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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 Atherothrombosis is the most frequent underlying cause of ischemic heart disease and cardiovascular (CV) disease and is the leading cause of death in Western societies.1 Acute coronary syndrome (ACS) and ischemic stroke are usually caused by acute thrombosis superimposed on a chronic atherosclerotic plaque that has erupted, a condition commonly called atherothrombosis.2 Atherothrombosis is a slowly progressive, degenerative disease of the large- and middle-sized elastic and muscular arteries, beginning with fatty streak formation in adolescence. When it progresses unabated, the streaks develop into plaques, culminating in thrombotic occlusions and CV events later in life.1 MI, myocardial infarction; PAD, peripheral artery disease. Fuster V, et al. Vasc Med. 1998;3: Rauch U, et al. Ann Intern Med. 2001;134: References 1 Fuster V, Badimon JH, Chesebro JJ. Atherothrombosis and clinical therapeutic approaches. Vasc Med. 1998;3: 2 Rauch U, Osende JI, Fuster V, Badimon JJ, Fayad Z, Chesebro JH. Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med. 2001;134:

3 Atherothrombosis* is the Leading Cause of Death Worldwide1
Pulmonary Disease 6.3 Injuries 9 AIDS 9.7 Cancer 12.6 Infectious Disease 19.3 Atherothrombosis is the underlying condition that results in events leading to myocardial infarction, ischemic stroke, and vascular death. As such, the leading cause of death of the estimated 55,694,000 people worldwide who died in 2000 was atherothrombosis, manifested as cardiovascular disease, ischemic heart disease and stroke (52% of deaths). Other main causes of death were AIDS (5%) pulmonary disease (6%) injuries (9%) cancer (12%) violent death (12%) infectious diseases (19%) Atherothrombosis (29%) Atherothrombosis* 22.3 5 10 15 20 25 30 Causes of Mortality (%) * Atherothrombosis defined as ischemic heart disease and cerebrovascular disease. 1 The World Health Report Geneva. WHO References The World Health Report Geneva: WHO; 2001.

4 Atherothrombosis Significantly Shortens Life
Atherothrombosis reduces life expectancy by around 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 A recent analysis of the data from the Framingham Heart Study was conducted to determine the impact of cardiovascular disease on life expectancy1. The study used 40 years of data collected on 5,070 patients who did not have cardiovascular disease (CVD) upon study entry. In this analysis, CVD was defined as coronary heart disease (ie, myocardial infarction (MI), angina pectoris, coronary insufficiency), cerebrovascular disease (ie, stroke, transient ischemic attack), congestive heart failure, and intermittent claudication. This definition of CVD covers all the manifestations of atherothrombosis; therefore the conclusions should directly relate to atherothrombosis. According to this analysis, more than 60% of men and women over 40 years of age will develop atherothrombotic disease at some point in their lives. For patients greater than 50 years of age, the development of atherothrombotic disease reduces life expectancy by 8 to 12 years. A 60-year-old man without atherothrombotic disease can expect to live to age 80, whereas the same person who has a history of acute MI can expect to live only an additional 10.8 years. A 60-year-old man with a history of stroke or congestive heart failure has a life expectancy of 7.98 years or 4.0 years, respectively. Although not shown on the slide, the life expectancy of a woman with CVD is slightly longer than that of a man, but life expectancy is still significantly shorter in the presence of CVD when compared with the life expectancy of a healthy woman.1 4 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: References Peeters A, Manus AA, Willekens F, et al. A cardiovascular life history. Eur Heart J. 2002;23:

5 Hospitalizations in the US Due to Vascular Disease
3.2 Million Hospital Admissions Cerebrovascular Disease Coronary Atherosclerosis Acute Myocardial Infarction Other Ischemic Heart Disease The National Hospital Discharge Survey is an annual survey conducted by the National Center for Health Statistics branch of the Centers for Disease Control and Prevention (CDC).1 According to the 1999 survey, heart disease accounted for 4.5 million hospital admissions, and cerebrovascular disease accounted for almost a million admissions. Of these, a total of 1.2 million admissions can be attributed to vascular disease.1 The majority of these admissions were due to cerebrovascular disease and coronary atherosclerosis, each accounting for almost a million hospital admissions.1 The next largest category was acute myocardial infarction (MI), which accounted for about 829,000 hospital admissions.1 Other types of ischemic heart disease made up the remaining 280,000 admissions. These diagnoses included unstable angina, coronary occlusion without MI, angina pectoris, coronary aneurysm, and chronic coronary insufficiency.1 References 1 Popovic JR, Hall MJ National Hospital Discharge Survey. Advance Data. Hyattsville, Md: National Center for Health Statistics;2001;319:1-20. 961,000 Admissions 1,153,000 Admissions 829,000 Admissions 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. High-blood pressure control 28,300 Diabetes care 13,600 Cholesterol management 6500 Smoking cessation 2700 Breast-cancer screening 2500 -blocker treatment 1700 Prenatal care 1500 Cervical-cancer screening 700 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 Coronary heart disease (CHD) is the single largest cause of death in Americans. According to American Heart Association national statistics, CHD caused more than 681,000 deaths in the United States in 1999, or 1 in every 5 deaths.1 This year, an estimated 1,100,000 Americans will have a new or recurrent coronary attack and about 45% of them will die. According to the National Heart, Lung, and Blood Institute’s Framingham Heart Study, about 550,000 new cases of angina occur each year.1 Over 12 million people alive today have a history of myocardial infarction, angina pectoris, or both.1 * 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 Statistics—2003 Update. References 1 American Heart Association Heart Disease and Stroke Statistics. Dallas, Tex: American Heart Association; 2003.

