冠心病治療策略的演變

冠心病治療策略的演變

TheStrategicChangesof

CoronaryHeartDiseaseTreatment1

冠心病治療觀念的改變

NovelChangesinConceptofElderlyCHDTreatmentLuminalstenosistovulnerableplaqueformation從重視管腔狹窄到易損斑塊Lipiddeposittoinflammatoryresponse

從注意脂質(zhì)沉積到炎癥反應(yīng)Vulnerableplaquetovulnerablepatient

從重視易損斑塊到易損病人SingleRFcontroltomulti-RFintervention從單一危險因素控制到多個危險因素聯(lián)合干預(yù)Standardizedtreatmenttoindividualizedtherapy從注重規(guī)范化治療到個體化治療2LuminalStenosis管腔狹窄VulnerablePlaque易損斑塊冠心病治療觀念改變之一

FirstChangeinConcept

ofCHDTreatment

3DegreeofCoronaryStenosis冠脈狹窄程度RiskofCHD冠心病嚴(yán)重度

動脈粥樣硬化的傳統(tǒng)觀念

TraditionalConceptofAtherosclerosis?4急性心梗前的冠脈狹窄程度

CoronaryArteryStenosispre-AMI<50%50-70%>70%

%ofDiameterStenosis%

ofthePatientsBargraphshowsseverityofcoronaryarterystenosisbeforeAMI(n=195,4studies)

68%patientshadstenosislessthan50%atbaseline86%patientshadstenosislessthan70%atbaselineFalketal.Circulation.1995;92:657.5降脂療法降低心臟事件但并不改變管腔狹窄

Lipid-loweringTherapiesDecreaseCardiacEventsbutNotStenosis

TrialCholesterolDecrease,%CardiacEventDecrease,%ChangeinStenosis,%FATS2380-1.1±3.7STARS1469-0.5±3.6STARS2389-1.5±4.0SCRIP16390.3±2.5PLAC119740.69LevineGN,KeaneyJFJr,VitaJA.Cholesterolreductionincardiovasculardisease:clinicalbenefitsandpossiblemechanisms.NEnglJMed..1995;332:512-521.PhilbinEF,PearsonTA.Howdoeslipid-loweringtherapyrapidlyreduceischemicevents?JMyocardIschemia..1994;6:13-18.PittB,ManciniGBJ,EllisSG,RosmanHS,ParkJ-S,McGovernME,forthePLACIinvestigators.Pravastatinlimitationofatherosclerosisinthecoronaryarteries(PLACI):reductioninatherosclerosisprogressionandclinicalevents.JAmCollCardiol..1995;26:1133-11396CoronaryArteryStenosisAndCardiacEvents

冠脈狹窄與心臟事件Plaquevolumeorseverityofcoronaryarterystenosismaynotbethekeyfactorforinducingcardiacevents.提示:冠脈狹窄并非心血管事件關(guān)鍵原因7ConceptofVulnerablePlaque

易損斑塊概念的提出In1989,Mullerandcolleaguesfirstused“vulnerableplaques”todescriberupture-proneplaquesastheunderlyingcauseofmostclinicalcoronaryevents.首倡易損斑塊破裂觀念A(yù)vulnerableplaqueoftenhasalargelipidpool,athincap,andmacrophage-denseinflammationonorbeneathitssurface.特征Vulnerableplaqueruptureordisruptioncausesbleedingintotheplaque,luminalthrombosis,and/orvasospasmthatmaycausesuddenflowobstructionandischemicinjury.破裂致血栓形成MullerJ,ToflerG,StoneP.Circadianvariationandtriggersofonsetofacutecardiovasculardisease.Circulation.1989;79:733–743.

