Pathogenesis of Atherosclerosis Erling Falk J. Am. Coll. Cardiol. 2006;47;C7-C12 doi:10.1016/j.jacc.2005.09.

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Journal of the American College of Cardiology 2006 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 47, No. 8 Suppl C ISSN 0735-1097/06/$32.00 doi:10.1016/j.jacc.2005.09.068

Pathogenesis of Atherosclerosis
Erling Falk, MD, PHD Aarhus, Denmark
Atherosclerosis is a multifocal, smoldering, immunoinammatory disease of medium-sized and large arteries fuelled by lipids. Endothelial cells, leukocytes, and intimal smooth muscle cells are the major players in the development of this disease. The most devastating consequences of atherosclerosis, such as heart attack and stroke, are caused by superimposed thrombosis. Therefore, the vital question is not why atherosclerosis develops but rather why atherosclerosis, after years of indolent growth, suddenly becomes complicated with luminal thrombosis. If thrombosis-prone plaques could be detected and thrombosis averted, atherosclerosis would be a much more benign disease. Approximately 76% of all fatal coronary thrombi are precipitated by plaque rupture. Plaque rupture is a more frequent cause of coronary thrombosis in men ( 80%) than in women ( 60%). Ruptured plaques are characterized by a large lipid-rich core, a thin brous cap that contains few smooth muscle cells and many macrophages, angiogenesis, adventitial inammation, and outward remodeling. Plaque rupture is the most common cause of coronary thrombosis. Ruptured plaques and, by inference, rupture-prone plaques have characteristic pathoanatomical features that might be useful for their detection in vivo by imaging. This article describes the pathogenesis of atherosclerosis, how it begets thrombosis, and the possibility to detect thrombosis-prone plaques and prevent heart attack. (J Am Coll Cardiol 2006;47:C712) 2006 by the American College of Cardiology Foundation

Atherosclerosis is by far the most frequent underlying cause of coronary artery disease, carotid artery disease, and peripheral arterial disease. Atherosclerosis alone is rarely fatal; it is thrombosis, superimposed on a ruptured or eroded atherosclerotic plaque, that precipitates the life-threatening clinical events such as acute coronary syndromes and stroke (13). Therefore, the vital question is not why atherosclerosis develops but rather why none or only few among many plaques within a given person apparently pass through a thrombosis-prone and dangerous phase during a lifetime (Fig. 1) (4). That is what it is all about; preventing the development of thrombosis-prone plaques and, if they already are there, nding and treating those who harbor them and are at high risk of loosing myocardium, brain, and/or life. This viewpoint describes the pathogenesis of atherosclerosis with this ambitious goal in mind.

atherogenicity of LDL (e.g., particle size, number, and composition) or increase the susceptibility of the arterial wall (e.g., permeability, glycation, inammation, and so on). The importance of risk factors beyond cholesterol is clearly documented by the great disparity in the expression of clinical disease among individuals with the same cholesterol level.

PROTECTIVE FACTORS
Alcohol, exercise, and high-density lipoprotein (HDL) and its major apolipoprotein, apoA-I, confer protection against diseases caused by atherothrombosis. Among other things, HDL/apoA-I prevents the atherogenic modications of LDL and promotes reverse cholesterol transport, which slows plaque progression and may induce rapid regression, documented in experimental studies and suggested by serial intravascular ultrasound examinations of patients with acute coronary syndrome (6,7).

ATHEROGENIC STIMULI
Among the many cardiovascular risk factors, elevated plasma cholesterol level is probably unique in being sufcient to drive the development of atherosclerosis, even in the absence of other known risk factors (5). If all adults had plasma cholesterol levels 150 mg/dl, symptomatic disease would be rare. The other risk factors, such as hypertension, diabetes, smoking, male gender, and possibly inammatory markers (e.g., C reactive protein, cytokines, and so on), appear to accelerate a disease driven by atherogenic lipoproteins, the rst of which being low-density lipoprotein (LDL). How they do it is uncertain, but they may either increase the
From the Department of Cardiology, Aarhus University Hospital (Skejby), Aarhus, Denmark. Supported by grants from the Danish Heart Foundation. Dr. William A. Zoghbi acted as guest editor. Manuscript received June 16, 2005; revised manuscript received September 12, 2005, accepted September 19, 2005.

