《动脉硬化血栓病理生理学PPT课件.ppt》由会员分享，可在线阅读，更多相关《动脉硬化血栓病理生理学PPT课件.ppt（39页珍藏版）》请在三一文库上搜索。
1、Atherothrombosis Pathophysiology,What 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 gener
2、alized 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 infa
3、rction; 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 the Leading Cause of Death Worldwide1,* Atherothrombosis defined as ischemic heart disease and cerebrovascular disease. 1 The World Health Report
4、2001. Geneva. WHO. 2001.,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,Analysis of data from the Framingham Heart Study. Peeters A, et al. Eur Heart J. 2002;
5、23:458-466.,Atherothrombosis 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 Cardiovascular Disease,-7.4 years,History of Stroke,-12 years,3.2 Million Hosp
6、ital Admissions,Coronary Atherosclerosis,Acute Myocardial Infarction,1,153,000 Admissions,829,000 Admissions,Hospitalizations in the US Due to Vascular Disease,Cerebrovascular Disease,961,000 Admissions,Vascular Disease,Other Ischemic Heart Disease,280,000 Admissions,Popovic JR, Hall MJ. Advance Dat
7、a. 2001;319:1-20.,Preventable Deaths,Approximately 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 ces
8、sation,Cholesterol management,Diabetes care,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;
9、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 Incid
10、ence 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 both,Epidemiology of Stroke in the United States,Prevalence 4.7 million cases Incidence 700,000 new or r
11、ecurrent strokes each year Morbidity/mortality Third leading cause of death 1 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 popul
12、ation1,2 20% of the population aged 70 Associated with 6-fold increase in CV mortality3 Underrecognized and undertreated4 Measurement simple, inexpensive, and noninvasive Appropriate for risk assessment and screening Patients at high risk need aggressive risk-factor modification and antiplatelet dru
13、gs4,PAD, peripheral artery disease; CV, cardiovascular. 1 Nicolaides AN. Symposium. Nov. 1997. 2 Hiatt WR, et al. Circulation. 1995; 91:1472-1479. 3 Criqui MH, et al. N Engl J Med. 1992; 326:381-386. 4 Hirsch AT, et al. JAMA. 2001;286:1317-1324.,Diabetes: Impact in United States,12 million people wi
14、th 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 2002,1 American Diabetes Association. Diabetes Care.
15、 2003;26:917-932. 2 Juvenile Diabetes Research Foundation International. Diabetes Figures, http:/www.jdrf.org.,Cerebral Ischemic stroke Transient ischemic attack Cardiac Myocardial infarction Angina pectoris (stable, unstable) Peripheral Arterial Disease Critical limb ischemia, claudication,Clinical
16、 Manifestations of Atherothrombosis,Overlap of Vascular Disease in Patients With Atherothrombosis,PAD, peripheral artery disease. Adapted from TransAtlantic 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,1
17、9%,30%,25%,4%,12%,7%,3%,Cerebral Disease,CAPRIE,Aronow & Ahn,Common Underlying Atherothrombotic Disease Process,MI, 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.,Atherothromboti
18、c 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 Event,* Death documented within 1 hour of an event attributed to CHD. Note:This chart is based on epide
19、miologic 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
20、-339. Wilterdink, JI, et al. Arch Neurol. 1992;49:857-863. Crique, MH, et al. N Engl J Med. 1992;326:381-386.,Unstable angina MI Ischemic stroke/TIA Critical leg ischemia Intermitent claudication CV death,ACS,Atherosclerosis,Stable angina/ Intermittent claudication,Atherothrombosis: A Generalized an
21、d 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.,Characteristics of Unstable and Stable Plaque,Thin fibrous cap,Inflammatory cells,Few SMCs
22、,Eroded endothelium,Activated macrophages,Thick fibrous cap,Lack of inflammatory cells,Foam cells,Intact endothelium,More SMCs,Libby P. Circulation. 1995;91:2844-2850.,Unstable,Stable,Plaque Rupture,Andrew Farb, MD by permission.,Risk Factors for Plaque Rupture,Impaired Fibrinolysis,Fibrinogen,Diabe