89多方位策略演變

Manysidedstrategicchanges診斷進(jìn)步：由以CAG為主導(dǎo)，到重視斑塊檢測技術(shù)的發(fā)展如IVUS、OCT；基礎(chǔ)研究方向：逐漸以穩(wěn)定易損斑塊以及減少斑塊破裂后血栓形成為方向；二級預(yù)防重點：也將由治療冠脈狹窄轉(zhuǎn)為易損斑塊的干預(yù)。<60micronCapLesion10CHDdevelopsin20~30years冠心病慢性病病程Plaqueruptureoccursin2~3hrs斑塊破裂快過過程DyslipidemiaAtherosclerosisPlaqueformationCHDACSHeartfailureLVdysfunction心臟事件的發(fā)發(fā)生ProgressionofCardiacEventsAMILVreconstruction11冠脈介入治療療的短處LimitationsofPCIAlthoughPCIcouldrelieveseverestenosisofcoronaryartery,itwouldn’tchangethebiologiccourseofAS,thustheproblemof“unstable”isstillunresolved.尚未能解決決斑塊不穩(wěn)穩(wěn)定問題12COURAGE臨床試驗BodenWE,etal.OptimalMedicalTherapywithorwithoutPCIforStablecoronaryDisease(NEJM.356:1503-1516;April12,2007)13COURAGE––研究設(shè)計計StudydesignofCOURAGEtrial加PCI組不加PCI組死亡率/MACE/ACS2287例例穩(wěn)定型心心絞痛患者者(他汀類,抗抗血小板板,ACEI/ARB,β-受受體阻滯劑劑)隨機(jī)化隨訪2.5-7Y14兩組主要終終點比較Thecomparisonofendpointswithtwogroups平均隨訪4.6年所有原因死死亡或非致致死性心肌肌梗死數(shù)單純優(yōu)化藥藥物治療組組:18.5%優(yōu)化藥物治治療+PCI組:19.0%P=0.6215隨訪心絞痛痛緩解率FreedomfromAnginaDuringLong-TermFollow-upCharacteristicPCI+OMTOMTCLINICALAnginafree–no.Baseline12%13%1Yr66%58%3Yr72%67%5Yr74%72%ThecomparisonbetweenthePCIgroupandthemedical-therapygroupwassignificantat1year(P<0.001)and3years(P=0.02)butnotatbaselineor5years.16震撼全球心心血管病學(xué)學(xué)界Grobalimpactoncardiologicalfield慢性穩(wěn)定性性冠心病/臨界狹窄窄病變者:現(xiàn)代藥物物治療效果果理想/病病人依從性性好COURAGEtrial:醫(yī)生應(yīng)該有有信心面對對這些病人人保護(hù)病人效效果和利益益的最大化化在病人身上上做有證據(jù)據(jù)的治療中西醫(yī)結(jié)合合應(yīng)受理解解和提倡17兩組總生存存率OverallSurvivalNumberatRiskMedicalTherapy113810731029 91771746830238PCI114910941051 92973348831244Years01234560.0PCI+OMTOMT7Hazardratio:0.8795%CI(0.65-1.16)P=0.3818穩(wěn)定易損斑斑塊的重要要作用StabilizationofVulnerablePlaquesThevascularpathophysiologicalresearchhasfocusedonstabilizingthevulnerableplaqueandinhibitingthrombosisafterplaquerupture.ThesecondarypreventionofCHDalsofocusedoninterventionofthevulnerableplaqueinadditiontotreatingluminalstenosisofcoronaryartery.