冠心病治療策略的演變課件

1、冠心病治療策略的演變2022/10/17冠心病治療策略的演變冠心病治療策略的演變2022/10/15冠心病治療策略的演變冠心病治療觀念的改變Novel Changes in Concept of Elderly CHDTreatment Luminal stenosis to vulnerable plaque formation 從重視管腔狹窄到易損斑塊 Lipid deposit to inflammatory response 從注意脂質(zhì)沉積到炎癥反應(yīng) Vulnerable plaque to vulnerable patient 從重視易損斑塊到易損病人Single RF contro

2、l to multi-RF intervention 從單一危險(xiǎn)因素控制到多個(gè)危險(xiǎn)因素聯(lián)合干預(yù)Standardized treatment to individualized therapy 從注重規(guī)范化治療到個(gè)體化治療冠心病治療策略的演變2冠心病治療觀念的改變Novel Changes in Luminal Stenosis管腔狹窄Vulnerable Plaque易損斑塊冠心病治療觀念改變之一First Change in Concept of CHD Treatment冠心病治療策略的演變3Luminal StenosisVulnerable PlaDegree of Coronary

3、Stenosis冠脈狹窄程度Risk of CHD冠心病嚴(yán)重度動(dòng)脈粥樣硬化的傳統(tǒng)觀念Traditional Concept of Atherosclerosis?冠心病治療策略的演變4Degree of Risk of CHD動(dòng)脈粥樣硬化的傳急性心梗前的冠脈狹窄程度Coronary Artery Stenosis pre-AMI70% % of Diameter Stenosis% of the PatientsBar graph shows severity of coronary artery stenosis before AMI (n=195, 4 studies) 68% patie

4、nts had stenosis less than 50% at baseline86% patients had stenosis less than 70% at baselineFalk et al. Circulation. 1995;92:657.冠心病治療策略的演變5急性心梗前的冠脈狹窄程度Coronary Artery S降脂療法降低心臟事件但并不改變管腔狹窄Lipid-lowering Therapies Decrease Cardiac Events but Not StenosisTrialCholesterol Decrease, %Cardiac Event Decr

5、ease, %Change in Stenosis, %FATS2380-1.1 3.7STARS1469-0.53.6STARS2389-1.5 4.0SCRIP16390.32.5PLAC 119740.69Levine GN, Keaney JF Jr, Vita JA. Cholesterol reduction in cardiovascular disease: clinical benefits and possible mechanisms. N Engl J Med. 1995;332:512-521.Philbin EF, Pearson TA. How does lipi

6、d-lowering therapy rapidly reduce ischemic events? J Myocard Ischemia. 1994;6:13-18. Pitt B, Mancini GBJ, Ellis SG, Rosman HS, Park J-S, McGovern ME, for the PLAC I investigators. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression an

7、d clinical events. J Am Coll Cardiol. 1995;26:1133-1139冠心病治療策略的演變6降脂療法降低心臟事件但并不改變管腔狹窄Lipid-loweCoronary Artery Stenosis And Cardiac Events冠脈狹窄與心臟事件Plaque volume or severity of coronary artery stenosis may not be the key factor for inducing cardiac events.提示:冠脈狹窄并非心血管事件關(guān)鍵原因冠心病治療策略的演變7Coronary Artery

8、Stenosis And CConcept of Vulnerable Plaque易損斑塊概念的提出In 1989, Muller and colleagues first used “vulnerable plaques” to describe rupture-prone plaques as the underlying cause of most clinical coronary events. 首倡易損斑塊破裂觀念A(yù) vulnerable plaque often has a large lipid pool, a thin cap, and macrophage-dense i

9、nflammation on or beneath its surface. 特征Vulnerable plaque rupture or disruption causes bleeding into the plaque, luminal thrombosis, and/or vasospasm that may cause sudden flow obstruction and ischemic injury. 破裂致血栓形成Muller J, Tofler G, Stone P. Circadian variation and triggers of onset of acute ca

10、rdiovascular disease. Circulation. 1989; 79:733743. 冠心病治療策略的演變8Concept of Vulnerable Plaque易冠心病治療策略的演變9冠心病治療策略的演變9多方位策略演變 Many sided strategic changes診斷進(jìn)步：由以CAG為主導(dǎo)，到重視斑塊檢測(cè)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(jí)預(yù)防重點(diǎn)：也將由治療冠脈狹窄轉(zhuǎn)為易損斑塊的干預(yù)。 60 micron CapLesion冠心病治療策略的演變10多方位策略演變 Many sided stra

