ATHEROSCLEROSIS

Atherosclerosis is characterized by intimal

lesions called atheromas (also called atheromatous or atherosclerotic plaques),
that protrude into vascular lumina. An atheromatous plaque consists of a raised
lesion with a soft, yellow, grumous core of lipid (mainly cholesterol and
cholesterol esters) covered by a firm, white fibrous cap. Besides obstructing
blood flow, atherosclerotic plaques weaken the underlying media and can
themselves rupture, causing acute catastrophic vessel thrombosis
Epidemiology
Atherosclerosis is much less prevalent in Central and South America, Africa, and
Asia. The mortality rate for IHD in the United States is among the highest in the
world and is approximately five times higher than that in Japan. Multiple risk
factors have a multiplicative effect; two risk factors increase the risk
approximately fourfold. When three risk factors are present (e.g., hyperlipidemia,
hypertension, and smoking), the rate of myocardial infarction is increased seven
times.
Major Constitutional Risk Factors for IHD

Pathogenesis
Atherosclerosis as a chronic inflammatory response of the arterial wall to
endothelial injury. Lesion progression occurs through interactions of modified
lipoproteins, monocyte-derived macrophages, T lymphocytes, and the normal
cellular constituents of the arterial wall.
Chronic endothelial injur endothelial dysfunction increased permeability,
leukocyte adhesion, and thrombosis Accumulation of lipoproteins (mainly LDL
and its oxidized forms) in the vessel wall Monocyte adhesion to the
endothelium, followed by migration into the intima and transformation into
macrophages and foam cells Platelet adhesion Factor release from activated
platelets, macrophages, and vascular wall cells, inducing SMC recruitment,
either from the media or from circulating precursors SMC proliferation and ECM
productionLipid
accumulation
both
extracellularly
and
within
cells
(macrophages and SMCs)
The accumulation of lipid-containing macrophages in the initima gives rise to
"fatty streaks". With further evolution, a fibrofatty atheroma consisting of
proliferated SMC, foam cells, extracellular lipid, and ECM is formed.
Endothelial Injury
o Endothelial loss due to any kind of injury-whether induced experimentally by
mechanical denudation, hemodynamic forces, immune complex deposition,
irradiation, or chemicals-results in intimal thickening; in the presence of highlipid diets, typical atheromas ensue. In the setting of intact but dysfunctional
ECs there is increased endothelial permeability, enhanced leukocyte adhesion,
and altered gene expression.
o The specific causes of endothelial dysfunction in early atherosclerosis are not
completely understood. Etiologic culprits include toxins from cigarette smoke,
homocysteine, and even infectious agents. Inflammatory cytokines (e.g.,
tumor necrosis factor, or TNF) can also stimulate the expression of proatherogenic genes in EC. Nevertheless, the two most important causes of
endothelial
dysfunction
are
hemodynamic
disturbances
and
hypercholesterolemia. Inflammation is also an important contributor.
Hemodynamic Disturbance
o

Plaques tend to occur at ostia of exiting vessels, branch points, and along the
posterior wall of the abdominal aorta, where there are disturbed flow patterns.
Nonturbulent laminar flow in other parts of the normal vasculature leads to the
induction of endothelial genes whose products (e.g., the antioxidant
superoxide dismutase) actually protect against atherosclerosis.

Lipids
o Lipids are typically transported in the bloodstream bound to specific
apoproteins (forming lipoprotein complexes). Dyslipoproteinemias can result
from mutations that encode defective apoproteins or alter the lipoprotein
receptors on cells, or from some other underlying disorder that affects the

circulating levels of lipids (e.g., nephrotic syndrome, alcoholism,

hypothyroidism, or diabetes mellitus). Common lipoprotein abnormalities
include (1) increased LDL cholesterol levels, (2) decreased HDL cholesterol
levels, and (3) increased levels of the abnormal Lp(a).
The dominant lipids in atheromatous plaques are cholesterol and cholesterol
esters. Genetic defects in lipoprotein uptake and metabolism that cause
hyperlipoproteinemia are associated with accelerated atherosclerosis. Thus,
homozygous familial hypercholesterolemia, caused by defective LDL receptors
and inadequate hepatic LDL uptake, can lead to myocardial infarction before
the age of 20 years. Lowering serum cholesterol by diet or drugs slows the
rate of progression of atherosclerosis, causes regression of some plaques, and
reduces the risk of cardiovascular events.
Chronic hyperlipidemia, particularly hypercholesterolemia, can directly impair
EC function by increasing local production of reactive oxygen species. Among
other effects, oxygen free radicals accelerate nitric oxide
decay, damping

