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1、Atherothrombosis Pathophysiology,What 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 generali
2、zed 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 stroke,MI,myocardial infarction;PAD,p
3、eripheral 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.,22.3,
4、19.3,12.6,9.7,9,6.3,0,5,10,15,20,25,30,Atherothrombosis*,Infectious Disease,Cancer,Injuries,Pulmonary Disease,AIDS,Causes of Mortality(%),Atherothrombosis Significantly Shortens Life,Analysis of data from the Framingham Heart Study.Peeters A,et al.Eur Heart J.2002;23:458-466.,Atherothrombosis reduce
5、s life expectancy by around 8-12 years in patients aged over 60 years1,Average Remaining Life Expectancy at Age 60(Men),0,4,8,12,16,20,Healthy,Years,History of AMI,-9.2 years,History of Cardiovascular Disease,-7.4 years,History of Stroke,-12 years,3.2 Million Hospital Admissions,Coronary Atheroscler
6、osis,Acute Myocardial Infarction,1,153,000 Admissions,829,000 Admissions,Hospitalizations in the USDue to Vascular Disease,Cerebrovascular Disease,961,000 Admissions,Vascular Disease,Other IschemicHeart Disease,280,000 Admissions,Popovic JR,Hall MJ.Advance Data.2001;319:1-20.,Preventable Deaths,Appr
7、oximately 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.,Cervical-cancer screening,Prenatal care,-blocker treatment,Breast-cancer screening,Smoking cessation,Cholesterol management,Diabetes care
8、,High-blood pressure control,*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 i
9、n 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
10、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 both,Epidemiology of Stroke in the United States,Prevalence4.7 million casesIncidence700,000 new or recurrent strokes each yearMorbidity/mortalityThird leading cause of deat
11、h1 of every 14 deaths(168,000 deaths)Stroke:a leading cause of long-term disability,American 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 morta
12、lity3Underrecognized and undertreated4Measurement simple,inexpensive,and noninvasiveAppropriate for risk assessment and screeningPatients at high risk need aggressive risk-factor modification and antiplatelet drugs4,PAD,peripheral artery disease;CV,cardiovascular.1Nicolaides AN.Symposium.Nov.1997.2H
13、iatt 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 diabetes1Diabetes is the 5th leading cause of death1Half of diabetic patients will experience kidney failure1Di
14、abetes is the leading cause of new adult cases of blindness2Direct 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,http:/.,CerebralIschemic strokeTran
15、sient ischemic attack CardiacMyocardial infarction Angina pectoris(stable,unstable)Peripheral Arterial Disease Critical limb ischemia,claudication,Clinical Manifestations of Atherothrombosis,Overlap of Vascular Disease in Patients With Atherothrombosis,PAD,peripheral artery disease.Adapted from Tran
16、sAtlantic Inter-Society Consensus Group.J Vasc Surg.2000;31:S16.,Coronary Disease,PAD,12%,33%,15%,5%,14%,13%,8%,Cerebral Disease,Coronary Disease,PAD,19%,30%,25%,4%,12%,7%,3%,Cerebral Disease,CAPRIE,Aronow&Ahn,Common Underlying Atherothrombotic Disease Process,MI,myocardial infarction;PAD,peripheral
17、 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 Rupture,Platelet Adhesion,Activation,and Aggregation,Thrombus Formation,MI,Atherothrombotic Stroke,PAD,Unstable Angina,Risk
18、of a Second Atherothrombotic Event,*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,pe
19、ripheral 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 d
20、eath,ACS,Atherosclerosis,Stable angina/Intermittent claudication,Atherothrombosis:A Generalized and Progressive Process,Thrombosis,Adapted from Libby P.Circulation.2001;104:365-372.,Atherothrombosis:Thrombus Superimposed on Atherosclerotic Plaque,Adapted from Falk E,et al.Circulation.1995;92:657-671
21、.,Characteristics of Unstable and Stable Plaque,Thin fibrous cap,Inflammatory cells,FewSMCs,Erodedendothelium,Activatedmacrophages,Thickfibrous cap,Lack ofinflammatory cells,Foam cells,Intactendothelium,MoreSMCs,Libby P.Circulation.1995;91:2844-2850.,Unstable,Stable,Plaque Rupture,Andrew Farb,MD by
22、permission.,Risk Factors for Plaque Rupture,Impaired Fibrinolysis,Fibrinogen,DiabetesMellitus,Cholesterol,Smoking,Cap Fatigue,Atheromatous Core(size/consistency),Cap Inflammation,Systemic Factors,Local Factors,Homocysteine,PlaqueRupture,Fuster V,et al.N Engl J Med.1992;326:310-318.Falk E,et al.Circu
23、lation.1995:92:657-671.,Cap Thickness/Consistency,Multiple Risk Factors for Atherothrombosis,MI,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 exercise,Genetic TraitsGenderPlA2,GeneralizedDiso
24、rdersAgeObesity,SystemicConditionsHypertensionHyperlipidemiaDiabetesHypercoagulable statesHomocysteinemia,Atherothrombotic Manifestations(MI,stroke,vascular death),InflammationElevated CRPCD40 Ligand,IL-6 Prothrombotic factors(F I and II)Fibrinogen,Local FactorsBlood flow patternsShear stressVessel
