CHAPTER 130 ATHEROSCLEROSIS, THROMBOSIS, AND CORONARY ARTERY DISEASE
CHAPTER 130 ATHEROSCLEROSIS, THROMBOSIS, AND CORONARY ARTERY DISEASE
MARK B. TAUBMAN
Introduction: Coronary Artery Disease and Thrombosis
Clinical Presentations of Coronary Artery Disease
Pathophysiology of Atherosclerotic Disease
Classification of Atherosclerotic Plaques
Animal Models of Atherosclerosis
Response-to-Injury Model of Atherosclerosis
Thrombosis and Plaque Rupture
Models of Acute Arterial Injury and Thrombus Formation
Molecular Basis of the Atherothrombotic State
Tissue Factor Pathway Inhibitor
The Fibrinolytic System: Plasminogen Activators
Plasminogen Activator Inhibitor 1
Plasminogen Activator Inhibitor 2 (PAI-2)
Receptor for UPA
Transgenic Mouse Models and the Fibrinolytic System
Prothrombin Fragments 1 and 2 and Fibrinopeptide A
Treatment of Acute Coronary Syndromes
Treatment of the Post-Mi Patient
Atherosclerosis manifested by cardiovascular, cerebrovascular, and peripheral vascular disease is the leading underlying cause of mortality in the United States and other industrialized countries. This disease is characterized by an inflammatory and proliferative response of the arterial wall and the subsequent development of thrombosis, often in association with plaque rupture. Many of the important developments in the treatment of acute coronary syndromes, such as the use of aspirin, thrombolytic drugs, and antiplatelet agents, have targeted the thrombotic component of atherosclerosis.
Tissue factor (TF) is thought to be a key determinant of plaque thrombogenicity and of the hypercoagulable state associated with acute arterial injury. The cellular source of plaque TF is likely to be macrophages and smooth-muscle cells (SMC). However, the location of the TF most important for initiating or propagating arterial thrombosis may be extracellular, arising from cell necrosis, apoptosis, and vesiculation from the cell surface. Circulating TF may also play an important role in determining the extent of arterial thrombosis. The fibrinolytic system is thought to provide the normal arterial wall with an antithrombotic surface. However, the role of plasminogen activators in protecting injured or atherosclerotic vessels against thrombosis remains controversial. Plasmin may also be important in mediating vascular remodeling by its effects on metalloproteinase activation and SMC proliferation and migration.
Acronyms and abbreviations that appear in this chapter include: ADP, adenosine diphosphate; CAD, coronary artery disease; CAPRIE study, Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events study; CARS, Coumadin Aspirin Reinfarction Study; EC, endothelial cells; EGF, epidermal growth factor; FGF, fibroblast growth factor; LPC, lysophosphatidylcholine; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1; MI, myocardial infarction; NO, nitric oxide; PAI-1, plasminogen activator inhibitor 1; PAs, plasminogen activators; PDGF, platelet-derived growth factor; PTCA, percutaneous transluminal coronary angioplasty; SK, streptokinase; SMC, smooth-muscle cells; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TGF-b, transforming growth factor beta; tPA, tissue-type plasminogen activator; UA, unstable angina; uPA, urokinase-type plasminogen activator; uPAR, uPA receptor.
INTRODUCTION: CORONARY ARTERY DISEASE AND THROMBOSIS
Atherosclerosis is the leading underlying cause of mortality in the United States and other industrialized countries.1,2 The major manifestations of atherosclerosis are coronary artery disease (CAD) (myocardial infarction (MI), angina, sudden death), cerebrovascular disease (ischemic stroke), and peripheral vascular disease (intermittent claudication, ischemic limbs). It is estimated that more than 1.5 million MIs occur annually in the United States, with approximately 500,000 resulting in death2. A substantial portion of these deaths (200–300,000) occur before patients reach the hospital, largely due to arrhythmias.2
An additional 200,000 deaths are attributable to stroke and peripheral vascular disease. Among survivors of MI, approximately 200,000 die annually from complications of heart failure; this number is rising as the incidence of death from acute MI falls.
The association of coronary atherosclerosis with thrombosis was first made in 1912 by Herrick,3 who noted thrombotic coronary occlusions in patients presenting with acute MI. Subsequently, the term coronary thrombosis entered the vernacular to describe MI. In an autopsy study of patients dying of MI in 1966, Constantinides4 demonstrated that thrombotic occlusion was associated with fractures of the fibrous lining of atherosclerotic plaques. A series of studies by Davies and colleagues5,6 and 7 further established the importance of plaque rupture as the cause of acute ischemic syndromes—MI, unstable angina (UA), and sudden death.
Studies demonstrating that coronary artery spasm might be an important cause of MI in patients with coronary atherosclerosis8,9 led to a reevaluation in the 1970s of the role of thrombosis as the precipitating event in acute coronary syndromes and raised a question as to whether the thrombus seen at autopsy was deposited subsequent to a vasospastic occlusive event.
In the 1980s, the identification of thrombosis on coronary angiography,10 and studies demonstrating the efficacy of intracoronary11 and intravenous12,13 thrombolysis in opening occluded coronary arteries refocused attention on thrombosis as the main cause of acute MI. The success of aspirin in the treatment of UA and in secondary prevention of MI13,14 further helped to establish thrombosis as a major cause of acute coronary events and also suggested that platelet aggregation played a critical role. The importance of platelet aggregation has been buttressed by the success of new antiplatelet agents in the treatment of acute coronary syndromes.15,16 Although the mechanism of coronary thrombosis remains to be fully elucidated, the inciting event in the majority of patients appears to be rupture of the atherosclerotic plaque.
The Framingham Heart Study was established in 1948 to examine factors associated with risk for CAD.17 To date, approximately 75 percent of the original Framingham Heart Study participants have died, the leading cause of death being CAD. The Framingham Heart Study was instrumental in defining the risk factors for CAD.18 Many other programs have subsequently provided important data to corroborate the Framingham findings and to establish additional risk factors (see Pasternak and colleagues19 and Table 130-1).
TABLE 130-1 RISK FACTORS FOR CORONARY ARTERY DISEASE
CLINICAL PRESENTATIONS OF CORONARY ARTERY DISEASE
Angina pectoris results from reversible myocardial ischemia and is characterized by episodic chest discomfort lasting for up to 20 min. Angina is the most common presentation of CAD, with a prevalence of greater than 20 percent in men ages 65 to 69 years and greater than 13 percent in women of similar age.2 The principal pathologic finding underlying typical angina is stenosis (>70%) of one or more coronary arteries.
UA is an acute coronary syndrome characterized by chest pain of new onset or an abrupt worsening of previously stable angina. Like stable angina, episodes are reversible and not associated with evidence of cardiac muscle damage. The risk of MI and death within a year of an episode of UA is as high as 15 percent.20,21,22 and 23
MI, death of cardiac muscle, is due to irreversible ischemia resulting from prolonged coronary artery occlusion. Sudden death is a frequent concomitant of MI and is due to the development of arrhythmias, usually ventricular fibrillation.
