动脉硬化血栓病理生理学

1、会计学1动脉硬化血栓病理生理学动脉硬化血栓病理生理学multiple vascular beds, including cerebral, coronary, and peripheral arteries nThe underlying disease leading to myocardial infarction (MI), peripheral arterial disease (PAD), ischemia and many forms of strokeMI, myocardial infarction; PAD, peripheral artery disease.Fuster

2、V, et al. Vasc Med. 1998;3:231-239.Rauch U, et al. Ann Intern Med. 2001;134:122-238.第1页/共45页*Atherothrombosis defined as ischemic heart disease and cerebrovascular disease.1The World Health Report 2001. Geneva. WHO. 2001.22.319.312.69.796.3051015202530Atherothrombosis*Infectious DiseaseCancerInjurie

3、sPulmonary DiseaseAIDSCauses of Mortality (%)第2页/共45页Analysis of data from the Framingham Heart Study.Peeters A, et al. Eur Heart J. 2002;23:458-466.Atherothrombosis reduces life expectancy by around 8-12 years in patients aged over 60 years1Average Remaining Life Expectancy at Age 60 (Men)048121620

4、HealthyYearsHistory of AMI-9.2 yearsHistory of Cardiovascular Disease-7.4 yearsHistory of Stroke-12 years第3页/共45页3.2 Million Hospital AdmissionsCoronary Atherosclerosis Acute Myocardial Infarction1,153,000 Admissions829,000 AdmissionsCerebrovascular Disease961,000 AdmissionsVascular DiseaseOther Isc

5、hemicHeart Disease280,000 AdmissionsPopovic JR, Hall MJ. Advance Data. 2001;319:1-20.第4页/共45页Approximately 57,000 deaths could be avoided each year in the US if patients were given appropriate care. National Committee for Quality Assurance. Washington, DC 2003.700Cervical-cancer screeningPrenatal ca

6、re -blocker treatmentBreast-cancer screeningSmoking cessationCholesterol managementDiabetes careHigh-blood pressure control1500170025002700650013,60028,300第5页/共45页* Based on data from the ARIC study of the National Heart, Lung, and Blood Institute, 1987-1994. Includes Americans hospitalized with def

7、inite or probable MI or fatal CHD, not including silent MIs. ACS, acute coronary syndrome; MI, myocardial infarction; ARIC, Atherosclerotic Risk in Communities, CHD, coronary heart disease. American Heart Association. Heart Disease and Stroke Statistics2003 Update.第6页/共45页American Heart Association.

8、 Heart Disease and Stroke Statistics2003 Update.第7页/共45页PAD, peripheral artery disease; CV, cardiovascular.1Nicolaides AN. Symposium. Nov. 1997. 2Hiatt WR, et al. Circulation. 1995; 91:1472-1479.3Criqui MH, et al. N Engl J Med. 1992; 326:381-386. 4Hirsch AT, et al. JAMA. 2001;286:1317-1324.第8页/共45页1

9、American Diabetes Association. Diabetes Care. 2003;26:917-932.2Juvenile Diabetes Research Foundation International. Diabetes Figures, .第9页/共45页CerebralIschemic strokeTransient ischemic attack CardiacMyocardial infarction Angina pectoris (stable, unstable)Peripheral Arterial Disease

10、 Critical limb ischemia, claudication第10页/共45页Overlap of Vascular Disease in Patients With AtherothrombosisPAD, peripheral artery disease.Adapted from TransAtlantic Inter-Society Consensus Group. J Vasc Surg. 2000;31:S16.Coronary DiseasePAD12%33%15%5%14%13%8%Cerebral DiseaseCoronary DiseasePAD19%30%

11、25%4%12%7%3%Cerebral DiseaseCAPRIEAronow & Ahn第11页/共45页MI, myocardial infarction; PAD, peripheral arterial disease; CV, cardiovascular.Ness J, et al. J Am Geriatr Soc. 1999;47:1255-1256. Schafer AI. Am J Med. 1996;101:199-209.Atherothrombotic Events (MI, Stroke, or CV Death)Plaque RupturePlatelet Ad

12、hesion, Activation, and AggregationThrombus FormationMIAtherothrombotic StrokePADUnstable Angina第12页/共45页Increased Risk vs General Population (%)Original EventMIStrokeMI5-7 timesgreater risk(includes death)*3-4 timesgreater risk(includes TIA)Stroke2-3 timesgreater risk (includes angina and sudden de

13、ath)*9 timesgreater riskPAD4 timesgreater risk*2-3 timesgreater risk (includes TIA) * Death documented within 1 hour of an event attributed to CHD.Note:This chart is based on epidemiologic data and is not intended to provide a direct basis for comparison of risks between event categories. MI, myocar

