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J Am Coll Cardiol, 2003; 41:7-14
© 2003 by the American College of Cardiology Foundation
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Pathogenetic concepts of acute coronary syndromes

Roberto Corti, MD*, Valentin Fuster, MD, PhD, FACC*,* and Juan Jose Badimon, PhD, FACC*

* Zena and Michael A. Wiener Cardiovascular Institute, The Mount Sinai School of Medicine, New York, New York, USA

Manuscript received May 7, 2002; accepted August 4, 2002.

* Reprint requests and correspondence: Dr. Valentin Fuster, Mount Sinai School of Medicine, Box 1030, New York, New York 10029 USA.
valentin.fuster{at}mssm.edu


   Abstract
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 Abstract
Initiation of atherothrombotic...
 References
 
The propensity of plaque to disrupt is a major determinant of future ischemic events. Although they are distinct from one another, the atherosclerotic and thrombotic processes appear to be interdependent and may be integrated under the term "atherothrombosis." It is now clear that plaque composition, rather than the percent stenosis, is a major determinant of plaque vulnerability. Plaque disruption seems to depend on both passive and active phenomena and is not purely mechanical. Inflammation (activation of monocytes/macrophages) is a major determinant of both plaque vulnerability and thrombogenicity as they relate to plaque disruption. In one-third of acute coronary syndromes, there is, however, no plaque disruption but only superficial erosion of a markedly stenotic, fibrotic plaque. In these cases, thrombus formation may be exacerbated by a hyperthrombogenic state present in patients with certain systemic risk factors. The endothelium plays a pivotal role in vascular homeostasis and hemostasis. This dynamic organ regulates blood thrombogenicity as well as contractile, secretory, and mitogenic activities in the vessel wall. Some classic risk factors induce endothelial dysfunction by reducing the bioavailability of nitric oxide, increasing tissue endothelin-1, and activating pro-inflammatory signaling pathways. Vascular hemostasis, which is the maintenance of blood fluidity and vascular integrity, is achieved by counter-balancing the intrinsic clotting tendency of blood. As a consequence of the central role of endothelial cells in hemostatic control, a dysfunctional endothelium will generate a pro-thrombotic environment favoring development of atherosclerotic lesions and thrombotic complications.

Abbreviations and Acronyms
  ACS = acute coronary syndrome(s)
  CRP = C-reactive protein
  ET = endothelin
  ICAM = intercellular adhesion molecule
  LDL = low-density lipoprotein
  MMP = matrix metalloproteinase
  NO = nitric oxide
  PGI = prostaglandin inhibitor
  SMC = smooth muscle cell(s)
  TF = tissue factor
  TFPI = tissue factor pathway inhibitor
  TIMP = tissue inhibitor of metalloproteinases
  VCAM = vascular cell adhesion molecule

Crucial advances in the understanding of the pathogenesis of atherosclerosis have been achieved during the last two decades. The two major historical hypotheses of pathogenesis, the "incrustation" and "lipid" hypotheses, have evolved into new concepts that integrate several factors contributing to the initiation and evolution of this disease (1–4). Dysfunctional endothelium and inflammation are now known to have pivotal roles in the initiation and progression of atherosclerotic disease and are considered to be promoters of the disease (Fig. 1). The atherosclerotic and thrombotic processes appear somewhat interdependent and may therefore be integrated under the term "atherothrombosis."



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  		Figure 1 Link between cardiovascular (CV) risk factors, endothelial dysfunction, inflammation, and acute coronary syndromes. Endothelial dysfunction can be caused by many pro-inflammatory atherogenic factors (i.e., oxidative stress, low shear stress, glycation end-products, smoking, probably infections). Initially, endothelial nitric oxide synthesis is decreased, leading to impairment of endothelial-dependent vasorelaxation; this represents one of the earliest changes of atherosclerosis. Endothelial cells thereafter increase expression of adhesion molecules (VCAM, ICAM-1, and so forth), which facilitate monocyte and platelet adherence to the vessel wall through their cell-surface integrin receptors. Inflammatory cells are responsible for the release of TF, the major trigger of the coagulation cascade. ACE = angiotensin converting enzyme; CNP = c-type natriuretic peptide; ICAM-1 = intercellular adhesion molecule; MCP-1 = monocyte chemoattractant protein-1; NFk = nuclear factor kappa; PDGF = platelet-derived growth factor; PGI2 = prostaglandin; TGF = transforming growth factor; VCAM = vascular cell adhesion molecule.