25、diameterArterial wall structure%arterial stenosis,Risk Factors for Ischemic Stroke,ModifiableHypertensionAtrial fibrillationCigarette smokingHyperlipidemiaAlcohol abuseCarotid stenosisPhysical inactivityObesityDiabetes,NonmodifiableAgeSexRace/EthnicityHeredity,RCA Wall,LAD Wall,Eccentric(“lipid-rich
26、”),Concentric(“fibrotic”),Ectatic(“remodeled”),Black-Blood Coronary Plaque MR,MR,magnetic resonance;LAD,left anterior descending;RCA,right coronary artery.Fayad ZA,et al.Circulation.2000;102:506-510.(with permission),LAD Wall,Evidence of Multiple“Vulnerable”Plaques in ACS,ACS,acute coronary syndrome
27、.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 infarction,Multiple“vulnerable”plaques detected in non-culprit segments 10-12,Culprit lesion(#8)detected withthrombus(red),Multiple“vulnerable”plaques de
28、tected in non-culprit segments 1-7,Multiple Complex Coronary Plaques in Patients With Acute MI,MI,myocardial infarction.Goldstein JA,et al.N Eng J Med.2000;343:915-922.(with permission),Culprit lesion,Multiple plaquesdetected,Multiple plaquesdetected,ACS,acute coronary syndrome.Rioufol G,et al.Circu
29、lation 2002;106:804-808.(with permission),Frequency of multiple active plaque ruptures beyond the culprit lesion,Patients(%),80%of Patients With 2 Plaques,N=24,Frequency of Multiple“Active”Plaques in Patients With ACS,ACS:Tip of the Atherothrombotic“Iceberg”,ACS,acute coronary syndrome;UA,unstable a
30、ngina;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 Plaques,Vascular Inflammation,Persistent Hyperreactive Platelets,Clinical,Subclinical,Acute Plaque
31、 Rupture ACS(UA/NSTEMI/STEMI),Hemostatic Plug Formation,Thrombin,AGGREGATION,Fibrin,HemostaticClot,Clotting,Platelet Aggregation,0 min,10 min,5 min,SECONDARY,PRIMARY,COAGULATION,Adapted from Ferguson JJ,et al.Antiplatelet Therapy in Clinical Practice.2000:15-35.,Adhesion,The Role of Platelets in Ath
32、erothrombosis,Aggregation,1,Activation,2,3,GP IIb/IIIa Inhibitors,1.Platelet Adhesion,2.Platelet Activation,Platelet,GP Ib,Plaque rupture,3.Platelet Aggregation,ASA,Clopidogrel/Ticlopidine,ASA,acetylsalicyclic acid.Cannon and Braunwald,Heart Disease.2001.,TxA2,Platelets Role in Thrombosis,Fibrin,Pla
33、telets,RBCs,White Thrombus,Fibrin,Platelets,RBCs,Coagulation Thrombus,High Flow Slow Flow,Platelets:Role in Thrombosis,RBCs,red blood cells.,ThrombinSerotoninEpinephrineCollagen,Activation,ActivatedPlatelet,COX,Degranulation,Gp IIb/IIIa fibrinogenreceptor,To neighboringplatelet,ClopidogrelTiclopidin
34、e,TXA,thromboxane;PDGF,platelet-derived growth factor.,Platelet Hyperreactivity Following ACS Predicts 5-Year Outcomes,Platelet Aggregability Status,0,10,20,30,40,50,Death,Cardiac Events,10.3,6.4,14.9,24.1,46.2,34.6,Patients(%),*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
35、.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 Instabili
36、ty,RANTES(Regulated on Activation,Normal T-cellExpressed and Secreted).Libby P,et al.Circulation.2001;103:1718-1720.,Inflammatory ModulatorsCD 40 ligandPlatelet factor 4RANTES,Unstable Plaque,ActivatedPlatelets,PlaqueRupture&Thrombosis,ThrombospondinPlatelet-derived growth factorNitric oxide,CD40L i
37、s 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 hy
38、drolysis and subsequent release of SCD40L from platelets.,The Shedding of Soluble SCD40L During Platelet Stimulation,SCD40L,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
39、permission),Inflammatory Modulators Produced by Platelets,TGF-5Stimulate smooth muscle cell biosynthesis,Nitric oxide3Effects on monocyte,leucocyte,endothelium,and smooth muscle cells,CD154(CD40 ligand)1,4Regulates macrophage and smooth muscle cell functions,RANTES2Influences macrophage adhesion to
40、endothelial cell,PF41Mediates shear-resistant arrest of monocytes to endothelium,Platelet,PDGF1 Induces proliferation of smooth muscle cells,Thrombospondin1Interacts with cell surface receptors,1Libby P,et al.Circulation.2001;103:1718-1720.2 von Hundelshausen P,et al.Circulation.2001;103:1772-1777.3
41、 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 Disease,Adapted from Andre P,et al.Circulation.2002:106:896-899.,Inflammationinduces produc
42、tion/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 cells,Heeschen C,et al.N Engl J Med.2003;348:1104-1111.(
43、with permission),Association Between Soluble CD40 Ligand Levels and the Rate of Cardiac Events,Time,Death or Nonfatal Myocardial Infarction(%),P=.13,P=.003,P=.004,P.001,0,15,30,45,60,75,0,2,4,6,8,10,MonocytePlatelet Aggregates(%),Soluble CD40 Ligand(g/Liter),r=0.75P.001,Level Of Soluble CD40 Ligand
44、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 Infarction,Follow-up(mo),High level,placebo,Low level,placebo,High level,abciximab,Low level,abciximab,
