Atheroma is a disease of the
intima of arteries
Atheroma is the accumulation
of lipid-rich material in the intima of arteries associated with cellular
reactions. The lesions are termed 'plaques'. Although atheroma is essentially a
disease of the tunica intima, it has an impact on the structure and function of
The macroscopic appearance of
atheroma varies according to the stage of evolution of a plaque.
Histologically, plaques show
varying amounts of free lipid, collagen, and macrophages containing lipid (foam
The earliest changes are small
fatty streaks, visible as pale areas beneath the endothelium in the aortic
segment on the left.
The central segment shows pearly white fibrolipid plaques, and the segment on
the right shows ulcerated advanced plaques with adherent fibrin-platelet
The plaque shows pale
lipid-rich areas and pink-stained fibrous areas.
Late in the fibrolipid plaque stage the media is thinned beneath the plaque.
Understanding of risk factors
for atheroma is largely based on epidemiological studies.
Atheroma is almost ubiquitous
in the Western world, virtually all adults developing the disease to some
degree. Fatty streaks can be seen in childhood, small fibrofatty atheromatous
plaques in teenagers and young adults, and complicated atheroma lesions in early
middle age; atheromatous lesions increase in number with age.
Epidemiological studies have
identified risk factors associated with atheroma development. These can be
• Constitutional factors
• Hard risk factors
• Soft risk factors.
(a) The pathogenesis of
atheroma is believed to be damage to the endothelium associated with a variety
of risk factors as coming later. This allows entry of cholesterol-rich
low-density lipoproteins (LDLs) into the intima.
(b) The lipid is taken up by
macrophages in the intima. Normal receptor-mediated uptake of lipid can be
bypassed by oxidization of LDL, which is taken up by a receptor-independent
pathway. In this way, excessive lipid accumulates in intimal macrophages to form
a visible pale bulge termed a 'fatty streak'.
(c) With development and
increased accumulation of lipid, macrophages release lipid into the intima.
Cytokines secreted by macrophages stimulate proliferation of intimal cells with
features of myofibroblasts. These cells secrete collagen and the plaque starts
to become fibrotic. At this stage lesions are raised and yellow (lipid plaques).
As the lesion develops, there is pressure atrophy of the media and the elastic
lamina is disrupted.
(d) Increased secretion of
collagen forms a dense fibrous cap to the plaque which is now hard and white (fibrolipid
plaque). The advanced plaque shows free lipid as well as lipid in macrophages.
Collagenization also affects the media, weakening the arterial wall. The
endothelium is fragile and often ulcerates, allowing platelet aggregation and
thrombosis. It is possible that platelet-derived growth factor causes further
development of plaques by stimulating cell proliferation.
The pathogenesis of atheroma
is still uncertain
There have been many
hypotheses as to the pathogenesis of atheroma, which must explain the origin of
the lipid seen in plaques, the reason for development of the cellular elements
of plaques and the relation to known risk factors for atheroma development.
The thrombogenic hypothesis
proposes that thrombus is incorporated into the intima of vessels, lipid being
derived from platelet membranes and cells stimulated to proliferate by
platelet-derived growth factors (PDGFs).
The clonal proliferation
hypothesis is based on observations that smooth muscle cells in plaques are
derived from one clone of cells, raising the possibility that atheroma is caused
by a primary abnormality in cell growth.
The lipid insudation
hypothesis proposes that LDLs are taken up into the intima, where they become
chemically oxidized to act as toxic, pro-inflammatory and chemotactic factors.
This is supported by the fact that antioxidant drugs can inhibit atherogenesis
in animals. The response to injury hypothesis proposes that the atheromatous
plaque is a response to chronic low-grade injury to the endothelium. Metabolic
disturbance to endothelial cells (as a result of haemodynamic stresses and toxic
effects of LDL) allows platelet adhesion, diffusion of plasma proteins, and
migration of monocytes into the intima of arteries. Platelets release PDGF and
this stimulates proliferation of intimal smooth muscle cells (myointimal cells).
These, in turn, synthesize excess collagen and elastin in the intima.
Oxidization of LDL facilitates its uptake into monocytes by
consequences of atheroma
Atheroma produces disease in
• Reduction of blood flow
through arteries. When atheroma affects small arteries, the enlargement of an
intimal atheromatous plaque may severely reduce the size of the lumen. The main
clinical implications are ischaemic heart disease. peripheral vascular disease.
and cerebrovascular disease.
• Predisposition to
thrombosis. If the fibrous cap over an atheromatous plaque breaks down, collagen
fibres in the abnormal intima are exposed to the circulating blood, and this
initiates the formation of thrombus In small-bone vessels, such as the coronary
or cerebral arteries, this thrombus may suddenly complete the occlusion of an
already narrowed artery. In larger vessels, such as the aorta, a plaque of mural
thrombus is formed, which may embolize to distal vessels.
• Bleeding into a plaque. If
there is breakdown of the fibrous cap of a plaque, blood may dissect into the
centre of the plaque, causing it to balloon into the vessel lumen and reducing
blood flow. This is occasionally seen in coronary arteries, leading to
• Weakening of vessel wall and
aneurys formation. Severe atheroma in the intima eventually leads to thinning of
the media, loss of smooth muscle cells and elastic fibres, and progressive
replacement by non contractile inelastic collagen. The media becomes
functionally incompetent and this leads to generalized dilatation of the artery
over a period of some years to form an aneurysm. The abdominalaorta is the most
common site for aneurysms secondary to atherosclerosis.