its vasodilator activity and thereby increasing local shear stress. With chronic
hyperlipidemia, lipoproteins accumulate within the intima. These lipids are
oxidized through the action of oxygen free radicals locally generated by
macrophages or ECs. Oxidized LDL is ingested by macrophages through a
scavenger receptor, distinct from the LDL receptor, resulting in foam-cell
formation. In addition, oxidized LDL stimulates the release of growth factors,
cytokines, and chemokines by ECs and macrophages that increase monocyte
recruitment into lesions. Finally, oxidized LDL is cytotoxic to ECs and SMCs and
can induce EC dysfunction.
Inflammation
o Inflammatory cells and mediators are involved in the initiation, progression,
and the complications of atherosclerotic lesions. Early in atherogenesis
dysfunctional arterial ECs express adhesion molecules that encourage
leukocyte adhesion; vascular cell adhesion molecule 1 (VCAM-1) in particular
binds monocytes and T cells. After these cells adhere to the endothelium, they
migrate into the intima under the influence of locally produced chemokines.
o Monocytes transform into macrophages and avidly engulf lipoproteins,
including oxidized LDL. Monocyte recruitment and differentiation into
macrophages (and ultimately into foam cells) is theoretically protective, since
these cells remove potentially harmful lipid particles. Over time, however,
progressive accumulation of oxidized LDL drives lesion progression. Thus,
macrophage activation (via oxidized LDL or T cells, see below) results in
cytokine production (e.g., TNF) that further increases leukocyte adhesion and
chemokine production that in turn propel mononuclear inflammatory cell
recruitment. Activated macrophages also produce reactive oxygen species,
aggravating LDL oxidation.T lymphocytes recruited to the intima interact with
macrophages and can generate a chronic immune inflammatory state.
Activated T cells in the growing intimal lesions elaborate inflammatory
cytokines, (e.g., interferon-), which in turn can stimulate macrophages as
well as ECs and SMCs.As a consequence of the chronic inflammatory state,
activated leukocytes and vascular wall cells release growth factors that
promote SMC proliferation and ECM synthesis.
Infection
o Herpesvirus, cytomegalovirus, and Chlamydia pneumoniae have all been
detected in atherosclerotic plaque but not in normal arteries, and
seroepidemiologic studies find increased antibody titers to C. pneumoniae in
patients with more severe atherosclerosis.
Smooth Muscle Proliferation
o Intimal SMC proliferation and ECM deposition convert a fatty streak into a
mature atheroma and contribute to the progressive growth of atherosclerotic
lesions. Recall that the intimal SMCs have a proliferative and synthetic
phenotype distinct from the underlying medial SMCs and, in fact, may
substantially derive from the recruitment of circulating precursors. Several
growth factors are implicated in SMC proliferation and ECM synthesis,
including platelet-derived growth factor (PDGF, released by locally adherent
platelets as well as by macrophages, ECs, and SMCs), fibroblast growth factor,
and transforming growth factor . The recruited SMCs synthesize ECM (notably

collagen), which stabilizes atherosclerotic plaques. However, activated

inflammatory cells in atheromas can cause intimal SMC apoptosis, and they
also increase ECM catabolism, resulting in unstable plaques.

Morphology
Fatty Streaks. Fatty streaks are composed of lipid-filled foam cells but are not
significantly raised and thus do not cause any disturbance in blood flow. They
begin as multiple minute yellow, flat spots that can coalesce into elongated
streaks, 1 cm long or longer. Fatty streaks can appear in the aortas of infants
younger than 1 year and are present in virtually all children older than 10 years.
Coronary fatty streaks begin to form in adolescence, at the same anatomic sites
that later tend to develop plaques.
Atherosclerotic Plaque. The key processes in atherosclerosis are intimal
thickening and lipid accumulation. Atheromatous plaques (also called fibrous or
fibrofatty plaques) impinge on the lumen of the artery and grossly appear white
to yellow; thrombosis superimposed over the surface of ulcerated plaques is
red-brown in color. Plaques vary from 0.3 to 1.5 cm in diameter but can
coalesce to form larger masses.
In descending order, the most extensively involved vessels are the lower
abdominal aorta, the coronary arteries, the popliteal arteries, the
internal carotid arteries, and the vessels of the circle of Willis. Vessels
of the upper extremities are usually spared, as are the mesenteric and renal
arteries, except at their ostia.
Atherosclerotic plaques have three principal components: (1) cells,
including SMCs, macrophages, and T cells; (2) ECM, including collagen,
elastic fibers, and proteoglycans; and (3) intracellular and