23、tes Mellitus,Cholesterol,Smoking,Cap Fatigue,Atheromatous Core (size/consistency),Cap Inflammation,Systemic Factors,Local Factors,Homocysteine,Plaque Rupture,Fuster V, et al. N Engl J Med. 1992;326:310-318. Falk E, et al. Circulation. 1995:92:657-671.,Cap Thickness/ Consistency,Multiple Risk Factors
24、 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.,Lifestyle Smoking Diet Lack of exercise,Genetic Traits Gender PlA2,Generalized Disorders Age Obesity,Systemic Conditions Hypertension Hyperl
25、ipidemia Diabetes Hypercoagulable states Homocysteinemia,Atherothrombotic Manifestations (MI, stroke, vascular death),Inflammation Elevated CRP CD40 Ligand, IL-6 Prothrombotic factors (F I and II) Fibrinogen,Local Factors Blood flow patterns Shear stress Vessel diameter Arterial wall structure % art
26、erial stenosis,Risk Factors for Ischemic Stroke,Modifiable Hypertension Atrial fibrillation Cigarette smoking Hyperlipidemia Alcohol abuse Carotid stenosis Physical inactivity Obesity Diabetes,Nonmodifiable Age Sex Race/Ethnicity Heredity,RCA Wall,LAD Wall,Eccentric (“lipid-rich”),Concentric (“fibro
27、tic”),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. Asak
28、ura 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 with thrombus (red),Multiple “vulnerable” p
29、laques detected 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 plaques detected,Multiple plaques detected,ACS, acute coronary syndrome. Ri
30、oufol G, et al. Circulation 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 co
31、ronary 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 Plaques,Vascular Inflammation,Persistent Hyperreactive Plate
32、lets,Clinical,Subclinical,Acute Plaque Rupture ACS (UA/NSTEMI/STEMI),Hemostatic Plug Formation,Thrombin,AGGREGATION,Fibrin,Hemostatic Clot,Clotting,Platelet Aggregation,0 min,10 min,5 min,SECONDARY,PRIMARY,COAGULATION,Adapted from Ferguson JJ, et al. Antiplatelet Therapy in Clinical Practice. 2000:1
33、5-35.,Adhesion,The Role of Platelets in Atherothrombosis,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.
34、 2001.,TxA2,Platelets Role in Thrombosis,Fibrin,Platelets,RBCs,White Thrombus,Fibrin,Platelets,RBCs,Coagulation Thrombus,High Flow Slow Flow,Platelets: Role in Thrombosis,RBCs, red blood cells.,Thrombin Serotonin Epinephrine Collagen,Activation,Activated Platelet,COX,Degranulation,Gp IIb/IIIa fibrin
35、ogen receptor,To neighboring platelet,Clopidogrel Ticlopidine,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
36、(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
37、 Inflammatory Mediators and Lead to Vascular Inflammation and Plaque Instability,RANTES (Regulated on Activation, Normal T-cellExpressed and Secreted). Libby P, et al. Circulation. 2001;103:1718-1720.,Inflammatory Modulators CD 40 ligand Platelet factor 4 RANTES,Unstable Plaque,Activated Platelets,P
38、laque Rupture & Thrombosis,Thrombospondin Platelet-derived growth factor Nitric 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 platelet-derived growth factor (PDGF), transf
39、orming 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 Stimulation,SCD40L, SCD40 ligand; PDGF, platelet-derived growth factor; TGF-, transforming gr
40、owth factor-beta; PF4, platelet factor 4; TSP,thrombospondin. Andre P, et al. Circulation. 2002:106:896-899. (with permission),Inflammatory Modulators Produced by Platelets,TGF-5 Stimulate smooth muscle cell biosynthesis,Nitric oxide3 Effects on monocyte, leucocyte, endothelium, and smooth muscle ce
41、lls,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 to endothelium,Platelet,PDGF1 Induces proliferation of smooth muscle cells,Thrombospondin1 Interacts with cell
42、 surface receptors,1 Libby 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
43、 Role of Platelet-Derived sCD40Ligand in Cardiovascular Disease,Adapted 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 reendothe
44、lialization 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. (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.001,0,15,3