動(dòng)脈硬化血栓病理生理學(xué)

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 -blocker treatmentBreast-cancer screeningSmoking cessationCholesterol managementDiabetes careHigh-blood pressure cont

8、rol1500170025002700650013,60028,300* 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 infarction; ARIC, Athe

9、rosclerotic 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 Americans will have a n

10、ew 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 yearMorbidity/mortali

11、tyThird 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 aged 70 Associated

12、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, cardiovascular.

13、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 of death1 Half

14、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 1American Diabetes Association. Diabetes Care. 2003;26:917-932.2Juvenile Diabetes Research Foundation Interna

15、tional. 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 in Patie

16、nts 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 Atherothrombotic D

17、isease 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 AggregationThromb

18、us 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)*9 time

19、sgreater 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, myocardial infarc

20、tion; 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.UnstableanginaMI Ischemic

21、 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 Plaq

22、ueAdapted 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;91:2844-2850.U

23、nstableStablePlaque 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 Med.

24、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.Lifestyle Smoking Diet Lack of exerc

25、iseGenetic Traits Gender PlA2GeneralizedDisorders Age ObesitySystemicConditions Hypertension Hyperlipidemia Diabetes Hypercoagulable states HomocysteinemiaAtherothrombotic Manifestations(MI, stroke, vascular death)Inflammation Elevated CRP CD40 Ligand, IL-6 Prothrombotic factors (F I and II) Fibrino

26、genLocal Factors Blood flow patterns Shear stress Vessel diameter Arterial wall structure % arterial stenosisRisk Factors for Ischemic StrokeModifiableHypertensionAtrial fibrillationCigarette smokingHyperlipidemiaAlcohol abuseCarotid stenosisPhysical inactivityObesityDiabetesNonmodifiableAgeSexRace/

27、EthnicityHeredityRCA 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 Mu

28、ltiple “Vulnerable” 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 “vulnerable”plaques detected in non-culprit segments 10-12Culprit l

29、esion (#8)detected withthrombus (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 plaquesdetectedMult

30、iple plaquesdetectedACS, 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

31、With ACSACS: Tip of the Atherothrombotic “Iceberg”ACS, 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 Coronar

32、y PlaquesVascular InflammationPersistent 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 Atheroth

33、rombosisAggregation1Activation23GP 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

34、Role in ThrombosisFibrinPlateletsRBCsWhite ThrombusFibrinPlateletsRBCsCoagulation ThrombusHigh Flow Slow FlowPlatelets: Role in ThrombosisRBCs, red blood cells.ThrombinSerotoninEpinephrineCollagenActivationActivatedPlateletDegranulationAspirinIIb/IIIa ClopidogrelTiclopidinePlatelet agonistsADPATPser

35、otonincalciummagnesiumAdhesive proteinsthrombospondinfibrinogenp-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 Pre

36、dicts 5-Year OutcomesPlatelet 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)Positive(n=26)ACS, acute coronary syndrome.* Relative risk compared to grou

37、p with negative aggregation.Adapted 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-

38、1720.Inflammatory Modulators CD 40 ligand Platelet factor 4 RANTESUnstable PlaqueActivatedPlateletsPlaqueRupture & Thrombosis Thrombospondin Platelet-derived growth factor Nitric oxideCD40L is activated by agonists such as ADP, thrombin, or collagen. The translocation of CD40L seems to coincide with

39、 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.The Shedding of Soluble SCD40L During Plate

40、let StimulationSCD40L, SCD40 ligand; PDGF, 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 TSPInflamma

41、tory Modulators Produced by PlateletsTGF-5 Stimulate smooth muscle cell biosynthesis Nitric 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 cel

42、lPF41 Mediates shear-resistant arrest of monocytes to endotheliumPlateletPDGF1 Induces 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

43、, et al. Circulation. 1998;97:108-112. 4 Hermann A, et al. Platelets. 2001;12:74-82. 5 Robbie L, et al. Ann N Y Acad Sci. 2001; 947:167-79.The Detrimental Role of Platelet-Derived sCD40Ligand in Cardiovascular DiseaseAdapted from Andre P, et al. Circulation. 2002:106:896-899. Inflammationinduces production/release of pro-inflamma