1、冠心病治療戰略的演化The Strategic Changes of Coronary Heart Disease Treatment冠心病治療觀念的改動Novel Changes in Concept of Elderly CHDTreatment Luminal stenosis to vulnerable plaque formation 從注重管腔狹窄到易損斑塊 Lipid deposit to inflammatory response 從留意脂質堆積到炎癥反響 Vulnerable plaque to vulnerable patient 從注重易損斑塊到易損病人Single RF

2、 control to multi-RF intervention 從單一危險要素控制到多個危險要素結合干涉Standardized treatment to individualized therapy 從注重規范化治療到個體化治療Luminal Stenosis管腔狹窄Vulnerable Plaque易損斑塊冠心病治療觀念改動之一First Change in Concept of CHD TreatmentDegree of Coronary Stenosis冠脈狹窄程度Risk of CHD冠心病嚴重度動脈粥樣硬化的傳統觀念Traditional Concept of Atheros

3、clerosis?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% patients had stenosis less than 50% at baseline86% patients had stenosis less than 70% at baselineFalk et al. Circula

4、tion. 1995;92:657.降脂療法降低心臟事件但并不改動管腔狹窄Lipid-lowering Therapies Decrease Cardiac Events but Not StenosisTrialCholesterol Decrease, %Cardiac Event Decrease, %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

5、reduction in cardiovascular disease: clinical benefits and possible mechanisms. N Engl J Med. 1995;332:512-521.Philbin EF, Pearson TA. How does lipid-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, fo

6、r the PLAC I investigators. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. J Am Coll Cardiol. 1995;26:1133-1Coronary Artery Stenosis And Cardiac Events冠脈狹窄與心臟事件Plaque volume or severity of coronary artery ste

7、nosis may not be the key factor for inducing cardiac events.提示:冠脈狹窄并非心血管事件關鍵緣由Concept 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 vulnerable plaque o

8、ften has a large lipid pool, a thin cap, and macrophage-dense inflammation 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. 破裂致血栓構成Muller J, Tofler G,

9、 Stone P. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989; 79:733743. 多方位戰略演化 Many sided strategic changes診斷提高：由以CAG為主導，到注重斑塊檢測技術的開展如IVUS、OCT；根底研討方向：逐漸以穩定易損斑塊以及減少斑塊破裂后血栓構成為方向；二級預防重點：也將由治療冠脈狹窄轉為易損斑塊的干涉。 60 micron CapLesionCHD develops in 2030 years 冠心病慢性病程

10、Plaque rupture occurs in 23 hrs 斑塊破裂快過程DyslipidemiaAtherosclerosisPlaque formationCHD ACSHeart failure LV dysfunction心臟事件的發生 Progression of Cardiac Events AMI LV reconstruction冠脈介入治療的短處Limitations of PCI Although PCI could relieve severe stenosis of coronary artery, it wouldnt change the biologic co

11、urse of AS, thus the problem of “unstable is still unresolved. 尚未能處理斑塊不穩定問題COURAGE臨床實驗 Boden WE, et al. Optimal Medical Therapy with or without PCI for Stable coronary Disease (NEJM.356:1503-1516;April 12,2007) COURAGE 研討設計Study design of COURAGE trial加PCI 組不加PCI組死亡率/ MACE/ACS 2287例穩定型心絞痛患者( 他汀類, 抗血

12、小板, ACEI/ARB, -受體阻滯劑)隨機化隨訪 2.5-7 Y兩組主要終點比較The comparison of endpoints with two groups平均隨訪4.6年 一切緣由死亡或非致死性心肌梗死數 單純優化藥物治療組:18.5% 優化藥物治療+PCI組:19.0% P=0.62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% 7

