2007) 20–26,治療,硝酸甘油（Nitroglycerin）腺苷（Adeno

48、sine）尼可地爾(KATP通道開放劑)（Nicorandil）維拉帕米（Verapamil）地爾硫卓（Diltiazem）硝普鈉（Sodium Nitroprusside）烏拉地爾（Urapidil）GP IIb/IIIa受體拮抗劑（GP IIb/IIIa receptor antagonist）,,Intracoronary Verapamil for Reversal of No-Reflow During Coron

49、ary Angioplasty for Acute Myocardial Infarction冠脈內(nèi)給予維拉帕米逆轉(zhuǎn)AMI冠狀動脈成形術(shù)中無復流,Cathet Cardiovasc Intervent 002;57:444–451.,,a consecutive series of 212 direct or rescue PTCAs for AMI，a TIMI flow grade < 3 was observed in

50、23 patients (10.8%)Ten of the 23 patients had received GP IIb/IIIa antagonists before PTCA,Cathet Cardiovasc Intervent 002;57:444–451.,,,A：LAD閉塞，B：球囊擴張后TIMI2級血流，C：支架植入后無血流，D：沿導絲送入灌注導管至支架遠端，注入維拉帕米1mg，E：保留灌注導管造影TIMI3級，F(xiàn)：

51、15MIN后造影,Cathet Cardiovasc Intervent 002;57:444–451.,Individual changes of TFC in 23 patients with no-reflow after intracoronary verapamil. The significant change of group mean standard deviation is also shown (P <