11、tegic CHD develops in 2030 years 冠心病慢性病程Plaque rupture occurs in 23 hrs 斑塊破裂快過(guò)程DyslipidemiaAtherosclerosisPlaque formationCHD ACSHeart failure LV dysfunction心臟事件的發(fā)生 Progression of Cardiac Events AMI LV reconstruction冠心病治療策略的演變11CHD develops in 2030 years 冠冠脈介入治療的短處Limitations of PCI Although PCI cou

12、ld relieve severe stenosis of coronary artery, it wouldnt change the biologic course of AS, thus the problem of “unstable” is still unresolved. 尚未能解決斑塊不穩(wěn)定問(wèn)題冠心病治療策略的演變12冠脈介入治療的短處Limitations of PCICOURAGE臨床試驗(yàn) Boden WE, et al. Optimal Medical Therapy with or without PCI for Stable coronary Disease (NEJ

13、M.356:1503-1516;April 12,2007) 冠心病治療策略的演變13COURAGE臨床試驗(yàn) Boden WE, et al. OCOURAGE 研究設(shè)計(jì)Study design of COURAGE trial加PCI 組不加PCI組死亡率/ MACE/ACS 2287例穩(wěn)定型心絞痛患者( 他汀類, 抗血小板, ACEI/ARB, -受體阻滯劑)隨機(jī)化隨訪 2.5-7 Y冠心病治療策略的演變14COURAGE 研究設(shè)計(jì)Study design of 兩組主要終點(diǎn)比較The comparison of endpoints with two groups平均隨訪4.6年 所有原因

14、死亡或非致死性心肌梗死數(shù) 單純優(yōu)化藥物治療組:18.5% 優(yōu)化藥物治療+PCI組:19.0% P=0.62冠心病治療策略的演變15兩組主要終點(diǎn)比較The comparison of en隨訪心絞痛緩解率Freedom from Angina During Long-Term Follow-upCharacteristicPCI + OMT OMT CLINICALAngina free no. Baseline12%13%1 Yr66%58%3 Yr72%67%5 Yr74% 72%The comparison between the PCI group and the medical-the

15、rapy group was significant at 1 year ( P0.001) and 3 years (P=0.02) but not at baseline or 5 years. 冠心病治療策略的演變16隨訪心絞痛緩解率Freedom from Angina D震撼全球心血管病學(xué)界Grobal impact on cardiological field慢性穩(wěn)定性冠心病/臨界狹窄病變者:現(xiàn)代藥物治療效果理想/病人依從性好 COURAGE trial:醫(yī)生應(yīng)該有信心面對(duì)這些病人保護(hù)病人效果和利益的最大化在病人身上做有證據(jù)的治療中西醫(yī)結(jié)合應(yīng)受理解和提倡冠心病治療策略的演變17震撼

16、全球心血管病學(xué)界Grobal impact on ca兩組總生存率Overall SurvivalNumber at RiskMedical Therapy 1138 1073 1029917 717 468 302 38PCI 1149 1094 1051929 733 488 312 44Years01234560.00.50.60.70.80.91.0PCI + OMTOMT7Hazard ratio: 0.8795% CI (0.65-1.16)P = 0.38冠心病治療策略的演變18兩組總生存率Overall SurvivalNumber 穩(wěn)定易損斑塊的重要作用Stabilizati

17、on of Vulnerable PlaquesThe vascular pathophysiological research has focused on stabilizing the vulnerable plaque and inhibiting thrombosis after plaque rupture. The secondary prevention of CHD also focused on intervention of the vulnerable plaque in addition to treating luminal stenosis of coronary

18、 artery. 防治重點(diǎn)應(yīng)是易損斑塊+狹窄問(wèn)題Kullo IJ, Edwards WD, Schwartz RS. Vulnerable plaque: pathobiology and clinical implications. Ann Intern Med 1998; 129(12):1050-60. Ozer K, Cilingiroglu M. Vulnerable plaque: definition, detection, treatment, and future implications. Curr Atheroscler Rep. 2005; 7(2):121-6冠心病治

