1、2022-11-11动脉硬化血栓病理生理动脉硬化血栓病理生理学学Atherothrombosis*is theLeading Cause of Death Worldwide1*Atherothrombosis defined as ischemic heart disease and cerebrovascular disease.1The World Health Report 2001.Geneva.WHO.2001.22.319.312.69.796.3051015202530Atherothrombosis*Infectious DiseaseCancerInjuriesPulmon
2、ary 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 reduces life expectancy by around 8-12 years in patients aged over 60 years1Average Remaining Life Expectancy
3、 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 Myocardial Infarction1,153,000 Admissions829,000 AdmissionsHospitalizations in the USDue to Vascular DiseaseC
4、erebrovascular Disease961,000 AdmissionsVascular DiseaseOther IschemicHeart Disease280,000 AdmissionsPopovic JR,Hall MJ.Advance Data.2001;319:1-20.Preventable DeathsApproximately 57,000 deaths could be avoided each year in the US if patients were given appropriate care.National Committee for Quality
5、 Assurance.Washington,DC 2003.700Cervical-cancer screeningPrenatal care-blocker treatmentBreast-cancer screeningSmoking cessationCholesterol managementDiabetes careHigh-blood pressure control1500170025002700650013,60028,300*Based on data from the ARIC study of the National Heart,Lung,and Blood Insti
6、tute,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,Atherosclerotic Risk in Communities,CHD,coronary heart disease.American Heart Association.Heart Disease and Stroke Statistics200
7、3 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 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
8、a history of MI,angina,or bothEpidemiology of Stroke in the United StatesPrevalence4.7 million casesIncidence700,000 new or recurrent strokes each yearMorbidity/mortalityThird leading cause of death1 of every 14 deaths(168,000 deaths)Stroke:a leading cause of long-term disabilityAmerican Heart Assoc
9、iation.Heart Disease and Stroke Statistics2003 Update.Peripheral Arterial Disease PAD affects 12%of the adult population1,220%of the population aged 70 Associated with 6-fold increase in CV mortality3Underrecognized and undertreated4Measurement simple,inexpensive,and noninvasiveAppropriate for risk
10、assessment and screeningPatients at high risk need aggressive risk-factor modification and antiplatelet drugs4PAD,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 a
11、l.JAMA.2001;286:1317-1324.Diabetes:Impact in United States 12 million people with diabetes1 Diabetes is the 5th leading cause 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 est
12、imated at$132 billion1 in 2002 1American Diabetes Association.Diabetes Care.2003;26:917-932.2Juvenile Diabetes Research Foundation International.Diabetes Figures,jdrf.org.CerebralIschemic strokeTransient ischemic attack CardiacMyocardial infarction Angina pectoris(stable,unstable)Peripheral Arterial
13、 Disease Critical limb ischemia,claudicationClinical Manifestations of AtherothrombosisOverlap 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%Cer
14、ebral DiseaseCoronary DiseasePAD19%30%25%4%12%7%3%Cerebral DiseaseCAPRIEAronow&AhnCommon Underlying Atherothrombotic 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.Atheroth
15、rombotic Events(MI,Stroke,or CV Death)Plaque RupturePlatelet Adhesion,Activation,and AggregationThrombus FormationMIAtherothrombotic StrokePADUnstable AnginaRisk of a Second Atherothrombotic Event*Death documented within 1 hour of an event attributed to CHD.Note:This chart is based on epidemiologic
16、data and is not intended to provide a direct basis for comparison of risks between event categories.MI,myocardial 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
17、al.Arch Neurol.1992;49:857-863.Crique,MH,et al.N Engl J Med.1992;326:381-386.UnstableanginaMI Ischemic stroke/TIACritical legischemiaIntermitentclaudicationCV deathACSAtherosclerosisStable angina/Intermittent claudicationAtherothrombosis:A Generalized and Progressive ProcessThrombosisAdapted from Li
