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Editors: Topol, Eric J.

Title: Textbook of Cardiovascular Medicine, 3rd Edition

Copyright Lippincott Williams & Wilkins

> Table of Contents > Section One - Preventive Cardiology > Chapter 1 - Atherosclerotic

Biology and Epidemiology of Disease

Chapter 1

Atherosclerotic Biology and Epidemiologyof Disease

James H.F. Rudd

John R. Davies

Peter L. Weissberg

Epidemiology of Cardiovascular DiseaseAtherosclerosis, 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 ep idemic 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 d isease 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 card iovascular

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 o f 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 over60% 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 AtherosclerosisTraditionally, atherosclerosis has been viewed as a degenerative d isease,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

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 r evascularization approaches,

targeting the largest and most visible or symptomatic lesions with coronary

angioplasty or bypass surgery.

Recently, for several reasons, this defeatist view of the pathogenesis and

progression of atherosclerosis has begun to change. First, careful descriptive

P.3

FIGURE 1.1. Trends in death rates for heart diseases: United States,

19001991. (Source: Feinleib M. Trends in heart d isease in the United

States [review]. Am J Med Sci1995;310[Suppl 1]:S8S14, with

permission.)

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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 severallarge-scale clinical trials have reported that drugs in particular, the HMG-CoA

reductase inhibitors (statins)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 mo lecular 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 compositionargues 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 RiskFactors

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

1990 Men, 30%; women, 27%

Undiagnosed hypertension 1960

1980

52%

29%

Mean serum cholesterol 1960

1990

225 mg/dL

208 mg/dL

Diabetes mellitus 1970 2.6%

1990 9.1%

Sedentary lifestyle 1970 41%

1985 27%

Obesity 1960 25%

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Normal Artery

The healthy artery consists of three histologically d istinct layers. Innermost andsurrounding 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 containsblood 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 VesselAtherosclerosis 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 subendo thelial

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

1990 38%

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

Baltimore: Williams & Wilkins, 1996.

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in an extensive collagenous extracellular matrix. Inflammatory cells are also

present in the fibrous cap, concentrated particularly in the shoulder

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 extendedsurface area of activated endothelial cells to hasten recruitment o f further

inflammatory cells as well as by promotion of intraplaque hemorrhage (13).

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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 CellsThe 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) mo lecule. 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 potentanti-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 differ ent 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-loweringmedication (24). Diabetics also have impaired endo thelial 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 t heir interaction, ONOO (peroxynitrite), is

a powerful oxidizing agent and can reach high concentrations in atheroscleroticlesions. This may result in cellular oxidative injury.

FIGURE 1.2. A. Death rates from CHD, men and women aged 3574,

2000, selected countries. B. Changes in death rates from CHD, men and

women aged 3574, between 1990 and 2000, selected countries.

P.4

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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 ofadvanced 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 atherogenesisis 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 junctionsthat bind neighboring endothelial cells. The rate of passive diffusion is increased

when circulating levels of LDL are elevated. In add ition, 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 t o LDL (36), impair vessel fibrinoly sis (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 chemokinesinparticular, 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 isthe initiation of rolling of monocytes and T cells along the endothelial cell

layer. This phenomenon is mediated

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 oxidizedlipids 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- (PPAR- a nuclear

transcription factor expressed at high levels in foam cells) (43). PPAR- agonists

(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-

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 d irect plaque regression in a rabbit

atheroma model (46). Clearly their u se 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 neutralizer 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 thesecytokines, 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

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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 wound healing response of surrounding VSMCs.

Vascular Smooth Muscle CellsVSMCs 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, -actin, and tropomyosin. Continued expression of

this contractile 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 ofsynthetic organelles. This migration of VSMCs from the media to the intima, and

the consequent change from a contractile to a synthetic 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 prot einases 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 producevarious 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 t he

only cell capable of synthesizing this cap, it follows that VSMCs play a pivo tal

role in maintaining plaque stability and protecting against the potentially fatal

thrombotic consequences of atherosclerosis (52).

Cellular Interactions and Lesion StabilityGenerally, 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 p resence 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 plateletaccumulation and activation, fibrin deposition, and intravascular thrombosis.

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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 (

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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 isimportant 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 CapRupture and Endothelial ErosionAtherosclerotic plaques become life threatening when they initiate clot formation

in the vessel lumen and disturb b lood 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 factorrich lipid

core to circulating blood, o r 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-

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,

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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 macrophagefoam 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

of plaque rupture or erosion with subsequent VSMC-driven repair.

Balance of Atherosclerosis: TherapeuticImplicationsAtherosclerosis is a dynamic process in which the balance between the

destructive influence of inflammatory cells and the r eactive, 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

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).

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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 t o a plaque-

stabilizing effect comes from animal studies that showed that statins reduced

inflammatory cell and increased VSMC content of p laques (90,91), changes that

would be expected to enhance stability. Dietary lip id 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 t hat

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 ruptu res, 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. Thisconclusion is supported by the results of all the large primary and secondary

prevention studies, which have demonstrated that statins (p ravastatin,

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 o f, 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 statinson nonatherosclerotic inflammation (100,101). Also, in the first study of its kind,

it has been shown that statins reduce inflammation and increase plaque collagen

FIGURE 1.3. Cellular interactions in the development and progression of

atherosclerosis. (Source: Weissberg PL. Atherogenesis: current

understanding of the causes of atheroma. Heart2000;83:247 252, with

permission.)

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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 d irect effects on endothelial cell function,

inflammatory cell number and activity, VSMC proliferation, platelet aggregation,

and thrombus formation (103,104,105,106,107). Evidence that non 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 o f statins as immune

modulators has been described, whereby major histocompatibility complex class

IImediated T-cell activation is reduced by a variety of statins (109). However,

the matter of nonlipid-lowering effects of statins is not yet proven beyond

doubt: several of the pleiotrop ic anti-inflammatory effects of statins (decreased

expression of MMPs, and tissue factor) o ccur in animals on a lipid-lowering d iet

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).

RestenosisRestenosis 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 o f 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 r eports

of early thrombotic occlusions of treated arteries, although longer term analysis

of the data suggest that t his 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.

Controversies and Personal PerspectivesMany 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 ext ent 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

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 ofdeveloping, 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, nuclearfactor- 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- driven matrix production,

that may lead to enhanced maintenance of the fibrous cap. Another important

example includes establishing the role of drugs targeting peroxisome

proliferatoractivated 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 p roteomics 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 orphan 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).

P.10

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The FutureIt 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 intravenousinfusion 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 p remature 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

testsbased 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 gr eatest risk of cardiovascular eventsand subsequent monitoring of plaque-modifying therapies.

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