動(dòng)脈硬化血栓病理生理學(xué)ppt課件

1、Atherothrombosis PathophysiologyWhat Is Atherothrombosis? The formation of a thrombus on an existing atherosclerotic plaque Atherothrombosis is a new term recognizing that atherosclerosis (plaque development) and acute thrombosis are integrally related to the presentation of vascular events A genera

2、lized progressive disease of large- and mid-size arteries that affects multiple vascular beds, including cerebral, coronary, and peripheral arteries The underlying disease leading to myocardial infarction (MI), peripheral arterial disease (PAD), ischemia and many forms of strokeMI, myocardial infarc

3、tion; PAD, peripheral artery disease.Fuster V, et al. Vasc Med. 1998;3:231-239.Rauch U, et al. Ann Intern Med. 2001;134:122-238.Atherothrombosis* is theLeading Cause of Death Worldwide1*Atherothrombosis defined as ischemic heart disease and cerebrovascular disease.1The World Health Report 2001. Gene

4、va. WHO. 2001.22.319.312.69.796.3051015202530Atherothrombosis*Infectious DiseaseCancerInjuriesPulmonary DiseaseAIDSCauses of Mortality (%)Atherothrombosis Significantly Shortens LifeAnalysis of data from the Framingham Heart Study.Peeters A, et al. Eur Heart J. 2002;23:458-466.Atherothrombosis reduc

5、es life expectancy by around 8-12 years in patients aged over 60 years1Average Remaining Life Expectancy at Age 60 (Men)048121620HealthyYearsHistory of AMI-9.2 yearsHistory of Cardiovascular Disease-7.4 yearsHistory of Stroke-12 years3.2 Million Hospital AdmissionsCoronary Atherosclerosis Acute Myoc

6、ardial Infarction1,153,000 Admissions829,000 AdmissionsHospitalizations in the USDue to Vascular DiseaseCerebrovascular Disease961,000 AdmissionsVascular DiseaseOther IschemicHeart Disease280,000 AdmissionsPopovic JR, Hall MJ. Advance Data. 2001;319:1-20.Preventable DeathsApproximately 57,000 deaths

7、 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 care -locker treatment-locker treatmentBreast-cancer screeningSmoking cessationCholesterol managementDiabetes careHigh-blo

8、od pressure control1500170025002700650013,60028,300* Based on data from the ARIC study of the National Heart, Lung, and Blood Institute, 1987-1994. Includes Americans hospitalized with definite or probable MI or fatal CHD, not including silent MIs. ACS, acute coronary syndrome; MI, myocardial infarc

9、tion; ARIC, Atherosclerotic Risk in Communities, CHD, coronary heart disease. American Heart Association. Heart Disease and Stroke Statistics2003 Update.Epidemiology of ACS in the United States Single largest cause of death 515,204 US deaths in 2000 1 in every 5 US deaths Incidence 1,100,000 America

10、ns will have a new or recurrent coronary attack each year and about 45% will die* 550,000 new cases of angina per year Prevalence 12,900,000 with a history of MI, angina, or bothEpidemiology of Stroke in the United StatesPrevalence4.7 million casesIncidence700,000 new or recurrent strokes each yearM

11、orbidity/mortalityThird leading cause of death1 of every 14 deaths (168,000 deaths)Stroke: a leading cause of long-term disabilityAmerican Heart Association. Heart Disease and Stroke Statistics2003 Update.Peripheral Arterial Disease PAD affects 12% of the adult population1,220% of the population age

12、d 70 Associated with 6-fold increase in CV mortality3Underrecognized and undertreated4Measurement simple, inexpensive, and noninvasiveAppropriate for risk assessment and screeningPatients at high risk need aggressive risk-factor modification and antiplatelet drugs4PAD, peripheral artery disease; CV,

13、 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.Diabetes: Impact in United States 12 million people with diabetes1 Diabetes is the 5th leading cause

14、 of death1 Half of diabetic patients will experience kidney failure1 Diabetes is the leading cause of new adult cases of blindness2 Direct and indirect diabetes costs were estimated at $132 billion1 in 2002 1 American Diabetes Association. Diabetes Care. 2003;26:917-932.2 Juvenile Diabetes Research