SUSCEPTIBILITY
The limited ability to predict clinical disease based on risk factor scores indicates that our knowledge about the individual susceptibility to atherogenic stimuli is inadequate (8 10). Experimental studies indicate that inactivation of genes coding for monocyte chemotactic protein-1 (MCP-1), its receptor on monocyte/macrophages (CCR2), and macrophage colony-stimulating factor has profound impact on the development of atherosclerosis in otherwise identical mice (5). Such disease susceptibility factors remain to be identied in humans. However, the susceptibility to atherothrombosis differs not only among individuals with similar risk factor scores (individual susceptibility) but also among different arterial

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Abbreviations and Acronyms HDL high-density lipoprotein LDL low-density lipoprotein MCP-1 monocyte chemotactic protein-1 NOS nitric oxide synthase VCAM-1 vascular cell adhesion molecule-1

segments from the same individual (arterial susceptibility). The endothelium is very sensitive to shear stress, and local hemodynamic conditions related to branching, low and oscillating shear, and reverse ow may offer some of the explanation for the fact that the coronary arteries are much more susceptible to atherosclerosis than the internal mammary arteries (11).

CELLULAR COMPONENTS OF ATHEROSCLEROSIS

Atherosclerosis is a chronic immunoinammatory, broproliferative disease of large and medium-sized arteries fuelled by lipid (5,12,13). Endothelial cells, leukocytes, and intimal smooth muscle cells are the major players in the development of this disease. Endothelial cells. In lesion-prone areas, atherosclerotic lesions begin to develop under an intact but leaky, activated, and dysfunctional endothelium. Later, endothelial cells may vanish and de-endothelialized (denuded) areas appear over advanced lesions, with or without platelets adhering to the exposed subendothelial tissue (14). Depending on size and concentration, plasma molecules and lipoprotein particles extravasate through the leaky and defective endothelium into the subendothelial space, where potentially atherogenic lipoproteins are retained and modied (e.g., oxidized) and become cytotoxic, proinammatory, chemotaxic, and proatherogenic. The mechanisms responsible for the atherogenic modication of LDL are unknown but could include oxidation mediated by myeloperoxidase, 15lipoxygenase, and/or nitric oxide synthase (NOS) (5). Nitric oxide is a potent oxidant produced by both endothelial cells and macrophages that appears to exert both protective and atherogenic effects, depending on its source of production. Nitric oxide produced by endothelial NOS has vasodilator function and is potentially atheroprotective. In contrast, nitric oxide produced via the much higher capacity inducible NOS in macrophages, serving antimicrobial functions based on its potent oxidative properties, is potentially proatherogenic. The endothelium becomes activated by atherogenic and proinammatory stimuli, and the expression of adhesion molecules, primarily vascular cell adhesion molecule-1 (VCAM-1), are up-regulated, and monocytes and T cells are recruited. Besides VCAM-1, other adhesion molecules, such as intercellular adhesion molecule-1, E selection, and P selection, probably contribute to the recruitment of bloodborne cells to the atherosclerotic lesion (12,13). Endothelial dysfunction as assessed clinically (impaired nitric oxide-mediated vasodilation) predicts clinical events