19、療策略的演變19穩(wěn)定易損斑塊的重要作用Stabilization of 動(dòng)脈粥樣硬化1. LDL透過(guò)內(nèi)皮細(xì)胞深入內(nèi)皮細(xì)胞間隙，單核細(xì)胞遷入內(nèi)膜，此即最早期。 2. Ox-LDL與巨噬細(xì)胞的清道夫受體結(jié)合而被攝取，形成巨噬源性泡沫細(xì)胞，對(duì)應(yīng)病理變化中的脂紋。 冠心病治療策略的演變20動(dòng)脈粥樣硬化1. LDL透過(guò)內(nèi)皮細(xì)胞深入內(nèi)皮細(xì)胞間隙，單核細(xì)動(dòng)脈粥樣硬化3. 動(dòng)脈中膜的血管平滑肌細(xì)胞（SMC）遷入內(nèi)膜，吞噬脂質(zhì)形成肌源性泡沫細(xì)胞，增生遷移形成纖維帽，對(duì)應(yīng)病理變化中的纖維斑塊。 4. Ox-LDL使上述兩種泡沫細(xì)胞壞死崩解，形成糜粥樣壞死物，粥樣斑塊形成。對(duì)應(yīng)病理變化中的粥樣斑塊。 冠心病治療策略

20、的演變21動(dòng)脈粥樣硬化3. 動(dòng)脈中膜的血管平滑肌細(xì)胞（SMC）遷入內(nèi)膜動(dòng)脈粥樣硬化的核心動(dòng)脈粥樣硬化形成的機(jī)理：關(guān)鍵環(huán)節(jié)在于Ox-LDL如何防止LDL被氧化成Ox-LDL成為治療和防止動(dòng)脈粥樣硬化的核心。 冠心病治療策略的演變22動(dòng)脈粥樣硬化的核心動(dòng)脈粥樣硬化形成的機(jī)理：關(guān)鍵環(huán)節(jié)在于Ox-關(guān)注動(dòng)脈粥樣硬化早期植物血凝素樣氧化低密度脂蛋白受體-1（LOX-1）的表達(dá)是血管內(nèi)皮細(xì)胞出現(xiàn)功能異常的最早期標(biāo)志，在粘附分子的產(chǎn)生及AS的形成中起重要作用。冠心病治療策略的演變23關(guān)注動(dòng)脈粥樣硬化早期植物血凝素樣氧化低密度脂蛋白受體-1（L細(xì)胞因子和生長(zhǎng)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

21、長(zhǎng)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)胞粘附冠心病治療策略的演變24細(xì)胞因子和生長(zhǎng)因子平滑肌細(xì)胞增生白細(xì)胞遷移細(xì)胞因子和生長(zhǎng)因子Lipid Deposit脂質(zhì)沉積Inflammatory Reaction炎癥反應(yīng)冠心病治療觀念改變之二Second Change in Concept of CHD Treatment 冠心病治療策略的演變25Inflammatory 冠心病治療觀念改變之二Secon逾百年之脂質(zhì)沉積學(xué)說(shuō)Lipid Deposition Theory“Lipid deposition theory” of atherosclerosis has been put forw

22、ard for 150 years based on the causal relationship between hyperlipidemia and AS. 高脂血癥與動(dòng)脈粥樣硬化關(guān)系This theory holds that lipid deposition on the artery wall leads to the AS plaques, and it has been dominated the pathogenesis of AS for a long time. Steinberg D, Joseph L，Witztum JL. Lipoproteins and athe

23、rogenesis: Current concepts. JAMA 1990; 264(23):3047-3052. 冠心病治療策略的演變26逾百年之脂質(zhì)沉積學(xué)說(shuō)Lipid Deposition ThInflammatory theory of AS was first presented by Virchow in 1856. 炎癥理論的提出“Endarteritis deformans” or atheroma - a product of an inflammatory process within the intima with the fibrous thickening evolv

24、ed as a consequence of a reactive fibrosis induced by proliferating connective tissue cells within the intima.The theory did not raise great attention at that time. 當(dāng)年未獲關(guān)注動(dòng)脈粥樣硬化炎癥學(xué)說(shuō)Inflammation Theory冠心病治療策略的演變27Inflammatory theory of AS was In recent years, AS was shown to have the basic manifestat

25、ion of inflammation 炎癥反應(yīng)的基本表現(xiàn)Degeneration變性Exudation 滲出 Proliferation 增生The cell-cell interaction is similar to other chronic inflammation diseases such as rheumatoid arthritis, chronic pancreatitis and hepatic cirrhosis.動(dòng)脈粥樣硬化炎癥學(xué)說(shuō)Inflammation Theory冠心病治療策略的演變28In recent years, AS was shown 動(dòng)脈粥樣硬化炎癥