13、2%The comparison between the PCI group and the medical-therapy group was significant at 1 year ( P0.001) and 3 years (P=0.02) but not at baseline or 5 years. 震撼全球心血管病學界Grobal impact on cardiological field慢性穩定性冠心病/臨界狹窄病變者:現代藥物治療效果理想/病人依從性好 COURAGE trial:醫生應該有自信心面對這些病人維護病人效果和利益的最大化在病人身上做有證據的治療中中醫結合應受了

14、解和提倡兩組總生存率Overall SurvivalNumber at RiskMedical Therapy 1 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穩定易損斑塊的重要作用Stabilization of Vulnerable PlaquesThe vascular pathophysiological research ha

15、s 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 artery. 防治重點應是易損斑塊+狹窄問題Kullo IJ, Edwards WD, Schwartz RS. Vulnerab

16、le 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動脈粥樣硬化1. LDL透過內皮細胞深化內皮細胞間隙，單核細胞遷入內膜，此即最早期。 2. Ox-LDL與巨噬細胞的清道夫受體結合而被攝取，構

17、成巨噬源性泡沫細胞，對應病理變化中的脂紋。 動脈粥樣硬化3. 動脈中膜的血管平滑肌細胞SMC遷入內膜，吞噬脂質構成肌源性泡沫細胞，增生遷移構成纖維帽，對應病理變化中的纖維斑塊。 4. Ox-LDL使上述兩種泡沫細胞壞死崩解，構成糜粥樣壞死物，粥樣斑塊構成。對應病理變化中的粥樣斑塊。 動脈粥樣硬化的中心動脈粥樣硬化構成的機理：關鍵環節在于Ox-LDL如何防止LDL被氧化成Ox-LDL成為治療和防止動脈粥樣硬化的中心。 關注動脈粥樣硬化早期植物血凝素樣氧化低密度脂蛋白受體-1LOX-1的表達是血管內皮細胞出現功能異常的最早期標志，在粘附分子的產生及AS的構成中起重要作用。細胞因子和生長因子平滑肌細

18、胞增生和泡沫細胞構成白細胞遷移細胞因子和生長因子細胞粘附分子LOX-1介導內皮細胞與單核細胞粘附Lipid Deposit脂質堆積Inflammatory Reaction炎癥反響冠心病治療觀念改動之二Second Change in Concept of CHD Treatment 逾百年之脂質堆積學說Lipid Deposition Theory“Lipid deposition theory of atherosclerosis has been put forward for 150 years based on the causal relationship between hype

19、rlipidemia and AS. 高脂血癥與動脈粥樣硬化關系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 atherogenesis: Current concepts. JAMA 1990; 264(23):3047-3052. Infl

20、ammatory theory of AS was first presented by Virchow in 1856. 炎癥實際的提出“Endarteritis deformans or atheroma - a product of an inflammatory process within the intima with the fibrous thickening evolved as a consequence of a reactive fibrosis induced by proliferating connective tissue cells within the in

21、tima.The theory did not raise great attention at that time. 當年未獲關注動脈粥樣硬化炎癥學說Inflammation TheoryIn recent years, AS was shown to have the basic manifestation of inflammation 炎癥反響的根本表現Degeneration變性Exudation 滲出 Proliferation 增生The cell-cell interaction is similar to other chronic inflammation diseases

22、 such as rheumatoid arthritis, chronic pancreatitis and hepatic cirrhosis.動脈粥樣硬化炎癥學說Inflammation Theory動脈粥樣硬化炎癥學說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

23、 pathogens 病原Chlamydia pneumoniae衣原體Cytomegalovirus巨細胞病毒Herpes virus皰疹病毒Helicobacter pylori幽門螺桿菌動脈粥樣硬化炎癥學說Inflammation TheoryIn 1999, a century later, Ross declared that AS is one of chronic inflammatory disease, based on his injury reaction theory.損傷反響實際的提出 (Ross,1999)Inflammatory BiomarkersAS炎癥生物學