防治重點應(yīng)應(yīng)是易損斑斑塊+狹窄窄問題KulloIJ,EdwardsWD,SchwartzRS.Vulnerableplaque:pathobiologyandclinicalimplications.AnnInternMed1998;129(12):1050-60.OzerK,CilingirogluM.Vulnerableplaque:definition,detection,treatment,andfutureimplications.CurrAtherosclerRep.2005;7(2):121-619動脈粥樣硬硬化1.LDL透過過內(nèi)皮細(xì)胞深入內(nèi)皮細(xì)細(xì)胞間隙，，單核細(xì)胞胞遷入內(nèi)膜膜，此即最最早期。2.Ox-LDL與巨噬細(xì)細(xì)胞的清道道夫受體結(jié)結(jié)合而被攝攝取，形成成巨噬源性泡泡沫細(xì)胞，對應(yīng)病理變變化中的脂紋。20動脈粥樣硬硬化3.動脈脈中膜的血血管平滑肌肌細(xì)胞（SMC）遷遷入內(nèi)膜，，吞噬脂質(zhì)質(zhì)形成肌源性泡沫沫細(xì)胞，增生遷移移形成纖維維帽，對應(yīng)應(yīng)病理變化化中的纖維斑塊。4.Ox-LDL使上述兩兩種泡沫細(xì)細(xì)胞壞死崩崩解，形成成糜粥樣壞壞死物，粥粥樣斑塊形形成。對應(yīng)應(yīng)病理變化化中的粥樣斑塊。21動脈粥樣硬硬化的核心心動脈粥樣硬硬化形成的的機(jī)理：關(guān)關(guān)鍵環(huán)節(jié)在在于Ox-LDL如何防止LDL被氧氧化成Ox-LDL成為治療療和防止動動脈粥樣硬硬化的核心心。22關(guān)注動脈粥粥樣硬化早早期植物血凝素素樣氧化低低密度脂蛋蛋白受體-1（LOX-1）的表達(dá)是是血管內(nèi)皮皮細(xì)胞出現(xiàn)現(xiàn)功能異常常的最早期期標(biāo)志，在在粘附分子子的產(chǎn)生及及AS的形形成中起重重要作用。。23細(xì)胞因子和生長因子平滑肌細(xì)胞增生和泡沫細(xì)胞形成白細(xì)胞遷移細(xì)胞因子和生長因子細(xì)胞粘附分子LOX-1介導(dǎo)內(nèi)皮細(xì)胞與單核細(xì)胞粘附24LipidDeposit脂質(zhì)沉積InflammatoryReaction炎癥癥反反應(yīng)應(yīng)冠心心病病治治療療觀觀念念改改變變之之二二SecondChangeinConceptofCHDTreatment25逾百百年年之之脂脂質(zhì)質(zhì)沉沉積積學(xué)學(xué)說說LipidDepositionTheory“Lipiddepositiontheory””ofatherosclerosishasbeenputforwardfor150yearsbasedonthecausalrelationshipbetweenhyperlipidemiaandAS.高脂血癥癥與動脈脈粥樣硬硬化關(guān)系系ThistheoryholdsthatlipiddepositiononthearterywallleadstotheASplaques,andithasbeendominatedthepathogenesisofASforalongtime.SteinbergD,JosephL，，WitztumJL.Lipoproteinsandatherogenesis:Currentconcepts.JAMA1990;264(23):3047-3052.26InflammatorytheoryofASwasfirstpresentedbyVirchowin1856.炎癥理論論的提出出“Endarteritisdeformans”oratheroma-aproductofaninflammatoryprocesswithintheintimawiththefibrousthickeningevolvedasaconsequenceofareactivefibrosisinducedbyproliferatingconnectivetissuecellswithintheintima.Thetheorydidnotraisegreatattentionatthattime.當(dāng)年未獲獲關(guān)注動脈粥樣樣硬化炎炎癥學(xué)說說InflammationTheory27Inrecentyears,ASwasshowntohavethebasicmanifestationofinflammation炎癥反應(yīng)應(yīng)的基本本表現(xiàn)Degeneration變變性Exudation滲滲出Proliferation增增生Thecell-cellinteractionissimilartootherchronicinflammationdiseasessuchasrheumatoidarthritis,chronicpancreatitisandhepaticcirrhosis.