1、Atherothrombosis Pathophysiology,動(dòng)脈粥樣硬化 臨床五班關(guān)瑞橋,What Is Atherothrombosis?,The formation of a thrombus on an existing atherosclerotic plaqueAtherothrombosis is a new term recognizing that atherosclerosis (plaque develo

2、pment) 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, coron

3、ary, and peripheral arteries The underlying disease leading to myocardial infarction (MI), peripheral arterial disease (PAD), ischemia and many forms of stroke,,Atherothrombosis* is theLeading Cause of Death Worldwide1

4、,,,,,,,,,,,,,,,,,,,,,,,22.3,19.3,12.6,9.7,9,6.3,0,5,10,15,20,25,30,Atherothrombosis*,Infectious Disease,Cancer,Injuries,Pulmonary Disease,AIDS,Causes of Mortality (%),Atherothrombosis Significantly Shortens Life,Atherot

5、hrombosis reduces 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 Cardiov

6、ascular Disease,,,-7.4 years,History of Stroke,,,-12 years,3.2 Million Hospital Admissions,Coronary Atherosclerosis,Acute Myocardial Infarction,,1,153,000 Admissions,829,000 Admissions,Hospitalizations in the USDue t

7、o Vascular Disease,Cerebrovascular Disease,961,000 Admissions,,,,Vascular Disease,Other IschemicHeart Disease,280,000 Admissions,,,,,,,Preventable Deaths,Approximately 57,000 deaths could be avoided each year in the US

8、 if patients were given appropriate care.,Cervical-cancer screening,Prenatal care,?-blocker treatment,Breast-cancer screening,Smoking cessation,Cholesterol management,Diabetes care,High-blood pressure control,,Peripheral

9、 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 noni

10、nvasiveAppropriate for risk assessment and screeningPatients at high risk need aggressive risk-factor modification and antiplatelet drugs4,,,CerebralIschemic strokeTransient ischemic attack CardiacMyocardial infarc

11、tion Angina pectoris (stable, unstable)Peripheral Arterial Disease Critical limb ischemia, claudication,Clinical Manifestations of Atherothrombosis,,Overlap of Vascular Disease in Patients With Atherothrombosis,,,,,,

12、,,,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,,,,,

13、,Atherothrombotic Events (MI, Stroke, or CV Death),Plaque Rupture,Platelet Adhesion, Activation, and Aggregation,Thrombus Formation,,,,MI,Atherothrombotic Stroke,PAD,,Unstable Angina,Risk of a Second Atherothrombotic Eve

14、nt,,,UnstableanginaMI Ischemic stroke/TIACritical legischemiaIntermitentclaudicationCV death,ACS,,,Atherosclerosis,,,Stable angina/ Intermittent claudication,,Atherothrombosis: A Generalized and Pro

15、gressive Process,,,,Thrombosis,,,,,Risk Factors for Plaque Rupture,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Impaired Fibrinolysis,,,,Fibrinogen,,DiabetesMellitus,,Cholesterol,,Smoking,,Cap Fatigue,,At

16、heromatous Core(size/consistency),,,Cap Inflammation,Systemic Factors,Local Factors,,Homocysteine,,,,,,,,,,PlaqueRupture,,,,,,,,,,,,,,,,Cap Thickness/ Consistency,Multiple Risk Factors for Atherothrombosis,,LifestyleS

17、mokingDietLack of exercise,Genetic TraitsGenderPlA2,GeneralizedDisordersAgeObesity,SystemicConditionsHypertensionHyperlipidemiaDiabetesHypercoagulable statesHomocysteinemia,,Atherothrombotic Manifestations(

18、MI, stroke, vascular death),,,,,InflammationElevated CRPCD40 Ligand, IL-6 Prothrombotic factors (F I and II)Fibrinogen,Local FactorsBlood flow patternsShear stressVessel diameterArterial wall structure% arteria

19、l stenosis,,,Risk Factors for Ischemic Stroke,ModifiableHypertensionAtrial fibrillationCigarette smokingHyperlipidemiaAlcohol abuseCarotid stenosisPhysical inactivityObesityDiabetes,NonmodifiableAgeSexRace/Et

20、hnicityHeredity,,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,,,,,,,,,Fibrin,P

21、latelets,RBCs,White Thrombus,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

22、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Fibrin,Platelets,RBCs,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

23、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

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27、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Coagulation Thrombus,High Flow Slow Flow,Platelets: Role in Thrombosis,RBCs, red blood cells.,,Platelets Release Inflammato

28、ry Mediators and Lead to Vascular Inflammation and Plaque Instability,,Inflammatory ModulatorsCD 40 ligandPlatelet factor 4RANTES,Unstable Plaque,ActivatedPlatelets,PlaqueRupture & Thrombosis,ThrombospondinPl

29、atelet-derived growth factorNitric oxide,,CD40L 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 platele

30、t-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 Solub

31、le SCD40L During Platelet Stimulation,,,,,,Inflammatory Modulators Produced by Platelets,,,TGF-ß5Stimulate smooth muscle cell biosynthesis,Nitric oxide3Effects on monocyte, leucocyte, endothelium, and smooth musc

32、le cells,CD154 (CD40 ligand)1,4Regulates macrophage and smooth muscle cell functions,RANTES2Influences macrophage adhesion to endothelial cell,PF41Mediates shear-resistant arrest of monocytes to endothelium,,Platelet

33、,,PDGF1 Induces proliferation of smooth muscle cells,Thrombospondin1Interacts with cell surface receptors,,,,,,,,,,,,,,,,The Detrimental Role of Platelet-Derived sCD40Ligand in Cardiovascular Disease,,Inflammation–i

34、nduces production/release of pro-inflammatory cytokines from vascular and atheroma cells Thrombosis – stabilizes platelet-rich thrombi Restenosis – prevents reendothelialization of the injured vess

35、el – contributes to activation and proliferation of smooth muscle cells,,,Association Between Soluble CD40 Ligand Levels and the Rate of Cardiac Events,Time,Death or Nonfatal Myocardial Infarction (%),P=.13,P=.0

36、03,P=.004,P<.001,,,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