26、學(xué)說(shuō)AS was no longer regarded as a simple disease of lipid deposition in the vessel wall, but also an advanced inflammatory reaction. In AS plaque of human, there was also evidence of several pathogens 病原Chlamydia pneumoniae衣原體Cytomegalovirus巨細(xì)胞病毒Herpes virus皰疹病毒Helicobacter pylori幽門(mén)螺桿菌冠心病治療策略的演變29動(dòng)脈粥

27、樣硬化炎癥學(xué)說(shuō)AS was no longer reg動(dòng)脈粥樣硬化炎癥學(xué)說(shuō)Inflammation TheoryIn 1999, a century later, Ross declared that AS is one of chronic inflammatory disease, based on his injury reaction theory.損傷反應(yīng)理論的提出 (Ross,1999)冠心病治療策略的演變30動(dòng)脈粥樣硬化炎癥學(xué)說(shuō)Inflammation TheoryInflammatory BiomarkersAS炎癥生物學(xué)標(biāo)志物Inflammatory Biomarkers白介

28、素-6反應(yīng)蛋白單核細(xì)胞趨化因子-1血清淀粉樣蛋白腫瘤壞死因子白介素-18白介素-10 細(xì)胞間黏附分子血管細(xì)胞黏附分子E-選擇素血管性假血友病因子髓過(guò)氧化物酶磷脂酶血漿脂蛋白相關(guān)性磷脂酶血管內(nèi)皮生長(zhǎng)因子胎盤(pán)生長(zhǎng)因子肝細(xì)胞生長(zhǎng)因子基質(zhì)金屬蛋白酶1，2，9妊娠相關(guān)血漿蛋白-ACD40配體P-選擇素冠心病治療策略的演變31Inflammatory BiomarkersAS炎癥生物學(xué)標(biāo)志物Hs-CRPC-Reactive Protein in CVDElevated hs-CRP levels in healthy populations predict vascular events such as

29、MI and stroke as well as the development of diabetes. Hs-CRP is a useful biomarker in risk prediction and treatment outcome assessment.Hs-CRP was also implicated directly in atherogenesis. CRP has been found in human atherosclerotic plaque and shown to cause endothelial cell dysfunction, oxidant str

30、ess and intimal hypertrophy in experimental models.It could also be a potential target of AS treatment and prevention. 高敏C反應(yīng)蛋白增高Wilson AM, Ryan MC, Boyle AJ. The novel role of C-reactive protein in cardiovascular disease: risk marker or pathogen. Int J Cardiol. 2006; 106(3):291-7. 冠心病治療策略的演變32AS炎癥生物

31、學(xué)標(biāo)志物Hs-CRPC-Reactive P基于幾種生化標(biāo)記物的心血管事件相對(duì)風(fēng)險(xiǎn)01.02.04.06.0Lipoprotein(a)LDLCHomocysteineTCApolipoprotein BTC:HDLChs-CRPhs-CRP + TC:HDLCRelative Risk of Future CV EventsCV, cardiovascular; TC, total cholesterol; LDLC, low-density lipoprotein cholesterol; HDL-C, high-density lipo-protein cholesterol; CRP,

32、 C-reative protein; hs-CRP, high-sensitivity C-reactive protein; TC, total cholesterol.Adapted from Rifai N, et al. Clin Chem. 2001;47:28-30.冠心病治療策略的演變33基于幾種生化標(biāo)記物的心血管事件相對(duì)風(fēng)險(xiǎn)01.02.04.06hs-CRP (mg/L)他汀治療6周對(duì)hs-CRP水平的影響The influence of Statins on hs-CRP levelJialal I et al. Circulation 2001;103:1933-1935

33、.6543210Baseline*Prava(40 mg/d)Simva(20 mg/d)Atorva(10 mg/d)*p0.025 vs. Baseline冠心病治療策略的演變34hs-CRP (mg/L)他汀治療6周對(duì)hs-CRP水平的影Vulnerable Plaque易損斑塊Vulnerable Patient易損病人冠心病治療觀念改變之三Third Change in Concept of CHD Treatment 冠心病治療策略的演變35Vulnerable Vulnerable 冠心病治療觀念易損病人概念的提出Definition of Vulnerable PatientV

34、ulnerable plaques are not the only culprit factors. Vulnerable blood and vulnerable myocardium play an important role in for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death.“Vulnerable patient is proposed to define subjects susceptible to an acute coronar

35、y syndrome or sudden cardiac death based on plaque, blood, or myocardial vulnerability.Naghavi M. et al. Circulation 2003; 108(14):1664-72.易損病人=易損斑塊+易損血液+易損心肌冠心病治療策略的演變36易損病人概念的提出Definition of Vulner A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed th

