AtheroSclerotic Biology and Epidemiology of Disease

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Editors: Topol, Eric J.

Title: Textbook of Cardiovascular Medicine, 3rd Edition
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> Table of Contents > Section One - Preventive Cardiology > Chapter 1 - Atherosclerotic
Biology and Epidemiology of Disease
Chapter 1
Atherosclerotic Biology and Epidemiology
of Disease
James H.F. Rudd

John R. Davies
Peter L. Weissberg
Epidemiology of Cardiovascular Disease

Atherosclerosis, with its complications, is the leading cause of mortality and
morbidity in the developed world. In the United States, a snapshot of the
population reveals that 60 million adults currently suffer from atherosclerotic
cardiovascular disease, which accounts for 42% of all deaths annually, at a cost
to the nation of $128 billion. Fortunately, despite this catastrophic burden of
disease, much evidence has emerged over the last decade suggesting that the
progression of atherosclerosis can be slowed or even reversed in many people
with appropriate lifestyle and drug interventions.
The origin of the current epidemic of cardiovascular disease can be traced back
to the time of industrialization in the 1700s. The three factors largely
responsible for this were an increase in the use of tobacco products, reduced
physical activity, and the adoption of a diet high in fat, calories, and cholesterol.
This rising tide of cardiovascular disease continued into the twentieth century,
but began to recede when data from the Framingham study identified a number
of modifiable risk factors for cardiovascular disease, including cigarette smoking,
hypertension, and hypercholesterolemia (1).
The number of deaths per 100,000 attributable to cardiovascular disease peaked

in the Western world in 1964 to 1965, since which time there has been a gradual
decline in death rates (Fig. 1.1) (2). The age-adjusted coronary heart disease
(CHD) mortality in the United States dropped by more than 40% and
cerebrovascular disease mortality by more than 50%, with the greatest
reductions being seen among whites and men. This reduction has occurred
despite a quadrupling of the proportion of the population older than 65 years of
age and has been due to a number of factors, particularly major health
promotion campaigns aimed at reducing the prevalence of Framingham risk
factors. Indeed, there has been a substantial change in the prevalence of
population cardiovascular risk factors over the last 30 years (Table 1.1). The war
is not won, however, and the decline in the death rate from cardiovascular
disease slowed in the 1990s (Fig. 1.2). This is likely owing to a large increase in
the prevalence of both obesity and type 2 diabetes mellitus, as well as a
resurgence of cigarette smoking in some sectors of society (3). Female death
rates from cardiovascular disease overtook male death rates in 1984 and have
shown a smaller decline over the last 30 years (4). The consequences of
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atherosclerosis are also beginning to be felt in less well-developed regions of the

globe (5), with death from atherosclerotic cardiovascular disease set to replace
infection as the leading cause of death in the Third World in the near future. This
phenomenon is further illustrated by the increase in CHD mortality in countries
of Eastern and Central Europe (most notably countries of the former Soviet
Union). For example, in the Ukraine the age standardized death rate in the year
2000 was just over 800 per 100,000 people representing an increase of over
60% when compared to 1990 (6).
A further note of caution should also be struck. Western countries are

experiencing a dramatic increase in the prevalence of heart failure. In the United
States, almost 5 million people carry a diagnosis of heart failure (7), thus
singling it out as an emerging epidemic (8). However, the determinants of this
epidemic have yet to be fully elucidated, with some epidemiologic studies
pointing toward hypertension as the driving factor (9) and others suggesting
CHD as the predominant cause (10).
Biology of Atherosclerosis
Traditionally, atherosclerosis has been viewed as a degenerative disease,
affecting predominantly older people, slowly progressing over many years, and
eventually leading to symptoms through mechanical effects of blood flow. The
perceived insidious and relentless nature of its development has meant that
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a somewhat pessimistic view of the potential to modify its progression by
medical therapy has held sway. There has been little emphasis on the diagnosis
and treatment of high-risk asymptomatic patients. Disease management has
instead been dominated by interventional revascularization approaches,
targeting the largest and most visible or symptomatic lesions with coronary
angioplasty or bypass surgery.
FIGURE 1.1. Trends in death rates for heart diseases: United States,
1900â€“1991. (Source: Feinleib M. Trends in heart disease in the United
States [review]. Am J Med Sci 1995;310[Suppl 1]:S8â€“S14, with
permission.)
Recently, for several reasons, this defeatist view of the pathogenesis and
progression of atherosclerosis has begun to change. First, careful descriptive
studies of the underlying pathology of atherosclerosis have revealed that

atherosclerotic plaques differ in their cellular composition and that the cell types
predominating in the plaque can determine the risk of fatal clinical events. A
high degree of plaque inflammation is particularly dangerous. Second, recent
epidemiologic work has identified many new potentially modifiable risk factors
for atherosclerosis, above and beyond those highlighted as a result of the
Framingham study (11). The third and most important reason is because several
large-scale clinical trials have reported that drugsâ€”in particular, the HMG-CoA
reductase inhibitors (statins)â€”are able to reduce the number of clinical events
in patients with established atherosclerosis and do so without necessarily
affecting the size of atherosclerotic plaques. These three strands of evidence
have shown that, rather than being an irreversibly progressive disease,
atherosclerosis is a dynamic, inflammatory process that may be amenable to
medical therapy. Understanding the cellular and molecular interactions that
determine the development and progression of atherosclerosis brings with it
opportunities to develop novel therapeutic agents targeting key molecular and
cellular interactions in its etiology. In addition, the recognition that the clinical
consequences of atherosclerosis depend almost entirely on plaque composition
argues for a new approach to diagnosis, with less emphasis placed on the degree
of lumen narrowing and more interest in the cellular composition of the plaque.
TABLE 1.1 Temporal Changes in Coronary Risk

Factors
Cigarette smoking 1960 Men, 55%; women, 33%
1990 Men, 30%; women, 27%
Undiagnosed hypertension 1960 52%

1980 29%
Mean serum cholesterol 1960 225 mg/dL

1990 208 mg/dL
Diabetes mellitus 1970 2.6%
1990 9.1%
Sedentary lifestyle 1970 41%
1985 27%
Obesity 1960 25%
1990 38%
From Miller M, Vogel RA. The practice of coronary disease prevention.