PATHOPHYSIOLOGY OF ATHEROSCLEROTIC DISEASE
CLASSIFICATION OF ATHEROSCLEROTIC PLAQUES
Studies in humans have been largely confined to pathologic examination at a single point in time of vessels taken at autopsy, plaques removed during surgical or percutaneous endarterectomies, and fragments removed during coronary atherectomies. These studies have been instrumental in establishing the progression of coronary atherosclerosis over decades.
The American Heart Association has classified atherosclerotic plaques into five phases (Fig. 130-1), based upon the work of Stary and colleagues.24 Phase 1 (types I–III) is characterized by a small plaque, often present during the first decade of life. Type I lesions are not apparent by gross examination and are characterized by isolated foam cells in the arterial wall. Type II lesions have a more abundant accumulation of foam cells organized to form a fatty streak, the first lesion that is apparent on gross examination. Type III lesions are characterized by a raised fatty streak, comprised of foam cells, increased number of SMC, and small extracellular accumulations of lipid. Phase 2 (types IV and Va) is characterized by nonobstructive “soft” lesions. Type IV lesions are characterized by diffuse extracellular lipid. Type Va lesions also have a high extracellular lipid content; however, the lipid is more localized and surrounded by a thin cap. The type Va lesion is thought to have the highest propensity to rupture.
FIGURE 130-1 Classification of atherosclerotic plaques based upon gross pathologic and clinical findings. Roman numerals and phases indicate histologic types, as classified by the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. (Reproduced with permission from Fuster V: Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 94:2013, 1994.)
Phase 3 and 4 are characterized by plaque rupture (Fig. 130-1) and thrombosis (phase 3 if mural, phase 4 if occlusive) and the development of a type VI complex lesion. Organization of the thrombus by connective tissue ultimately results in severely stenotic (type Vb) or occlusive (type Vc) fibrotic lesions. In some cases, type Va lesions do not rupture and progress to type Vb and Vc lesions, characterized by thick fibrous caps comprised of SMC and collagen. These lesions become increasingly stenotic over time.
ANIMAL MODELS OF ATHEROSCLEROSIS
Most animals are resistant to atherosclerosis and do not develop plaques when raised on normal laboratory chow. Virtually all models of atherosclerosis have therefore relied on the use of high-fat, high-cholesterol diets, many of which more closely simulate the diet of individuals in industrialized countries. Normal and Watanabe heritable hyperlipidemic rabbits25,26 primarily develop fatty streaks when kept on atherogenic diets, although prolonged feeding can result in more advanced lesions. Similarly, dietary-induced atherosclerosis in pigs27 leads to early lesions. Hypercholesterolemic diets in nonhuman primates28,29,30 and 31 generate lesions ranging from fatty streaks to more advanced fibrous plaques.
Perhaps the most important advance in the study of atherosclerosis has been the development of transgenic and knockout mouse models (reviewed in Breslow32). Normal mice and rats fail to develop atherosclerotic lesions, even when fed diets rich in cholesterol and fat. Mice deficient in apolipoprotein E (ApoE–/–), the major protein constituent of HDL, have severe hypercholesterolemia and develop all lesion types, including advanced lesions with necrotic cores and fibrous caps.33 Similarly, mice lacking the LDL receptor (LDLR–/–) have extremely high cholesterol levels and develop severe lesions.34 Mice overexpressing apolipoprotein B, the major protein constituent of LDL, have cholesterol levels and profiles similar to those seen in hypercholesterolemic humans but develop less severe lesions.35 The use of these transgenic animal models has allowed investigators to study the molecular events associated with the development of atherosclerosis under conditions in which lesion progression is greatly accelerated. Furthermore, by mating these mice with those deficient in a specific gene hypothesized to be important in atherosclerosis, one can establish the role of that gene in plaque development or progression. For example, an important role for monocyte chemoattractant protein-1 (MCP-1) in plaque development has been established by generating LDLR–/– mice that are also lacking MCP-1,36 or ApoE–/– mice lacking the MCP-1 receptor, CCR2.37 Both mice have a 50 percent reduction in plaque size and macrophage-derived foam cell accumulation within the lesions. An even greater reduction in plaque size and foam cell accumulation has been found when the mice overexpressing apolipoprotein B are mated to the MCP-1–/– mice.38 Despite the power of atherosclerotic mouse models, their lesions remain distinct from those of humans in two critical aspects: They do not rupture spontaneously, and they do not display intramural thrombosis.
RESPONSE-TO-INJURY MODEL OF ATHEROSCLEROSIS
Data derived from studies on animal models of atherosclerosis and the examination of pathologic specimens from human disease have led to a widely accepted hypothesis, first advanced by Ross and colleagues, that atherosclerosis develops as a response to injury.39,40 This hypothesis views atherosclerosis as a normal wound-healing process designed to repair an insult to the arterial wall. The first line of defense against atherosclerosis is a normal endothelial layer. The endothelium provides a nonadherent, nonthrombogenic surface, helps in the formation of the basement membrane, and acts as a semipermeable barrier to and from the underlying media. Normal endothelium also promotes vasodilatation by the secretion of nitric oxide (NO) and prostacyclin (see Chap. 114). The atherosclerotic process is thought to begin with damage to this layer, resulting in endothelial dysfunction. Endothelial dysfunction does not require denudation or severe damage. It may occur in response to circulating factors, such as tumor necrosis factor a (TNF-a) and interleukin-1 (reviewed in Pober and Cotran41 and Libby and coworkers42) or mechanical forces, such as shear stress and cyclic stretch.43,44 Many of the established risk factors for CAD (Table 130-1) are thought to act by causing injury to the normal endothelial surface.
Table 130-2 lists some of the properties of dysfunctional endothelium.45,46 Endothelial dysfunction is associated with a decrease in the production of vasorelaxants, such as NO, and an increase in the secretion of vasoconstrictors, such as endothelin-1. Dysfunctional endothelium also provides a more thrombogenic surface, as a result of an increase in platelet adherence, activation of the coagulation cascade, and perhaps down-regulation of fibrinolysis. “Activated” endothelial cells may also up-regulate the synthesis of SMC growth factors and may down-regulate the synthesis of factors that normally inhibit SMC growth and migration.
TABLE 130-2 PROPERTIES OF NORMAL AND DYSFUNCTIONAL ATHEROSCLEROTIC ENDOTHELIUM
One of the most important properties of dysfunctional endothelium is enhanced permeability, manifested in part by transport of LDL into the vessel wall.47 These lipids may be modified by the endothelium. The most important modification appears to be oxidation.48 Oxidized LDL is toxic to endothelial cells (EC) and also acts as an activator of SMC and macrophages.49,50 and 51 Oxidized LDL may also stimulate tissue factor synthesis in SMC, EC, and macrophages, thereby promoting a procoagulant state.