caused by atherothrombosis, and it generally is assumed that this form of endothelial dysfunction equates with endothelial activation as described previously in which atheroprotective mechanisms are lost and atherothrombosis promoted. Regarding hard clinical end points, the anti-inammatory and antithrombotic properties of the endothelium, however, may be more important than vasodilator function (15). It is indeed thought-provoking that the mere presence of atherogenic risk factors is associated with endothelial dysfunction not only in atherosclerosis-susceptible arteries but also in arteries that are relatively resistant to atherosclerosis (e.g., the brachial artery) and even in the microcirculation. Thus, impaired endothelium-mediated vasodilation is related to atherothrombosis but not necessarily causally. Leukocytes. One of the earliest cellular responses in atherogenesis is the focal recruitment of circulating monocytes and, to a lesser extent, T lymphocytes (12,13). The persistence of this cellular response seems to underlie disease progression. B lymphocytes and plasma cells are rare in the intimal plaque but may be abundantly present in adventitia next to advanced intimal disease (16). Activated mast cells may be found both in plaque and adventitia, particularly in culprit lesions causing acute ischemic events (17). Neutrophils are rare in uncomplicated atherosclerosis but have been

Figure 1. Plaque heterogeneity within a given patient. (A) Cross section of a coronary artery cut just distal to a bifurcation. The atherosclerotic plaque to the left (circumex branch) is brotic and partly calcied, whereas the plaque to the right (marginal branch) is lipid-rich with a nonoccluding thrombus superimposed. (B) Higher magnication of the plaque-thrombus interface reveals that the brous cap over the lipid-rich core is extremely thin, inamed, and ruptured with a real defecta gapin the cap. Both arteries contain contrast medium injected postmortem. Trichrome stain, staining collagen blue and thrombus red.

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described in thrombosed coronary plaques, probably recruited as a response to plaque rupture (18). The mere adhesion to the endothelium is, of course, not enough for blood-borne cells to arrive in the lesion, transendothelial migration also is required. As to that, one or more chemokines (chemotactic cytokines) are necessary. Experimental studies indicate that the most important atherogenic chemoattractants are oxidized LDL and MCP-1 (12). Monocyte chemotactic protein-1 is a powerful chemokine and its receptor on monocyte/macrophages (CCR2) may be up-regulated enormously during plaque development, from 3,000/cell in the resting state to 60,000/cell when stimulated. Monocyte chemotactic protein-1 attracts potently both monocytes and T cells (but not neutrophils and B cells) and most likely plays a fundamental role in the recruitment of these cells. Endothelial cells, smooth muscle cells, and macrophages all contribute to overexpression of MCP-1 in atherosclerosis. Thus, once within the intima, monocyte-derived macrophages may recruit themselves by secreting MCP-1. Cytokines (e.g., interleukin-8) also may play a role in monocyte-macrophage trafcking (5). Within intima, the monocytes differentiate into macrophages and internalize the atherogenic lipoproteins via socalled scavenger receptors, of which SR-A and CD36 have been demonstrated to play quantitatively signicant roles in experimental atherosclerosis. The development of lipid-loaded macrophages containing massive amounts of cholesteryl esters (foam cells) is a hallmark of both early and late atherosclerotic lesions. With continuing supply of atherogenic lipoproteins, the macrophages eat until they die because, in contrast to the native LDL receptor, scavenger receptors are not downregulated by cellular cholesterol accumulation. The death of macrophages by apoptosis and necrosis contributes to the formation of a soft and destabilizing lipid-rich core within the plaque. On the other hand, macrophages may under appropriate conditions (low LDL and high HDL) shrink by efuxing cellular cholesterol to extracellular HDL via membrane transporters, the initial step in reverse cholesterol transport (57). Aside from their scavenger function, macrophages also possess destabilizing and thrombogenic properties by expressing matrix-degrading proteolytic enzymes (e.g., matrix metalloproteinases) and tissue factor (12). Thus, these innate protective cells initially recruited to combat cytotoxic lipids, turn into devastating friendly re during the progression of atherothrombosis. Immune activation is ongoing in atherosclerotic lesions (13,19). Although lymphocytes are not required for the development of atherosclerosis, the immune system modulates the progression of the disease. There are a number of candidate antigens in the lesion that could be responsible for immune activation, including modied LDL, heat-shock proteins, beta-2-glycoprotein I, and microbial antigens. Of these, the most extensive data support an important role for oxidized LDL, which is abundantly present in atherosclerotic plaques, where it is recognized by T cells (13,19). The up-regulated expression of the immune mediator CD40 and