Baltimore: Williams & Wilkins, 1996.
Normal Artery
The healthy artery consists of three histologically distinct layers. Innermost and
surrounding the lumen is the tunica intima, which comprises a single layer of
endothelial cells in close proximity to the internal elastic lamina. The tunica
media surrounds the internal elastic lamina, and its composition varies
depending on the type of artery. The tunica media of the smallest arterial
vessels, arterioles, comprises a single layer of vascular smooth muscle cells
(VSMCs). Small arteries have a similar structure but with a thicker layer of
medial VSMCs. Arterioles and small arteries are termed resistance vessels
because they contribute vascular resistance and, hence, directly affect blood
pressure. At the opposite end of the spectrum are large elastic or conduit
arteries, named for the high proportion of elastin in the tunica media. The tunica
media of all arteries is contained within a connective tissue layer that contains
blood vessels and nerves and that is known as the tunica adventitia. In normal
arteries, the vessel lumen diameter can be altered by contraction and relaxation
of the medial VSMCs in response to a variety of systemic and locally released
signals.
Atherosclerotic Vessel
Atherosclerosis is primarily a disease affecting the intimal layer of elastic
arteries. For reasons that remain largely unknown, some arterial beds appear
more prone than others. Coronary, carotid, cerebral, and renal arteries and the
aorta are most often involved. The arteries supplying the lower limbs are also
vulnerable to disease. Interestingly, the internal mammary artery is almost
always spared, making it an invaluable vessel for coronary bypass surgery.
Atherosclerotic lesions develop over many years and pass through several
overlapping stages. Histologically, the earliest lesion is a subendothelial
accumulation of lipid-laden macrophage foam cells and associated T lymphocytes
known as a fatty streak. Fatty streaks are asymptomatic and nonstenotic.
Postmortem examinations have shown that they are present in the aorta at the
end of the first decade of life, are present in the coronary arteries by the
second, and begin to appear in the cerebral circulation by the third decade. With
time, the lesion progresses and the core of the early plaque becomes necrotic,
containing cellular debris, crystalline cholesterol, and inflammatory cells,
particularly macrophage foam cells. This necrotic core becomes bounded on its
luminal aspect by an endothelialized fibrous cap, consisting of VSMCs embedded
in an extensive collagenous extracellular matrix. Inflammatory cells are also

present in the fibrous cap, concentrated particularly in the â€œshoulderâ€
regions, where T cells, mast cells, and especially macrophages have a tendency
to accumulate. Advanced lesions may become increasingly complex, showing
evidence of calcification, ulceration, new microvessel formation, and rupture or
erosion (12). Microvessels within the plaque may play important roles in the
formation of macrophage-rich vulnerable atheroma by providing an extended
surface area of activated endothelial cells to hasten recruitment of further
inflammatory cells as well as by promotion of intraplaque hemorrhage (13).
FIGURE 1.2. A. Death rates from CHD, men and women aged 35â€“74,
2000, selected countries. B. Changes in death rates from CHD, men and
women aged 35â€“74, between 1990 and 2000, selected countries.
P.4
P.5
Thus, the composition of atherosclerotic plaques is variable, dynamic and
complex, and it is the interaction between the various cell types within a plaque
that determines the progression, complications, and outcome of the disease.
Cellular Roles in Atherogenesis
Endothelial Cells
The endothelium plays a central role in maintaining vascular health by virtue of
its vital anti-inflammatory and anticoagulant properties. Many of these
characteristics are mediated by the nitric oxide (NO) molecule. This molecule
was discovered in the 1980s, having been isolated from lipopolysaccharide-
primed macrophages (14). NO is synthesized by endothelial cells under the
control of the enzyme endothelial NO synthase (NOS) and has a number of anti-
atherogenic properties. First, it acts as a powerful inhibitor of platelet
aggregation on endothelial cells. Second, it can reduce inflammatory cell
recruitment into the intima by abrogating the expression of genes involved in
this process, such as those encoding intercellular adhesion molecule-1 (ICAM-1),
vascular cell adhesion molecule-1 (VCAM-1), P-selectin, and monocyte
chemoattractant protein-1 (MCP-1) (15,16,17). There is some evidence that NO
may also reduce lipid entry into the arterial intima (18). NO is also a potent
anti-inflammatory molecule and, depending on concentration, may be a
scavenger or a producer of potentially destructive oxygen free radicals, such as
peroxynitrite (19,20,21). The earliest detectable manifestation of atherosclerosis
is a decrease in the bioavailability of NO in response to pharmacologic or
hemodynamic stimuli (22). This may occur for two reasons. Either there may be
decreased manufacture of NO because of endothelial cell dysfunction, or
increased NO breakdown may take place. There is evidence that both
mechanisms may be important in different situations (23). Many atherosclerosis
risk factors can lead to impaired endothelial function and reduced NO
bioavailability. For example, hyperlipidemic patients have reduced NO-dependent
vasodilatation, which is reversed when patients are treated with lipid-lowering
medication (24). Diabetics also have impaired endothelial function, occurring
primarily as a result of impaired NO production. There is, however, some
evidence to suggest that increased oxidative stress leading to enhanced NO
breakdown may also be a factor in early endothelial dysfunction (25). Similarly,
other risk factors for atherosclerosis, such as hypertension and cigarette
smoking, are associated with reduced NO bioavailability (26,27). In cigarette
smokers, endothelial impairment is thought to be caused by enhanced NO
degradation by oxygen-derived free-radical agents such as the superoxide ion.
There are also other consequences of an increased reactivity between NO and
superoxide species. The product of their interaction, ONOOâ€“ (peroxynitrite), is
a powerful oxidizing agent and can reach high concentrations in atherosclerotic
lesions. This may result in cellular oxidative injury.
Another consequence of endothelial cell dysfunction that occurs in early

atherosclerosis is the expression of surface-bound selectins and adhesion
molecules, including P-selectin, ICAM-1, and VCAM-1. These molecules attract
and capture circulating inflammatory cells and facilitate their migration into the
subendothelial space (22). Normal endothelial cells do not express these
molecules, but their appearance may be induced by abnormal arterial shear
stress, subendothelial oxidized lipid, and, in diabetic patients, the presence of
advanced glycosylation products in the arterial wall. The importance of selectins
and adhesion molecules in the development of atherosclerosis is demonstrated in
experiments using mice, which lack their expression. These animals develop
smaller lesions with a lower lipid content and fewer inflammatory cells than
control mice when fed a lipid-rich diet (28). Animal models have reinforced the
importance of inflammatory cell recruitment to the pathogenesis of
atherosclerosis, but because inflammatory cells are never seen in the intima in
the absence of lipid, the results suggest that subendothelial lipid accumulation is
also necessary for the development of atherosclerosis.
The tendency for atherosclerosis to occur preferentially in particular sites may

be explained by subtle variations in endothelial function. This is probably caused
by variations in local blood flow patterns, especially conditions of low flow, which
can influence expression of a number of endothelial cell genes, including those
encoding ICAM-1 and endothelial NOS (29,30). In addition to flow speed, flow
type can have a direct effect on cell morphology. In areas of laminar flow
(atheroprotective flow), endothelial cells tend to have an ellipsoid shape,
contrasting with the situation found at vessel branch points and curves, where
turbulent flow (atherogenic flow) induces a conformational change toward
polygonal-shaped cells (31). Such cells have an increased permeability to low-
density lipoprotein (LDL) cholesterol and may promote lesion formation (32).
These data are consistent with the idea that the primary event in atherogenesis
is endothelial dysfunction. The endothelium can be damaged by a variety of
means, leading to dysfunction and, by unknown mechanisms, subsequent
subendothelial lipid accumulation. In this situation, the normal homeostatic
features of the endothelium break down; it becomes more adhesive to
inflammatory cells and platelets, it loses its anticoagulant properties, and there
is reduced bioavailability of NO. Importantly, endothelial function is improved by
drugs that have been shown to substantially reduce death from vascular disease,
including statins and angiotensin-converting enzyme inhibitors (33,34).
Inflammatory Cells
LDL from the circulation is able to diffuse passively through the tight junctions
that bind neighboring endothelial cells. The rate of passive diffusion is increased
when circulating levels of LDL are elevated. In addition, other lipid fractions may
be important in atherosclerosis. Lipoprotein(a) has the same basic molecular
structure as LDL, with an additional apolipoprotein(a) element attached by a
disulfide bridge. It has been shown to be highly atherogenic (35), accumulate in
the arterial wall in a manner similar to LDL (36), impair vessel fibrinolysis (37),
and stimulate smooth muscle cell proliferation (38). The accumulation of
subendothelial lipids, particularly when at least partly oxidized, is thought to
stimulate the local inflammatory reaction that initiates and maintains activation
of overlying endothelial cells. The activated cells express a variety of selectins
and adhesion molecules and also produce a number of chemokinesâ€”in
particular, MCP-1, whose expression is upregulated by the presence of oxidized
LDL in the subendothelial space (39). Interestingly, the protective effect of high-
density lipoprotein (HDL) against atherosclerotic vascular disease may be partly
explained by its ability to block endothelial cell expression of adhesion molecules
(40,41). Chemokines are proinflammatory cytokines responsible for
chemoattraction, migration, and subsequent activation of leukocytes. Mice
lacking the MCP-1 gene develop smaller atherosclerotic lesions than normal
animals (42). The first stage of inflammatory cell recruitment to the intima is
the initiation of â€œrollingâ€ of monocytes and T cells along the endothelial cell
layer. This phenomenon is mediated
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by the selectin molecules, which selectively bind ligands found on these
inflammatory cells. The subsequent firm adhesion to and migration of leukocytes
through the endothelial cell layer depends on the endothelial expression of
adhesion molecules such as ICAM-1 and VCAM-1 and their binding to appropriate
receptors on inflammatory cells. Once present in the intima, monocytes
differentiate into macrophages under the influence of chemokines such as
macrophage colony-stimulating factor. Such molecules also stimulate the
expression of the scavenger receptors that allow macrophages to ingest oxidized
lipids and to develop into macrophage foam cells, the predominant cell in an
early atherosclerotic lesion. The formation of scavenger receptors is also
regulated by peroxisome proliferator-activated receptor- ³ ‫( خ‬PPAR- ³ ‫ خ‬a nuclear
transcription factor expressed at high levels in foam cells) (43). PPAR- ³ ‫ خ‬agonists
(glitazones), which are used to treat patients with type 2 diabetes, have been
shown to have many anti-atherogenic effects, including increasing production of
NO (44), decreased endothelial inflammatory cell recruitment and reduced
vascular endothelial growth factor (VEGF) expression (45). Also, PPAR- ³ ‫خ‬
agonists can reduce the lipid content of plaques by enhancing reverse cholesterol
transport from plaque to liver. Positive results with these drugs in patients with
type 2 diabetes are emerging. As well as reducing matrix metalloproteinase
(MMP) 9 levels, glitazones also significantly ameliorated C-reactive protein (CRP)
and CD40 ligand levels, as well as causing direct plaque regression in a rabbit
atheroma model (46). Clearly their use in large clinical trials in patients without
diabetes as anti-atheroma drugs is awaited with interest.
In early atherosclerosis at least, the macrophage can be thought of as

performing a predominantly beneficial role as a â€œneutralizerâ€ of potentially
harmful oxidized lipid components in the vessel wall. However, macrophage foam
cells also synthesize a variety of proinflammatory cytokines and growth factors
that contribute both beneficially and detrimentally to the evolution of the plaque.
Some of these factors are chemoattractant (osteopontin) and growth-enhancing
(platelet-derived growth factor) for VSMCs (12,47). Under the influence of these
cytokines, VSMCs migrate from the media to the intima, where they adopt a
synthetic phenotype, well-suited to matrix production and protective fibrous cap
formation.
However, activated macrophages have a high rate of apoptosis. Once dead, they
release their lipid content, which becomes part of the core of the plaque, thereby
contributing to its enlargement. The apoptotic cells also contain high
concentrations of tissue factor, which may invoke thrombosis if exposed to
circulating platelets (48). Interestingly, the selective glycoprotein 2b3a receptor
antagonist abciximab has been shown to have an effect on the levels of tissue
factor found in monocytes. In an in vitro study by Steiner (49), the drug
attenuated both the amount of tissue factor and its RNA levels. As tissue factor
is a potent instigator of the clotting cascade, this role may explain part of the
protective effect of abciximab on the microcirculation of patients with acute

coronary syndromes (50).
It is now generally recognized that the pathologic progression and consequences

of atherosclerotic lesions are determined by dynamic interactions between
inflammatory cells recruited in response to subendothelial lipid accumulation,
and the local reparative â€œwound healingâ€ response of surrounding VSMCs.
Vascular Smooth Muscle Cells

VSMCs reside mostly in the media of healthy adult arteries, where their role is to
regulate vascular tone. Thus, medial VSMCs contain large amounts of contractile
proteins, including myosin, ‫خ‬±-actin, and tropomyosin. Continued expression of
this â€œcontractileâ€ phenotype is maintained by the influence of extracellular
proteins in the media, which act via integrins in the VSMC membrane. In
atherosclerosis, however, the cells become influenced by cytokines produced by
activated macrophages and endothelial cells. Under these influences, VSMCs
migrate to the intima and undergo a phenotypic change characterized by a
reduction in content of contractile proteins and a large increase in the number of
synthetic organelles. This migration of VSMCs from the media to the intima, and
the consequent change from a contractile to a â€œsyntheticâ€ phenotype, was
previously thought to be a crucial step in the development of atherosclerosis in
the modified response to injury hypothesis discussed previously. More recently,
it has been recognized that intimal VSMCs in atherosclerotic plaques bear a
remarkable similarity to VSMCs found in the early developing blood vessels (51),
suggesting that intimal VSMCs may be performing a beneficial, reparative role
rather than a destructive one in atherosclerosis. VSMCs are well-equipped for
this action. First, they can express the proteinases that they require to break
free from the medial basement membrane and allow them to migrate to the site
of inflammation or injury in response to chemokines. Second, they can produce
various growth factors, including VEGF and platelet-derived growth factor, that
act in an autocrine loop to facilitate their proliferation at the site of injury.
Finally, and most important, they produce large quantities of matrix proteins, in
particular glycosaminoglycans, elastin, and collagen isoforms 1 and 3, necessary
to repair the vessel and form a fibrous cap over the lipid-rich core of the lesion.
This fibrous cap separates the highly thrombogenic lipid-rich plaque core from
circulating platelets and the proteins of the coagulation cascade and also confers
structural stability to the atherosclerotic lesion. And because the VSMC is the
only cell capable of synthesizing this cap, it follows that VSMCs play a pivotal
role in maintaining plaque stability and protecting against the potentially fatal
thrombotic consequences of atherosclerosis (52).
Cellular Interactions and Lesion Stability

Generally, early atherosclerosis progresses without symptoms until a lesion
declares itself in one of two ways. As discussed, macrophage foam cells may
undergo apoptosis, especially in the presence of high concentrations of oxidized
LDL. Their cellular remnants then become part of an enlarging lipid-rich core.
Plaque size thus increases, and there may be a consequent reduction in vessel
lumen area. At times of increased demand, such as exercise, this may be
sufficient to cause ischemic symptoms such as angina. More hazardous is if the
plaque presents with disruption of the fibrous cap, leading to exposure of the
thrombogenic lipid core. This is likely to result in subsequent platelet
accumulation and activation, fibrin deposition, and intravascular thrombosis.
Depending on factors such as collateral blood supply, extent of arterial

thrombus, and local fibrinolytic activity, the end result may be arterial occlusion
and downstream necrosis.
By studying the pathology of ruptured plaques, several characteristics have been

identified that seem to be predictive of the risk of rupture in individual lesions
(53). Plaques that are vulnerable to rupture tend to have thin fibrous caps (<65
‫ﺁ‬µm) with a high ratio of inflammatory cells to VSMCs and contain a lipid core
that occupies more than 50% of the volume of the plaque. Of these, the most
important is the cellular composition of the fibrous cap. Plaques containing a
heavy inflammatory cell infiltrate and relatively few VSMCs have the highest
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risk of rupture (54). Interestingly, in the coronary tree, such high-risk plaques
are usually located in the proximal portions of the main arteries (55). Recently,
evidence of the importance of intraplaque hemorrhage from microvessels in
plaque destabilization has emerged. It is thought that the leaking vessels initiate
platelet and red cell phagocytosis by plaque macrophages, causing them to
become activated and tipping the balance toward plaque rupture (56).
Inflammatory cells in plaques act to promote plaque rupture by a number of

synergistic mechanisms. First, activated T cells produce proinflammatory
cytokines, typified by IFN- ³ ‫ خ‬, that directly inhibit VSMC proliferation (57) and
almost completely shut down collagen synthesis (58,59). Thus, VSMCs in the
vicinity of activated T cells in plaques are poorly able to lay down or repair
extracellular matrix. Second, macrophage-derived inflammatory cytokines, in
particular interleukin-1 ² ‫ خ‬and tumor necrosis factor-‫خ‬± along with IFN- ³ ‫ خ‬from T
cells, are synergistically cytotoxic for VSMCs, causing depletion in cell number
by apoptosis (60). These cytokines are found at high levels in vulnerable plaques
(61). Third, activated macrophages can induce VSMC apoptosis by direct
cellâ€“cell contact (62). Finally, and probably most important, macrophages
secrete a variety of matrix metalloproteinases that degrade the matrix
components of the fibrous cap by proteolytic cleavage of its protein components
(52). The production of matrix metalloproteinases is upregulated by
inflammatory mediators such as tumor necrosis factor-‫خ‬±. As well as being under
threat from such an array of insults, VSMCs themselves within the fibrous cap of
a mature plaque have a reduced ability to proliferate (63,64) and an enhanced
susceptibility to apoptosis (65). Thus, inflammatory cells can destroy the fabric
of the fibrous cap, and resident VSMCs are poorly equipped to compensate,
particularly in the presence of inhibitory inflammatory cytokines. It is important
to note that all of these features can be present in small, hemodynamically
insignificant plaques that are clinically silent and angiographically invisible.
Thus, plaque composition is far more important than plaque size in determining
outcome.
Inflammatory Markers in Atherosclerosis

The cell biology of plaque development and subsequent rupture illustrates that
atherosclerosis is fundamentally an inflammatory condition. Confirmation of this
inflammatory basis has come from several studies of different patient
populations that have all demonstrated a correlation between levels of markers
of systemic inflammation, principally CRP, and risk of a clinical event owing to
plaque rupture (66,67,68,69,70). However, unlike in other systemic
inflammatory conditions, such as rheumatoid arthritis, levels of CRP in
atherosclerosis are characteristically not elevated above the conventional normal
range, and a correlation between CRP level and coronary events was
demonstrated only after development of a highly sensitive assay for CRP that
was capable of measuring levels below the lower limit of detection of
conventional assays. The risk of clinical events associated with an elevated CRP
seems to be independent of the presence of other Framingham risk factors for
atherosclerosis. Elevated CRP also predicts near-term plaque rupture events as
well those up to 20 years in the future, suggesting that inflammation is
important in both early and late atherosclerosis (71). Additionally, CRP level
accurately indicates the likelihood of sudden cardiac death, a condition usually
associated with multiple atherosclerotic plaque ruptures (72). However, despite
initial enthusiasm, large meta-analyses have suggested that the relative risk of a
cardiovascular event is increased by only approximately 1.5 times in those
people with a baseline elevated CRP (above 3 mg/dL) (73,74). With such a
modest predictive value, it may be that the routine measurement of CRP alone in
asymptomatic patients is not yet justified for accurate disease prediction.
Similar, although less compelling, correlations with clinical events have also
been published for other markers of inflammation, including soluble ICAM-1,
VCAM-1, P-selectin, and interleukin-6 (the primary driver of CRP production)
(75,76,77,78). Results of these studies have been interpreted by some as
indicating that atherosclerosis arises as a consequence of a systemic
inflammatory process (e.g., chronic infection) and by others that it reflects the
inflammatory processes of atherosclerosis itself. However, there is accumulating
evidence in favor of the latter interpretation.
Two Forms of Plaque Disruption: Fibrous Cap

Rupture and Endothelial Erosion
Atherosclerotic plaques become life threatening when they initiate clot formation
in the vessel lumen and disturb blood flow. This can occur in two different ways.
Either there can be fibrous cap rupture, with consequent exposure of the
thrombogenic extracellular matrix of the cap and the tissue factorâ€“rich lipid
core to circulating blood, or less commonly, there is erosion of the endothelial
cells covering the fibrous cap, also potentially leading to the formation of a
platelet-rich thrombus. Endothelial erosion probably accounts for approximately
30% of acute coronary syndromes overall and seems particularly common in
women (79). Both forms of plaque disruption invariably lead to local platelet
accumulation and activation. This may result in triggering of the clotting
cascade, thrombus formation, and, if extensive, complete vessel occlusion.
Platelet-rich thrombus contains chemokines and mitogens, in particular platelet-
derived growth factor and thrombin that induce migration and proliferation of
VSMCs from the arterial media to the plaque and transforming growth factor- ² ‫خ‬
that contributes to healing of the disrupted lesion (80). Platelets also express
CD40 on their cell membrane, which causes local endothelial cell activation,
resulting in the recruitment of more inflammatory cells to the lesion and
perpetuating the cycle of inflammation, rupture, and thrombosis. However,
fibrous cap rupture or erosion does not invariably lead to vessel occlusion. Up to
70% of plaques causing high-grade stenosis contain histologic evidence of
previous subclinical plaque rupture with subsequent repair (81). This is
particularly likely to occur if high blood flow through the vessel prevents the
accumulation of a large occlusive thrombus. Thus, nonocclusive plaque rupture
induces formation of a new fibrous cap over the organizing thrombus, which
restabilizes the lesion but at the expense of increasing its size. Because this
occurs suddenly, there is little opportunity for adaptive remodeling of the artery,
and the healed lesion may now impede flow sufficiently to produce ischemic
symptoms. This explains why patients who have previously had normal exercise
tolerance may suddenly develop symptoms of stable angina pectoris. It also
follows that if lesions can grow as a consequence of repeated episodes of silent
rupture and repair, an inhibition of plaque rupture rate will reduce progression of
atherosclerosis. Therefore, atheromatous plaques may become larger by two
methods. The first is a gradual increase in size as a consequence of macrophage
foam cell accumulation and incorporation of apoptotic cells into an enlarging
necrotic lipid-laden plaque core. The second is a stepwise increase in size
because of repeated, often silent episodes
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of plaque rupture or erosion with subsequent VSMC-driven repair.
Balance of Atherosclerosis: Therapeutic

Implications
Atherosclerosis is a dynamic process in which the balance between the
destructive influence of inflammatory cells and the reactive, stabilizing effects of
VSMCs determines outcome (Fig. 1.3). This balance can be tipped toward plaque
rupture by factors such as an atherogenic lipoprotein profile, high levels of lipid
oxidation, local free radical generation, and genetic variability in expression and
activity of certain central inflammatory molecules. For example, an association
between plaque progression and a polymorphism in the stromelysin-1 gene
promoter has been described (82). Until recently, it was also thought that
infectious organisms might be involved in atherosclerosis, either as plaque
initiators or as having some role in initiating plaque rupture. Chlamydia
pneumoniae is found in plaques, localizing at high concentrations within
macrophages, but is rarely found in normal arteries (83). Although these data
imply a pathologic association between the
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presence of chlamydia infection and atherosclerosis, neither a causative role nor
an association between serum markers of infection and ischemic heart disease
has been established. Although animal work has shown that healthy rabbits
nasally inoculated with chlamydia develop extensive atherosclerosis (84), the
situation appears to be somewhat different in humans. Two large prospective
studies and an extensive meta-analysis of previous data failed to show any
association between serum markers of infection with chlamydia and incidence of
or mortality from ischemic heart disease (85,86). These results effectively
excluded a strong association but allowed the possibility of a weaker link. This
hypothesis has now been effectively rejected after several negative trials of
antibiotics in coronary artery disease (87,88,89).
FIGURE 1.3. Cellular interactions in the development and progression of

atherosclerosis. (Source: Weissberg PL. Atherogenesis: current
understanding of the causes of atheroma. Heart 2000;83:247â€“252, with
permission.)
The balance can be tipped toward plaque stability by a reduction in plaque

inflammation or an increase in VSMC-driven repair. Lipid reduction, by whatever
means, reduces clinical events. Evidence that this may be due to a plaque-
stabilizing effect comes from animal studies that showed that statins reduced
inflammatory cell and increased VSMC content of plaques (90,91), changes that
would be expected to enhance stability. Dietary lipid lowering in rabbits also
reduced the number of microvessels in the aortic intima, suggesting another
mechanism of favorably altering the biology of plaques (92).
More important, however, evidence from human clinical studies also points to a
plaque-stabilizing effect of statins. Despite angiographic studies showing that
statins produce only a small, hemodynamically insignificant reduction in lumen
stenosis (93,94), more sensitive intravascular ultrasound studies have shown
beyond doubt that statins can halt lesion enlargement in the coronary arteries,
with the most benefit being seen with higher doses of the most potent drugs
(95). Statins can also reduce new lesion formation, and, importantly, the number
of new vessel occlusions. These arise after a plaque ruptures, leading to an
occlusive thrombus in the context of a well-collateralized myocardial circulation.
This seems to imply that statins stabilize plaques by reducing rupture rate. This
conclusion is supported by the results of all the large primary and secondary
prevention studies, which have demonstrated that statins (pravastatin,
simvastatin, and lovastatin) produce major reductions in events owing to plaque
rupture, such as myocardial infarction and stroke (34,96,97,98,99). Because
statins have only a modest effect on plaque size but cause profound reductions
in the number of clinical events, these studies highlight the inadequacy of
angiography for the prediction of clinical events and suggest that statins have
beneficial effects on plaque inflammation in addition to, or as a result of, their
lipid-lowering effects. Importantly, this notion is supported by the observation
that the reduction in clinical events due to statin therapy is accompanied by a
parallel reduction in CRP levels that is unlikely to be caused by effects of statins
on nonatherosclerotic inflammation (100,101). Also, in the first study of its kind,
it has been shown that statins reduce inflammation and increase plaque collagen
content in human carotid artery atherosclerosis (102). However, the various

statins do differ in their anti-inflammatory effect; in the REVERSAL study,
atorvastatin achieved a far greater reduction in CRP than pravastatin (95);
whether this has important clinical relevance is not yet known.
Statin drugs may help to stabilize plaques in a number of different ways. It is

known that they can exert direct effects on endothelial cell function,
inflammatory cell number and activity, VSMC proliferation, platelet aggregation,
and thrombus formation (103,104,105,106,107). Evidence that nonâ€“lipid-
lowering effects may be important in vivo comes from animal studies in which
pravastatin caused beneficial changes in plaque composition (but not size), even
when lipid levels were maintained at pretreatment levels (91). Additionally, in
mice, simvastatin has direct anti-inflammatory effects comparable to those of
indomethacin (108). Recently, a newly recognized effect of statins as immune
modulators has been described, whereby major histocompatibility complex class
IIâ€“mediated T-cell activation is reduced by a variety of statins (109). However,
the matter of nonâ€“lipid-lowering effects of statins is not yet proven beyond
doubt: several of the pleiotropic anti-inflammatory effects of statins (decreased
expression of MMPs, and tissue factor) occur in animals on a lipid-lowering diet
alone, without exposure to drugs of any kind (110). In addition, the
administration of other forms of anti-inflammatory drugs to patients with
atherosclerosis does not seem to confer any clinical benefit and may do harm;
the cyclooxygenase-2 (COX-2) class of drugs are a case in point, causing a
doubling of the rate of myocardial infarction in one study (111).
Restenosis
Restenosis describes the late loss of gain in lumen diameter achieved
immediately after balloon dilatation of an atherosclerotic plaque. For many
years, it has been thought of as an undesirable response to vascular injury.
However, in effect, it represents an extreme form of plaque stabilization.
Whether performed on a stable or unstable plaque, balloon angioplasty causes
endothelial disruption and often substantial damage to the full thickness of the
vessel wall. The initial thrombotic response that would otherwise lead to early
vessel occlusion is prevented by antiplatelet and antithrombotic therapy. There
then follows a reparative response driven by medial VSMCs and adventitial
myofibroblasts. The former form a matrix-rich neointima over the exposed
plaque, whereas the latter produce a collagenous matrix in the adventitia. The
net result is that the adventitial reaction â€œsplintsâ€ the vessel and prevents
the positive remodeling that would normally allow expansion of the vessel to
accommodate the neointima. However, although this phenomenon may lead to
angiographic or clinical restenosis, much more important, it renders the lesion
stable, making the likelihood of a further plaque rupture at that site extremely
remote. In effect, by stimulating a vigorous VSMC repair response, balloon
angioplasty tips â€œthe balance of atherosclerosisâ€ in favor of plaque stability.
This phenomenon undoubtedly underlies the success of angioplasty in the
treatment of acute myocardial infarction. Most of the adverse effects of the
response to balloon angioplasty on remodeling can be countered by deployment
of a stent, particularly the drug-eluting variety, where significant restenosis is
rarely encountered. The drugs used to coat the stents are antiproliferative
agents, and are highly effective at eliminating restenosis (112). However, by
impairing the synthetic ability of the VSMCs of the cap, there have been reports
of early thrombotic occlusions of treated arteries, although longer term analysis
of the data suggest that this is not frequent (113). Nevertheless, drug-eluting
stents are likely to become universally used in the catheter laboratory in the
near future.
Controversies and Personal Perspectives

Many issues concerning the initiation and progression of atherosclerosis remain
to be resolved. In particular, controversy persists over the extent to which
endothelial dysfunction precedes or is the consequence of intimal lipid
accumulation; the relative contributions of endothelial erosion and plaque
rupture to clinical events; and the extent to which statins achieve their plaque-
stabilizing effects directly via lipid lowering or by their so-called pleiotropic
effects on the intercellular interactions that lead to plaque rupture. Integral to
this
P.10
last issue is the outstanding question of what is the optimal level of lipid
reduction. In other words, is lower LDL always better?
Despite these controversies, it is certain that drug treatment will become

increasingly prominent in the management of patients with, and at high risk of
developing, atherosclerosis. Improvements in drug design will come from a
number of complementary approaches. First, improvement will come by
modifications of existing molecules, based on understanding how currently
available drugs such as statins and angiotensin-converting enzyme inhibitors
influence plaque progression. This will include evaluation of how other lipid-
modifying strategies, such as inhibiting cholesterol absorption in the gut and
modifying the balance between pro- and anti-atherogenic lipoproteins and
triglycerides, might influence the atherosclerotic process. Second, improvements
will come by targeting molecular interactions known to be involved in
atherogenesis. Likely candidates include endothelial adhesion molecules, MMPs,
inflammatory cytokines and their signaling molecules, in particular, nuclear
factor-‫ خ؛‬B and its downstream transcriptional activators. Here the challenge lies
in identifying pathways or molecular species that are specific for atherosclerosis
whose modification will not compromise the normal inflammatory response to
pathogens. This approach will include developing regulators of VSMC behavior,
such as modulators of transforming growth factor- ² ‫ خ‬â€“driven matrix production,
that may lead to enhanced maintenance of the fibrous cap. Another important
example includes establishing the role of drugs targeting peroxisome
proliferatorâ€“activated receptors in modifying inflammation and the vascular
consequences of the metabolic syndrome that links insulin resistance, diabetes,
hypertension, and dyslipidemia with premature atherosclerosis. The third
approach is to use new technologies such as proteomics to design new
therapeutic molecules and gene array technologies to identify new molecular
targets in vascular disease. In addition, as a consequence of sequencing the
human genome, a number of â€œorphanâ€ receptors have already been
identified that might provide vascular-specific targets for novel therapies.
Finally, local drug delivery to high-risk plaques with drug-eluting stents has been
proposed as a means of reducing risk of rupture (plaque passivation) (115,116).
This approach will need better methods of identifying high-risk plaques, which
will probably include invasive imaging data derived from IVUS and thermography
coupled with noninvasive methods such as high-resolution molecular magnetic
resonance imaging and possibly Fluorodeoxyglucose positron emission
tomography (FDG-PET) (117,118).
The Future
It is almost inconceivable that advances in our understanding of the
atherosclerotic disease process will not lead to the development of new anti-
atheroma drugs that will act synergistically with statins and angiotensin-
converting enzyme inhibitors. For example, a novel HDL-like molecule has
recently been shown to reduce atheroma burden when given by intravenous
infusion over 5 weeks to a high-risk group of patients (114). Furthermore, we
predict that advances in genetics and diagnostics will combine with therapeutic
advances to produce substantial reductions in premature cardiovascular deaths.
Thus, new gene polymorphisms and mutations will be identified that confer
increased likelihood either of developing atheroma or of experiencing its
consequences. This will lead, in turn, to better prescription of lifestyle
modifications and better targeting of current and new therapies for primary
prevention of cardiovascular events. This approach will be led by new diagnostic
testsâ€”based on specific circulating markers of vascular inflammation and
imaging of the inflammatory process underlying plaque ruptureâ€”that will allow
better preclinical diagnosis of patients at greatest risk of cardiovascular events
and subsequent monitoring of plaque-modifying therapies.
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AtheroSclerotic Biology and Epidemiology of Disease

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AtheroSclerotic Biology and Epidemiology of Disease

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Ovid: Textbook of Cardiovascular Medicine Page 1 of 26

Editors: Topol, Eric J.

James H.F. Rudd

Epidemiology of Cardiovascular Disease

The number of deaths per 100,000 attributable to cardiovascular disease peaked

atherosclerosis are also beginning to be felt in less well-developed regions of the

A further note of caution should also be struck. Western countries are

studies of the underlying pathology of atherosclerosis have revealed that

TABLE 1.1 Temporal Changes in Coronary Risk

Cigarette smoking 1960 Men, 55%; women, 33%

1990 Men, 30%; women, 27%

Undiagnosed hypertension 1960 52%

Mean serum cholesterol 1960 225 mg/dL

Diabetes mellitus 1970 2.6%

Sedentary lifestyle 1970 41%

Obesity 1960 25%

From Miller M, Vogel RA. The practice of coronary disease prevention.

in an extensive collagenous extracellular matrix. Inflammatory cells are also

Cellular Roles in Atherogenesis

Another consequence of endothelial cell dysfunction that occurs in early

The tendency for atherosclerosis to occur preferentially in particular sites may

In early atherosclerosis at least, the macrophage can be thought of as

protective effect of abciximab on the microcirculation of patients with acute

It is now generally recognized that the pathologic progression and consequences

Vascular Smooth Muscle Cells

Cellular Interactions and Lesion Stability

Depending on factors such as collateral blood supply, extent of arterial

By studying the pathology of ruptured plaques, several characteristics have been

Inflammatory cells in plaques act to promote plaque rupture by a number of

Inflammatory Markers in Atherosclerosis

Two Forms of Plaque Disruption: Fibrous Cap

Balance of Atherosclerosis: Therapeutic

FIGURE 1.3. Cellular interactions in the development and progression of

The balance can be tipped toward plaque stability by a reduction in plaque

content in human carotid artery atherosclerosis (102). However, the various

Statin drugs may help to stabilize plaques in a number of different ways. It is

Controversies and Personal Perspectives

Despite these controversies, it is certain that drug treatment will become

3. Cooper R, Cutler J, Desvigne-Nickens P, et al. Trends and disparities in

5. Reddy KS, Yusuf S. Emerging epidemic of cardiovascular disease in

6. British Heart Foundation Health Promotion Research Group. Coronary

8. Braunwald E. Shattuck lectureâ€”cardiovascular medicine at the turn of

18. Cardona-Sanclemente LE, Born GV. Effect of inhibition of nitric oxide

19. Anggard E. Nitric oxide: mediator, murderer, and medicine [see

20. Bhagat K, Vallance P. Nitric oxide 9 years on. J R Soc Med

21. Hobbs AJ, Higgs A, Moncada S. Inhibition of nitric oxide synthase as a

22. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med

23. Li H, Forstermann U. Nitric oxide in the pathogenesis of vascular disease.

26. Heitzer T, Just H, Munzel T. Antioxidant vitamin C improves endothelial

29. Resnick N, Yahav H, Khachigian LM, et al. Endothelial gene regulation by

30. Topper JN, Cai J, Falb D, et al. Identification of vascular endothelial

32. Gimbrone MA, Jr. Vascular endothelium, hemodynamic forces, and

33. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-

35. Poon M, Zhang X, Dunsky KG, et al. Apolipoprotein(a) induces monocyte

36. Rath M, Niendorf A, Reblin T, et al. Detection and quantification of

37. Loscalzo J, Weinfeld M, Fless GM, et al. Lipoprotein(a), fibrin binding,

39. Boring L, Gosling J, Cleary M, et al. Decreased lesion formation in CCR2-

41. Calabresi L, Franceschini G, Sirtori CR, et al. Inhibition of VCAM-1

42. Gosling J, Slaymaker S, Gu L, et al. MCP-1 deficiency reduces

43. Tontonoz P, Nagy L, Alvarez JG, et al. PPARgamma promotes

44. Calnek DS, Mazzella L, Roser S, et al. Peroxisome proliferator-activated

45. Panigrahy D, Singer S, Shen LQ, et al. PPARgamma ligands inhibit

49. Steiner S, Seidinger D, Huber K, et al. Effect of glycoprotein IIb/IIIa

50. CAPTURE investigators. Randomised placebo-controlled trial of abciximab