Journal of the American College of Cardiology Vol. 47, No.

8 Suppl C
© 2006 by the American College of Cardiology Foundation ISSN 0735-1097/06/$32.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2005.09.068

Pathogenesis of Atherosclerosis
Erling Falk, MD, PHD
Aarhus, Denmark
Atherosclerosis is a multifocal, smoldering, immunoinflammatory 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, athero-
sclerosis 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 fibrous cap that contains few smooth muscle
cells and many macrophages, angiogenesis, adventitial inflammation, and outward remodel-
ing. 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:C7–12) © 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 pe-
ripheral 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
(1–3). Therefore, the vital question is not why atheroscle-
rosis 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, finding 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.
ATHEROGENIC STIMULI
Among the many cardiovascular risk factors, elevated
plasma cholesterol level is probably unique in being suffi-
cient 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 inflammatory
markers (e.g., C reactive protein, cytokines, and so on),
appear to accelerate a disease driven by atherogenic lipopro-
teins, the first 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.
atherogenicity of LDL (e.g., particle size, number, and
composition) or increase the susceptibility of the arterial
wall (e.g., permeability, glycation, inflammation, 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 modifications 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).
SUSCEPTIBILITY
The limited ability to predict clinical disease based on risk
factor scores indicates that our knowledge about the indi-
vidual 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 mac-
rophage colony-stimulating factor has profound impact on
the development of atherosclerosis in otherwise identical
mice (5). Such disease susceptibility factors remain to be
identified 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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Pathogenesis of Atherosclerosis April 18, 2006:C7–12

caused by atherothrombosis, and it generally is assumed that

Abbreviations and Acronyms this form of endothelial dysfunction equates with endothe-
HDL ⫽ high-density lipoprotein lial activation as described previously in which atheroprotec-
LDL ⫽ low-density lipoprotein tive mechanisms are lost and atherothrombosis promoted.
MCP-1 ⫽ monocyte chemotactic protein-1 Regarding hard clinical end points, the anti-inflammatory and
NOS ⫽ nitric oxide synthase
VCAM-1 ⫽ vascular cell adhesion molecule-1
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
segments from the same individual (arterial susceptibility).
atherosclerosis-susceptible arteries but also in arteries that
The endothelium is very sensitive to shear stress, and local
are relatively resistant to atherosclerosis (e.g., the brachial
hemodynamic conditions related to branching, low and
artery) and even in the microcirculation. Thus, impaired
oscillating shear, and reverse flow may offer some of the
endothelium-mediated vasodilation is related to athero-
explanation for the fact that the coronary arteries are much
thrombosis but not necessarily causally.
more susceptible to atherosclerosis than the internal mam-
Leukocytes. One of the earliest cellular responses in
mary arteries (11).
atherogenesis is the focal recruitment of circulating mono-
cytes and, to a lesser extent, T lymphocytes (12,13). The
CELLULAR COMPONENTS OF ATHEROSCLEROSIS
persistence of this cellular response seems to underlie disease
Atherosclerosis is a chronic immunoinflammatory, fibroprolif- progression. B lymphocytes and plasma cells are rare in the
erative disease of large and medium-sized arteries fuelled by intimal plaque but may be abundantly present in adventitia
lipid (5,12,13). Endothelial cells, leukocytes, and intimal next to advanced intimal disease (16). Activated mast cells
smooth muscle cells are the major players in the develop- may be found both in plaque and adventitia, particularly in
ment of this disease. culprit lesions causing acute ischemic events (17). Neutro-
Endothelial cells. In lesion-prone areas, atherosclerotic phils are rare in uncomplicated atherosclerosis but have been
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 modified
(e.g., oxidized) and become cytotoxic, proinflammatory, che-
motaxic, and proatherogenic. The mechanisms responsible for
the atherogenic modification of LDL are unknown but could
include oxidation mediated by myeloperoxidase, 15-
lipoxygenase, 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
proinflammatory stimuli, and the expression of adhesion
molecules, primarily vascular cell adhesion molecule-1
(VCAM-1), are up-regulated, and monocytes and T cells Figure 1. Plaque heterogeneity within a given patient. (A) Cross section of
are recruited. Besides VCAM-1, other adhesion molecules, a coronary artery cut just distal to a bifurcation. The atherosclerotic plaque
to the left (circumflex branch) is fibrotic and partly calcified, whereas the
such as intercellular adhesion molecule-1, E selection, and P plaque to the right (marginal branch) is lipid-rich with a nonoccluding
selection, probably contribute to the recruitment of blood- thrombus superimposed. (B) Higher magnification of the plaque-thrombus
borne cells to the atherosclerotic lesion (12,13). interface reveals that the fibrous cap over the lipid-rich core is extremely
thin, inflamed, and ruptured with a real defect—a gap—in the cap. Both
Endothelial dysfunction as assessed clinically (impaired arteries contain contrast medium injected postmortem. Trichrome stain,
nitric oxide-mediated vasodilation) predicts clinical events staining collagen blue and thrombus red.