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 It has been estimated that approximately 700,000 new or recurrent strokes occur each year in the United States. The 2003 Heart Disease and Stroke Statistics of the American Heart Association reports that approximately 168,000 deaths occurred from stroke.1 Nearly 1 in every 14 deaths in the United States is attributable to stroke. Stroke is the third leading cause of death behind heart disease and cancer.1 Although the outcome of stroke is often fatal, there are approximately 4,700,000 stroke survivors alive today. The quality of life is usually decreased following the event, as stroke is a leading cause of serious, long-term disability.1 American Heart Association. Heart Disease and Stroke Statistics—2003 Update. References 1 American Heart Association. Heart Disease and Stroke Statistics—2003 Update. Dallas, TX, Last accessed October 22, 2003.

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 Peripheral arterial disease (PAD) is a highly prevalent atherosclerotic syndrome that affects approximately 8 to 12 million people in the United States and is associated with significant morbidity and mortality.4 The consequences of PAD are considerable because of its high prevalence, high rate of nonfatal cardiovascular (CV) ischemic events (myocardial infarction, stroke, etc), increased mortality, and diminished quality of life.4 The ankle-brachial index is a simple, relatively inexpensive, and accurate diagnostic tool for PAD.2 Unfortunately, underdiagnosis of PAD in primary care may be a barrier to effective secondary prevention of the high ischemic CV risk associated with PAD.4 PAD, peripheral artery disease; CV, cardiovascular. 1 Nicolaides AN. Symposium. Nov Hiatt WR, et al. Circulation. 1995; 91: 3 Criqui MH, et al. N Engl J Med. 1992; 326: Hirsch AT, et al. JAMA. 2001;286: References 1 Nicolaides AN, Delis K. Intermittent foot and calf compression: effects on arterial blood flow and value in treatment of intermittent claudication. Abstract presented at 24th Annual Symposium on Current, Critical Problems, New Horizons and Techniques in Vascular and Endovascular Surgery. November 1997. 2 Hiatt WR, Hoag S, Hamman RF. Effect of diagnostic criteria on the prevalence of peripheral arterial disease. Circulation. 1995;91: 3 Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326: 4 Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;286:

10 Diabetes: Impact in United States
12 million people with 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. 2003;26: 2 Juvenile Diabetes Research Foundation International. Diabetes Figures,

11 Clinical Manifestations of Atherothrombosis
Cerebral Ischemic stroke Transient ischemic attack Cardiac Myocardial infarction Angina pectoris (stable, unstable) Peripheral Arterial Disease Critical limb ischemia, claudication Vascular disease is the result of a generalized process that may affect any of several vascular beds involving the cerebral, coronary, and peripheral arteries1. Cerebrovascular disease in cerebral arteries may precipitate a transient ischemic attack (TIA) or an ischemic stroke. A TIA, by definition, lasts for fewer than 24 hours. The majority clear within 1 hour. A TIA may be a warning of an impending stroke, with the risk for a stroke being 4% to 8% during the first month following a TIA and 24% to 29% during the next 5 years.1 Coronary vascular disease produces a spectrum of ischemic coronary syndromes that include stable angina, unstable angina, non–ST-segment elevation myocardial infarction (NSTEMI; also known as non–Q-wave MI), and ST-segment elevation (STEMI; also known as Q-wave MI).2 Peripheral arterial disease (PAD) produces a variety of symptoms ranging from intermittent claudication to pain at rest.3 Patients with the most serious form of PAD develop a critical limb ischemia that produces pain at rest and threatens the viability of the limb by increasing the risk for gangrene and necrosis.3 PAD is a strong marker for cardiovascular disease. References 1 Feinberg WM, Albers GW, Barnett HJ, et al. Guidelines for the management of transient ischemic attacks. Circulation. 1994;89: 2 American Heart Association. Heart Disease and Stroke Statistics–2003 Update. Available at: 3 Weitz JI, Byrne J, Clagett GP, et al. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation. 1996;94:

12 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% Atherothrombosis can occur in any of several vascular beds, including those involving coronary, cerebral, and peripheral arteries; it is the underlying condition that may lead to a myocardial infarction (MI), stroke, or PAD. These atherosclerotic conditions often coexist, thereby increasing the risk for an ischemic event such as MI or stroke. PAD PAD PAD, peripheral artery disease. Adapted from TransAtlantic Inter-Society Consensus Group. J Vasc Surg. 2000;31:S16. References TransAtlantic Inter-Society Consensus Group. J Vasc Surg. 2000;31:S16.