動脈粥粥樣硬硬化炎炎癥學(xué)學(xué)說InflammationTheory28動脈粥粥樣硬硬化炎炎癥學(xué)學(xué)說ASwasnolongerregardedasasimplediseaseoflipiddepositioninthevesselwall,butalsoanadvancedinflammatoryreaction.InASplaqueofhuman,therewasalsoevidenceofseveralpathogens病原Chlamydiapneumoniae衣衣原體體Cytomegalovirus巨細(xì)細(xì)胞病病毒Herpesvirus皰皰疹病毒Helicobacterpylori幽門門螺桿菌29動脈粥樣硬硬化炎癥學(xué)學(xué)說InflammationTheoryIn1999,acenturylater,RossdeclaredthatASisoneofchronicinflammatorydisease,basedonhisinjuryreactiontheory.損傷反應(yīng)理理論的提出出(Ross,1999)30InflammatoryBiomarkersAS炎癥生生物學(xué)標(biāo)志志物InflammatoryBiomarkers白介素-6ＣＣ反反應(yīng)蛋白單核細(xì)胞趨趨化因子-1血清清淀粉樣蛋蛋白Ａ腫瘤壞死因因子α白介素-18白介素-10細(xì)胞間黏黏附分子子血管細(xì)胞胞黏附分分子E-選擇擇素血管性假假血友病病因子髓過氧化化物酶磷脂酶血漿脂蛋蛋白相關(guān)關(guān)性磷脂脂酶血管內(nèi)皮皮生長因因子胎盤生長長因子肝細(xì)胞生生長因子子基質(zhì)金屬屬蛋白酶酶1，2，，9妊娠相關(guān)關(guān)血漿蛋蛋白-ACD40配體P-選擇擇素31AS炎癥癥生物學(xué)學(xué)標(biāo)志物物Hs-CRPC-ReactiveProteininCVDElevatedhs-CRPlevelsinhealthypopulationspredictvasculareventssuchasMIandstrokeaswellasthedevelopmentofdiabetes.Hs-CRPisausefulbiomarkerinriskpredictionandtreatmentoutcomeassessment.Hs-CRPwasalsoimplicateddirectlyinatherogenesis.CRPhasbeenfoundinhumanatheroscleroticplaqueandshowntocauseendothelialcelldysfunction,oxidantstressandintimalhypertrophyinexperimentalmodels.ItcouldalsobeapotentialtargetofAStreatmentandprevention.高敏C反反應(yīng)蛋白白增高WilsonAM,RyanMC,BoyleAJ.ThenovelroleofC-reactiveproteinincardiovasculardisease:riskmarkerorpathogen.IntJCardiol.2006;106(3):291-7.32基于幾種種生化標(biāo)標(biāo)記物的的心血管管事件相相對風(fēng)險險01.02.04.06.0Lipoprotein(a)LDLCHomocysteineTCApolipoproteinBTC:HDLChs-CRPhs-CRP+TC:HDLCRelativeRiskofFutureCVEventsCV,cardiovascular;TC,totalcholesterol;LDLC,low-densitylipoproteincholesterol;HDL-C,high-densitylipo-proteincholesterol;CRP,C-reativeprotein;hs-CRP,high-sensitivityC-reactiveprotein;TC,totalcholesterol.AdaptedfromRifaiN,etal.ClinChem.2001;47:28-30.33hs-CRP(mg/L)他汀治療療6周對對hs-CRP水平的影影響TheinfluenceofStatinsonhs-CRPlevelJialalIetal.Circulation2001;103:1933-1935.6543210Baseline***Prava

