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Biology and Epidemiology of Disease
Chapter 1
Atherosclerotic Biology and Epidemiology
of Disease
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).
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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
P.3
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,
1900–1991. (Source: Feinleib M. Trends in heart disease in the United
States [review]. Am J Med Sci 1995;310[Suppl 1]:S8–S14, with
permission.)
Recently, for several reasons, this defeatist view of the pathogenesis and
progression of atherosclerosis has begun to change. First, careful descriptive
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1990 9.1%
1985 27%
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1990 38%
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
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FIGURE 1.2. A. Death rates from CHD, men and women aged 35–74,
2000, selected countries. B. Changes in death rates from CHD, men and
women aged 35–74, 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.
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, ONOO– (peroxynitrite), is
a powerful oxidizing agent and can reach high concentrations in atherosclerotic
lesions. This may result in cellular oxidative injury.
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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 chemokines—in
particular, MCP-1, whose expression is upregulated by the presence of oxidized
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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 “rolling†of monocytes and T cells along the endothelial cell
layer. This phenomenon is mediated
P.6
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.
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
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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.
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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
P.8
of plaque rupture or erosion with subsequent VSMC-driven repair.
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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
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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 “splints†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 “the balance of atherosclerosis†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
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stents are likely to become universally used in the catheter laboratory in the
near future.
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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
tests—based on specific circulating markers of vascular inflammation and
imaging of the inflammatory process underlying plaque rupture—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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