24、標志物Inflammatory Biomarkers白介素-6反響蛋白單核細胞趨化因子-1血清淀粉樣蛋白腫瘤壞死因子白介素-18白介素-10 細胞間黏附分子血管細胞黏附分子E-選擇素血管性假血友病因子髓過氧化物酶磷脂酶血漿脂蛋白相關性磷脂酶血管內皮生長因子胎盤生長因子肝細胞生長因子基質金屬蛋白酶1，2，9妊娠相關血漿蛋白-ACD40配體P-選擇素AS炎癥生物學標志物Hs-CRPC-Reactive Protein in CVDElevated hs-CRP levels in healthy populations predict vascular events such as MI and

25、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 stress and

26、 intimal hypertrophy in experimental models.It could also be a potential target of AS treatment and prevention. 高敏C反響蛋白增高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. 基于幾種生化標志物的心血管事件相對風險01.02.

27、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, C-reative protein; hs-CRP, high-sensitivity C-

28、reactive protein; TC, total cholesterol.Adapted from Rifai N, et al. Clin Chem. 2001;47:28-30.hs-CRP (mg/L)他汀治療6周對hs-CRP程度的影響The influence of Statins on hs-CRP levelJialal I et al. Circulation 2001;103:1933-1935.6543210Baseline*Prava(40 mg/d)Simva(20 mg/d)Atorva(10 mg/d)*p0.025 vs. BaselineVulnerabl

29、e Plaque易損斑塊Vulnerable Patient易損病人冠心病治療觀念改動之三Third Change in Concept of CHD Treatment 易損病人概念的提出Definition of Vulnerable PatientVulnerable plaques are not the only culprit factors. Vulnerable blood and vulnerable myocardium play an important role in for the development of acute coronary syndromes, my

30、ocardial infarction, and sudden cardiac death.“Vulnerable patient is proposed to define subjects susceptible to an acute coronary 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 A quantitativ

31、e method for cumulative risk assessment of vulnerable patients needs to be developed that 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 su

32、dden coronary deathsVulnerable plaque is the main, but not the unique cause for acute cardiovascular eventsVulnerable blood 易損血液prone to thrombosis 易于血栓構成Vulnerable myocardium 易損心肌prone to fatal arrhythmia 易發生致命性心律失常易損病人Vulnerable Patient治療上的創新性開展Development of Innovative Therapies脂質堆積 Lipid deposit

33、調理血脂 Regulating Blood Lipid藥物: 擴冠 Drugs：Nitrates, CaA手術 Surgery：PCI、CABG穩定斑塊 Stabilizing Plaque，血管維護vas protection，抗炎 anti-inflammatory，抗栓(抗血小板、抗凝) Anti-thrombosis (anti-platelet,anticoagulation)早期識別；重預防 Early Identification and Prevention冠脈狹窄 Coronary Stenosis易損斑塊、破裂、血栓構成 Vulnerable Plaque, Rupture

34、, Thrombosis易損患者 Vulnerable PatientsEBM 研討所得(Aspirin)Experience from EBM抗血小板治療的困惑Certain puzzled problem on anti-platelet therapy顱內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; 遠超1.8-2.1CURE 研討可適當減量包括首劑負荷量Aspirin resistance概念的爭議臨床Aspirin resistance : 減少事件/未能消除事件 AA基因多態性/無效或不利結果生

35、化Aspirin resistance : 出血時間延伸/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危險要素單一控制危險要素復雜干涉冠心病治療觀念改動之四Sixth Change in Concept of CHD Treatment DiabetesDyslipidemiaHypertensionObesity病人是整體整體干涉/整體醫學多重危險要素的干涉Interventions for multi-

36、RF單一危險要素的治療常可使病人心腦血管病危險下降20%30%，意味著還有70%80%的剩余危險需求降低 Polypill:心臟病一/二級予防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)目的: 55歲以上運用,可降低心腦血管事件80%; Target: for those aged 55 or above, could lower cardiocerebra