Another feature of dysfunctional endothelium is the up-regulation of proinflammatory molecules, including endothelial-leukocyte adhesion molecules and leukocyte chemoattractants.45,52 One of the earliest morphologic events in the development of a plaque is the adherence of circulating leukocytes, particularly monocytes, to the endothelium.27,28 and 29 Adherent monocytes subsequently migrate into the arterial wall, and along with some activated SMC, ingest modified lipids and lipoproteins and become lipid-filled foam cells, ultimately generating a visible type II fatty streak. Monocytes also differentiate into activated macrophages that secrete cytokines, growth factors, metalloproteinases, and procoagulant molecules. Among the cytokines are a variety of chemoattractants, such as MCP-1, that stimulate further leukocyte migration. Among the growth factors are platelet-derived growth factor (PDGF) and fibroblast growth factors (FGFs), which stimulate SMC to proliferate, migrate, and synthesize extracellular matrix, thereby enlarging the fatty streaks and ultimately generating large plaques (type III). More advanced lesions (type IV and Va) are characterized by necrosis of foam cells, leading to the development of a lipid-rich core surrounded by a thin cap comprised of SMC, macrophages, and matrix. The lipid-rich core also contains high levels of tissue factor,53 presumably derived from activated macrophages and SMC.
THROMBOSIS AND PLAQUE RUPTURE
Thrombosis is often the final event leading to catastrophic arterial occlusion. The steps leading to acute thrombosis are not fully understood. Plaque rupture is thought to play a major role in the majority of cases (Fig. 130-2).54,55 and 56 Plaque rupture often involves “vulnerable” plaques with large lipid cores and thin fibrous caps.57,58 Features of plaque vulnerability include the presence of an inflammatory cell infiltrate, made up of macrophages and T lymphocytes.59,60 These inflammatory cells, along with activated SMC, elaborate cytokines42 and metalloproteinases.61 The metalloproteinases are a family of enzymes (see Libby60 for review) that degrade extracellular matrix and may thus help disrupt the fibrous cap. Mechanical stress may also play an important role in plaque rupture.62,63 In about 25 percent of cases, thrombosis is associated with superficial erosion of the plaque surface rather than rupture.59,64 Erosion-related thrombosis often occurs in the setting of a severely stenotic vessel dominated by a heavily calcified “stable” plaque that is rich in proteoglycan matrix and SMC and lacks a superficial lipid core.59
FIGURE 130-2 Morphologic characteristics of an advanced atherosclerotic plaque. Hematoxylin and eosin stain (original magnification ×25) of a human left main coronary artery, showing a necrotic core (NC) and fibrous cap (FC). Arrows depict site of plaque rupture. A thrombus (T) can be seen in the lumen (L). (Courtesy Dr. John T. Fallon, Mount Sinai School of Medicine, NY.)
MODELS OF ACUTE ARTERIAL INJURY AND THROMBUS FORMATION
Models of acute arterial injury have been used for several decades to examine changes in the vessel wall associated with the development of atherosclerosis, but it is not clear to what extent the molecular events associated with acute injury reflect those occurring during chronic atherosclerosis. The development of percutaneous transluminal coronary angioplasty (PTCA), and more recently coronary artery stenting, to treat CAD has stimulated interest in arterial injury models, because they may reflect events associated with these procedures. In particular, the development of intimal hyperplasia in response to injury is thought to be an important contributor to restenosis after angioplasty and stenting.
Thrombus formation is commonly associated with acute arterial injury induced by PTCA65 and stenting.66 Although acute thrombosis can result in rapid and total occlusion of the vessel lumen, it can largely be prevented by the use of platelet inhibitors and anticoagulants. Thrombosis is also a common feature of many animal models of arterial injury. When the arterial endothelium is denuded, circulating platelets rapidly adhere to the surface, in part through the interaction between von Willebrand factor and glycoprotein (Gp)Ib (reviewed in Shafer67). Collagen and thrombin stimulate platelet activation, causing the release of arachidonic acid and the subsequent formation of thromboxane A2. Adenosine diphosphate (ADP) is secreted by activated platelets and induces further platelet activation. This results in conformational changes in glycoprotein IIb/IIIa and platelet aggregation. Additional thrombin is generated on the platelet surface, leading to fibrin deposition.
The presence and extent of fibrin deposition varies with the degree of injury (superficial or deep), the type of vessel (carotid, femoral, aorta, or coronary), the state of the vessel prior to injury (normal, cholesterol fed, previously injured), and the species. In the pig carotid balloon injury model,68,69 superficial injury, defined as endothelial denudation and no medial injury, is associated with platelet deposition but no fibrin generation. Deeper injury, defined by the presence of a medial tear, results in marked platelet accumulation and fibrin generation.
Balloon injury to normal rodent arteries is associated with platelet deposition without fibrin, even when medial smooth muscle injury is present.70,71,72,73 and 74 Platelet-fibrin microthrombi are found when previously injured arteries are subjected to a second injury.70,71,73,75,76 Treatment of these doubly injured rabbits with intravenous heparin reduces platelet accumulation by approximately 50 percent,71 suggesting that activation of the coagulation cascade may be involved.
MOLECULAR BASIS OF THE ATHEROTHROMBOTIC STATE
A number of molecules have been implicated in the development of the athero-thrombotic state. Some of these will be discussed in detail in the following sections.
TF is a low-molecular-weight transmembrane protein that initiates the extrinsic clotting cascade and is considered the major initiator of coagulation and hemostasis77,78 and 79 (see Chap. 112). TF was first identified as a component of human atherosclerotic plaques in 197280 and currently is considered the major initiator of thrombosis associated with acute coronary syndromes.
TF IN THE NORMAL ARTERIAL WALL
Although EC, SMC, macrophages, and fibroblasts synthesize TF, its distribution in the normal arterial wall is not uniform. TF mRNA and antigen are abundant in the adventitia of normal arteries,81,82 but they are minimal in normal intima and media. The constitutive expression of TF in the adventitia allows for rapid hemostasis in the event of external injury to the blood vessel and presumably evolved to prevent hemorrhage. In contrast, the expression of active TF on the luminal surface could be potentially catastrophic by initiating intraarterial thrombosis.
TF IN ATHEROSCLEROTIC PLAQUES
TF antigen has been detected in all cellular elements comprising the atherosclerotic plaque (see Fig. 130-3).53,82,83,84,85 and 86 TF is most abundant in the foam cells, macrophages, and intimal SMC located in the fibrous cap and tissues surrounding the lipid-rich necrotic core. TF antigen is also present in the medial SMC and EC overlying the plaque. TF antigen is also abundant in the extracellular matrix of the intima and within the necrotic core.53,86
FIGURE 130-3 Expression of tissue factor in a human atherosclerotic plaque. Human coronary artery stained with an antibody to tissue factor. Staining is most prominent in the necrotic core (between arrows). Original magnification ×25. (Courtesy Dr. John T. Fallon, Mount Sinai School of Medicine, NY.)