36、at may include variables listed below.Vulnerable plaques 易損斑塊prone to rupture 易于破裂with high likelihood of thrombotic complications and rapid progressionPlaque rupture accounts for nearly 70% of fatal AMI and/or sudden coronary deathsVulnerable plaque is the main, but not the unique cause for acute c

37、ardiovascular eventsVulnerable blood 易損血液prone to thrombosis 易于血栓形成Vulnerable myocardium 易損心肌prone to fatal arrhythmia 易發(fā)生致命性心律失常易損病人Vulnerable Patient冠心病治療策略的演變37 A quantitative method for cum治療上的創(chuàng)新性發(fā)展Development of Innovative Therapies脂質(zhì)沉積 Lipid deposit調(diào)節(jié)血脂 Regulating Blood Lipid藥物: 擴(kuò)冠 Drugs：Nitra

38、tes, CaA手術(shù) Surgery：PCI、CABG穩(wěn)定斑塊 Stabilizing Plaque，血管保護(hù)vas protection，抗炎 anti-inflammatory，抗栓(抗血小板、抗凝) Anti-thrombosis (anti-platelet,anticoagulation)早期識(shí)別；重預(yù)防 Early Identification and Prevention冠脈狹窄 Coronary Stenosis易損斑塊、破裂、血栓形成 Vulnerable Plaque, Rupture, Thrombosis易損患者 Vulnerable Patients冠心病治療策略的演

39、變38治療上的創(chuàng)新性發(fā)展Development of InnoEBM 研究所得(Aspirin)Experience from EBM冠心病治療策略的演變39EBM 研究所得(Aspirin)冠心病治療策略的演變39抗血小板治療的困惑Certain puzzled problem on anti-platelet therapy顱內(nèi)出血胃腸道出血鼻腔出血胸膜腔出血皮下出血（aspirin 75-100mg/d, clopidogril 75mg/d) 高齡尤多見(jiàn); 遠(yuǎn)超1.8-2.1（CURE 研究）可適當(dāng)減量（包括首劑負(fù)荷量）冠心病治療策略的演變40抗血小板治療的困惑Certain puzz

40、led probAspirin resistance概念的爭(zhēng)議臨床Aspirin resistance : 減少事件/未能消除事件 AA基因多態(tài)性/無(wú)效或不利結(jié)果生化Aspirin resistance : 出血時(shí)間延長(zhǎng)/TXA2抑制合成/刺激血小板聚集 0.4-83.0% Dalen JE,et al:Am J Med,2007,120:1-4 Loordkipandize M,et al:Pharmaco Ther,2006,112:733-743冠心病治療策略的演變41Aspirin resistance概念的爭(zhēng)議臨床Aspir危險(xiǎn)因素單一控制危險(xiǎn)因素復(fù)雜干預(yù)冠心病治療觀念改變之四Six

41、th Change in Concept of CHD Treatment 冠心病治療策略的演變42危險(xiǎn)因素危險(xiǎn)因素冠心病治療觀念改變之四Sixth CDiabetesDyslipidemiaHypertensionObesity病人是整體整體干預(yù)/整體醫(yī)學(xué)冠心病治療策略的演變43DiabetesDyslipidemiaHypertensi多重危險(xiǎn)因素的干預(yù)Interventions for multi-RF單一危險(xiǎn)因素的治療?？墒共∪诵哪X血管病危險(xiǎn)下降20%30%，意味著還有70%80%的剩余危險(xiǎn)需要降低 冠心病治療策略的演變44多重危險(xiǎn)因素的干預(yù)Interventions for muPo

42、lypill:心臟病一/二級(jí)予防Polypill Approach for Class I & II Preventionof Cardiac Diseases組成:辛伐他汀40mg, ACEI(賴諾普利), 半量噻嗪類利尿劑(或阿替洛爾25mg),低劑量阿司匹林,葉酸; Composition: Simvastatin 40mg, Lisinopril, half-dose Atenolol, low dose aspirin, folic acid (BMJ 2003; 326:1407, 1419, 1423, 1427)目標(biāo): 55歲以上使用,可降低心腦血管事件80%; Target: for those aged 55 or above, could lower cardiocerebral incidence by 80%爭(zhēng)議: 激烈; Dispute: Fierce A strategy to reduce cardiovascular disease by more than 80%冠心病治療策略的演變45Polypill:心臟病一/二級(jí)予防Polypill ApA