its ligand CD154 by all cell types present in advanced atherosclerotic lesions promotes lesion formation in atherosclerosis-prone mice (13). Smooth muscle cells. Only endothelial cells, macrophages, and a few T cells participate in the development of the early and asymptomatic foam-cell lesion, the fatty streak. In disease progression, the immunoinammatory response is joined by a broproliferative response mediated by intimal smooth muscle cells. These cells are responsible for healing and repair after arterial injury. If the atherogenic stimuli persist over the course of years, as they often do, the reparative response may become so voluminous and dominating that lumen is lost, blood ow is reduced, and ischemia sets in (Fig. 2) (20). Nevertheless, smooth muscle cells and the collagen-rich matrix they produce do confer stability to plaques, protecting them against much more ominous consequences; plaque rupture and thrombosis (21). The smooth muscle cell is the principal connective tissueproducing cell in the normal (the soil) and diseased (atherosclerotic) intima (21). Because of the repairing and protective capabilities of smooth muscle cells, their recruitment, proliferation, and synthetic activities are considered benecial, whereas senescence, impaired function, and/or death of these cells most likely are detrimental, suggested by the local loss of smooth muscle cells where plaques tear apart (rupture). It is unknown why smooth muscle cells are lacking at rupture sites, but apoptotic cell death could play an important role (22,23).

SPECIAL FEATURES OF ATHEROSCLEROTIC PLAQUES

Lipid-rich core. Early in atherogenesis, the atherogenic lipoproteins are cleared from the intima by the scavenging macrophages, giving rise to intracellular lipid accumulation (foam cell formation). This in-principle protective function may be overwhelmed and turned into a detrimental disease-

Figure 2. Average composition of advanced coronary plaque. Pie diagram illustrating the average composition of advanced atherosclerotic plaques ( 75% stenosis by histology) in the coronary artery tree in fatal myocardial infarction (20). Hypocellular tissues (brosis, calcium, and necrosis) constitute by far the most voluminous plaque components.

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causing pathway when the foam cells die and leave the lipid behind as a soft, destabilizing, and rather inert necrotic (atheromatous) core within the plaque (Fig. 1). Atherogenic lipoproteins also may be retained and accumulate within intima without rst passing through foam cells (24). The lipid-rich atheromatous core is avascular, hypocellular, soft-like gruel, and totally devoid of supporting collagen. Its size is, of course, critical for the stability of a plaque. Cell death. During the progression of atherosclerosis, endothelial cells, macrophages, and smooth muscle cells die by apoptosis or necrosis (the former probably prevails). Disintegration of foam cells and loss of smooth muscle cells may have detrimental consequences, leading to the formation of a destabilizing lipid-rich core and a fragile and ruptureprone brous cap (22). Furthermore, apoptosis contributes dramatically to the high tissue factor activity and thrombogenicity of the lipid-rich core (25). The paradoxical observation that a plaque may growth even though cell death appears to exceed cell proliferation is probably because cell renewal is mediated by inux (recruitment) of new cells rather than local cell division. During regression of atherosclerosis induced by cholesterol lowering in animals, inammatory cells (macrophages) disappear, but their fate remains elusive. Many macrophages appear to die within the lesion, but others probably emigrate from regressive plaques (26). Calcication. Focal calcication in atherosclerotic plaques is very common and increases with age (27). The total amount of calcicationthe coronary artery calcium scoreis a genuine marker of coronary plaque burden and provides prognostic information beyond that provided by traditional risk factor scoring (28). Plaque calcication is to some extent active and controlled, resembling calcication in