TF activity has been detected in 90 percent of specimens from directional coronary atherectomies84 and may be attenuated by the presence of tissue factor pathway inhibitor (TFPI).87 In studies employing an ex vivo perfusion system, the lipid rich necrotic core, an abundant source of TF, was found to be the most thrombogenic component of the plaque.88,89 Macrophages and intimal SMC are the most likely source of the TF found in the core. This TF may derive from cell debris, may be released during apoptosis,90 or may be shed from the plasma membrane of activated healthy cells.91 Plaque rupture may thus expose active TF to circulating blood, leading to acute thrombosis.
TF IN ANIMAL MODELS OF ARTERIAL INJURY
TF mRNA and activity are induced in the media as an early event (1 to 2 h) after arterial balloon injury in animals,92,93,94 and 95 returning to baseline levels after several days. However, TF antigen subsequently accumulates throughout the developing neointima in these animal models.53
Animal models of injury to normal arteries are not often associated with the deposition of fibrin or the generation of thrombi. This suggests that the induction of TF mRNA and protein in the arterial wall is not sufficient to establish arterial thrombosis. The presence of an intact internal elastic lamina separating the media from the lumen, the rapid accumulation of platelets on the luminal surface, and the rapid secretion of matrix by injured SMC may effectively prevent newly synthesized medial TF from coming into contact with circulating blood and initiating coagulation. In addition, the TF antigen and activity identified in the media may be intracellular or encrypted on the cell surface (discussed in detail below) and therefore ineffective in initiating thrombosis. TF exposed on the cell surface may also rapidly associate with TFPI or other inhibitors. Sequential arterial injury is more frequently associated with fibrin deposition and mural thrombosis.70,71,73,75 This may be due in part to the immediate exposure of intimal TF.
A number of animal studies93,96,97,98,99 and 100 have provided evidence that TF also plays a role in intimal hyperplasia. Studies using inhibitors of TF activity have also provided evidence that TF expression is critical to the development of platelet-fibrin thrombi after sequential arterial injury.75,76
CIRCULATING TF AND THROMBOSIS
TF is present in whole blood and plasma.101,102,103 and 104 Plasma TF levels are elevated in patients with sickle cell disease,103 disseminated intravascular coagulation,101 and acute MI.102 Circulating TF may play a primary role in the initiation or propagation of arterial thrombosis.104 Thrombi that form on normal porcine arterial media and on collagen-coated glass slides perfused for 5 min with native human blood contain TF antigen, and antibodies against TF markedly reduce thrombus formation on both surfaces. TF antigen is most abundant in membrane vesicles that cluster near the surface of platelets. Thus circulating TF may adhere to exposed surfaces and may act alone or in concert with TF located in the injured vessel wall to propagate arterial thrombosis. The source of this circulating TF is unknown, but it is likely that it derives from blood leukocytes or endothelial cells.
REGULATION OF TF BY CELLS OF THE ARTERIAL WALL
In most models of acute arterial injury, the endothelial is denuded, and SMC are the most likely source of TF activity. In models in which injury is produced on a substrate of atherosclerosis, macrophages rapidly accumulate in the intima and media and thus provide a second source of TF. In established atherosclerotic plaques, macrophages appear to be the most abundant source of TF, followed by intimal SMC, and to a much lesser degree medial SMC and regenerating endothelium.
TF is a member of the class of “immediate early” genes, which are expressed at low levels in quiescent cells and rapidly induced by serum and growth factors.105 Under most circumstances, the induction of TF occurs principally at the level of transcription, although increases in TF mRNA stability are also partly responsible (reviewed in Edgington and coworkers77). In addition to its regulation by serum and growth factors, TF is also induced by a variety of cytokines, endotoxin lipopolysaccharide (LPS), antigen-antibody complexes, lymphocyte products, and lipoproteins (see Table 130-3). Many of these agents are found in abundance in atherosclerotic plaques and in the injured arterial wall.
TABLE 130-3 ACTIVATORS AND INHIBITORS OF TISSUE FACTOR SYNTHESIS IN CELLS OF THE ARTERIAL WALL
TF is induced in EC and monocytes by modified and oxidized forms of LDL.106,107 This raises the possibility that hypercholesterolemia may directly promote thrombosis, even at an early stage in plaque development. TF is also induced during monocyte-macrophage differentiation in cell culture.108 The differentiation of monocytes to macrophages is an early event in the development of atherosclerotic lesions and occurs concomitantly with migration of monocytes into the arterial wall. The induction of TF by thrombin in SMC and EC109,110 and 111 is also intriguing, because thrombin is an end-product of TF activation. Thus, thrombin may be part of a positive feedback loop, helping to perpetuate a procoagulant state. TF is also induced by laminar shear stress in cultured EC and fibroblasts.112,113
Mammalian TF promoter regions share striking sequence similarities, suggesting that the mechanism of TF gene regulation is highly conserved.114,115,116 and 117 Human TF gene regulation involves several elements, working either cooperatively or singly (reviewed in Mackman118). Basal TF gene expression is regulated by a series of Sp1 sites. Induction of TF by growth factors and cytokines in EC and monocytes is dependent upon two AP-1 sites and an NFkB-site. These sites have been implicated in the regulation of many genes by growth factors, cytokines, and mediators of inflammation. TF transcription thus appears to be part of an extensive genetic program induced by processes such as growth, inflammation, and wound healing.
TF EXPRESSION ON CELL SURFACES
Under virtually all culture conditions, the induction of TF mRNA is accompanied by the accumulation of TF protein and an increase in procoagulant activity. A critical determinant of whether TF expression in atherosclerotic or injured vessels leads to a procoagulant state is whether the protein is present in an active state and is accessible to the circulation. Studies employing monolayers of SMC, EC, fibroblasts, and macrophages have found that, although TF protein is present on the cell surface, the majority of surface TF is not active.91,111,119,120,121,122,123,124 and 125 This “encrypted” or “latent” TF can be activated by processes that alter the structure or phospholipid composition of the cell membrane or cause cell lysis. It is likely that much of the TF present in cells of the arterial wall or atherosclerotic plaque is similarly encrypted or intracellular. Thus, in addition to inducing de novo TF synthesis, arterial injury and plaque rupture may convert encrypted TF already present in the arterial wall into active TF. Release of intracellular TF as a consequence of cell necrosis or apoptosis may also be important in generating a procoagulant state within the arterial wall.
TF IN CELL-DERIVED MICROPARTICLES
A substantial amount of TF antigen in the atherosclerotic plaque appears to be located in the extracellular matrix or in the lipid-rich necrotic core. Cultured cells can release TF into the culture medium in microparticles or small vesicles.90,91,126,127 These particles presumably bud from the cell surface as a normal consequence of cellular metabolism, rather than as a consequence of necrosis or apoptosis. TF-containing microparticles may be an important source of procoagulant activity in the arterial wall.