(40mg/d)Simva

(20mg/d)Atorva

(10mg/d)*p<0.025vs.Baseline34VulnerablePlaque易損斑塊VulnerablePatient易損病人冠心病治療療觀念改變變之三ThirdChangeinConceptofCHDTreatment35易損病人概概念的提出出DefinitionofVulnerablePatientVulnerableplaquesarenottheonlyculpritfactors.Vulnerablebloodandvulnerablemyocardiumplayanimportantroleinforthedevelopmentofacutecoronarysyndromes,myocardialinfarction,andsuddencardiacdeath.“Vulnerablepatient"isproposedtodefinesubjectssusceptibletoanacutecoronarysyndromeorsuddencardiacdeathbasedonplaque,blood,ormyocardialvulnerability.NaghaviM.etal.Circulation2003;108(14):1664-72.易損病人=易損斑塊塊+易損血血液+易損損心肌36Aquantitativemethodforcumulativeriskassessmentofvulnerablepatientsneedstobedevelopedthatmayincludevariableslistedbelow.Vulnerableplaques易損斑塊pronetorupture易于破裂withhighlikelihoodofthromboticcomplicationsandrapidprogressionPlaqueruptureaccountsfornearly70%offatalAMIand/orsuddencoronarydeathsVulnerableplaqueisthemain,butnottheuniquecauseforacutecardiovasculareventsVulnerableblood易損血液pronetothrombosis易于血栓形形成Vulnerablemyocardium易損心肌pronetofatalarrhythmia易發(fā)生致命命性心律失失常易損病人VulnerablePatient37治療上的創(chuàng)新新性發(fā)展DevelopmentofInnovativeTherapies脂質(zhì)沉積Lipiddeposit調(diào)節(jié)血脂RegulatingBloodLipid藥物:擴(kuò)冠冠Drugs：Nitrates,CaA手術(shù)Surgery：：PCI、CABG穩(wěn)定斑塊StabilizingPlaque，血管保護(hù)vasprotection，抗炎anti-inflammatory，抗栓(抗血小小板、抗凝)Anti-thrombosis(anti-platelet,anticoagulation)早期識別；重重預(yù)防EarlyIdentificationandPrevention冠脈狹窄CoronaryStenosis易損斑塊、破破裂、血栓形形成VulnerablePlaque,Rupture,Thrombosis易損患者VulnerablePatients38EBM研究所得(Aspirin)ExperiencefromEBM39抗血小板治療療的困惑Certainpuzzledproblemonanti-platelettherapy顱內(nèi)出血／胃胃腸道出血／／鼻腔出血／／胸膜腔出血血／皮下出血血．．．（aspirin75-100mg/d,clopidogril75mg/d)高齡尤多見;遠(yuǎn)超1.8-2.1％（CURE研究）可適當(dāng)減量（（包括首劑負(fù)負(fù)荷量）40Aspirinresistance概念念的的爭爭議議臨床床Aspirinresistance:減少事件件/未能能消除事事件AA基因因多態(tài)性性/無效效或不利利結(jié)果生化Aspirinresistance:出血時間間延長/TXA2抑制制合成/刺激血血小板聚聚集0.4-83.0%DalenJE,etal:AmJMed,2007,120:1-4LoordkipandizeM,etal:PharmacoTher,2006,112:733-74341危險因素素單一控制制危險因素素復(fù)雜干預(yù)預(yù)冠心病治治療觀念念改變之之四SixthChangeinConceptofCHDTreatment42DiabetesDyslipidemiaHypertensionObesity病人是整整體整體干預(yù)預(yù)/整體體醫(yī)學(xué)43多重危險險因素的的干預(yù)Interventionsformulti-RF單一危險險因素的的治療常常可使病病人心腦腦血管病病危險下下降20%－30%，，意味著還還有70%－80%的的剩余危危險需要要降低44Polypill:心心臟病一一/二級級予防PolypillApproachforClassI&IIPreventionofCardiacDiseases組成:辛伐伐他汀汀40mg,ACEI(賴賴諾普普利),半半量量噻嗪嗪類利利尿劑劑(或或阿替替洛爾爾25mg),低劑劑量阿阿司匹匹林,葉酸酸;Composition:Simvastatin40mg,Lisinopril,half-doseAtenolol,lowdoseaspirin,folicacid(BMJ2003;326:1