bone, and both lipid and connective tissue may calcify. In coronary arteries, calcication is almost always caused by atherosclerosis; medial calcication (Mnckebergs calcinosis) is exceedingly rare. Clinical observations suggest that culprit lesions responsible for acute coronary syndromes generally are less calcied than plaques responsible for stable angina, and the pattern of plaque calcication also differs (29,30). Neovascularization and intraplaque hemorrhage. Angiogenesis is frequent in advanced atherosclerosis. It is probably a marker of ongoing disease activity and may thus characterize high-risk plaques (3134). Endothelial proliferation and sprouting usually originates from vasa vasorum in adventitia and extends through media into the base of the plaque, where neovascularization is most conspicuous. The new microvessels are fragile, are leaky, and express cellular adhesion molecules (VCAM-1, intercellular adhesion molecule-1), resulting in local extravasation of plasma proteins, erythrocytes (bleeding), and inammatory cells. Thus, angiogenesis and inammation often coexist and could mediate rapid plaque progression (3134). Regardless of the integrity of the plaque surface, extravasated erythrocytes are common in neovascularized areas, but there is no convincing evidence that these low-pressure bleedings may precipitate rupture of the plaque surface and/or acute luminal thrombosis (35). Neovascularization disappears with plaque regression induced by cholesterol lowering in animals. Vascular remodeling and luminal stenosis. During plaque development, remodeling of the artery takes place, in which the ow-limiting potential of the intimal plaque may be attenuated (expansive remodeling) or accentuated (constrictive remodeling) by reactive changes in the underlying vessel wall. Plaques assumed to be rupture-prone (so-called inamed thin-cap broatheroma) and those responsible for

Table 1. Worldwide, 1,114 (76%) of 1,460 Fatal Coronary Thrombi Were Precipitated by Plaque Rupture
Patients Hospital, Hospital, Hospital, AMI SCD Hospital, AMI Hospital, AMI Coroner, SCD Hospital, AMI Hospital, AMI Coroner, SCD Medical exam, SCD Hospital, AMI Coroner, Hospital, AMI Coroner, SCD Hospital, AMI Hospital, AMI Hospital, AMI Medical exam, SCD Total AMI SCD Age (yrs)* 58 62 66 53 67 67 65 70 63 69 61 69 48 n 19 17 40 88 91 20 76 49 32 61 83 85 20 202 291 61 100 125 1,460 Rupture 19 17 39 71 68 19 69 40 26 39 52 71 12 143 218 56 81 74 1,114 100% 100% 98% 81% 75% 95% 91% 82% 81% 64% 63% 84% 60% 71% 75% 92% 81% 59% 76% Study Chapman, 1965 Constantinides, 1966 Friedman et al., 1966 Bouch et al., 1970 Sinapius, 1972 Friedman et al., 1973 Horie et al., 1978 Falk, 1983 Tracy et al., 1985 El Fawal et al., 1987 Yutani et al., 1987 Richardson et al., 1989 van der Wal et al., 1994 Davies, 1997 Arbustini et al., 1999 Shi et al., 1999 Kojima et al., 2000 Virmani et al., 2000 Worldwide

*Mean. For details, see Falk et al. (41). not reported; AMI acute myocardial infarction; SCD

sudden coronary death.

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JACC Vol. 47, No. 8 Suppl C April 18, 2006:C712 Table 2. Features Associated With Plaque Rupture
Structural Large and soft lipid-rich core Thin and collagen-poor brous cap Cellular Lack of SMCs at rupture site Accumulation of MACRs at rupture site Function Impaired matrix synthesis (SMC-related) Increased matrix breakdown (MACR-derived MMPs) Remodeling Expansive (outward) vascular remodeling Others Adventitial inammation and neovascularization
MACR cell. macrophages; MMP matrix metalloproteinase; SMC smooth muscle