extracellular lipid. Typically, the superficial fibrous cap is composed of SMCs

and relatively dense collagen. Beneath and to the side of the cap (the
"shoulder") is a more cellular area containing macrophages, T cells, and SMCs.
Deep to the fibrous cap is a necrotic core, containing lipid (primarily
cholesterol and cholesterol esters), debris from dead cells, foam cells (lipidladen macrophages and SMCs), fibrin, variably organized thrombus, and other
plasma proteins; the cholesterol content is frequently present as crystalline
aggregates that are washed out during routine tissue processing and leave
behind only empty "clefts." At the periphery of the lesions, there is usually
neovascularization (proliferating small blood vessels). Typical atheromas
contain relatively abundant lipid, but some plaques ("fibrous plaques") are
composed almost exclusively of SMCs and fibrous tissue.
Plaques generally continue to change and progressively enlarge through cell
death and degeneration, synthesis and degradation (remodeling) of ECM, and
organization of thrombi. Moreover, atheromas often undergo calcification.
Patients with advanced coronary calcification appear to be at increased risk for
coronary events.
Rupture, ulceration, or erosion of the luminal surface of atheromatous
plaques exposes the bloodstream to highly thrombogenic substances and
induces thrombus formation. Such thrombi can partially or completely occlude
the lumen and lead to downstream ischemia. If the patient survives the initial
vascular occlusion, thrombi may become organized and incorporated into the
growing plaque. Hemorrhage into a plaque. Rupture of the overlying fibrous
cap or of the thin-walled vessels in the areas of neovascularization can cause
intra-plaque hemorrhage; a contained hematoma may expand the plaque or
induce plaque rupture. Atheroembolism. Plaque rupture can discharge debris
into the bloodstream, producing microemboli composed of plaque contents.
Aneurysm formation. Atherosclerosis-induced pressure or ischemic atrophy of
the underlying media, with loss of elastic tissue, causes weakness of the vessel
wall and development of aneurysms that may rupture
.
Natural History of Atherosclerosis
Atherosclerosis primarily affects elastic arteries (e.g., aorta, carotid, and iliac
arteries) and large and medium-sized muscular arteries (e.g., coronary and
popliteal arteries). In small arteries, atheromas can gradually occlude lumina,
compromising blood flow to distal organs and cause ischemic injury. Moreover,
atherosclerotic plaques can undergo acute disruption and precipitate thrombi
that further obstruct blood flow. In large arteries, plaques are destructive,
encroaching on the subjacent media and weakening the affected vessel wall,
causing aneurysms that can rupture. Moreover, atheromas can be friable,
fragmenting atheroemboli into downstream circulations. It is important to
emphasize that atherosclerosis is a slowly evolving lesion usually requiring many
decades to become significant. However, acute plaque changes (e.g., rupture,
thrombosis, or hematoma formation) can rapidly precipitate clinical sequelae
Symptomatic atherosclerotic disease most often involves the arteries supplying
the heart, brain, kidneys, and lower extremities. Myocardial infarction (heart
attack), cerebral infarction (stroke), aortic aneurysms, and peripheral vascular
disease (gangrene of the legs) are the major consequences of atherosclerosis.
Atherosclerosis also takes a toll through other consequences of acutely or
chronically diminished arterial perfusion, such as mesenteric occlusion, sudden
cardiac death, chronic IHD, and ischemic encephalopathy. The effects of vascular
occlusion ultimately depend on arterial supply and tissue metabolic demand;
details will be discussed in greater detail in subsequent organ-specific chapters.

Prevention of Atherosclerotic Vascular Disease

Primary prevention programs aimed at either delaying atheroma formation or
encouraging regression of established lesions in persons who have not yet
suffered a serious complication of atherosclerosis. Secondary prevention
programs intended to prevent recurrence of events such as myocardial
infarction or stroke in symptomatic patients.
Primary prevention of atherosclerosis-related complications typically involves risk
factor identification and modification of those that are amenable to
intervention: cessation of cigarette smoking, control of hypertension, weight
loss, exercise, and lowering total and LDL blood cholesterol levels while
increasing HDL (e.g., by diet or through statins). Interestingly, statin use may
also modulate the inflammatory state of the vascular wall. Several lines of
evidence suggest that risk factor stratification and reduction should even begin
in childhood.
Secondary prevention involves the judicious use of aspirin
(anti-platelet
agent), statins, and beta blockers (to limit cardiac demand), as well as surgical
interventions (e.g., coronary artery bypass surgery, carotid endarterectomy).
These can successfully reduce recurrent myocardial or cerebral events.
Between 1963 (the peak year) and 2000 there has been an approximately 50%
decrease in the death rate from IHD and a 70% decrease in deaths from
strokes, a reduction in mortality that alone has largely increased the average
life expectancy in the United States by 5 years. Three main contributors to this
impressive improvement have been (1) prevention of atherosclerosis through
recognition of risk factors and changes in life style (e.g., reduced cigarette
smoking, reduced consumption of cholesterol, and control of hypertension); (2)
improved methods of treatment of myocardial infarction and other
complications of IHD; and (3) prevention of recurrences in patients who have
previously suffered serious atherosclerosis-related clinical events.