 
Atherothrombosis is a systemic disease involving the intima of large- and medium-sized arteries, including the aorta, carotid, coronary, and peripheral arteries. Secondary changes may occur in the underlying media and adventitia, particularly in the more advanced stages of the disease (5). The biological processes involving the media are probably responsible for vessel wall remodeling (outward expansion) during plaque growth and for plaque disruption. Disrupted atherosclerotic plaques exhibit a higher incidence of eccentric expansion (also known as positive remodeling), larger plaque areas, and a higher incidence of disruption of the internal elastic lamina compared with non-disrupted plaques (6).

For unknown reasons, some arteries, such as the brachial and internal mammary, are highly resistant to atherothrombosis. In addition, although the epicardial coronary arteries appear to be the most susceptible, intramyocardial arteries are highly resistant to atherosclerosis.

Atherothrombotic plaques are composed mainly of connective tissue extracellular matrix (including collagen, proteoglycans, fibronectin elastic fibers), lipids (crystalline cholesterol, cholesteryl esters, phospholipids), inflammatory cells (monocyte-derived macrophages, T-lymphocytes), smooth muscle cells (SMC), thrombi, and calcium deposits (7,8). Varying proportions of these components occur in different plaques, thus giving rise to a spectrum of lesions. Post-mortem studies have revealed striking heterogeneity in plaque morphology and composition in the various vessel territories, even in the same individual.

Evidence indicates that both plaque composition and its propensity to rupture are major determinants of future ischemic events. Disruption-prone plaques in the coronary arteries, the so-called "high-risk" or "vulnerable" plaques, tend to have a thin fibrous cap, a large lipid core, and a high macrophage content (9). Acute coronary syndromes (ACS) often result from disruption of such modestly stenotic, lipid-rich, vulnerable plaques, which are not detectable by X-ray angiography, leading to thrombotic complications (10). By contrast with vulnerable plaques in the coronary artery, the disruption-prone, high-risk plaques in the carotid arteries are severely stenotic. Therefore, viewed from the more global perspective of systemic atherothrombotic disease, the term "high-risk" plaque, rather than the classic term "vulnerable" plaque (that implies only the presence of a lipid-rich core) is more appropriate for defining a disruption-prone plaque.

There is striking heterogeneity in the composition of human atherothrombotic plaques, even within the same individual. Therefore, reliable, noninvasive imaging tools that are able to detect early atherothrombotic disease in the various regions and characterize the composition of the plaques are clinically desirable (11). Such tools will improve our understanding of the pathophysiological mechanisms underlying the atherothrombotic processes and allow us to risk-stratify the disease more effectively. Also, these tools may permit optimal tailoring of treatment and allow direct monitoring of the vascular response.


   Initiation of atherothrombotic disease: the role of the endothelium
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 Abstract
 Initiation of atherothrombotic...
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The past two decades have highlighted the pivotal role of the endothelium in preserving vascular homeostasis (by controlling vasomotion) and hemostasis (by balancing pro- and anti-thrombotic properties). The endothelium, the inner layer of blood vessels, is a dynamic autocrine and paracrine organ. It regulates contractile, secretory, and mitogenic activities in the vessel wall, as well as blood thrombogenicity, by producing several locally active substances (Fig. 2).



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  		Figure 2 Pathogenesis of plaque development. Endothelial dysfunction and inflammatory processes are crucial in the initiation and progression of atherosclerotic lesions. The major goal of endothelial activity is to maintain constant hemostatic and hemorheologic conditions through a balanced production of several vasoactive and thrombotic/antithrombotic substances. Arrow = promotion; dashed line = inhibition. CAM = cell adhesion molecules; CRP = C-reactive protein; ET = endothelin; FDP = fibrin degrading products; MCP-1 = monocyte chemoattractant protein-1; M-CSF = macrophage colony-stimulating factor; MMP = metalloproteinase; NO = nitric oxide; PAI-1 = plasminogen activator inhibitor-1; PGI2 = prostaglandin; SMC = smooth muscle cells; TF = tissue factor; tPA = tissue plasminogen activator; TXA2 = thromboxane A2; VEGF = vascular endothelial growth factor. Reproduced with permission from Lippincott, Williams and Wilkins.

 
"Vascular homeostasis," defined as the ability of the vascular system to maintain normal hemorheological conditions, is guaranteed by adequate control of vasomotion through the balanced production of potent vasodilators such as nitric oxide (NO) and vasoconstrictors such as endothelin-1 (ET-1).