15、Foundation International. Diabetes Figures, .CerebralIschemic strokeTransient ischemic attack CardiacMyocardial infarction Angina pectoris (stable, unstable)Peripheral Arterial Disease Critical limb ischemia, claudicationClinical Manifestations of AtherothrombosisOverlap of Vascular Disease

16、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%25%4%12%7%3%Cerebral DiseaseCAPRIEAronow & AhnCommon Underlying Atherothro

17、mbotic Disease ProcessMI, 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 Adhesion, Activation, and Aggregati

18、onThrombus FormationMIAtherothrombotic StrokePADUnstable AnginaRisk of a Second Atherothrombotic EventIncreased 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 death

19、)*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, myocardia

20、l infarction; TIA, transient aschemic attack, PAD, peripheral artery disease.Adult Treatment Panel II. Circulation. 1994;89:1333-3.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.UnstableanginaMI Isc

21、hemic stroke/TIACritical legischemiaIntermitentclaudicationCV deathACSAtherosclerosisStable angina/ Intermittent claudicationAtherothrombosis: A Generalized and Progressive ProcessThrombosisAdapted from Libby P. Circulation. 2001;104:365-372.Atherothrombosis: Thrombus Superimposed on Atherosclerotic

22、 PlaqueAdapted from Falk E, et al. Circulation. 1995;92:657-671.Characteristics of Unstable and Stable PlaqueThin fibrous capInflammatory cellsFewSMCsErodedendotheliumActivatedmacrophagesThickfibrous capLack ofinflammatory cellsFoam cellsIntactendothelium MoreSMCsLibby P. Circulation. 1995;91:2844-2

23、850.UnstableStablePlaque RuptureAndrew Farb, MD by permission.Risk Factors for Plaque RuptureImpaired FibrinolysisFibrinogenDiabetesMellitusCholesterolSmokingCap FatigueAtheromatous Core(size/consistency)Cap InflammationSystemic FactorsLocal FactorsHomocysteinePlaqueRuptureFuster V, et al. N Engl J

24、Med. 1992;326:310-318.Falk E, et al. Circulation. 1995:92:657-671.Cap Thickness/ ConsistencyMultiple Risk Factors for AtherothrombosisMI, myocardial infarction.Adapted from Yusuf S, et al. Circulation. 2001;104:2746-2753.Drouet L. Cerebrovasc Dis. 2002;13(suppl 1):1-6.LifestyleSmokingDietLack of exe

25、rciseGenetic TraitsGenderPlA2GeneralizedDisordersAgeObesitySystemicConditionsHypertensionHyperlipidemiaDiabetesHypercoagulable statesHomocysteinemiaAtherothrombotic Manifestations(MI, stroke, vascular death)InflammationElevated CRPCD40 Ligand, IL-6 Prothrombotic factors (F I and II)FibrinogenLocal F

26、actorsBlood flow patternsShear stressVessel diameterArterial wall structure% arterial stenosisRisk Factors for Ischemic StrokeModifiableHypertensionAtrial fibrillationCigarette smokingHyperlipidemiaAlcohol abuseCarotid stenosisPhysical inactivityObesityDiabetesNonmodifiableAgeSexRace/EthnicityHeredi

27、tyRCA WallLAD WallEccentric (“l(fā)ipid-rich)Concentric (“fibrotic)Ectatic (“remodeled)Black-Blood Coronary Plaque MRMR, magnetic resonance; LAD, left anterior descending; RCA, right coronary artery.Fayad ZA, et al. Circulation. 2000;102:506-510. (with permission)LAD WallEvidence of Multiple “Vulnerable

28、 Plaques in ACSACS, acute coronary syndrome.Asakura M, et al. J Am Coll Cardiol. 2001;37:1284-1288. (with permission)Angiographic & angioscopic images in 58-year-old man with anterior myocardial infarctionMultiple “vulnerableplaques detected in non-culprit segments 10-12Culprit lesion (#8)detected w