407,1419,1423,1427)目標(biāo):55歲歲以上上使用用,可可降低低心腦腦血管管事件件80%;Target:forthoseaged55orabove,couldlowercardiocerebralincidenceby80%爭議:激激烈;Dispute:FierceAstrategytoreducecardiovasculardiseasebymorethan80%45ADVANCE臨床試驗ADVANCETrial:furtherPROGRESSwithHOPE歐洲心心臟病病學(xué)會會(ESC)2007年會會上ADVANCE研究究結(jié)果果公布布：納納入入20個國國家11140例2型糖糖尿病病患者者，結(jié)結(jié)果表表明(4.3年年），，與安安慰劑劑組相相比，，培哚哚普利利2mg+吲吲達(dá)帕帕胺0.625mg復(fù)復(fù)方制制劑組組總死死亡、、心血血管性性死亡亡、冠冠脈事事件、、腎臟臟事件件、新新發(fā)生生微蛋蛋白尿尿的比比例均均顯著著降低低(by9%)。。研究結(jié)果提提示，對血壓正常常的糖尿病病患者，適適當(dāng)?shù)慕祲簤褐委熓怯杏幸娴?，認(rèn)為是一一種更高效效、更科學(xué)學(xué)的“風(fēng)險險控制”治治療策略。。JournalofHumanHypertension(2007)21,911-913Lancet(2007)370(9590):829-84046Steno-2臨床試驗2型糖尿病病患者多為為中老年患患者，且常常合并多重重心血管危危險因素。。Steno-2研研究平均隨隨訪13.3年的結(jié)結(jié)果發(fā)現(xiàn)，，與多因素素常規(guī)治療療組相比，，采用多因因素強(qiáng)化治治療(平均均7.8年年)組全因因死亡、心心血管性死死亡和復(fù)合合心血管事事件的發(fā)生生率分別顯顯著降低46%、57%和59%。該研究提示示，應(yīng)盡早綜合合強(qiáng)化控制制血糖、血血壓和血脂脂等指標(biāo)，以減少心心血管事件件的發(fā)生，，多重危險險因素強(qiáng)化化干預(yù)具遠(yuǎn)遠(yuǎn)期益處。。G?deP,etal.NEnglJMed.EffectofaMultifactorialInterventiononMortalityintype2Diabetes;Feb7,2008;358:580-59147Steno-2臨床試驗48規(guī)范化治療療個體化治療療冠心病治療療觀念改變變之五SeventhChangeinConceptofCHDTreatment49有證據(jù)的個個體化醫(yī)學(xué)學(xué)Evidence-basedPersonalizedMedicineTheRightDoseofTheRightdrugforTheRightIndicationforTheRightPatientatTheRightTime.與傳統(tǒng)因時時因地因人人有相通道道理。Likenedtothetraditionalnotionof““righttime,rightplaceandrightpeople’.醫(yī)學(xué)——以以人為本,無論中西西Peopleforemost,whetherwestmedicineorTCM.50關(guān)注機(jī)體自自身修復(fù)血管新生是是慢性炎癥癥反應(yīng)的重重要組成部部分和自然然反應(yīng)，是是一種對缺缺氧缺血損損傷的代償償機(jī)制。在在冠心病的的二級預(yù)防防中，應(yīng)當(dāng)當(dāng)更關(guān)注對對于這一自自然過程的的調(diào)節(jié)?？刂仆馔鈦碇轮虏∫蛞蛩卣{(diào)動內(nèi)內(nèi)在修修復(fù)機(jī)機(jī)制51謝謝大大家！！529、靜夜四無鄰鄰，荒居舊業(yè)業(yè)貧。。1月-231月-23Saturday,January7,202310、雨中黃葉樹樹，燈下白頭頭人。。21:33:1221:33:1221:331/7/20239:33:12PM11、以我獨沈久久，愧君相見見頻。。1月-2321:33:1321:33Jan-2307-Jan-2312、故故人人江江海海別別，，幾幾度度隔隔山山川川。。。。21:33:1321:33:1321:33Saturday,January7,202313、乍見翻疑夢夢，相悲各問問年。。1月-231月-2321:33:1321:33:13January7,202314、他鄉(xiāng)生白白發(fā)，舊國國見青山。。。07一月月20239:33:13下下午21:33:131月-2315、比不了了得就不不比，得得不到的的就不要要。。。。一月239:33下午午1月-2321:33January7,202316、行行動動出出成成果果，，工工作作出出財財富富。。。。2023/1/721:33:1321:33:1307January202317、做前，能能夠環(huán)視四四周；做時時，你只能能或者最好好沿著以腳腳為起點的的射線向前前。。9:33:13下午9:33下下午21:33:131月-239、沒沒有有失失敗敗，，只只有有暫暫時時停停止止成成功功！！。。1月月-231月月-23Saturday,January7,202310、很多多事情情努力力了未未必有有結(jié)果果，但但是不不努力力卻什什么改改變也也沒有有。。。21:33:1321:33:1321:331/7/20239:33:13PM11、成成功功就就是是日日復(fù)復(fù)一一日日那那一一點點點點小小小小努努力力的的積積累累。。。。1月月-2321:33:1321:33Jan-2307-Jan-2