14、dial infarction; TIA, transient aschemic attack, PAD, peripheral artery disease.Adult Treatment Panel II. Circulation. 1994;89:1333-1363.Kannel, WB. J Cardiovasc Risk. 1994;1:333-339.Wilterdink, JI, et al. Arch Neurol. 1992;49:857-863. Crique, MH, et al. N Engl J Med. 1992;326:381-386.第13页/共45页Unsta

15、bleanginaMI Ischemic stroke/TIACritical legischemiaIntermitentclaudicationCV deathACSAtherosclerosisStable angina/ Intermittent claudicationAtherothrombosis: A ThrombosisAdapted from Libby P. Circulation. 2001;104:365-372.第14页/共45页Adapted from Falk E, et al. Circulation. 1995;92:657-671.第15页/共45页Thi

16、n fibrous capInflammatory cellsFewSMCsErodedendotheliumActivatedmacrophagesThickfibrous capLack ofinflammatory cellsFoam cellsIntactendothelium MoreSMCsLibby P. Circulation. 1995;91:2844-2850.UnstableStable第16页/共45页Andrew Farb, MD by permission.第17页/共45页Impaired FibrinolysisFibrinogenDiabetesMellitu

17、sCholesterolSmokingCap FatigueAtheromatous Core(size/consistency)Cap InflammationSystemic FactorsLocal FactorsHomocysteinePlaqueRuptureFuster V, et al. N Engl J Med. 1992;326:310-318.Falk E, et al. Circulation. 1995:92:657-671.Cap Thickness/ Consistency第18页/共45页MI, myocardial infarction.Adapted from

18、 Yusuf S, et al. Circulation. 2001;104:2746-2753.Drouet L. Cerebrovasc Dis. 2002;13(suppl 1):1-6.Lifestyle Smoking Diet Lack of exerciseGenetic Traits Gender PlA2GeneralizedDisorders Age ObesitySystemicConditions Hypertension Hyperlipidemia Diabetes Hypercoagulable states HomocysteinemiaAtherothromb

19、otic Manifestations(MI, stroke, vascular death)Inflammation Elevated CRP CD40 Ligand, IL-6 Prothrombotic factors (F I and II) FibrinogenLocal Factors Blood flow patterns Shear stress Vessel diameter Arterial wall structure % arterial stenosis第19页/共45页第20页/共45页RCA WallLAD WallEccentric (“lipid-rich”)

20、Concentric (“fibrotic”) Ectatic (“remodeled”)MR, magnetic resonance; LAD, left anterior descending; RCA, right coronary artery.Fayad ZA, et al. Circulation. 2000;102:506-510. (with permission)LAD Wall第21页/共45页Evidence of Multiple “Vulnerable” Plaques in ACSACS, acute coronary syndrome.Asakura M, et

21、al. J Am Coll Cardiol. 2001;37:1284-1288. (with permission)Angiographic & angioscopic images in 58-year-old man with anterior myocardial infarctionMultiple “vulnerable”plaques detected in non-culprit segments 10-12Culprit lesion (#8)detected withthrombus (red) Multiple “vulnerable” plaques detected

22、in non-culprit segments 1-7第22页/共45页MI, myocardial infarction.Goldstein JA, et al. N Eng J Med. 2000;343:915-922. (with permission)Culprit lesionMultiple plaquesdetectedMultiple plaquesdetected第23页/共45页ACS, acute coronary syndrome.Rioufol G, et al. Circulation 2002;106:804-808. (with permission)Freq

23、uency of multiple active plaque ruptures beyond the culprit lesionPatients (%)80% of Patients With 2 Plaques N=24Frequency of Multiple “Active” Plaques in Patients With ACS第24页/共45页ACS: Tip of the Atherothrombotic “Iceberg”ACS, acute coronary syndrome; UA, unstable angina; NSTEMI, non-ST-segment ele

24、vation myocardial infarction; STEMI, ST-segment elevation myocardial infarction. Adapted from Goldstein JA. J Am Coll Cardiol. 2002;39:1464-1467.Presence of Multiple Coronary PlaquesVascular InflammationPersistent Hyperreactive PlateletsClinicalSubclinicalAcute Plaque Rupture ACS (UA/NSTEMI/STEMI)第2

25、5页/共45页AGGREGATIONCOAGULATIONAdapted from Ferguson JJ, et al. Antiplatelet Therapy in Clinical Practice. 2000:15-35.第26页/共45页AdhesionAggregation1Activation23第27页/共45页GP IIb/IIIa Inhibitors1. Platelet Adhesion2. Platelet ActivationPlateletGP Ib Plaque ruptureActivated Platelet GP IIb/IIIa 3. Platelet