Chronic minimal injury to the arterial endothelium is physiological and is often the result of a disturbance in the pattern of blood flow at bending points and near bifurcations of the arterial tree (2). The endothelium responds to mechanical and chemical signals from the blood by releasing mediators that modulate vascular tone and structure, platelet function, coagulation, and monocyte adhesion (Fig. 2).

Some of the classic cardiovascular risk factors have been recognized to induce endothelial dysfunction by reducing the bioavailability of NO, increasing tissue ET-1 content (12), and activating pro-inflammatory signaling pathways such as nuclear factor kappa B (13). The nuclear factor kappa B signaling transduction pathway is an essential regulator of the transcription of a number of pro-inflammatory genes, such as those that lead to the expression of many cytokines, enzymes, and adhesion molecules (i.e., intercellular adhesion molecule 1 [ICAM-1], vascular-cell adhesion molecule 1 [VCAM-1], and E-selectin) (14). In hypercholesterolemia, for example, endothelium-dependent relaxation is impaired, while contraction and adhesion of monocytes and platelets are enhanced. However, pharmacologic correction of hyperlipidemia by statins has been shown to improve or normalize endothelial function in patients (15). Recent studies have demonstrated that patients with coronary endothelial vasomotor dysfunction, in the presence of a variety of stimuli, have an increased risk of clinical events, definitively linking these cardiovascular risk factors to atherogenesis and clinical events (16,17).

"Vascular hemostasis," defined as the ability of the vascular system to maintain blood fluidity and vascular integrity, is achieved by counter-balancing the intrinsic clotting tendency of the blood (Fig. 2). Von Willebrand factor is one protein involved in the clotting tendency of the blood as it mediates platelet-to-platelet activity and interactions between platelets and the vessel wall (18). Both types of interaction are vital in maintaining the balance between bleeding and clotting. In physiological conditions, the normal endothelium actively supports the fluid state of flowing blood and prevents the activation of circulating cells. In this context, NO and prostaglandin are the most recognized platelet inhibitors of all the endothelial-borne agents.

Endothelial dysfunction and breaches of endothelial integrity trigger a series of biochemical and molecular reactions that serve to stop blood flow and repair the vessel wall. The first steps in repairing the vessel wall and preventing excessive blood loss are vasoconstriction, platelet adhesion, and fibrin formation at the place of the injury, which causes a hemostatic aggregate to form. Platelet aggregation is mediated through several agents, including adenosine diphosphate, thromboxane A2, and matrix metalloproteinase-2 (MMP-2). Also, the extrinsic coagulation cascade is activated through the interaction between vascular tissue factor (TF) and flowing blood, leading to the in vivo generation of thrombin, a major agonist of platelet activation and thrombin formation. Fibrin interacts with activated platelets to form a mesh structure that is indispensable for the adequate consistency and stability of the adhesive mural thrombus.

Because endothelial cells play a central role in controlling hemostasis, a dysfunctional endothelium will generate a pro-thrombotic environment favorable to the development of atherosclerotic lesions and thrombotic complications.

Atherosclerotic plaque progression.   Endothelial dysfunction is considered the precursor that initiates the atherosclerotic process and is characterized by the increased expression of adhesion molecules (e.g., selectins, VCAMs, and ICAMs) that participate in "homing" and infiltrating monocytes (3,15). The monocytes migrate into the sub-endothelium, where they transform into macrophages (Fig. 2).

This differentiation process includes the up-regulation of various receptors, including CD36 and the scavenger receptor A, that are responsible for the internalization of oxidized low-density-lipoprotein (LDL). Once they are lipid-enriched, macrophages transform into foam cells leading to the formation of fatty streaks. These activated macrophages release mitogens and chemo-attractants that perpetuate the process by recruiting additional macrophages and vascular SMC from the media into the injured media (Fig. 2). This may eventually compromise the vascular lumen. The recruited SMC and macrophages will significantly contribute to plaque growth, not only by increasing their number but also by synthesizing extracellular matrix components. The ratio between SMC and macrophages plays an important role in plaque vulnerability because of the lytic activity involved. Macrophages are able to elaborate MMPs. These enzymes contribute to plaque disruption and thrombus formation by digesting the extracellular matrix (4).