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acute coronary syndromes usually are relatively large and associated with expansive remodeling, which tends to preserve a normal lumen. In contrast, plaques responsible for stable angina usually are smaller but, nevertheless, often are associated with more severe luminal narrowing because of concomitant constrictive remodeling (36). Smoking and diabetes mellitus have been linked to constrictive remodeling but, otherwise, the reason for these different modes of remodeling is unknown. Experimental studies indicate that processes in adventitia could play a decisive role in remodeling. Plaque rupture. The term plaque rupture is used for A plaque with deep injury with a real defect or gap in the brous cap that had separated its lipid-rich atheromatous core from the owing blood, thereby exposing the thrombogenic core of the plaque (37). This is the most common cause of coronary artery thrombosis. Nonfatal thrombosis. Plaque rupture is not a rare event in the development of coronary atherosclerosis. It is particularly frequent and often multiple in acute coronary syndromes (38). Rupture of the plaque surface is followed by variable amounts of hemorrhage into the plaque and luminal thrombosis, causing sudden and rapid but often clinically silent progression of the lesion. It is probably the most important mechanism underlying the episodic (versus linear) progression of coronary lesions observed by serial angiography (39,40). Fatal thrombosis. A recent extensive review of the literature revealed that plaque rupture is responsible for 76% of all fatal heart attacks caused by coronary thrombosis worldwide (Table 1) (41). The remaining 24% are caused by plaque erosion and other less well-dened mechanisms. Plaque rupture is a more frequent cause of coronary thrombosis in men ( 80%) than in women ( 60%). Except for gender and menopause, no particular risk factors consistently have been connected with a particular type of coronary plaque or mechanism of thrombosis. Pathoanatomical features of ruptured plaques and, by inference, plaques assumed to be rupture-prone (vulnerable) are shown in Table 2, and potential targets for their detection by imaging are highlighted in Figure 3.

Fibrin and platelets. During atherogenesis, multiple sites of endothelial denudation and plaque rupture develop and heal. When subendothelial tissue is exposed, platelets adhere and brin forms. The magnitude of this thrombotic response depends on the thrombogenic stimulus; plaque rupture probably is much more thrombogenic than plaque erosion. In the pathogenesis of arterial thrombosis, platelet aggregation is responsible for the initial ow obstruction but brin formation is necessary for the subsequent stabilization of the platelet-rich thrombosis. Thus, both platelets and brin may accumulate over ruptured and eroded plaques. Contribution of bone marrow-derived cells. Bone marrowderived macrophages play a critical role in the initiation and progression of atherosclerosis. However, conventional wisdom says that endothelial cells and intimal smooth muscle cells reside within the arterial wall and proliferate, migrate, and secrete what might be needed for expedient healing and repair after injury (21). Therefore, it came as an incredible

Figure 3. Molecular and structural targets for imaging. Cross section of a coronary artery containing plaque assumed to be rupture-prone. Potential targets for imaging are highlighted. They comprise: 1) the large lipid-rich necrotic core (orange asterisk), 2) thin brous cap (blue arrows), 3) expansive remodeling (green arrow), and 4) vasa vasorum and neovascularization (red open circles).