13 Common Underlying Atherothrombotic Disease Process
Atherothrombotic Stroke Unstable Angina MI PAD Platelet Adhesion, Activation, and Aggregation Plaque Rupture Thrombus Formation Acute coronary syndrome (ACS), stroke, and peripheral arterial disease (PAD) are all caused by the same underlying disease process—vascular disease.1 ACS is a classic example of the result of progression of vascular disease to an ischemic event, with platelets playing a central role in the development of the thrombi and subsequent ischemic events. In ACS, rupture or erosion of an atherosclerotic plaque leads to platelet adhesion, activation, and aggregation, resulting in the formation of a platelet-rich thrombus. Patients who have vascular disease in one vascular bed have an increased lifetime risk for a thrombotic event (eg, myocardial infarction, stroke, and cardiovascular death).2 Clopidogrel is a potent, noncompetitive inhibitor of ADP-induced platelet aggregation. Clopidogrel inhibits the binding of ADP to platelet membrane receptors. The effect of clopidogrel on ADP binding is irreversible and, thus, lasts for the duration of platelet life, about 7 days.3 The inhibition is also specific and does not significantly affect cyclooxygenase activity or arachidonic acid metabolism.4 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: Schafer AI. Am J Med. 1996;101: References 1 Schafer AI. Antiplatelet therapy. Am J Med. 1996;101: 2 Ness J, Aronow WS. Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital-based geriatrics practice. J Am Geriatr Soc. 1999;47: 3 Plavix® (clopidogrel bisulfate) prescribing information. Scnofi-Syntholabo. Revised May 2002. 4 Schrör K. The basic pharmacology of ticlopidine and clopidogrel. Platelets. 1993;4:

14 Risk of a Second Atherothrombotic Event
Increased Risk vs General Population (%) Original Event MI Stroke 5-7 times greater risk (includes death)* 3-4 times greater risk (includes TIA) 2-3 times greater risk (includes angina and sudden death)* 9 times greater risk PAD 4 times greater risk* 2-3 times greater risk (includes TIA) Patients presenting with one type of atherothrombotic event are at increased risk for a second event, frequently in a different vascular territory.1 This demonstrates that once a patient manifests atherothrombotic disease, the patient is at high risk for future events. Data for the associated risk increase in events were taken from different sources, but show that the risk of a second vascular event can increase 2 to 9-fold.1 The increase in risk of events was based on a 10-year follow-up, except for the risk of stroke following stroke, which measures subsequent risk per year.1-3 References 1 Kannel WB. Risk factors for atherosclerotic cardiovascular outcomes in different arterial territories. J Cardiovasc Risk. 1994;1: 2 Wilterdink JI, Easton JD. Vascular event rates in patients with atherosclerotic cerebrovascular disease. Arch Neurol. 1992;49: 3 Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326: * 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 Atherothrombosis: A Generalized and Progressive Process
Unstable angina MI Ischemic stroke/TIA Critical leg ischemia Intermitent claudication CV death ACS Atherosclerosis Atherosclerosis is an ongoing process affecting mainly large- and medium-sized arteries; it can begin in childhood and progress throughout a person’s lifetime.1 Stable atherosclerotic plaques may encroach on the lumen of the artery and cause chronic ischemia, resulting in (stable) angina pectoris or intermittent claudication, depending on the vascular bed affected.2 Unstable atherosclerotic plaques may rupture, leading to the formation of a platelet-rich thrombus that partially or completely occludes the artery and causes acute ischemic symptoms.2,3 References 1 Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001;104: 2 Rauch U, Osende JI, Fuster V, et al. Thrombus formation on atherosclerotic plaques: pathogenesis and critical consequences. Ann Intern Med. 2001;134: 3 Yeghiazarians Y, Braunstein JB, Askari A, et al. Unstable angina pectoris. N Eng J Med. 2000;342: Stable angina/ Intermittent claudication Adapted from Libby P. Circulation. 2001;104:

16 Atherothrombosis: Thrombus Superimposed on Atherosclerotic Plaque
Atherosclerotic plaque has 2 main components: a soft, lipid-rich core and a hard, collagen-rich fibrous cap. In stable plaques, a thick fibrous cap may represent >70% of plaque volume. It stabilizes the plaque and prevents it from undergoing rupture. In contrast, unstable plaque has a thin fibrous cap and is at greater risk for rupture. In unstable plaque, the lipid-rich core may represent the majority of the plaque volume. The core is rich in extracellular lipids, which are formed by trapping blood-derived lipids, notably low-density lipoprotein, or by lipid-filled macrophages, known as foam cells. The plaque destabilizes due to inflammation by foam cells and other inflammatory mediators that make the plaque more vulnerable to rupture. This commonly occurs at the junction of the plaque and the less diseased vessel wall. As a result, the lipid core may be exposed to flowing blood leading to platelet-mediated thrombus formation. Falk reviewed the work of other investigators regarding the severity of stenosis and its association with the risk of MI. Results showed that >86% of MIs resulted from lesions that were <70% stenosed. Most experts prior to Falk thought that patients had heart attacks because of blockages that increased in size until they blocked the blood vessel and caused a heart attack.1 Based on the findings of Falk, we now know the primary cause of a heart attack is the rupture of unstable plaques that are <70% stenosed and are clinically silent. Approximately 200 patients from 4 studies were studied to generate these results, which have been confirmed in other studies.1 Adapted from Falk E, et al. Circulation. 1995;92: References 1 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92: 2 Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:

17 Characteristics of Unstable and Stable Plaque
Lack of inflammatory cells Inflammatory cells Thin fibrous cap Thick fibrous cap Few SMCs More SMCs Atherosclerotic plaques have 2 main components—a soft lipid-rich core and a hard collagen-rich fibrous cap.1 In stable plaques, a thick fibrous cap may represent >70% of plaque volume. It stabilizes the plaque and prevents it from undergoing rupture.1 In contrast, unstable plaques have a thin fibrous cap and are at greater risk for rupture. In unstable plaques, the lipid-rich core may represent the majority of the plaque volume.1 Falk reviewed the work of other investigators regarding severity of stenosis and its association with the risk of MI. Results showed that >86% of MIs resulted from lesions that were <70% stenosed.1 Most experts prior to Falk thought that patients had heart attacks because of blockages that increased in size until they eventually blocked the blood vessel and caused a heart attack. Based on the findings by Falk, we now know the primary cause of heart attacks is the rupture of unstable plaques that are <70% stenosed and are clinically silent. Approximately 200 patients from 4 studies were used to generate these results, which have been confirmed in other studies. Intact endothelium Eroded endothelium Activated macrophages Foam cells Libby P. Circulation. 1995;91: References 1 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92: 2 Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:

18 Plaque Rupture Andrew Farb, MD by permission.
The structure of the plaque may contribute to its propensity for disruption. Lesions that rupture characteristically have a markedly eccentric configuration (ie, the plaque is not uniform around the vessel circumference) and a large soft core of necrotic debris and lipid, and is covered by a thin fibrous cap. Fissures frequently occur at the junction of the fibrous cap and the adjacent normal arterial wall (plaque-free segment), a location that is associated with high circumferential stress.2 Platelet and vessel wall interactions and thrombus formation are modulated by the interplay of:1 Vascular factors, such as extent of arterial injury and nature of the exposed substrate Systemic factors, such as hyperlipidemia, Lp(a), catecholamine levels, smoking, and diabetes, as well as prothrombic states and poor thrombolytic states Local rheology, such as high sheer rates in stenosed arteries References 1 Badimon L, Badimon JJ, Fuster V. Pathogenesis of thrombosis. In: Verstraete M, Fuster V, Topol EJ. Cardiovascular Thrombosis. 2nd ed. Philadelphia, Pa: Lippincott-Raven; 1998:39-40. 2 Cotran RS, Kumar V, Robbins, SL. Robbins Pathologic Basis of Disease. 5th ed. Philadelphia, Pa: W.B. Saunders;1994:105, 526. Andrew Farb, MD by permission.

19 Risk Factors for Plaque Rupture
Local Factors Systemic Factors Cap Fatigue Smoking Cholesterol Atheromatous Core (size/consistency) Diabetes Mellitus Fibrinogen Cap Thickness/ Consistency Homocysteine Cap Inflammation Impaired Fibrinolysis Several local and systemic risk factors for plaque rupture have been identified. Local factors include the size and consistency of the atheromatous core, the thickness and collagen content of the fibrous cap, inflammation within the cap, and “cap fatigue.”1 Increased size and the consistency of the atheromatous core are associated with a greater risk for plaque rupture. Aortic plaques that have a core that occupies >40% of the plaque volume are especially vulnerable to rupture. The consistency of the extracellular lipids (especially cholesterol) in the core affects the risk for rupture. Cholesterol esters soften plaque and make it less stable and highly thrombogenic.1 Plaque rupture occurs most commonly at sites where the cap is thinnest, contains lower amounts of collagen, and is infiltrated with macrophages.1 Ruptured fibrous caps are heavily infiltrated by activated macrophage foam cells, indicating that an inflammatory process is ongoing. Foam cells that infiltrate the fibrous cap weaken the plaque by reducing its tensile strength. By comparison, an increased number of smooth muscle cells in the cap stabilizes the plaque and makes rupture less likely.1 Finally, in “cap fatigue,” mechanical and hemodynamic forces—including high blood flow velocity and elevated blood pressure—continually stress the cap and are likely to increase the risk for plaque rupture.1 There is increasing evidence that a number of systemic factors—including smoking, high cholesterol, diabetes, elevated homocysteine, and stress—enhance atherosclerotic processes and increase the risk for plaque rupture and thrombogenesis.1,2 These factors may all be related through platelet activation and reduced fibrinolysis associated with elevated fibrinogen levels. High plasma fibrinogen is an independent risk factor for coronary artery disease. Similarly, elevation of factor VII, which is associated with menopause, is also associated with an increase in coronary events. Notably, elevated fibrinogen levels are associated with age, diabetes, smoking, obesity, hyperlipidemia, and emotional stress. Thus, many risk factors may share common final pathways.2 References 1 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92: 2 Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326: Plaque Rupture Fuster V, et al. N Engl J Med. 1992;326: Falk E, et al. Circulation. 1995:92:

20 Multiple Risk Factors for Atherothrombosis
Generalized Disorders Age Obesity Lifestyle Smoking Diet Lack of exercise 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 Atherosclerosis is a disease that develops over several decades. Risk factors such as smoking or hypertension, hyperlipidemia, and hyperglycemia, with or without obesity, can promote its development.1 Risk factors such as age, sex, race or ethnicity, and heredity are not modifiable. Yet, they are important risk factors.2 Stroke incidence doubles each decade after age 55 years, and age is the single most important risk factor for stroke.2 Sex and race, ethnicity, or both are also important risk factors, with the incidence of stroke greater in men and some Hispanic and African American groups being at a greater risk for stroke compared with whites.2 Relative risk is greater if a parent has a history of stroke or a transient ischemic attack, and paternal history carries a greater risk than maternal history.2 Local factors in arterial territories—including blood flow parameters, vessel diameter, and arterial wall structure—participate in atherothrombotic disease manifestation.1-2 Advances in pathophysiological insight into atherosclerosis have provided markers of inflammation that are targets for measurement to assess risk. Potential targets that should be measured to assess risk include C-reactive peptide, interleukin-6, prothrombic factors, and fibrinogen.1-2 The presentation of the multiple risk factors for atherothrombosis simply highlights the importance of a disease that is the leading cause of death worldwide. References 1 Yusuf S, Reddy S, Ounpuu S, et al. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation. 2001;104: 2 Drouet L. Atherothrombosis as a systemic disease. Cerebrovasc Dis. 2002;13(suppl 1):1-6. 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: Drouet L. Cerebrovasc Dis. 2002;13(suppl 1):1-6.

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 Modifiable Risk Factors for Stroke Age: Most important risk factor. The incidence of stroke doubles each decade after age 55. Sex: Age-adjusted incidence greater in men; total mortality greater in women due to longer lifespan.1 Race and ethnicity: Greater risk for some Hispanic groups and blacks compared with whites. Family history: Increased risk if one parent has a history of stroke or transient ischemic attack; paternal history carries a greater risk than maternal history. Nonmodifiable Factors for Stroke Hypertension: Most important risk factor; treatment reduces risk by up to 50%. Atrial fibrillation (nonvalvular): Warfarin or aspirin is recommended. Smoking: Smoking cessation programs (including nicotine replacement) should be strongly promoted and family members involved. Hyperlipidemia: Lipoprotein analysis recommended if total cholesterol is 240 mg/dL or HDL is <35 mg/dL. Alcohol: AHA recommends 2 drinks/day for men and 1 drink/day for nonpregnant women. Carotid stenosis: Data on carotid endarterectomy for asymptomatic cases are controversial; evaluate carefully before recommending surgery. Physical inactivity: 30 minutes/day of moderate-intensity physical activity reduces risks for stroke. Obesity: Promotes several risk factors for stroke; abdominal obesity (men) and weight gain (women) are independent risk factors. Diabetes mellitus (type 1 and 2): Treatment reduces diabetes-associated stroke risk, but not the risk from microvascular damage secondary to diabetes. Homocysteine: Levels increase with age; no standard cutoff, but stroke risk is associated with 16 mol/L. References 1 Goldstein, LB, et al. Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation. 2001;103:

22 Black-Blood Coronary Plaque MR
LAD Wall LAD Wall RCA 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: (with permission)

23 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) The formation of vulnerable plaques is part of a pan-coronary process. The number of yellow plaques and thrombis in the left anterior descending coronary artery, left circumflex artery, and the right coronary artery were evaluated angiographically in 32 patients undergoing catherization 1 month after myocardial infarction (MI). The mean number of yellow plaques detected in a coronary artery, excluding the culprit lesion, was 3.2 ± 1.7. Yellow plaques were equally prevalent in the infarct-related and non–infarct-related coronary arteries (3.7 ± 1.6 vs 3.4 ± 1.8 plaques per artery, P=NS). Angioscopic images from a 58-year old man who had an anterior wall MI reveal a culprit lesion in numbers 8 and 9, along with a thrombus. Multiple other vulnerable yellow plaques were detected throughout the coronary vasculature (1-7 and 10-12). Vulnerable plaques exist in the culprit lesion and in the nonculprit segments. Treatment should be designed to prevent future ischemic events due to the culprit or nonculprit lesions. References 1 Asakura M, Ueda Y, Yamaguchi O, et al. Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study. J Am Coll Cardiol. 2001;37: Multiple “vulnerable” plaques detected in non-culprit segments 10-12 ACS, acute coronary syndrome. Asakura M, et al. J Am Coll Cardiol. 2001;37: (with permission)