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 JACC Vol. 47, No. 8 Suppl C
April 18, 2006:C7–12
described in thrombosed coronary plaques, probably re-
cruited 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, trans-
endothelial migration also is required. As to that, one or
more chemokines (chemotactic cytokines) are necessary. Ex-
perimental studies indicate that the most important athero-
genic 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 po-
tently 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 trafficking (5).
Within intima, the monocytes differentiate into macro-
phages and internalize the atherogenic lipoproteins via so-
called scavenger receptors, of which SR-A and CD36 have
been demonstrated to play quantitatively significant 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 down-
regulated 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 appropri-
ate conditions (low LDL and high HDL) shrink by effluxing
cellular cholesterol to extracellular HDL via membrane trans-
porters, the initial step in “reverse cholesterol transport” (5–7).
Aside from their scavenger function, macrophages also possess
destabilizing and thrombogenic properties by expressing
matrix-degrading proteolytic enzymes (e.g., matrix metallopro-
teinases) and tissue factor (12). Thus, these innate protective
cells initially recruited to combat cytotoxic lipids, turn into
devastating friendly fire during the progression of athero-
thrombosis.
Immune activation is ongoing in atherosclerotic lesions
(13,19). Although lymphocytes are not required for the
development of atherosclerosis, the immune system modu-
lates the progression of the disease. There are a number of
candidate antigens in the lesion that could be responsible for
immune activation, including modified 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 atheroscle-
rotic plaques, where it is recognized by T cells (13,19). The
up-regulated expression of the immune mediator CD40 and
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Falk C9
Pathogenesis of Atherosclerosis
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 immunoinflammatory response is joined by a
fibroproliferative 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 flow 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, protect-
ing them against much more ominous consequences; plaque
rupture and thrombosis (21).
The smooth muscle cell is the principal connective tissue-
producing cell in the normal (the “soil”) and diseased
(atherosclerotic) intima (21). Because of the repairing and
protective capabilities of smooth muscle cells, their recruit-
ment, proliferation, and synthetic activities are considered
beneficial, 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 (fibrosis, calcium, and necrosis) con-
stitute by far the most voluminous plaque components.
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Pathogenesis of Atherosclerosis April 18, 2006:C7–12

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 accu-
mulate within intima without first passing through foam
cells (24). The lipid-rich atheromatous core is avascular,
hypocellular, soft-like gruel, and totally devoid of support-
ing collagen. Its size is, of course, critical for the stability of
a plaque.
Cell death. During the progression of atherosclerosis, en-
dothelial cells, macrophages, and smooth muscle cells die by
apoptosis or necrosis (the former probably prevails). Disin-
tegration 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 rupture-
prone fibrous cap (22). Furthermore, apoptosis contributes
dramatically to the high tissue factor activity and thrombo-
genicity of the lipid-rich core (25). The paradoxical obser-
vation that a plaque may growth even though cell death
appears to exceed cell proliferation is probably because cell
renewal is mediated by influx (recruitment) of new cells
rather than local cell division. During regression of athero-
sclerosis induced by cholesterol lowering in animals, inflam-
matory cells (macrophages) disappear, but their fate remains
elusive. Many macrophages appear to die within the lesion,
but others probably emigrate from regressive plaques (26).
Calcification. Focal calcification in atherosclerotic plaques
is very common and increases with age (27). The total
amount of calcification—the coronary artery calcium
score—is a genuine marker of coronary plaque burden and
provides prognostic information beyond that provided by
traditional risk factor scoring (28). Plaque calcification is to
some extent active and controlled, resembling calcification in
bone, and both lipid and connective tissue may calcify. In
coronary arteries, calcification is almost always caused by
atherosclerosis; medial calcification (Mönckeberg’s calcinosis)
is exceedingly rare. Clinical observations suggest that culprit
lesions responsible for acute coronary syndromes generally are
less calcified than plaques responsible for stable angina, and the
pattern of plaque calcification also differs (29,30).
Neovascularization and intraplaque hemorrhage. Angio-
genesis is frequent in advanced atherosclerosis. It is probably
a marker of ongoing disease activity and may thus charac-
terize high-risk plaques (31–34). Endothelial proliferation
and sprouting usually originates from vasa vasorum in adven-
titia and extends through media into the base of the plaque,
where neovascularization is most conspicuous. The new mi-
crovessels are fragile, are leaky, and express cellular adhesion
molecules (VCAM-1, intercellular adhesion molecule-1), re-
sulting in local extravasation of plasma proteins, erythrocytes
(bleeding), and inflammatory cells. Thus, angiogenesis and
inflammation often coexist and could mediate rapid plaque
progression (31–34). 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 in-
duced by cholesterol lowering in animals.
Vascular remodeling and luminal stenosis. During plaque
development, remodeling of the artery takes place, in which
the flow-limiting potential of the intimal plaque may be
attenuated (expansive remodeling) or accentuated (constric-
tive remodeling) by reactive changes in the underlying vessel
wall. Plaques assumed to be rupture-prone (so-called in-
flamed thin-cap fibroatheroma) and those responsible for