TISSUE FACTOR PATHWAY INHIBITOR
TFPI is an endogenous Kunitz-type proteinase inhibitor that directly inhibits activated factor X and, in a factor Xa-dependent fashion, produces feedback inhibition of the factor VIIa/TF catalytic complex (reviewed in Broze128 and Mann and colleagues129 and Chap. 113). The second Kunitz domain inhibits factor Xa, whereas the first Kunitz domain inhibits factor VIIa in the TF-factor VIIa complex. In addition to attenuating TF activity, TFPI may directly inhibit SMC proliferation.130
TFPI is made predominantly by EC,131,132 although SMC may provide a second source.133 TFPI is highly bound to lipoproteins, particularly LDL, but is rapidly released by heparin and other negatively charged ions. Circulating TFPI, normally found at a concentration of 1 to 2 nM, probably modulates TF activity. Because lysophosphatidylcholine (LPC), a component of oxidized LDL, has been shown to decrease levels of TFPI in EC,134 LPC accumulating in the atherosclerotic vascular wall may suppress TFPI synthesis, attenuating the antithrombotic properties of the endothelium.
Sixty percent of TFPI-deficient (TFPI(K1)–/–) mice die of yolk sac hemorrhage between embryonic days 9.5 and 11.5.135 Animals that progress beyond embryonic day 11.5 develop normally but die in late gestation of hemorrhage, particularly in the central nervous system. These animals exhibit intravascular thrombosis, suggesting that the hemorrhage is a consequence of a consumptive coagulopathy consistent with unregulated TF-factor VIIa activity.
TFPI antigen and mRNA have been detected in the adventitia of normal arteries.136 Low levels of TFPI mRNA have also been detected in medial SMC,136 whereas TFPI antigen has been found in medial SMC and intimal endothelium of normal human coronary arteries.133 In contrast, high levels of TFPI antigen and mRNA have been found in EC, SMC within the fibrous cap, and macrophages within the shoulder region of human carotid endarterectomy specimens and in early fatty streaks of hypercholesterolemic rabbits.87 Areas rich in TFPI also stain prominently for TF antigen.
In animal models, TFPI treatment has been shown to attenuate intimal hyperplasia and stenosis after balloon injury98,100 and to prevent thrombotic arterial reocclusion after tPA-mediated thrombolysis.137 The role of exogenous TFPI in treating human disease remains to be determined.
THE FIBRINOLYTIC SYSTEM: PLASMINOGEN ACTIVATORS
The fibrinolytic system is thought to play an important role in offsetting the effects of increased TF expression in the arterial wall. This is underscored by the success of activators of fibrinolysis in revascularization in the setting of acute MI (see below). A general scheme of the fibrinolytic system is shown in Chap. 116. Fibrinolysis requires the generation of plasmin from plasminogen, an inactive proenzyme. The active plasmin degrades fibrin, as well as other extracellular matrix proteins.
Plasminogen activators (PAs) convert plasminogen to plasmin. Plasmin cleaves fibrin, thus acting as an endogenous thrombolytic agent. Two types of plasminogen activator have been identified, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). EC of the normal arterial wall secrete tPA, but little or no uPA.138,139,140,141 and 142 Low levels of tPA mRNA and antigen have also been detected in SMC of normal arteries.142
PLASMINOGEN ACTIVATORS IN ATHEROSCLEROTIC PLAQUES
The secretion of tPA by normal EC is thought to be important in maintaining an antithrombotic surface, but experimental data are conflicting regarding PAs in atherosclerotic lesions.142,143,144,145,146 and 147 PA activity may be modulated by the presence of plasminogen activator inhibitor-1 (PAI-1).
PLASMINOGEN ACTIVATORS IN ARTERIAL INJURY
In animal models, after balloon arterial injury, uPA activity in carotid arteries rapidly increases, reaching a maximum between 16 and 24 h, whereas tPA activity appears at 3 days148; uPA and tPA mRNA increase steadily, reaching a maximum at 7 days. The induction of PAs, particularly uPA, may prevent fibrin accumulation. It remains to be determined whether a similar induction of PAs occurs after human coronary angioplasty.
OTHER ROLES FOR PAs IN ATHEROSCLEROSIS
The expression of PAs in atherosclerotic and injured vessels may serve functions other than fibrinolysis. Plasmin has been shown to activate latent cytokines, such as transforming growth factor beta (TGF-b) and basic FGF.149,150 The activation of TGF-b by plasmin has been implicated in the suppression of SMC proliferation151 and migration152 in cell culture. Apo(a) overexpressing mice display decreased plasminogen activation and increased atherosclerosis.153 It is thought that this is in part due to the ability of lipoprotein(a) to inhibit plasmin generation and therefore to inhibit TGF-b.
Plasmin also activates metalloproteinases, such as collagenase and stromelysin,154 which may serve to promote SMC migration and proliferation. In the rat carotid artery injury model, most of the induced tPA is present in the media before the SMC migrated into the intima.148 Tranexamic acid, a synthetic inhibitor of plasmin activity, reduces SMC migration by 73 percent after arterial balloon injury,155 suggesting that in this model the effect of plasmin in promoting migration may be more important than its effect on TGF-b–mediated growth suppression. In contrast, continuous infusion of tPA for 7 days causes an 80 percent decrease in intimal hyperplasia in hypercholesterolemic animals subjected to balloon injury of the common iliac artery.156 The administration of exogenous tPA may therefore have a significantly different effect on the arterial wall than that of endogenously regulated PAs.
PLASMINOGEN ACTIVATOR INHIBITOR 1
Plasminogen activator inhibitor 1 is the major physiologic inhibitor of tPA and uPA.157 PAI-1 is found in the circulation largely in association with platelets and to a lesser extent in plasma.158 Plasma PAI-1 is bound to vitronectin,159 and its level displays a circadian rhythm, with a peak in the morning and a trough in the evening, inverse to that of tPA.160 Higher PAI-1 levels are seen with increases in age,161 blood pressure, triglyceride levels, and body mass162; the levels correlate with insulin resistance.163 PAI-1 binds to fibrin and forms a stable complex with tPA or uPA.164 This inhibits plasmin activation and protects the thrombus from lysis. PAI-1 may also limit the efficacy of exogenous thrombolytic agents.165,166
Increased PAI-1 levels and/or reduced fibrinolysis have been found in patients with coronary artery disease (reviewed in Prisco and colleagues167), angina,168,169 and 170 and MI.171,172 and 173 Increased plasma PAI-1 activity has also been found in patients with stroke174 and carotid atherosclerosis.175 Increased circulating PAI-1 has also been shown to correlate with decreased patency of coronary arteries after thrombolytic therapy for acute MI.173 In contrast, decreased levels of PAI-1 activity after PTCA have been associated with reduced risk of restenosis.176
EXPRESSION OF PAI-1 IN ATHEROSCLEROTIC PLAQUES
There is little PAI-1 in normal vessels,157 but significant amounts are present in all three cellular components of atherosclerotic plaques: SMC, EC, and macrophages.157,177 Highest levels are detected in SMC and macrophages around the necrotic core.147,178,179 PAI-1 colocalizes in human atherosclerotic coronary arteries with other components of the plasminogen activator system, including tPA, uPA, and uPA receptor (uPAR). However, levels of PAI-1 appear to be substantially higher.147,180,181 and 182
In addition to its presence in atherosclerotic plaques, PAI-1 has also been identified in extracts of thrombi. Levels of PAI-1 antigen in these thrombi are substantially higher (as much as 2000-fold) than that found in circulating blood and also much higher than that of tPA or the tPA-PAI-1 complex.180,181,183 This is likely due to the accumulation of platelets within the thrombus.
