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Atherothrombosis Pathophysiology. What Is Atherothrombosis? The formation of a thrombus on an existing atherosclerotic plaque Atherothrombosis is a new.

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Presentation on theme: "Atherothrombosis Pathophysiology. What Is Atherothrombosis? The formation of a thrombus on an existing atherosclerotic plaque Atherothrombosis is a new."— Presentation transcript:

1 Atherothrombosis Pathophysiology

2 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 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 stroke MI, myocardial infarction; PAD, peripheral artery disease. Fuster V, et al. Vasc Med. 1998;3: Rauch U, et al. Ann Intern Med. 2001;134:

3 Atherothrombosis* is the Leading Cause of Death Worldwide 1 *Atherothrombosis defined as ischemic heart disease and cerebrovascular disease. 1 The World Health Report Geneva. WHO Atherothrombosis* Infectious Disease Cancer Injuries Pulmonary Disease AIDS Causes of Mortality (%)

4 Atherothrombosis Significantly Shortens Life Analysis of data from the Framingham Heart Study. Peeters A, et al. Eur Heart J. 2002;23: Atherothrombosis reduces life expectancy by around 8-12 years in patients aged over 60 years 1 Average Remaining Life Expectancy at Age 60 (Men) Healthy Years History of AMI -9.2 years History of Cardiovascular Disease -7.4 years History of Stroke -12 years

5 3.2 Million Hospital 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 Data. 2001;319:1-20.

6 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 Cervical-cancer screening Prenatal care -blocker treatment Breast-cancer screening Smoking cessation Cholesterol management Diabetes care High-blood pressure control ,600 28,300

7 *Based on data from the ARIC study of the National Heart, Lung, and Blood Institute, 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 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 both

8 Epidemiology of Stroke in the United States Prevalence 4.7 million cases Incidence 700,000 new or recurrent 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.

9 Peripheral Arterial Disease PAD affects 12% of the adult population 1,2 20% of the population aged >70 Associated with 6-fold increase in CV mortality 3 Underrecognized and undertreated 4 Measurement simple, inexpensive, and noninvasive Appropriate for risk assessment and screening Patients at high risk need aggressive risk-factor modification and antiplatelet drugs 4 PAD, peripheral artery disease; CV, cardiovascular. 1 Nicolaides AN. Symposium. Nov Hiatt WR, et al. Circulation. 1995; 91: Criqui MH, et al. N Engl J Med. 1992; 326: Hirsch AT, et al. JAMA. 2001;286:

10 Diabetes: Impact in United States 12 million people with diabetes 1 Diabetes is the 5th leading cause of death 1 Half of diabetic patients will experience kidney failure 1 Diabetes is the leading cause of new adult cases of blindness 2 Direct and indirect diabetes costs were estimated at $132 billion 1 in American Diabetes Association. Diabetes Care. 2003;26: Juvenile Diabetes Research Foundation International. Diabetes Figures,

11 Cerebral Ischemic stroke Transient ischemic attack Cardiac Myocardial infarction Angina pectoris (stable, unstable) Peripheral Arterial Disease Critical limb ischemia, claudication Clinical Manifestations of Atherothrombosis

12 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 19% 30%25% 4%12% 7% 3% Cerebral Disease CAPRIEAronow & Ahn

13 Common Underlying Atherothrombotic Disease Process MI, myocardial infarction; PAD, peripheral arterial disease; CV, cardiovascular. Ness J, et al. J Am Geriatr Soc. 1999;47: Schafer AI. Am J Med. 1996;101: Atherothrombotic Events (MI, Stroke, or CV Death) Plaque Rupture Platelet Adhesion, Activation, and Aggregation Thrombus Formation MI Atherothromboti c Stroke PADUnstable Angina

14 Risk of a Second Atherothrombotic Event Increased Risk vs General Population (%) Original EventMIStroke MI5-7 times greater risk (includes death)* 3-4 times greater risk (includes TIA) Stroke2-3 times greater risk (includes angina and sudden death)* 9 times greater risk PAD4 times greater risk* 2-3 times greater 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: Kannel, WB. J Cardiovasc Risk. 1994;1: Wilterdink, JI, et al. Arch Neurol. 1992;49: Crique, MH, et al. N Engl J Med. 1992;326:

15 Unstable angina MI Ischemic stroke/TIA Critical leg ischemia Intermitent claudication CV death ACS Atherosclerosis Stable angina/ Intermittent claudication Atherothrombosis: A Generalized and Progressive Process Thrombosis Adapted from Libby P. Circulation. 2001;104:

16 Atherothrombosis: Thrombus Superimposed on Atherosclerotic Plaque Adapted from Falk E, et al. Circulation. 1995;92:

17 Characteristics of Unstable and Stable Plaque Thin fibrous cap Inflammatory cells Few SMCs Eroded endothelium Activated macrophages Thick fibrous cap Lack of inflammatory cells Foam cells Intact endothelium More SMCs Libby P. Circulation. 1995;91: UnstableStable

18 Plaque Rupture Andrew Farb, MD by permission.

19 Risk Factors for Plaque Rupture Impaired Fibrinolysis Fibrinogen Diabetes 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: Falk E, et al. Circulation. 1995:92: Cap Thickness/ Consistency

20 Multiple Risk Factors for Atherothrombosis MI, myocardial infarction. Adapted from Yusuf S, et al. Circulation. 2001;104: 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 Hyperlipidemia 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 % arterial stenosis

21 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

22 RCA WallLAD Wall Eccentric (lipid-rich)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: (with permission) LAD Wall

23 Evidence of Multiple Vulnerable Plaques in ACS ACS, acute coronary syndrome. Asakura M, et al. J Am Coll Cardiol. 2001;37: (with permission) Angiographic & angioscopic images in 58-year-old man with anterior myocardial infarction Multiple vulnerable plaques detected in non-culprit segments Culprit lesion (#8) detected with thrombus (red) Multiple vulnerable plaques detected in non-culprit segments 1-7

24 Multiple Complex Coronary Plaques in Patients With Acute MI MI, myocardial infarction. Goldstein JA, et al. N Eng J Med. 2000;343: (with permission) Culprit lesion Multiple plaques detected Multiple plaques detected Multiple plaques detected Multiple plaques detected

25 ACS, acute coronary syndrome. Rioufol G, et al. Circulation 2002;106: (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

26 ACS: 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: Presence of Multiple Coronary Plaques Vascular Inflammation Persistent Hyperreactive Platelets Clinical Subclinical Acute Plaque Rupture ACS (UA/NSTEMI/STEMI)

27 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.

28 Adhesion The Role of Platelets in Atherothrombosis Aggregation 1 Activation 2 3

29 GP IIb/IIIa Inhibitors 1. Platelet Adhesion 2. Platelet Activation Platelet GP Ib Plaque rupture Activated Platelet GP IIb/IIIa 3. Platelet Aggregation ASA, Clopidogrel/Ticlopidine ASA, Clopidogrel/Ticlopidine ASA, acetylsalicyclic acid. Cannon and Braunwald, Heart Disease TxA2 Fibrinogen Platelets Role in Thrombosis

30 Fibrin PlateletsRBCs White Thrombus Fibrin PlateletsRBCs Coagulation Thrombus High Flow Slow Flow Platelets: Role in Thrombosis RBCs, red blood cells.

31 Thrombin Serotonin Epinephrine Collagen ADP Activation TXA 2 Activated Platelet COX Degranulation Aspirin Gp Gp IIb/IIIafibrinogenreceptor To neighboring platelet Clopidogrel Ticlopidine Platelet agonists ADP ATP serotonin calcium magnesium Adhesive proteins thrombospondin fibrinogen p-selectin vWF Coagulation factors factor V factor XI PAI-1 Inflammatory factors platelet factor 4 CD 154 (CD 40 ligand) PDGF IV Gp IIb/IIIa Inhibitors TXA, thromboxane; PDGF, platelet-derived growth factor.

32 Platelet Hyperreactivity Following ACS Predicts 5-Year Outcomes Platelet Aggregability Status Death Cardiac Events Patients (%) *RR=1.6 (CI ) Negative (n=94) *RR=1.6 (CI ) *RR=5.4 (CI ) *RR=3.1 (CI ) 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:

33 Platelets Release Inflammatory Mediators and Lead to Vascular Inflammation and Plaque Instability RANTES (Regulated on Activation, Normal T-cell Expressed and Secreted). Libby P, et al. Circulation. 2001;103: Inflammatory Modulators CD 40 ligand Platelet factor 4 RANTES Unstable Plaque Activated Platelets Plaque Rupture & Thrombosis Thrombospondin Platelet-derived growth factor Nitric oxide

34 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), 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 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: (with permission) ADP Thrombin Collagen CD4OL sCD4OL GP IIb-IIIa Antagonists PDGF TGF PF4 TSP

35 Inflammatory Modulators Produced by Platelets TGF-ß 5 Stimulate smooth muscle cell biosynthesis Nitric oxide 3 Effects on monocyte, leucocyte, endothelium, and smooth muscle cells CD154 (CD40 ligand) 1,4 Regulates macrophage and smooth muscle cell functions RANTES 2 Influences macrophage adhesion to endothelial cell PF4 1 Mediates shear- resistant arrest of monocytes to endothelium Platelet PDGF 1 Induces proliferation of smooth muscle cells Thrombospondin 1 Interacts with cell surface receptors 1 Libby P, et al. Circulation. 2001;103: von Hundelshausen P, et al. Circulation. 2001;103: Wever RMF, et al. Circulation. 1998;97: Hermann A, et al. Platelets. 2001;12: Robbie L, et al. Ann N Y Acad Sci. 2001; 947:

36 The Detrimental Role of Platelet-Derived sCD40Ligand in Cardiovascular Disease Adapted from Andre P, et al. Circulation. 2002:106: 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 cells

37 Heeschen C, et al. N Engl J Med. 2003;348: (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

38 Monocyte–Platelet Aggregates (%) Soluble CD40 Ligand ( g/Liter) r =0.75 P<.001 Level Of Soluble CD40 Ligand and MonocytePlatelet Activation in 161 Patients With Chest Pain Heeschen C, et al. N Engl J Med. 2003:348: (with permission)

39 Heeschen C, et al. N Engl J Med. 2003;348: 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

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