24 Multiple Complex Coronary Plaques in Patients With Acute MI
Multiple plaques detected Multiple plaques detected Culprit lesion Multiple complex coronary plaques may be found in patients with acute myocardial infarction (MI). A culprit lesion and multiple other plaques can be detected in the above angiograms shown. In one study, Goldstein and colleagues analyzed angiograms from 253 patients for complex coronary plaques to document multiple unstable plaques in patients with acute MI. Single complex coronary plaques were identified in 60% of patients; multiple plaques were found in 40% of patients. The patients with multiple complex coronary plaques were less likely to undergo primary angioplasty and more likely to require urgent bypass surgery. In addition, the presence of multiple complex plaques was associated with an increased incidence of recurrent acute coronary syndrome, repeated angioplasty, and coronary-artery bypass surgery, in the year following MI. Multiple complex coronary plaques are commonly found in patients with acute MI and are associated with adverse clinical outcomes. References 1 Goldstein JA, Demetriou D, Grines CL, et al. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med. 2000;343: MI, myocardial infarction. Goldstein JA, et al. N Eng J Med. 2000;343: (with permission)

25 Frequency of Multiple “Active” Plaques in Patients With ACS
80% of Patients With  2 Plaques N=24 Patients (%) Rioufol and colleagues reported the results of an analysis of the 3 coronary arteries by systematic intravascular ultrasound scan in 24 male patients referred for percutaneous coronary intervention. The authors reported >79% of patients had ruptures of coronary atherosclerotic plaque other than the culprit lesion. Of these, 70% occurred in an artery separate from the artery with the culprit lesion. Of the patients studied, 12.5 % had at least one rupture in all 3 arteries studied. Note that in 20% of patients studied, no additional ruptures were found besides the culprit lesion (gray bar on far left of graph). From these studies, one can conclude that although a single lesion is clinically active in patients with acute coronary syndrome, the syndrome seems to be associated with pancoronary destabilization. References 1 Rioufol G, Finet G, Ginon I, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation. 2002;106: Frequency of multiple active plaque ruptures beyond the culprit lesion ACS, acute coronary syndrome. Rioufol G, et al. Circulation 2002;106: (with permission)

26 Acute Plaque Rupture ACS (UA/NSTEMI/STEMI) Persistent Hyperreactive
ACS: Tip of the Atherothrombotic “Iceberg” Acute Plaque Rupture ACS (UA/NSTEMI/STEMI) Clinical Subclinical Acute coronary syndromes—including unstable angina, non–ST–segment elevation myocardial infarction and ST–elevation myocardial infarction—share a common underlying pathophysiologic link of plaque rupture. Goldstein reviewed data that support the concept of plaque instability in many patients as a pan-coronary process, reflecting systemic inflammatory and metabolic factors that destabilize plaques in several locations—not only those containing culprit lesions—and are responsible for acute ischemic events. Many ulcerated plaques are not sufficiently disrupted to be detected angiographically and patients who are likely to have unstable coronary artery disease have lipid-rich inflamed vulnerable plaques that have yet to ulcerate and rupture. Goldstein suggested, “(t)herefore, angiographic documentation of plaque rupture undoubtedly represents only the, ‘tip of the iceberg,’ of plaque instability.” References Goldstein JA. Angiographic plaque complexity: the tip of the unstable plaque iceberg. J Am Coll Cardiol. 2002;39: 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 ;39:

27 Hemostatic Plug Formation
PRIMARY AGGREGATION Platelet Aggregation Clotting Hemostatic Clot Fibrin SECONDARY COAGULATION Thrombin Hemostasis: the termination of bleeding by mechanical or chemical means or by the complex coagulation process of the body, involving vasoconstriction, platelet aggregation, and thrombin and fibrin synthesis1. Primary hemostasis is the process of platelet-plug formation at sites of injury. It occurs within seconds of injury and is of prime importance in stopping blood loss.2 Secondary hemostasis describes the reactions of the plasma coagulation system to vascular injury that results in fibrin formation. It takes several minutes before this process is completed. The fibrin strands strengthen the primary hemostatic plug. This reaction is particularly important in larger vessels to prevent recurrent bleeding hours or days after the initial injury.2 Although presented here as separate events, primary and secondary hemostasis are closely linked. For example, activated platelets accelerate plasma coagulation, and products of the plasma coagulation reaction, such as thrombin, stimulate platelet aggregation.2 0 min 5 min 10 min Adapted from Ferguson JJ, et al. Antiplatelet Therapy in Clinical Practice. 2000:15-35. References 1 Mosby’s Pocket Dictionary of Medicine, Nursing and Allied Health. 5th ed. St. Louis, MO: Mosby-Year Book Inc;1998:7500. 2 Ferguson JJ. The physiology of normal platelet function. In: Ferguson JJ, Chronos N, Harrington RA; Antiplatelet Therapy in Clinical Practice. London: Martin Dunitz; 2000:15-35.

28 The Role of Platelets in Atherothrombosis
1 Adhesion 3 Aggregation On the left is a scanning electron micrograph (SEM) of adherent platelets. Platelets adhere to cell surfaces through their cell surface adhesion molecules and membrane receptors such as glycoprotein Ib/IX (GP Ib/IX), the ligand for von Willebrand factor. On the right is an SEM showing aggregated platelets forming a first hemostatic plug. When activation occurs, the glycoprotein IIb/IIIa membrane receptor (GP IIb/IIIa) is exposed. This receptor forms bridges using fibrinogen, which result in platelet aggregation. Without this aggregation, the platelet "plug" would rapidly be washed downstream by flowing blood. Platelet activation also exposes a phospholipid surface (meeting place) upon which coagulation proteins carry out their reactions. The sequential activation of these coagulation factors ultimately leads to the formation of fibrin, which is critical for stabilizing the hemostatic plug. 2 Activation References Colman RW, Hirsh J, Marder VJ, Salzman EW. Overview of the thrombotic process and its therapy. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and Thrombosis. 3rd ed. Philadelphia, Pa: J.B. Lippincott; 1994:1153. Cotran RS, Kumar V, Robbins SL, eds. Robbins Pathologic Basis of Disease. 5th ed. Philadelphia, Pa: W.B. Saunders; 1994:

29 Clopidogrel/Ticlopidine GP IIb/IIIa Inhibitors
Platelets Role in Thrombosis 1. Platelet Adhesion Platelet GP Ib 2. Platelet Activation Activated Platelet GP IIb/IIIa Plaque rupture 3. Platelet Aggregation ASA, Clopidogrel/Ticlopidine TxA2 Fibrinogen Primary hemostasis: process of platelet adhesion (a), activation (b), and aggregation (c). Platelets initiate thrombosis at the site of a ruptured plaque: the first step is platelet adhesion (a) via the glycoprotein Ib receptor in conjunction with von Willebrand factor. This is followed by platelet activation (b), which leads to a shape change in the platelet, degranulation of the alpha and dense granules, and expression of GP IIb/IIIa receptors on the platelet surface with activation of the receptor, such that it can bind fibrinogen.2 The final step is platelet aggregation (c), in which fibrinogen (or von Willebrand factor) binds to the activated GP IIb/IIIa receptors of two platelets.2 Aspirin and clopidogrel act to decrease platelet activation3 whereas the glycoprotein IIb/IIIa inhibitors inhibit the final step of platelet aggregation.2 References 1 Cannon CP and Braunwald E. Heart Disease 2 Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and nonST-segment elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. 2000;36: 3 Cannon CP, on behalf of the Caprie Investigators. Effectiveness of clodipogrel versus aspirin in preventing acute myocardial infarction in patients with sympotomatic atherothrombosis (CAPRIE trial). Am J Cardiol. 2002;90: GP IIb/IIIa Inhibitors ASA, acetylsalicyclic acid. Cannon and Braunwald, Heart Disease 3

30 Platelets: Role in Thrombosis
High Flow Slow Flow Fibrin RBCs Platelets Fibrin RBCs Platelets Thrombi are composed of fibrin and blood cells. The relative proportion of one type of cell to another and to fibrin is influenced by hemodynamic factors; therefore, the proportions differ in arterial vs venous thrombosis. Arterial thrombi formed under conditions of high flow are composed mainly of platelet aggregates bound together by fibrin strands. The resulting thrombi are sometimes referred to as "white" thrombi because they have few red blood cells. These thrombi are usually flat, tightly adherent, and relatively small. Arterial thrombi usually occur in association with preexisting vascular disease, the most common of which is atherosclerosis. They produce clinical manifestations by inducing tissue ischemia, primarily through the obstruction of local blood flow. Venous thrombi form in areas of stasis and are composed of red cells with a large amount of interspersed fibrin and relatively fewer platelets. These "red" thrombi are large, friable casts of the venous channel with branching arms that may extend into tributary veins. Too often such thrombi have only a weak proximal attachment to the venous intima, usually at a valve or a bifurcation, and may detach and embolize to occlude downstream vessels. Venous thrombi usually occur in the lower limbs, particularly in the deep veins of the calf or thigh. They are usually silent, but produce acute symptoms if they cause inflammation of the vessel wall or obstruction to flow, damage the venous valves, or embolize into the pulmonary circulation. References Hirsh J, et al. Pathogenesis of Thrombosis. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 3rd ed. Coleman RW, Hirsh J, Marder VJ, Salzman EW (eds). Philadelphia: JB Lippincott Company;1994: White Thrombus Coagulation Thrombus RBCs, red blood cells.

31 Aspirin   Activated Platelet Clopidogrel Ticlopidine ADP
To neighboring platelet IV Gp IIb/IIIa Inhibitors TXA2 Gp IIb/IIIa fibrinogen receptor Aspirin Thrombin Serotonin Epinephrine Collagen COX Activation 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 Degranulation Adapted from Ferguson JJ, et al. In: Antiplatelet Therapy in Clinical Practice. London: martin Dunitz; 2000:15-35. Platelet agonists ADP ATP serotonin calcium magnesium TXA, thromboxane; PDGF, platelet-derived growth factor.