PAI-1 IN ARTERIAL INJURY
In animal models, PAI-1 mRNA is not detectable in uninjured carotid arteries but is rapidly induced (within 3 h) by balloon arterial injury.184,185 PAI-1 induction is first detected in the adventitia, and within 24 h in the media. PAI-1 antigen and mRNA subsequently accumulate over time in neointimal SMC and EC. The induction of PAI-1 activity follows the same time course. PAI-1 is also increased in animal models of arterial thrombosis.186 PAI-1 mRNA increases in EC and macrophages juxtaposed to the thrombus and in SMC adjacent to the neointima.
CELLULAR REGULATION OF PAI-1
PAI-1 is secreted by EC, SMC, fibroblasts, macrophages, and hepatocytes.187,188 and 189 Its synthesis is upregulated in SMC and EC by cytokines (interleukin 1, TNF-a), TGF-b, basic FGF, PDGF, angiotensin II, plasminogen, and a thrombin190,191,192,193,194 and 195 a-thrombin, a potent stimulator of TF, also stimulates synthesis of PAI-1 in cultured SMC.196,197 Therefore, thrombin is part of two positive procoagulant feedback loops, potentiating the synthesis of TF and PAI-1. SMC from atherosclerotic arteries also express higher levels of PAI-1, in association with decreased levels of tPA.198
Lipoprotein(a), a risk factor for coronary artery disease, induces PAI-1 antigen, activity, and steady-state mRNA levels in EC.199 SMC and macrophages may play an important role in regulating the synthesis of PAI-1 by cultured EC.189,200 Quiescent SMC appear to inhibit PAI-1 production by EC, whereas proliferating and atherosclerotic SMC may secrete a soluble factor that stimulates PAI-1 production by EC. Differentiated macrophages also secrete a soluble factor that regulates endothelial cell PAI-1 production.
PLASMINOGEN ACTIVATOR INHIBITOR 2 (PAI-2)
A second inhibitor of PAs, PAI-2, also has been identified.201 PAI-2 is found largely as an intracellular protein. Therefore, its role in regulating thrombosis is unclear. It is possible that under conditions of cell injury, PAI-2 is released into the extracellular matrix and can contribute to inhibiting fibrinolysis (for review see Bachmann202).
RECEPTOR FOR UPA
In addition to generating plasmin, PAs may also have direct effects on the arterial wall through interactions with cell surface receptors. The uPAR is a transmembrane glycoprotein, which is thought to be critical for localizing the activity of uPA to the cell surface, accelerating plasminogen activation, delaying PAI-1 inhibition of plasminogen activation,203 and regulating the clearance of uPA.204 uPAR is expressed by cultured EC, macrophages, and SMC.205,206 The induction of uPAR in SMC is common to a number of growth agonists, including epidermal growth factor (EGF), TGFb, basic FGF, PDGF, phorbol esters, and a thrombin.206,207
uPAR expression is also upregulated at the leading edge of migrating SMC,208 EC,209 and monocytes.210 Studies suggest that uPAR may be involved in integrin-mediated cell adhesion and migration through interactions with vitronectin (reviewed in Wei and colleagues211) and the Mac-1 receptor (CD11b/CD18).212,213 Binding of uPA to uPAR has also been implicated in intracellular signaling via tyrosine phosphorylation,214,215 macrophage protease expression,216 growth,217,218 and chemotaxis.214,215 These effects do not require uPA enzymatic activity and can be initiated by enzymatically inactive fragments of uPA.219
uPAR expression is up-regulated in SMC and macrophages of early lesions of cholesterol-fed animals.220 The expression of uPAR is also markedly increased in the intima of human coronary atherosclerotic lesions147,207 and in SMC and macrophages of thickened saphenous vein grafts.207 The significance of increased uPAR in atherosclerosis is unknown.
TRANSGENIC MOUSE MODELS AND THE FIBRINOLYTIC SYSTEM
Studies of transgenic mice lacking one or more of the components of the fibrinolytic system have provided considerable insights into the role of plasminogen activation in mediating arterial thrombosis and intimal hyperplasia (reviewed in Carmeliet and Collen221).
In plasminogen-deficient (Plg–/–) mice, wound healing (i.e., neointima formation and reendothelialization) after vascular injury is significantly impaired.222 In Plg–/– mice, SMC accumulate at the uninjured borders but fail to migrate into the necrotic center. Proliferation of SMC is not affected. Analogous abnormalities in the healing of skin wounds were also noted.223
tPA AND uPA DEFICIENCY
uPA–/– mice, either alone or in combination with tPA–/–, have less intimal hyperplasia in response to arterial injury.224 SMC accumulate at the uninjured borders but fail to migrate into the necrotic center. Cultured uPA–/– SMC also demonstrated decreased migratory capacity. In contrast, tPA–/– mice do not exhibit altered intimal hyperplasia or SMC migration.
In PAI-1–/– mice subjected to arterial injury, wound healing is significantly enhanced, and there is increased neointima formation.225 Proliferation of SMC is not affected by PAI- 1 deficiency. However, SMC originating from the uninjured borders migrate into the necrotic center of the arterial wound more rapidly than wild-type SMC. There are no differences in reendothelialization of the injured arteries. PAI-1 deficiency in mice is associated with increased thrombolysis.226
uPAR-deficient (uPAR–/–) mice have no abnormalities of fertility, development, or hemostasis,227 and skin wounds heal normally.228 They also have no abnormalities in intimal hyperplasia or SMC migration after vascular injury.229 uPA becomes bound to the cell surface of uPAR+/+ cells, whereas it binds to the pericellular space around uPAR–/–cells. This suggests that binding of uPA to uPAR is not required to provide sufficient uPA-mediated plasmin proteolysis to allow SMC migration into the vascular lesion.
a2-antiplasmin (a2-AP) is the principal inhibitor of plasmin and plays an important role in determining clot lysis.230 a2-AP circulates in the blood at a concentration of approximately 1 µM, over 1000-fold higher than PAI-1. Small amounts have been detected in human platelets.231 a2-AP can be cross-linked to fibrin via factor XIII.232 High concentrations of PAI-1 and a2-AP have been found in extracts prepared from human thrombi.180
Evidence links elevated levels of fibrinogen with coronary atherosclerosis and ischemic vascular events. Fibrinogen is synthesized in the liver and circulates at a concentration of 200 to 400 mg/dl. Increased levels of fibrinogen correlate positively with most risk factors for coronary artery disease, including menopause,233 obesity,233,234 elevated levels of LDL cholesterol and lipoprotein(a),233 hypertension,235 and diabetes mellitus.236 Levels increase in patients who smoke237 and may decrease with smoking cessation.233,238 Levels also decrease with increasing levels of HDL cholesterol.233 Levels of fibrinogen have been shown to be increased in patients with stroke and MI (reviewed in Wilhelmsen239 and Kannel and colleagues240). In the Framingham Study,240 Northwick Park Heart Study,241 and Bezafibrate Infarction Prevention (BIP) Study,242 an elevated fibrinogen level was found to be an independent risk factor for MI. A meta-analysis of six prospective studies found an odds ratios for cardiovascular events for the upper versus the lowest tercile of 2.3 and strengthened the concept that fibrinogen levels are an independent variable for cardiovascular disease.243
PROTHROMBIN FRAGMENTS 1 AND 2 AND FIBRINOPEPTIDE A
Patients with UA and MI appear to have a hypercoagulable state and display increased levels of prothrombin fragments 1 and 2 and fibrinopeptide A.244,245,246 and 247 Fibrinopeptide A levels return quickly to normal, suggesting that activation may occur only during the acute thrombotic event. Levels of prothrombin fragments 1 and 2 may remain elevated for as long as 6 months,247 suggesting that some abnormality may persist after the acute event. This appears to be independent of the extent of coronary artery disease.