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20. Kragel AH, Reddy SG, Wittes JT, Roberts WC. Morphometric analysis of the composition of atherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarction and in sudden coronary death. Circulation 1989;80:174756. 21. Schwartz SM, Virmani R, Rosenfeld ME. The good smooth muscle cells in atherosclerosis. Curr Atheroscler Rep 2000;2:4229. 22. Geng YJ, Libby P. Progression of atheroma: a struggle between death and procreation. Arterioscler Thromb Vasc Biol 2002;22:1370 80. 23. Kolodgie FD, Petrov A, Virmani R, et al. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation 2003;108:3134 9. 24. Guyton JR. Phospholipid hydrolytic enzymes in a cesspool of arterial intimal lipoproteins: a mechanism for atherogenic lipid accumulation. Arterioscler Thromb Vasc Biol 2001;21:884 6. 25. Tedgui A, Mallat Z. Apoptosis as a determinant of atherothrombosis. Thromb Haemost 2001;86:420 6. 26. Llodr J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ. Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci USA 2004;101:11779 84. 27. Hoffmann U, Brady TJ, Muller J. Cardiology patient page. Use of new imaging techniques to screen for coronary artery disease. Circulation 2003;108:e50 3. 28. Pletcher MJ, Tice JA, Pignone M, Browner WS. Using the coronary artery calcium score to predict coronary heart disease events: a systematic review and meta-analysis. Arch Intern Med 2004;164:128592. 29. Beckman JA, Ganz J, Creager MA, Ganz P, Kinlay S. Relationship of clinical presentation and calcication of culprit coronary artery stenoses. Arterioscler Thromb Vasc Biol 2001;21:1618 22. 30. Ehara S, Kobayashi Y, Yoshiyama M, et al. Spotty calcication typies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study. Circulation 2004;110:3424 9. 31. Barger AC, Beeuwkes R 3rd, Lainey LL, Silverman KJ. Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med 1984;310:1757. 32. Kolodgie FD, Gold HK, Burke AP, et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003;349:2316 25. 33. Virmani R, Kolodgie FD, Burke AP, et al. Atherosclerotic plaque progression and vulnerability to rupture angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005;25:205461. 34. Casscells W, Hassan K, Vaseghi MF, et al. Plaque blush, branch location, and calcication are angiographic predictors of progression of mild to moderate coronary stenoses. Am Heart J 2003;145:81320. 35. Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med 1984;310:1137 40. 36. Vink A, Schoneveld AH, Richard W, et al. Plaque burden, arterial remodeling and plaque vulnerability: determined by systemic factors? J Am Coll Cardiol 2001;38:718 23. 37. Schaar JA, Muller JE, Falk E, et al. Terminology for high-risk and vulnerable coronary artery plaques. Eur Heart J 2004;25:1077 82. 38. Falk E. Multiple culprits in acute coronary syndromes: systemic disease calling for systemic treatment. Ital Heart J 2000;1:835 8. 39. Mann J, Davies MJ. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart. 1999;82:265 8. 40. Burke AP, Kolodgie FD, Farb A, et al. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation 2001;103:934 40. 41. Falk E, Shah PK, Fuster V. Atherothrombosis and thrombosis-prone plaques. In: Fuster V, Alexander RW, ORourke RA, et al, editors. Hursts the Heart. 11th edition. New York, NY: McGraw-Hill, 2004:112339. 42. Sata M. Circulating vascular progenitor cells contribute to vascular repair, remodeling, and lesion formation. Trends Cardiovasc Med 2003;13:249 53. 43. Caplice NM, Bunch TJ, Stalboerger PG, et al. Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation. Proc Natl Acad Sci USA 2003;100: 4754 9. 44. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593 600.

surprise when experimental studies suggested that many of the healing smooth muscle cells originated in the bone marrow and were brought to the injured vessel wall with the circulating blood (42). Supportive human observations also have been published, and the challenge is to use this potential in the retardation and stabilization of atherosclerosis in humans (43,44). Mobilization of atheroprotective cells from the bone marrow and promoting their homing to thrombosis-prone plaques may be a new way to stabilize atherosclerosis against thrombosis and its devastating consequences.
Reprint requests and correspondence: Dr. Erling Falk, Department of Cardiology, Aarhus University Hospital (Skejby), Brendstrupgaardsvej, DK-8200 Aarhus N, Denmark. E-mail: erling.falk@ki.au.dk.

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Pathogenesis of Atherosclerosis Erling Falk J. Am. Coll. Cardiol. 2006;47;C7-C12 doi:10.1016/j.jacc.2005.09.068 This information is current as of November 1, 2011
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