Atherosclerosis

Atherosclerosis is a degenerative disease of large- and
medium-sized arteries with a predisposition for critical
arterial beds such as the coronaries, which supply
heart muscle with nutritive, oxygenated blood. The
disease is characterized by the progressive formation
of an atheromatous plaque upon the innermost
layer of the arterial wall. This build-up of fatty material
reduces the bore of the artery whilst also causing
hardening and loss of elasticity of the arterial wall.
Plaque formation is preceded by a reduced ability of
the arterial smooth muscle to relax. Atherosclerosis
is the principal cause of cardiovascular and cerebrovascular
disease, leading to heart attacks and strokes,
respectively.
The causal relationship between high blood cholesterol
levels and atherosclerosis is well established
(Levine et al., 1995). Hypercholesterolaemia may
be thought of as any plasma cholesterol level above
160 mg/100 mL. Cholesterol-lowering therapy is effective
in both the primary prevention of coronary
artery disease and the secondary prevention of subsequent
cardiac events in patients with established
coronary disease.
4.5.1 Association between high blood
cholesterol and atherosclerosis
An early demonstration of the link between hypercholesterolaemia
and atherosclerosis took place
in 1913 when Anitschkow in Russia observed that
feeding pure cholesterol to rabbits produced elevated
blood cholesterol levels as well as atherosclerosis in
the aorta and coronary arteries.
The causal relationship between high blood cholesterol
levels and atherosclerosis is demonstrated
unequivocally by the genetic disorder familial hypercholesterolaemia
(FH). This disorder is an example of
an inborn error of metabolism and is due to impaired
production of the LDL receptor. There are two forms
of FH: a heterozygous form and a more severe homozygous
form. FH heterozygotes inherit one mutant
gene and number about one in 500 people in most
ethnic groups. The cells of these individuals produce
approximately half the normal number of LDL receptors.
As a result, LDL is removed from the circulation
at half the normal rate, the lipoprotein accumulates
in blood to levels twofold above normal, and heart
attacks occur typically in the fourth and fi fth decades
of life. If two heterozygotes of the opposite sex have a
child, that child has a one in four chance of inheriting
two copies of the mutant gene, one from each parent.
Such FH homozygotes (about one in a million
people) have plasma LDL levels 6–10-fold above
normal. Heart attacks can occur at the age of two and
are almost inevitable by the age of 20 (Goldstein &
Brown, 1987).
4.5.2 The lesions of atherosclerosis
The wall of a typical artery is composed of three coats.
The innermost coat, the tunica intima, consists of an
Background biochemistry 81
inner endothelium, a subendothelial layer of delicate
fi broelastic connective tissue and an external band of
elastic fi bres, which may be absent in many vessels.
The middle coat, the tunica media, consists chiefl y of
circularly arranged smooth muscle cells. The outer
coat, the tunica adventitia, is composed principally of
connective tissue, most of the elements of which run
parallel to the long axis of the vessel. The structure and
relative thickness of each coat vary according to the
type and size of the vessel.
The lesions of atherosclerosis represent a continuum
from the early fatty streak to the intermediate
fi brofatty lesion to the mature fi brous plaque. Early
lesions are commonly found at intimal sites where
changes in blood fl ow occur at branches and curves
in the arterial system. Changes in the mature lesion
involve all three coats of the arterial wall. Not all fatty
streaks progress to fi brous plaques; some remain stable
or regress and disappear.
The fatty streak
The fatty streak is composed mainly of an aggregation
of lipid-fi lled macrophages and smooth muscle cells
known as foam cells within the intima. The overlying
endothelium is frequently thinned and distorted by
the subjacent foam cells. Blood monocytes are continuously
recruited to the evolving fatty streak where
they differentiate into macrophages.
The fi brofatty lesion
This intermediate lesion is characterized by necrosis
of the foam cells with the release of foam cell lipids
to the interstitium. There is mitogen-stimulated
proliferation of smooth muscle cells and subsequent
synthesis of collagen, elastin and proteoglycans.
Monocyte recruitment continues and the endothelium
begins to fragment.
The fi brous plaque
The fi brous plaque comprises a dense cap of fi brous
connective tissue containing multiple layers of
smooth muscle cells that occupy slit-like spaces. Foam
cells accumulate at the shoulders of the plaque. Beneath
the fi brous cap is a region rich in macrophages,
T lymphocytes and smooth muscle cells, and beneath
that is a core of extracellular lipid, cholesterol crystals,
necrotic debris and calcifi cation. Microvascular channels
ramify throughout the thickened lesion, presumably
to provide nutrients and oxygen to the cells.
Although there may be severe atherosclerotic narrowing
of arteries, atherosclerosis alone rarely results
in occlusion, defi ned as complete obliteration of the
arterial lumen. However, rheological forces may cause
the plaque to rupture or fi ssure, resulting in haemorrhage
into the plaque, thrombosis and occlusion.
This happening is a major cause of myocardial infarction.