29、iththrombus (red) Multiple “vulnerable plaques detected in non-culprit segments 1-7Multiple Complex Coronary Plaques in Patients With Acute MIMI, myocardial infarction.Goldstein JA, et al. N Eng J Med. 2000;343:915-922. (with permission)Culprit lesionMultiple plaquesdetectedMultiple plaquesdetectedA

30、CS, acute coronary syndrome.Rioufol G, et al. Circulation 2002;106:804-808. (with permission)Frequency of multiple active plaque ruptures beyond the culprit lesionPatients (%)80% of Patients With 2 Plaques 051015202530012345N=24Frequency of Multiple “Active Plaques in Patients With ACSACS: Tip of th

31、e Atherothrombotic “IcebergACS, acute coronary syndrome; UA, unstable angina; NSTEMI, non-ST-segment elevation 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 Infla

32、mmationPersistent Hyperreactive PlateletsClinicalSubclinicalAcute Plaque Rupture ACS (UA/NSTEMI/STEMI)Hemostatic Plug FormationAGGREGATIONCOAGULATIONAdapted from Ferguson JJ, et al. Antiplatelet Therapy in Clinical Practice. 2000:15-35.AdhesionThe Role of Platelets in AtherothrombosisAggregation1Act

33、ivation23GP IIb/IIIa Inhibitors1. Platelet Adhesion2. Platelet ActivationPlateletGP Ib Plaque ruptureActivated Platelet GP IIb/IIIa 3. Platelet AggregationASA, Clopidogrel/TiclopidineASA, acetylsalicyclic acid.Cannon and Braunwald, Heart Disease. 2001. TxA2FibrinogenPlatelets Role in ThrombosisFibri

34、nPlateletsRBCsWhite ThrombusFibrinPlateletsRBCsCoagulation ThrombusHigh Flow Slow FlowPlatelets: Role in ThrombosisRBCs, red blood cells.ThrombinSerotoninEpinephrineCollagenActivationActivatedPlateletDegranulationAspirinClopidogrelTiclopidinePlatelet agonistsADPATPserotonincalciummagnesiumAdhesive p

35、roteinsthrombospondinfibrinogenp-selectinvWFCoagulation factorsfactor Vfactor XIPAI-1Inflammatory factorsplatelet factor 4CD 154 (CD 40 ligand)PDGFIV Gp IIb/IIIaInhibitorsTXA, thromboxane; PDGF, platelet-derived growth factor.Platelet Hyperreactivity Following ACS Predicts 5-Year OutcomesPlatelet Ag

36、gregability 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)Positive(n=26)ACS, acute coronary syndrome.* Relative risk compared to group with negative aggregation.Adap

37、ted from Trip MD, et al. N Engl J Med. 1990;322:1549-1554.Platelets Release Inflammatory Mediators and Lead to Vascular Inflammation and Plaque InstabilityRANTES (Regulated on Activation, Normal T-cellExpressed and Secreted).Libby P, et al. Circulation. 2001;103:1718-1720.Inflammatory ModulatorsCD 4

38、0 ligandPlatelet factor 4RANTESUnstable PlaqueActivatedPlateletsPlaqueRupture & ThrombosisThrombospondinPlatelet-derived growth factorNitric oxideCD40L is activated by agonists such as ADP, thrombin, or collagen. The translocation of CD40L seems to coincide with the presence of release-granule conte

39、nts, 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.The Shedding of Soluble SCD40L During Platelet StimulationSCD40L, SCD40 ligand; P

40、DGF, platelet-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 TSPInflammatory Modulators Produced by PlateletsT

41、GF-5Stimulate smooth muscle cell biosynthesis Nitric oxide3Effects on monocyte, leucocyte, endothelium, and smooth muscle cellsCD154 (CD40 ligand)1,4Regulates macrophage and smooth muscle cell functionsRANTES2Influences macrophage adhesion to endothelial cellPF41Mediates shear-resistant arrest of monocytes to endotheliumPlateletPDGF1 Induces proliferation of smooth muscle cellsThrombospondin1Interacts with cell surface receptors1 Libby P , et al. Circulation. 2001;103:1718-1720. 2 von Hundelshausen P , et al. Circulation. 2001;103:1772-1777. 3 Wever RMF, et