The rate of progression of atherosclerotic lesions is variable and poorly understood. It might be expected that atherogenesis and lesion progression are linear. However, coronary angiographic studies have demonstrated that progression in humans is neither linear nor predictable. An analysis of various studies unexpectedly revealed that over 75% of myocardial infarcts occur in areas supplied by mildly stenosed (<50%) coronary arteries identified in a previous angiogram (19). Nevertheless, on the basis of pathological findings, plaque development can be divided into slow or rapid progression.

Slow plaque progression
As previously discussed, endothelial dysfunction underlies slow progression by facilitating the internalization of circulating lipids and monocytes, ultimately leading to foam cell formation and release of mitogenic and growth factors. The continuing infiltration of monocytes/macrophages into plaques is partly dependent on factors such as endothelial adhesion molecules (i.e., VCAM-1), monocyte chemotactic protein-1, monocyte colony, stimulating factor, and interleukin-2 for lymphocytes. Macrophages may eventually undergo apoptotic death in what appears to be a defensive strategy to protect the vessel wall from an excess accumulation of lipoproteins. Although it is still uncertain whether apoptotic death triggers the release of MMPs, this phenomenon probably leads to the shedding of membrane microparticles, causing exposure of phosphatidylserine on the cell surface and conferring a potent procoagulant activity. The shed particles account for almost all of the TF activity present in plaque extract and may be a major contributor in the initiation of the coagulation cascade and thrombosis after plaque disruption (20). Such phenomena initiate the phase of rapid plaque growth.

Rapid plaque growth
Rapid plaque growth is thrombus-mediated. Evidence suggests that plaque rupture, subsequent thrombosis, and fibrous thrombus organization are also important in the progression of atherosclerosis in both asymptomatic patients and those with stable angina. Plaque disruption with subsequent change in plaque geometry and thrombosis results in a complicated lesion. Such a rapid change in atherosclerotic plaque geometry may result in acute occlusion or subocclusion with clinical manifestations of unstable angina or other ACS. More frequently, however, the rapid changes seem to result in a mural thrombus without evident clinical symptoms. This type of thrombus may be a main contributor to the progression of atherosclerosis. A number of local and systemic circulating factors may influence the degree and duration of thrombus deposition at the time of disruption of the coronary plaque (Table 1) (21). The thrombus may then either be partially lysed or become replaced in the process of vascular repair response (Fig. 3).


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  		Table 1 Factors Modulating Platelet-Arterial Wall Interaction

 


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  		Figure 3 Acute coronary syndromes typically derive from atherosclerotic plaque disruption. Lipid-rich lesions (A) account for 70% of acute coronary occlusions. The shoulder regions of the plaque often have a thinner fibrous cap that is highly infiltrated with macrophages and are prone to rupture. Mural thrombi on disrupted or ulcerated plaques may progress to occlusive thrombi or be partially lysed and be replaced in the process of organization by the vascular repair response (B).

 
ACS and plaque disruption
Angiographically, fairly small coronary lesions may be associated with acute progression to severe stenosis or total occlusion and may eventually account for as many as two-thirds of the patients who develop unstable angina or other ACS (19). The degree of plaque disruption (ulceration, fissure, or erosion) or substrate exposure is a key factor in determining thrombogenicity at the local arterial site. In fact, thrombogenicity of a disrupted human atherosclerotic plaque can be predicted by its content on TF activity. In an experimental setting in which disrupted human aortic plaques were exposed to flowing blood at high shear rates, the lipid core was found to be the most thrombogenic of the various plaque components. The lipid core also showed the most intense TF staining when compared with other components (22,23). Residual mural thrombus also appears to be highly thrombogenic (24).

The unpredictable and episodic progression is most probably caused by disruption of lipid-rich type IV and type V plaques with subsequent thrombus formation. This changes the plaque geometry and leads to acute or intermittent silent plaque growth or acute symptomatic, occlusive coronary syndromes (Fig. 3). Plaque disruption seems to depend on both passive and active phenomena.

Passive process—physical and structural variables
Passive plaque disruption is related to physical forces, and it occurs most frequently where the fibrous cap is weakest, that is, where it is thinnest and most heavily infiltrated by foam cells. For eccentric plaques, this is often the shoulder or between the plaque and the adjacent vessel wall. Three major factors determine the vulnerability of the fibrous cap: 1) circumferential wall stress or cap "fatigue"; 2) location, size, and consistency of the atheromatous core; and 3) blood-flow characteristics, particularly the impact of flow on the proximal aspect of the plaque (i.e., configuration and angulation of the plaque) (25).

