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Atherothrombosis PathophysiologyWhat Is Atherothrombosis?The formation of a thrombus on an existing atherosclerotic plaqueAtherothrombosis 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 death515,204 US deaths in 20001 in every 5 US deathsIncidence1,100,000 Americans will have a new or recurrent coronary attack each year and about 45%will die*550,000 new cases of angina per yearPrevalence12,900,000 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.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 N=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 FormationThrombinThrombinAGGREGATIONFibrinFibrinHemostaticHemostaticClotClotClottingClottingPlatelet AggregationPlatelet Aggregation0 min0 min10 min10 min5 min5 minSECONDARYSECONDARYPRIMARYPRIMARYCOAGULATIONAdapted from Ferguson JJ,et al.Antiplatelet Therapy in Clinical Practice.2000:15-35.GP 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.ThrombinSerotoninEpinephrineCollagenADPADPActivationTXATXA2 2ActivatedPlateletCOXCOXDegranulationAspirin GpGp IIb/IIIa fibrinogenfibrinogenreceptorreceptorTo neighboringTo neighboringplateletplateletClopidogrelTiclopidinePlatelet 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-IIIaAntagonistsPDGFTGF PF4TSPInflammatory 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.Inflammationinduces 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 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)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-up(mo)High level,placeboLow level,placeboHigh level,abciximabLow level,abciximab
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