Homocysteine is a sulfhydryl-containing amino acid produced by demethylation of methionine. Folate and vitamin B12 are required for remethylation of homocysteine to methionine, and therefore levels of homocysteine are related inversely to levels of folate and B12. Very high levels of homocysteine were initially found in the blood of patients with homocystinuria, an autosomal recessive disease characterized by skeletal abnormalities, ocular lens dislocation, mental retardation, premature atherosclerosis, and a predisposition toward thromboembolic events.248 Most cases of homocystinuria are due to a deficiency in the enzyme, cystathionine b-synthase, which is involved in the catabolic transsulfuration of homocysteine.249,250 More moderate elevations of homocysteine appear to be an independent risk factor for coronary artery disease, peripheral vascular disease, and stroke (reviewed in Welch and Loscalzo251). In some studies, the correlation extends into the “normal” range (5–15 mmol/liter) and does not appear to have a threshold. Homocysteine levels are reduced by treatment with folic acid, alone or in combination with vitamins B6 or B12.252
Homocysteine is toxic to cultured EC and causes endothelial damage and desquamation in animal models.253,254 and 255 The effects of homocysteine may in part be due to its oxidation and the formation of superoxide and hydrogen peroxide.256 Homocysteine has numerous effects on endothelial and platelet function that may promote a prothrombotic state. These include an increase in platelet consumption,257 inactivation of protein C,258 a decrease in prostacyclin synthesis and an increase in the synthesis of thromboxane A2.259,260 Homocysteine also causes alterations in von Willebrand factor secretion,261 increased factor V262 and TF expression,263 inhibition of thrombomodulin264 and heparan sulfate expression,265 and modulation of binding of tPA to EC.266 Homocysteine enhances the binding of lipoprotein(a) to fibrin267 and thus may potentiate the thrombotic properties of lipoprotein(a).268,269 and 270
Lipoprotein(a) consists of an LDL particle complexed with apolipoprotein(a).271 Lipoprotein(a) is synthesized in the liver and circulates in the blood at concentrations ranging from 1 mg/dl to 100 mg/dl, but usually is less than 20 mg/dl. Levels correlate with those of LDL cholesterol.272 Higher levels are present at menopause and in patients with diabetes mellitus and acute MI.272,273 High levels of lipoprotein(a) have been found in patients with familial hypercholesterolemia274 and in siblings and offspring of patients with early coronary artery disease.275 Several large studies have found that lipoprotein(a) is an independent risk factor for serious cardiovascular events, including MI and death.276,277,278 and 279 Other studies, however, have failed to confirm this.280,281 Lipoprotein(a) has also been associated with an increased incidence of coronary artery disease in Asian populations282 but not in American blacks.283
Several mechanisms have been proposed to explain the relationship between lipoprotein(a), atherosclerosis and thrombosis (reviewed in Harpel284 and Hajjar and Nachman285). Lipoprotein(a) has been found in atherosclerotic plaques.286,287 Lipoprotein(a) displaces plasminogen from sites on fibrin and fibrinogen and inhibits plasminogen activation by streptokinase (SK) and tPA.288 Lipoprotein(a) may similarly inhibit endogenous fibrinolytic activity.289 Lipoprotein(a) also increases the release of PAI-1 and down-regulates plasmin generation in EC.199 Lipoprotein(a) may enhance the delivery of LDL cholesterol to the vessel wall290 and thus promotes foam cell development. High levels of lipoprotein(a) may also interfere with activation of latent growth factors, such as TGFb, which may be important in regulating SMC proliferation.
TREATMENT OF ACUTE CORONARY SYNDROMES
Guidelines for the treatment of stable angina can be found in a document prepared by the task force of the European society of cardiology.291 Treatment of unstable angina includes bed rest, supplemental O2, and pain management. Nitrates remain the choice for the immediate relief of angina.20,292,293 However, tolerance can develop within 24 h.294 It is important to note that “rebound” angina and even MI can occur after abrupt cessation of nitrates.293 Although nitrates are highly effective for pain management, they have not been shown to reduce the incidence of MI or death in UA. b-blockers have also been shown to be effective in relieving symptoms and in reducing the incidence of MI in patients with UA (reviewed in Yusuf and coworkers295). In view of their beneficial effect on secondary prevention of MI and sudden death, b-blockers are usually continued indefinitely.
Although aspirin may have limited effects on anginal pain, several large trials have demonstrated that aspirin prevents MI and death in patients with UA by as much as 50 percent.14,296,297,298 and 299 Aspirin, 325 mg, is thus given immediately to most patients with UA or suspected MI and continued indefinitely at 81 mg/day or more.
Intravenous heparin, most often given as a 5000-unit bolus every 6 h or as a bolus followed by a continuous infusion, is one of the preferred treatment modalities for UA.297,298,300,301 and 302 In some studies, heparin has been shown to be effective in relieving angina.297,302 Heparin has also been shown to reduce death and MI as compared to placebo,300 but it is not clear whether heparin alone is more or less effective than aspirin. Several studies have suggested that the combination of heparin and aspirin is most beneficial.298,303,304 Subcutaneous heparin has also been shown to be effective in reducing angina and ischemia.297
Low-molecular-weight heparins have been proposed as an alternative to standard heparin because they are easier to administer, and there is no need to monitor therapy. Comparisons with standard heparin are conflicting, with some studies demonstrating improved efficacy for low-molecular-weight heparin,304,305 whereas others suggest no difference.306 In these studies, most patients have also been treated with aspirin.