Active process—MMPs and TF
The process of plaque disruption is, however, not purely mechanical. Inflammation, for instance, plays a pivotal role in plaque disruption. Atherectomy specimens from patients with ACS reveal areas very rich in macrophages (9), and these cells are capable of degrading extracellular matrix by secretion of proteolytic enzymes such as MMPs (collagenases, gelatinases, stromelysins, and others). These enzymes may weaken the fibrous cap and predispose it to rupture (26). Indeed, the MMPs and their co-secreted tissue inhibitors of metalloproteinases (TIMP), TIMP-1 and TIMP-2, are crucial for vascular remodeling. Certain MMPs may be particularly active in destabilizing plaques.

Tissue factor, a small-molecular-weight glycoprotein, initiates the extrinsic clotting cascade and is believed to be a major regulator of coagulation, hemostasis, and thrombosis (27). Recent studies have demonstrated an increased TF expression either directly in the coronary arteries or indirectly in the plasma of patients with unstable angina or myocardial infarction compared with patients with stable angina (20). Co-localization analysis of coronary atherectomy specimens (culprit lesions) from patients with unstable angina showed a strong relationship between TF and macrophages (28). This relationship suggests a cell-mediated thrombogenicity in patients with unstable angina and ACS. Furthermore, recent observations obtained from similar human coronary and carotid artery specimens showed that TF is often co-localized in macrophage apoptotic death and released microparticles rather than in biologically active macrophages (29). Specific inhibition of vascular TF by TF pathway inhibitor (TFPI) was associated with a significant reduction of acute thrombus formation in lipid-rich plaques (Fig. 4) (30). Interestingly, in the pig model of arterial injury, TFPI administration during percutaneous coronary angioplasty prevented acute thrombus formation without increasing the bleeding complications, and it reduced intima hyperplasia without affecting SMC growth (Fig. 5) (31). Such observations document the role of TF activity in acute arterial thrombosis after atherosclerotic plaque disruption and may lead to the development of a new therapeutic strategy in the prevention of ACS.



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  		Figure 4 Effect of the inhibition of vascular tissue factor activity by recombinant TF pathway inhibitor (rTFPI) on the thrombogenicity of human atherosclerotic lesions (30). (A) Representative immunophotograph of control. (B) rTFPI-treated human lipid-rich atherosclerotic lesions. rTFPI was associated with a significant reduction of acute thrombus formation, both platelet and fibrin(ogen) thrombus component, in human lipid-rich plaques. Reproduced with permission from Lippincott, Williams and Wilkins.

 


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  		Figure 5 Inhibition of tissue factor (TF) by TF pathway inhibitor (TFPI) reduces thrombus formation and intima hyperplasia after porcine coronary angioplasty (49). Administration of TFPI during coronary angioplasty prevented acute thrombus formation (B). Note the presence of mural thrombus (black arrow) and intramural hemorrhage (white arrow) in the control animal (A) despite similar vascular injury, as confirmed by the disruption of the internal elastic lamina and part of the media present in both A and B. Similarly, TFPI significantly reduced the proliferative response in porcine coronary arteries (D) 28 days after angioplasty as compared with control animals (C). Adapted from Roque M, et al. J Am Coll Cardiol 2000;36:2303–10 (31).

 
ACS and blood thrombogenicity
In one-third of ACS, particularly in sudden coronary death, there is no disruption of a small lipid-rich plaque but only a superficial erosion of a markedly stenotic and fibrotic plaque (32). Thrombus formation in such cases may depend on a hyperthrombogenic state triggered by systemic factors (Table 1). Indeed, systemic factors, including elevated LDL cholesterol, cigarette smoking, hyperglycemia, hemostasis, and others, are associated with increased blood thrombogenicity (5).

Cardiovascular risk factors and hyperthrombogenicity
Elevated LDL cholesterol levels have been found to increase blood thrombogenicity and growth of thrombi under defined rheology conditions (33,34). Reducing LDL cholesterol levels with statins was shown to decrease thrombus growth by approximately 20% (34). The question is, to what extent does such an antithrombotic effect—for example, with statins (documented in large prospective clinical trials)—contribute to the reduction of total vascular events, including death, coronary events, and stroke (35,36).