32 Platelet Hyperreactivity Following ACS Predicts 5-Year Outcomes
(CI ) Death 50 46.2 *RR=5.4 (CI ) Cardiac Events 40 34.6 *RR=1.6 (CI ) 30 24.1 Patients (%) *RR=1.6 (CI ) 20 14.9 10.3 10 6.4 Platelet aggregation offers useful prognostic information after myocardial infarction (MI). Investigators assessed platelet aggregation in 149 patients post-MI within 3 months of the index event. Spontaneous platelet aggregation (SPA) was graded as negative when there was no aggregation within 20 minutes of the addition of a platelet intermediate when aggregation occurred between 10 and 20 minutes and positive when aggregation occurred within 10 minutes. Clinical outcomes, including cardiac events—nonfatal recurrent MI or cardiac death (defined as death occurring in hospital post-MI or death occurring suddenly without previous symptoms or within 24 hours of the onset of new symptoms of heart disease)—were recorded over 5 years. A total of 14.9% SPA-negative patients experienced at least 1 cardiac event over 5 years vs 24.1% of SPA-intermediate patients and 46.2% of SPA-positive patients. The relative risk (RR) for a cardiac event was 1.6 (95% CI range: ) in patients in the SPA-intermediate group and 3.1 (95% CI range: ) in those in the SPA-positive group. Mortality was also highest in the SPA-positive group (34.6%) compared with the SPA-intermediate and SPA-negative groups (10.3% and 6.4%, respectively). Compared with patients in the SPA-negative group, the RR for death was 1.6 (95% CI range: ) in patients in the SPA-intermediate group and 5.4 (95% CI range: ) in those in the SPA-positive group. Overall, a positive association between platelet hyperreactivity and both cardiac events and mortality was demonstrated in post-MI patients over 5 years. 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: References Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med. 1990;322:

33 Plaque Rupture & Thrombosis
Platelets Release Inflammatory Mediators and Lead to Vascular Inflammation and Plaque Instability Activated Platelets Inflammatory Modulators CD 40 ligand Platelet factor 4 RANTES Thrombospondin Platelet-derived growth factor Nitric oxide Plaque Rupture & Thrombosis Inflammation promotes thrombus formation by mediating endothelial cell function. Platelets contribute to thrombus formation by producing inflammatory modulators and responding to thrombotic stimuli. Inflammatory modulators produced by platelets include platelet-derived growth factor (PDGF), platelet factor 4, CD 154 (CD 40 ligand), the T-cell cytokine that is “regulated on activation, normal T expressed and secreted” (RANTES), thrombospondin, transforming growth factor-β, and nitric oxide. These modulators contribute to thrombus formation through a number of mechanisms. For example: increases interleukin-6 production, which, in turn, increases the production of the procoagulants fibrinogen and PAI-1 platelet factor 4 is a chemokine CD 154 is a cell-surface–based signaling system that induces tissue factor expression and subsequent thrombus formation, and RANTES contributes to macrophage adhesion to endothelial cells by acting as a bridge Unstable Plaque RANTES (Regulated on Activation, Normal T-cellExpressed and Secreted). Libby P, et al. Circulation. 2001;103: References Libby P, Simon DI. Inflammation and thrombosis: The clot thickens. Circulation. 2001;103:

34 The Shedding of Soluble SCD40L During Platelet Stimulation
ADP Thrombin Collagen CD4OL sCD4OL GP IIb-IIIa Antagonists PDGF TGF PF4 TSP 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: (with permission)

35 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 Although physicians acknowledge the key role of platelets in arterial thrombosis, most only consider them to be responders to thrombotic stimuli. However, recent studies attribute an important regulatory role to platelets as a source of inflammatory mediators.1 Platelet-factor 4, which belongs to a CXC chemokine family of inflammatory modulators, can mediate shear-resistant arrest of monocytes to endothelium.1 Deposition of the “regulated on activation, normal T-cell–expressed and secreted” (RANTES) cytocine by platelets triggers shear-resistant monocyte arrest on inflamed or atherosclerotic endothelium and may thereby play a pivotal role in the pathogenesis of inflammatory and atherosclerotic disease.2 Nitric oxide is a principal factor involved in the antiatherosclerotic properties of the endothelium; it interferes with monocyte and leucocyte adhesion to the endothelium, as well as platelet-vessel interaction, and it has been shown to inhibit vascular smooth cell proliferation and migration.3 CD154 (CD40 ligand) has been found in atheroma-associated cells, and ligation of CD40 has been shown to regulate smooth muscle and endothelial cell functions relevant for the pathogenesis of atherosclerosis.1,4 Thrombospondin interacts with various cell surface receptors.1 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: 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: References 1 Libby P, Simon DI. Inflammation and thrombosis: The clot thickens. Circulation. 2001;103: 2 von Hundelshausen P, et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation. 2001;103: 3 Wever RMF, Lüscher TF, Consento F, et al. Atherosclerosis and the two faces of endothelial nitirc oxide synthase. Circulation. 1998;97: 4 Hermann A et al. Platelet CD40 ligand (CD40L)-subcellualr localization, regulation of expression, and inhibition by clopidogrel. Platelets. 2001;12:74-82.

36 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:

37 Death or Nonfatal Myocardial Infarction (%)
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: (with permission)

38 Soluble CD40 Ligand (g/Liter) Monocyte–Platelet Aggregates (%)
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 15 30 45 60 75 Monocyte–Platelet Aggregates (%) Heeschen C, et al. N Engl J Med. 2003:348: (with permission)

39 Death or Nonfatal Myocardial Infarction (%)
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:

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