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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 generalized 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 infarction;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.Geneva.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 reduces 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 Myocardial 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 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 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 infarction;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 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 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 Association.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 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 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 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 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 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 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.Atherothrombotic Events(MI,Stroke,or CV Death)Plaque RupturePlatelet Adhesion,Activation,and AggregationThrombus 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 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,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 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 Libby 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 ofinflammatory 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 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/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 exerciseGenetic TraitsGenderPlA2GeneralizedDisordersAgeObesitySystemicConditionsHypertensionHyperlipidemiaDiabetesHypercoagulable statesHomocysteinemiaAtherothrombotic Manifestations(MI,stroke,vascular death)InflammationElevated CRPCD40 Ligand,IL-6 Prothrombotic factors(F I and II)FibrinogenLocal FactorsBlood flow patternsShear stressVessel diameterArterial wall structure%arterial stenosisRisk Factors for Ischemic StrokeModifiableHypertensionAtrial fibrillationCigarette smokingHyperlipidemiaAlcohol abuseCarotid 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.Circulation.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”plaques 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)Culprit 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 051015202530012345N=24Frequency of Multiple“Active”Plaques 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 Coronary PlaquesVascular InflammationPersistent Hyperreactive PlateletsClinicalSubclinicalAcute Plaque Rupture ACS(UA/NSTEMI/STEMI)Hemostatic Plug FormationThrombinAGGREGATIONFibrinHemostaticClotClottingPlatelet Aggregation0 min10 min5 minSECONDARYPRIMARYCOAGULATIONAdapted from Ferguson JJ,et al.Antiplatelet Therapy in Clinical Practice.2000:15-35.AdhesionThe Role of Platelets in AtherothrombosisAggregation1Activation23GP 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 ThrombosisFibrinPlateletsRBCsWhite ThrombusFibrinPlateletsRBCsCoagulation ThrombusHigh Flow Slow FlowPlatelets:Role in ThrombosisRBCs,red blood cells.ThrombinSerotoninEpinephrineCollagenActivationActivatedPlateletCOXDegranulationAspirinGp IIb/IIIa fibrinogenreceptorTo neighboringplateletClopidogrelTiclopidinePlatelet agonistsADPATPserotonincalciummagnesiumAdhesive 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 OutcomesPlatelet 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 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;103:1718-1720.Inflammatory ModulatorsCD 40 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 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,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 PlateletsTGF-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 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 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.Inflammation induces production/release of pro-inflammatory cytokines from vascular and atheroma 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 Rate of Cardiac Events0510152024 h72 h30 d6 mo1st quintile2nd quintile3rd quintile4th quintile5th quintileTimeDeath 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)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 Infarction051015200123456Follow-up(mo)High level,placeboLow level,placeboHigh level,abciximabLow level,abciximab
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