Smoking increases sympathetic nerve activity (37) and, therefore, catecholamine release, which may potentiate platelet activation and increase fibrinogen levels. Catecholamine-dependent effects in the circulating blood could explain not only the increase in the incidence of sudden death and acute cardiovascular events after emotional and physical stress but also the circadian distribution of these events (38).

Diabetic patients, especially those whose diabetes is poorly controlled, have increased blood thrombogenicity (39). Platelets from patients with diabetes have been shown to have increased reactivity and hyper-aggregability and expose a variety of activation-dependent adhesion proteins (40). Abnormal platelet function is reflected by increased platelet consumption and increased accumulation of platelets on the altered vessel wall.

TF pathway and hyperthrombogenicity
Recent observations indicate that the hyperthrombogenic states associated with high LDL cholesterol, cigarette smoking, and diabetes may share a common biological pathway: activation of leukocyte-platelet interactions associated with the release of TF and thrombin activation. Specifically, more leukocyte-platelet aggregates circulate in the blood of patients with diabetes mellitus. The pro-thrombotic state in diabetes is also associated with an increased expression of monocyte procoagulant activity in the presence of diabetic microalbuminuria. The increased procoagulant activity in diabetes is attributed to leukocytes, which may in part activate the TF pathway (41) and contribute to the high blood thrombogenicity in diabetic patients (40).

Recent studies have found increased levels of circulating TF antigen in patients with cardiovascular disease. Circulating TF has been associated with increased blood thrombogenicity in patients with unstable angina (42) and chronic coronary artery disease (43). Blood levels of TF have also been shown to predict outcome in patients with unstable angina (44).

As previously described, lipid-rich atherosclerotic plaques contain TF associated with macrophages within the lesion (23) and may account, in large part, for the high thrombogenicity of these lesions. Tissue factor has also been identified within thrombi formed in the coronary arteries. In addition, specific inhibition of the TF pathway by TFPI significantly reduces plaque thrombogenicity (30). The TFPI is usually expressed in the adventitial layer of large arteries, and in atherosclerotic vessels, TFPI is expressed by macrophages in focal areas in the plaque. Local production of TFPI may regulate pro-coagulant activity and thrombotic events within atherosclerotic plaques (45).

Aside from apoptotic macrophages and microparticles from atherosclerotic plaques, activated monocytes in the circulating blood seem to be a source of TF microparticles and may represent the result of activation by the previously mentioned risk factors and others, thus contributing to thrombotic events. Within the context of the possibly pro-inflammatory or pro-thrombotic effects on the circulating blood exerted by high LDL cholesterol, cigarette smoking, and diabetes, there is evolving evidence that circulating monocytes and white blood cells may be involved in TF expression and thrombogenicity (46). Indeed, the predictive value for coronary events of high levels of C-reactive protein (CRP) may be a manifestation of such systemic phenomena (47).

C-reactive protein, similar to fibrinogen, is a protein of the acute-phase response and a sensitive marker of low-grade inflammation. Increased levels of CRP have been reported to predict acute coronary events (47), and CRP seems to be a useful marker in the prediction of thrombotic events. Whether CRP reflects the inflammatory component of atherosclerotic plaques or of the circulating blood, and whether it is a surrogate marker or a biologically active element in plaque development of thrombus formation at the site of the atherosclerotic vessel, are not known (48). However, recent studies support the hypothesis that CRP is an activator of blood monocyte and vessel-wall endothelial cells (49).

Conclusions
Increasing evidence supports the centrality of the role of endothelial dysfunction in the initiation and progression of atherothrombotic disease. Inflammation is involved in plaque disruption—mainly through the production of enzymes able to digest the fibrous cap—and also in the production of TF, which is the most important modulator of blood coagulation and thrombosis. Endothelial dysfunction and the release of TF by inflammatory and apoptotic cells are essential to hemostatic control and, therefore, closely related to the thrombotic process. In addition, a pro-inflammatory effect of the circulating blood has been postulated. In this context, a treatment strategy designed to improve endothelial dysfunction and reduce inflammation at the level of the vessel wall, as well as in the circulating blood, may have important implications in the prevention of ACS. There is a need for further investigation into the effect that certain risk factors have on the activation of inflammation in the vessel wall and circulating blood, and such an investigation would probably demonstrate that TF and CRP are the key local and systemic factors in the process of atherothrombosis.


   Acknowledgments
 
The authors are grateful to Bob Guerra for his editorial assistance.


   Footnotes
 
Please refer to the Trial Appendix at the back of this supplement for the complete list of clinical trials.


   References
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