Although oral anticoagulation has little place in the acute treatment of UA, it may reduce the incidence of significant cardiac events in the longer term.299,307 Although the ATACS study suggested a possible benefit of the combination of low-dose warfarin and aspirin at 12 weeks in patients with UA, the much larger Coumadin Aspirin Reinfarction Study (CARS) study, which examined patients after MI, failed to show such benefit.308
Despite its role in the treatment of patients with acute MI, thrombolytic therapy does not appear to benefit patients with UA and may in fact paradoxically increase the incidence of MI.309,310,311,312,313 and 314
Abciximab, a monoclonal antibody fragment to the platelet glycoprotein IIb/IIIa receptor has been evaluated in high-risk patients (e.g., those with UA, recent MI, or high-risk angiographic lesions) undergoing angioplasty with or without stent placement315,316,317 and 318 and was found to produce significant decreases in short- and long-term clinical events. The CAPTURE trial, which focused on patients with UA, also showed a significant benefit in clinical outcomes with abciximab treatment, even before percutaneous coronary intervention.319
Small molecule antagonists of glycoprotein IIb/IIIa (tirofiban, integrilin, lamifiban) have also been studied and been found safe and efficacious in the treatment of UA when combined with heparin.320,321,322,323,324 and 325
Treatment of UA patients with hirudin, an antithrombin isolated from the leech, results in lower rates of death, nonfatal MI, or refractory angina as compared to heparin.326,327 and 328 Hirulog, a synthetic antithrombin peptide has also been shown to control anginal symptoms329 and to reduce the incidence of death and MI330 in patients with UA. Whereas hirudin has been found to be more effective than heparin in reducing serious events after angioplasty in patients with UA,331 hirulog has failed to show a similar benefit.332
In many centers, intervention with PTCA and, when appropriate, stent placement, is the treatment of choice for UA, with an initial success rate of greater than 90 percent. Complication rates of interventions are high, however, and include a greater than 5 percent incidence of MI, a greater than 5 percent incidence of emergency bypass surgery, and a higher restenosis rate.333,334,335 and 336 Also of note is a higher rate of acute closure, often successfully treated with thrombolytic agents.337,338 The timing of angioplasty remains controversial, with some studies supporting the use of heparin or aspirin for 24 to 48 h prior to PTCA,339 and others showing no benefit by waiting.340 Prior to the advent of PTCA, bypass surgery was frequently employed for the treatment of patients with UA refractory to medical treatment.341 Because of the relatively high 1-year mortality in patients with UA (often approaching 20 percent),342,343 bypass surgery was also widely employed after initial medical stabilization. Because of the predilection of many centers for early angiography and PTCA in patients with UA, bypass surgery in the acute setting has been largely relegated to failed PTCA or for patients with left main or triple vessel disease. Bypass surgery after medical stabilization continues to be the procedure of choice in patients with severe disease.
Initial treatment of acute MI includes careful monitoring, supplemental O2, and management of pain with morphine sulfate. Based upon its beneficial effects on mortality in several large trials,13,14,296,297 aspirin, 325 mg per day, is given immediately upon diagnosis and is continued indefinitely at a dose of at least 81 mg/day. Nitrates are effective for the treatment of peri- and post-MI angina. Although early studies of nitrates in acute MI suggested a significant reduction in mortality,344 recent large-scale trials have failed to confirm these benefits.345,346
Thrombolysis is the cornerstone of reperfusion therapy for acute MI and is considered in all patients with ST segment elevation who present within 12 h from the onset of symptoms. Virtually all studies have shown a significant reduction in mortality with pooled data from over 60,000 patients demonstrating an overall reduction of 18 percent.12,13,347,348 There is an inverse relationship between the time to onset of treatment and the survival benefit, with patients treated in the first hour having the highest benefit349 and those treated after 12 h having none.350,351 Absolute contraindications for thrombolytic therapy are active bleeding and recent stroke, trauma, or major surgery. Relative contraindications are severe hypertension (>180/110 mm Hg), previous cerebrovascular history, prior gastrointestinal hemorrhage, active menstruation, pregnancy, prolonged cardiopulmonary resuscitation, recent surgery and recent noncompressible vascular puncture, or ongoing warfarin therapy.
Several large trials have examined the effects of different thrombolytic regimens on mortality. The GISSI-2 trial352 found no significant difference in the 30-day mortality of 20,749 patients randomized to t-PA or SK. The ISIS-3 trial found no difference in mortality among 41,299 patients randomized to t-PA, streptokinase, or anistreplase.353 In contrast, GUSTO-I, which evaluated 41,021 patients,354 found that accelerated alteplase t-PA, administered over 90 min with intravenous heparin, reduced 30-day mortality by 15 percent (1 percent absolute mortality benefit) as compared to streptokinase with intravenous or subcutaneous heparin, or the combination of t-PA and streptokinase with intravenous heparin. The differences correlated with earlier complete infarct vessel patency and were maintained at 1 year of follow-up.354,355 Based upon this study, t-PA is used in more than 75 percent of patients treated in the United States.
In centers that can provide short transit times to the cardiac catheterization laboratory, PTCA has been used as an alternative to thrombolysis. PTCA is also used as a “rescue” for unsuccessful thrombolysis, particularly in patients with large MIs. Rescue PTCA has been associated with a decrease in mortality and improvement in left ventricular function, particularly in patients treated within 2 h of unsuccessful thrombolysis.356,357,358 and 359 In contrast, PTCA performed immediately after successful thrombolysis is associated with a higher mortality, a more frequent need for emergency bypass surgery, and no improvement in left ventricular function.360,361 and 362 The experience with stenting for acute MI has shown a significant reduction in death, reinfarction, or reintervention as compared with balloon dilatation alone.363,364 and 365 Because of the success of thrombolysis, the use of bypass surgery in acute MI is limited.
TREATMENT OF THE POST-MI PATIENT
After the initial treatment of acute MI, attention focuses on “secondary” prevention. This includes aggressive risk factor modification, such as cessation of smoking, decreasing LDL cholesterol (with diet or lipid-lowering agents), weight reduction, and regular physical activity. Several pharmacologic interventions are also routinely employed.
b-blockers remain a cornerstone of post-MI treatment.344,366,367 and 368 Angiotensin converting enzyme inhibitors have been shown to increase survival, reduce the incidence of heart failure, reduce the incidence of reinfarction, and decrease the need for revascularization in patients with acute MI and left ventricular dysfunction.345,346,369,370 and 371
A large number of clinical studies have supported the use of aspirin for secondary prevention after MI.13,372,373 and 374 Although there remains some question as to the dosage necessary to provide a maximal effect on secondary prevention, regimens of 81 to 325 mg/day of aspirin is in widespread use in post-MI patients. A meta-analysis of six randomized trials calculated a 13 percent reduction in cardiovascular mortality, a 31 percent reduction in the rate of nonfatal MI, and a 42 percent reduction in nonfatal strokes with long-term aspirin treatment.375 The CAPRIE study found a similar event rate in patients treated with clopidogrel (75 mg/day) as compared to aspirin (325 mg/day).376
Several studies of warfarin in post-MI patients showed a reduction in risk for death and reinfarction but an increase in serious bleeding episodes.299,307,377 The recent CARS study found no improvement with the combination of full-dose aspirin and low-dose warfarin when compared with aspirin alone and also suggested an increase in bleeding.308 Warfarin has been associated with decreased risk for embolic events in patients with echocardiographic evidence of left ventricular thrombus.378,379 The use of warfarin after MI is limited largely to patients with this complication.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn