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Atherothrombosis Pathophysiology

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

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Atherothrombosis Pathophysiology

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  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;3:231-239. Rauch U, et al. Ann Intern Med. 2001;134:122-238.

  3. Atherothrombosis* is theLeading Cause of Death Worldwide1 6.3 Pulmonary Disease Injuries 9 AIDS 9.7 Cancer 12.6 19.3 Infectious Disease 22.3 Atherothrombosis* 0 5 10 15 20 25 30 Causes of Mortality (%) * Atherothrombosis defined as ischemic heart disease and cerebrovascular disease. 1 The World Health Report 2001. Geneva. WHO. 2001.

  4. Atherothrombosis Significantly Shortens Life Atherothrombosis reduces life expectancy by around 8-12 years in patients aged over 60 years1 Average Remaining Life Expectancy at Age 60 (Men) 20 -7.4 years 16 -9.2 years -12 years 12 Years 8 4 0 Healthy History of Cardiovascular Disease History of AMI History of Stroke Analysis of data from the Framingham Heart Study. Peeters A, et al. Eur Heart J. 2002;23:458-466.

  5. Hospitalizations in the USDue to Vascular Disease Vascular Disease 3.2 Million Hospital Admissions Cerebrovascular Disease Coronary Atherosclerosis Acute Myocardial Infarction Other IschemicHeart Disease 961,000 Admissions 1,153,000 Admissions 829,000 Admissions 280,000 Admissions Popovic JR, Hall MJ. Advance Data. 2001;319:1-20.

  6. 28,300 13,600 6500 2700 2500 1700 1500 700 Preventable Deaths Approximately 57,000 deaths could be avoided each year in the US if patients were given appropriate care. High-blood pressure control Diabetes care Cholesterol management Smoking cessation Breast-cancer screening -blocker treatment Prenatal care Cervical-cancer screening National Committee for Quality Assurance. Washington, DC 2003.

  7. Epidemiology of ACS in the United States • Single largest cause of death • 515,204 US deaths in 2000 • 1 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 * 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 Statistics—2003 Update.

  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 Statistics—2003 Update.

  9. Peripheral Arterial Disease • PAD affects 12% of the adult population1,2 • 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 drugs4 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.

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

  11. Overlap of Vascular Disease in Patients With Atherothrombosis CAPRIE Aronow & Ahn Cerebral Disease Coronary Disease Cerebral Disease Coronary Disease 25% 7% 30% 15% 13% 33% 3% 8% 4% 12% 5% 14% 19% 12% PAD PAD PAD, peripheral artery disease. Adapted from TransAtlantic Inter-Society Consensus Group. J Vasc Surg. 2000;31:S16.

  12. Common Underlying Atherothrombotic Disease Process Atherothrombotic Stroke Unstable Angina MI PAD Platelet Adhesion, Activation, and Aggregation Thrombus Formation Plaque Rupture Atherothrombotic Events (MI, Stroke, or CV Death) 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.

  13. Risk 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, 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.

  14. Atherothrombosis: A Generalized and Progressive Process Thrombosis UnstableanginaMI Ischemic stroke/TIA Critical legischemia Intermitentclaudication CV death ACS Atherosclerosis Stable angina/ Intermittent claudication Adapted from Libby P. Circulation. 2001;104:365-372.

  15. Atherothrombosis: Thrombus Superimposed on Atherosclerotic Plaque Adaptedfrom Falk E, et al. Circulation. 1995;92:657-671.

  16. Characteristics of Unstable and Stable Plaque Unstable Stable Lack ofinflammatory cells Inflammatory cells Thickfibrous cap Thin fibrous cap FewSMCs MoreSMCs Intactendothelium Erodedendothelium Activatedmacrophages Foam cells Libby P. Circulation. 1995;91:2844-2850.

  17. Plaque Rupture Andrew Farb, MD by permission.

  18. Risk Factors for Plaque Rupture Systemic Factors Local Factors • Cap Fatigue Smoking Cholesterol • Atheromatous Core(size/consistency) • DiabetesMellitus • Fibrinogen • Cap Thickness/ Consistency • Homocysteine • Cap Inflammation • Impaired Fibrinolysis PlaqueRupture Fuster V, et al. N Engl J Med. 1992;326:310-318. Falk E, et al. Circulation. 1995:92:657-671.

  19. Multiple Risk Factors for Atherothrombosis • Lifestyle • Smoking • Diet • Lack of exercise • Generalized • Disorders • Age • Obesity • Systemic • Conditions • Hypertension • Hyperlipidemia • Diabetes • Hypercoagulable states • Homocysteinemia Atherothrombotic Manifestations (MI, stroke, vascular death) • Genetic Traits • Gender • PlA2 • 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 MI, myocardial infarction. Adapted from Yusuf S, et al. Circulation. 2001;104:2746-2753. Drouet L. Cerebrovasc Dis. 2002;13(suppl 1):1-6.

  20. Modifiable Hypertension Atrial fibrillation Cigarette smoking Hyperlipidemia Alcohol abuse Carotid stenosis Physical inactivity Obesity Diabetes Nonmodifiable Age Sex Race/Ethnicity Heredity Risk Factors for Ischemic Stroke

  21. Black-Blood Coronary Plaque MR LAD Wall RCA Wall LAD Wall Eccentric (“lipid-rich”) Concentric (“fibrotic”) Ectatic (“remodeled”) MR, magnetic resonance; LAD, left anterior descending; RCA, right coronary artery. Fayad ZA, et al. Circulation. 2000;102:506-510. (with permission)

  22. Evidence of Multiple “Vulnerable” Plaques in ACS Angiographic & angioscopic images in 58-year-old man with anterior myocardial infarction Multiple “vulnerable” plaques detected in non-culprit segments 1-7 Culprit lesion (#8) detected with thrombus (red) Multiple “vulnerable” plaques detected in non-culprit segments 10-12 ACS, acute coronary syndrome. Asakura M, et al. J Am Coll Cardiol. 2001;37:1284-1288. (with permission)

  23. Multiple Complex Coronary Plaques in Patients With Acute MI Multiple plaques detected Multiple plaques detected Culprit lesion MI, myocardial infarction. Goldstein JA, et al. N Eng J Med. 2000;343:915-922. (with permission)

  24. Frequency of Multiple “Active” Plaques in Patients With ACS 80% of Patients With  2 Plaques N=24 Patients (%) Frequency of multiple active plaque ruptures beyond the culprit lesion ACS, acute coronary syndrome. Rioufol G, et al. Circulation 2002;106:804-808. (with permission)

  25. ACS: Tip of the Atherothrombotic “Iceberg” Acute Plaque Rupture ACS (UA/NSTEMI/STEMI) Clinical Subclinical Persistent Hyperreactive Platelets Presence of Multiple Coronary Plaques Vascular Inflammation 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.

  26. Hemostatic Plug Formation PRIMARY AGGREGATION Platelet Aggregation Clotting Hemostatic Clot Fibrin SECONDARY Thrombin COAGULATION 0 min 10 min 5 min Adapted fromFerguson JJ, et al. Antiplatelet Therapy in Clinical Practice. 2000:15-35.

  27. Activated Platelet GP IIb/IIIa Fibrinogen Platelets Role in Thrombosis 1. Platelet Adhesion Platelet GP Ib 2. Platelet Activation Plaque rupture 3. Platelet Aggregation ASA, Clopidogrel/Ticlopidine TxA2 GP IIb/IIIa Inhibitors ASA, acetylsalicyclic acid. Cannon and Braunwald, Heart Disease. 2001.

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

  29. IV Gp IIb/IIIa Inhibitors Aspirin TXA2 ADP Adhesive proteins thrombospondin fibrinogen p-selectin vWF Platelet agonists ADP ATP serotonin calcium magnesium Coagulation factors factor V factor XI PAI-1 Inflammatory factors platelet factor 4 CD 154 (CD 40 ligand) PDGF Activated Platelet Clopidogrel Ticlopidine To neighboring platelet Gp IIb/IIIa fibrinogen receptor Thrombin Serotonin Epinephrine Collagen COX Activation   Degranulation TXA, thromboxane; PDGF, platelet-derived growth factor.

  30. Platelet Hyperreactivity Following ACS Predicts 5-Year Outcomes *RR=3.1 (CI 1.6-5.8) Death 46.2 50 *RR=5.4 (CI 2.2-13.4) Cardiac Events 40 34.6 *RR=1.6 (CI 0.7-3.5) 30 24.1 Patients (%) *RR=1.6 (CI 0.5-5.5) 20 14.9 10.3 6.4 10 0 Negative (n=94) Intermediate (n=29) Positive (n=26) Platelet Aggregability Status 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.

  31. Platelets Release Inflammatory Mediators and Lead to Vascular Inflammation and Plaque Instability ActivatedPlatelets • Inflammatory Modulators • CD 40 ligand • Platelet factor 4 • RANTES • Thrombospondin • Platelet-derived growth factor • Nitric oxide PlaqueRupture & Thrombosis Unstable Plaque RANTES (Regulated on Activation, Normal T-cellExpressed and Secreted). Libby P, et al. Circulation. 2001;103:1718-1720.

  32. CD4OL ADP Thrombin Collagen • PDGF • TGF • PF4 • TSP sCD4OL GP IIb-IIIa Antagonists The Shedding of Soluble SCD40L During Platelet Stimulation 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. 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 permission)

  33. Inflammatory Modulators Produced by Platelets PF41 • Mediates shear-resistant arrest of monocytes to endothelium PDGF1 • Induces proliferation of smooth muscle cells CD154 (CD40 ligand)1,4 • Regulates macrophage and smooth muscle cell functions RANTES2 • Influences macrophage adhesion to endothelial cell Platelet Thrombospondin1 • Interacts with cell surface receptors Nitric oxide3 • Effects on monocyte, leucocyte, endothelium, and smooth muscle cells TGF-ß5 • Stimulate smooth muscle cell biosynthesis 1 Libby P, et al. Circulation. 2001;103:1718-1720. 2 von Hundelshausen P, etal. 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.

  34. The Detrimental Role of Platelet-Derived sCD40Ligand in Cardiovascular Disease • 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 Adapted from Andre P, et al. Circulation. 2002:106:896-899.

  35. Association Between Soluble CD40 Ligand Levels and the Rate of Cardiac Events P<.001 P=.004 P=.003 Death or Nonfatal Myocardial Infarction (%) P=.13 Time Heeschen C, et al. N Engl J Med. 2003;348:1104-1111. (with permission)

  36. Level Of Soluble CD40 Ligand and Monocyte—Platelet Activation in 161 Patients With Chest Pain 10 8 6 Soluble CD40 Ligand (g/Liter) 4 2 r=0.75 P<.001 0 0 15 30 45 60 75 Monocyte–Platelet Aggregates (%) Heeschen C, et al. N Engl J Med. 2003:348:1104-1111. (with permission)

  37. Kaplan-Meier Curves Showing Cumulative Incidence of Death or Nonfatal Myocardial Infarction High level, placebo Death or Nonfatal Myocardial Infarction (%) Low level, abciximab High level, abciximab Low level, placebo Follow-up (mo) Heeschen C, et al. N Engl J Med. 2003;348:1104-1111.

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