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

Total AMI ⫹ SCD 1,460 1,114 ⫽ 76% 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 Falk C11
April 18, 2006:C7–12 Pathogenesis of Atherosclerosis

Table 2. Features Associated With Plaque Rupture Fibrin and platelets. During atherogenesis, multiple sites
Structural of endothelial denudation and plaque rupture develop and
Large and soft lipid-rich core heal. When subendothelial tissue is exposed, platelets ad-
Thin and collagen-poor fibrous cap here and fibrin forms. The magnitude of this thrombotic
Cellular
response depends on the thrombogenic stimulus; plaque
Lack of SMCs at rupture site
Accumulation of MACRs at rupture site rupture probably is much more thrombogenic than plaque
Function erosion. In the pathogenesis of arterial thrombosis, platelet
Impaired matrix synthesis (SMC-related) aggregation is responsible for the initial flow obstruction but
Increased matrix breakdown (MACR-derived MMPs) fibrin formation is necessary for the subsequent stabilization
Remodeling
of the platelet-rich thrombosis. Thus, both platelets and
Expansive (outward) vascular remodeling
Others fibrin may accumulate over ruptured and eroded plaques.
Adventitial inflammation and neovascularization Contribution of bone marrow-derived cells. Bone marrow-
MACR ⫽ macrophages; MMP ⫽ matrix metalloproteinase; SMC ⫽ smooth muscle
derived macrophages play a critical role in the initiation and
cell. progression of atherosclerosis. However, conventional wis-
dom says that endothelial cells and intimal smooth muscle
acute coronary syndromes usually are relatively large and cells reside within the arterial wall and proliferate, migrate,
associated with expansive remodeling, which tends to pre- and secrete what might be needed for expedient healing and
serve a normal lumen. In contrast, plaques responsible for repair after injury (21). Therefore, it came as an incredible
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 remodel-
ing 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
fibrous cap that had separated its lipid-rich atheromatous
core from the flowing blood, thereby exposing the throm-
bogenic 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 particu-
larly frequent and often multiple in acute coronary syn-
dromes (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 lin-
ear) progression of coronary lesions observed by serial
angiography (39,40).
Fatal thrombosis. A recent extensive review of the litera-
ture 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-defined 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. Figure 3. Molecular and structural targets for imaging. Cross section of a
Pathoanatomical features of ruptured plaques and, by coronary artery containing plaque assumed to be rupture-prone. Potential
inference, plaques assumed to be rupture-prone (vulnerable) targets for imaging are highlighted. They comprise: 1) the large lipid-rich
necrotic core (orange asterisk), 2) thin fibrous cap (blue arrows), 3)
are shown in Table 2, and potential targets for their expansive remodeling (green arrow), and 4) vasa vasorum and neovascu-
detection by imaging are highlighted in Figure 3. larization (red open circles).

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 C12 Falk
Pathogenesis of Atherosclerosis
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, De-
partment of Cardiology, Aarhus University Hospital (Skejby),
Brendstrupgaardsvej, DK-8200 Aarhus N, Denmark. E-mail:
erling.falk@ki.au.dk.
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