26、 AggregationASA, Clopidogrel/TiclopidineASA, acetylsalicyclic acid.Cannon and Braunwald, Heart Disease. 2001. TxA2FibrinogenPlatelets Role in Thrombosis第28页/共45页FibrinPlateletsRBCsWhite ThrombusFibrinPlateletsRBCsCoagulation ThrombusHigh Flow Slow FlowRBCs, red blood cells.第29页/共45页ThrombinSerotonin

27、EpinephrineCollagenActivationActivatedPlateletDegranulationAspirinIIb/IIIa ClopidogrelTiclopidinePlatelet agonistsADPATPserotonincalciummagnesiumAdhesive proteinsthrombospondinfibrinogenp-selectinvWFCoagulation factorsfactor Vfactor XIPAI-1Inflammatory factorsplatelet factor 4CD 154 (CD 40 ligand)PD

28、GFIV Gp IIb/IIIaInhibitorsTXA, thromboxane; PDGF, platelet-derived growth factor.第30页/共45页Platelet Aggregability Status01020304050Death Cardiac Events10.36.414.9Patients (%)*RR=1.6(CI 0.5-5.5)Negative(n=94)*RR=1.6(CI 0.7-3.5)*RR=5.4(CI 2.2-13.4)*RR=3.1(CI 1.6-5.8)Intermediate(n=29)Positi

29、ve(n=26)ACS, acute coronary syndrome.* Relative risk compared to group with negative aggregation.Adapted from Trip MD, et al. N Engl J Med. 1990;322:1549-1554.第31页/共45页Platelets Release RANTES (Regulated on Activation, Normal T-cellExpressed and Secreted).Libby P, et al. Circulation. 2001;103:1718-1

30、720.Inflammatory Modulators CD 40 ligand Platelet factor 4 RANTESUnstable PlaqueActivatedPlateletsPlaqueRupture & Thrombosis Thrombospondin Platelet-derived growth factor Nitric oxide第32页/共45页CD40L is activated by agonists such as ADP, thrombin, or collagen. The translocation of CD40L seems to coinc

31、ide with the presence of release-granule contents, including platelet-derived growth factor (PDGF), transforming growth factor beta, platelet factor 4, and thrombospondin. GP IIb/IIIa antagonists block the hydrolysis and subsequent release of SCD40L from platelets.SCD40L, SCD40 ligand; PDGF, platele

32、t-derived growth factor; TGF-, transforming growth factor-beta; PF4, platelet factor 4; TSP,thrombospondin.Andre P, et al. Circulation. 2002:106:896-899. (with permission)ADPThrombinCollagenCD4OL sCD4OL GP IIb-IIIaAntagonists PDGF TGF PF4 TSP第33页/共45页TGF-5 Stimulate smooth muscle cell biosynthesis N

33、itric oxide3 Effects on monocyte, leucocyte, endothelium, and smooth muscle cellsCD154 (CD40 ligand)1,4 Regulates macrophage and smooth muscle cell functionsRANTES2 Influences macrophage adhesion to endothelial cellPF41 Mediates shear-resistant arrest of monocytes to endotheliumPlateletPDGF1 Induces

34、 proliferation of smooth muscle cellsThrombospondin1 Interacts with cell surface receptors1Libby P, et al. Circulation. 2001;103:1718-1720. 2 von Hundelshausen P, et al. Circulation. 2001;103:1772-1777. 3 Wever RMF, et al. Circulation. 1998;97:108-112. 4 Hermann A, et al. Platelets. 2001;12:74-82. 5

35、 Robbie L, et al. Ann N Y Acad Sci. 2001; 947:167-79.第34页/共45页The Detrimental Role Adapted from Andre P, et al. Circulation. 2002:106:896-899. Inflammationinduces production/release of pro-inflammatory cytokines from vascular and atheroma cells Thrombosis stabilizes platelet-rich thrombi Restenosis

36、prevents reendothelialization of the injured vessel contributes to activation and proliferation of smooth muscle cells第35页/共45页Heeschen C, et al. N Engl J Med. 2003;348:1104-1111. (with permission)Association Between Soluble CD40 Ligand Levels and the Rate of Cardiac EventsTimeDeath or Nonfatal Myoc

37、ardial Infarction (%)P=.13P=.003P=.004P.001第36页/共45页015304560750246810MonocytePlatelet Aggregates (%)Soluble CD40 Ligand ( g/Liter)r =0.75P.001Level Of Soluble CD40 Heeschen C, et al. N Engl J Med. 2003:348:1104-1111. (with permission)第37页/共45页Heeschen C, et al. N Engl J Med. 2003;348:1104-1111.Death or Nonfatal Myocardial Infarction (%)Kaplan-Meier Curves Showing Cumulative Incidence of Death or Nonfatal Myocardial InfarctionFollow-