18、bby P.Circulation.2001;104:365-372.Atherothrombosis:Thrombus Superimposed on Atherosclerotic PlaqueAdapted from Falk E,et al.Circulation.1995;92:657-671.Characteristics of Unstable and Stable PlaqueThin fibrous capInflammatory cellsFewSMCsErodedendotheliumActivatedmacrophagesThickfibrous capLack ofi
19、nflammatory cellsFoam cellsIntactendothelium MoreSMCsLibby P.Circulation.1995;91:2844-2850.UnstableStablePlaque RuptureAndrew Farb,MD by permission.Risk Factors for Plaque RuptureImpaired FibrinolysisFibrinogenDiabetesMellitusCholesterolSmokingCap FatigueAtheromatous Core(size/consistency)Cap Inflam
20、mationSystemic FactorsLocal FactorsHomocysteinePlaqueRuptureFuster V,et al.N Engl J 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.Drou
21、et 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 HomocysteinemiaAtherothrombotic Manifestations(MI,stroke,vascular death)Inflammati
22、on 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 stenosisRisk Factors for Ischemic StrokeModifiableHypertensionAtrial fibrillationCigarette smokingHyperlipidemiaAlcohol abuseCar
23、otid stenosisPhysical inactivityObesityDiabetesNonmodifiableAgeSexRace/EthnicityHeredityRCA WallLAD WallEccentric(“lipid-rich”)Concentric(“fibrotic”)Ectatic(“remodeled”)Black-Blood Coronary Plaque MRMR,magnetic resonance;LAD,left anterior descending;RCA,right coronary artery.Fayad ZA,et al.Circulati
24、on.2000;102:506-510.(with permission)LAD WallEvidence of Multiple“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”plaque
25、s detected in non-culprit segments 10-12Culprit lesion(#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)Cul
26、prit lesionMultiple plaquesdetectedMultiple 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 N=24Frequency of Multiple“Active”Plaques
27、 in Patients 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 Corona
28、ry 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 Atherothrom
29、bosisAggregation1Activation23GP 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 Thr
30、ombosisFibrinPlateletsRBCsWhite ThrombusFibrinPlateletsRBCsCoagulation ThrombusHigh Flow Slow FlowPlatelets:Role in ThrombosisRBCs,red blood cells.ThrombinSerotoninEpinephrineCollagenActivationActivatedPlateletDegranulationAspirinIIb/IIIa ClopidogrelTiclopidinePlatelet agonistsADPATPserotonincalcium
31、magnesiumAdhesive 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 Predicts 5-Year Outc
32、omesPlatelet Aggregability Status01020304050Death Cardiac Events10.36.414.924.146.234.6Patients(%)*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 aggr
33、egation.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;103:1718-1720.Inflammatory Modulators
34、 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 the presence of release-granule
35、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 Platelet StimulationSCD40L,SCD40 ligand;PDGF
36、,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 Platelets TGF-5 Stimula
37、te smooth muscle cell biosynthesis Nitric oxide3 Effects on monocyte,leucocyte,endothelium,and smooth muscle cells CD154 (CD40 ligand)1,4 Regulates macrophage and smooth muscle cell functions RANTES2 Influences macrophage adhesion to endothelial cell PF41 Mediates shear-resistant arrest of monocytes
38、 to endotheliumPlatelet PDGF1 Induces proliferation of smooth muscle cells Thrombospondin1 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.Pla
39、telets.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-inflammatory cytokines from vascular and atheroma
40、 cells Thrombosis stabilizes platelet-rich thrombi Restenosis prevents reendothelialization of the injured vessel contributes to activation and proliferation of smooth muscle cellsHeeschen C,et al.N Engl J Med.2003;348:1104-1111.(with permission)Association Between Soluble CD40 Ligand Levels and the
41、 Rate of Cardiac EventsTimeDeath or Nonfatal Myocardial Infarction(%)P=.13P=.003P=.004P.001015304560750246810MonocytePlatelet Aggregates(%)Soluble CD40 Ligand(g/Liter)r=0.75P.001Level Of Soluble CD40 Ligand and MonocytePlatelet Activation in 161 Patients With Chest Pain Heeschen C,et al.N Engl J Med.2003:348:1104-1111.(with permission)
