Atherosclerosis
Atherosclerosis is a disease of the larger arteries. It begins in childhood with
localized accumulations of lipid within the arterial intima, termed fatty
streaks. By middle age some of these develop into atherosclerotic
plaques, focal lesions where the arterial wall is grossly abnormal. Plaques
may be several centimetres across, and are most common in the aorta, the
coronary and internal carotid arteries, and the circle of
Willis. An advanced atherosclerotic plaque, illustrated on the right of
Figure 37, demonstrates several features.
1. The arterial wall is focally
thickened by intimal smooth muscle cell proliferation and the deposition of
fibrous connective tissue, forming a hard fibrous cap. This projects
into the vascular lumen, restricting the flow of blood, and often causes ischaemia in the
tissue region served by the artery.
2. A soft pool of extracellular
lipid and cell debris accumulates beneath the fibrous cap (athera is
Greek for ‘gruel’ or ‘porridge’). This weakens the arterial wall, so that the
fibrous cap may fissure or tear away. As a result, blood enters the lesions and
thrombi (blood clots) are formed. These thrombi, or the material leaking
from the ruptured lesion, may be carried to the upstream vascular bed to embolize
(plug) smaller vessels. A larger thrombus may totally occlude (block) the
artery at the site of the lesion. This causes myocardial infarction or stroke
if it occurs in a coronary or cerebral artery, respectively.
3. The endothelium over the lesion
is partially or completely lost. This can lead to ongoing formation of thrombi,
causing intermittent flow occlusion as in unstable angina.
4. The medial smooth muscle layer
under the lesion degenerates. This weakens the vascular wall, which may distend
and eventually rupture (an aneurysm). Aneurysms are especially common in
the abdominal aorta.
Atherosclerotic arteries may also demonstrate spasms or
reduced vasodilatation. This worsens the restriction of the blood flow and
promotes thrombus formation (see Chapters 42 and 44).
The risk of developing atherosclerosis is in part genetically
determined. The incidence of clinical consequences of atherosclerosis such as
ischaemic heart disease rises with age, especially after age 40. Atherosclerosis is much more common in men than in
women. This difference is probably due to a protective effect of oestrogen, and
progressively disappears after menopause. Important risk factors that
predispose towards atherosclerosis include smoking, hypertension, diabetes and
high serum cholesterol.
The most widely accepted hypothesis for the pathogenesis
of atherosclerosis proposes that it is initiated by endothelial injury or
dysfunction. Plaques tend to develop in areas of variable haemodynamic
shear stress (e.g. where arteries branch or bifurcate). The endothelium is
especially vulnerable to damage at such sites, as evidenced by increased
endothelial cell turnover and permeability. Endothelial dysfunction promotes
the adhesion of monocytes, white blood cells which
burrow beneath the endothelial monolayer and become macrophages.
Macrophages normally have an important role during inflammation, the body’s
response to injury and infection. They do so by acting as scavenger cells to
remove dead cells and foreign material, and also by subsequently releasing cytokines
and growth factors to promote healing. As described below, however,
macrophages in the arterial wall can be abnormally activated, causing a type of
slow inflammatory reaction, which eventually results in advanced and clinically
dangerous plaques.
Lipoproteins transport
cholesterol and other lipids in the bloodstream (see Chapter 36). Elevated
levels of one type of lipoprotein, low-density lipoprotein (LDL), are
associated with atherosclerosis. Native LDL is not atherogenic. However,
oxidative modification of LDL by oxidants derived from macrophages and
endothelial and smooth muscle cells can lead to the generation of highly
atherogenic oxidized LDL within the vascular wall.
Oxidized LDL is thought to promote atherogenesis through
several mechanisms (upper panel of Figure 37). Oxidized LDL is chemotactic for
(i.e. attracts) circulating monocytes, and increases the expression of
endothelial cell adhesion molecules to which monocytes attach. The monocytes
then penetrate the endothelial monolayer, lodge beneath it and mature into
macrophages. Cellular uptake of native LDL is normally highly regulated.
However, certain cells, including macrophages, are unable to control their
uptake of oxidized LDL, which occurs via scavenger receptors. Once
within the vascular wall, macrophages therefore accumulate large quantities of
oxidized LDL, eventually becoming the cholesterol-laden foam cells forming
the fatty streak.
As shown in the lower left of Figure 37, stimulation of
macrophages and endothelial cells by oxidized LDL causes these cells to
release cytokines. T lymphocytes may also enter the vascular wall and release
cytokines. Additional cytokines are released by platelets aggregating on the
endothelium at the site at which it has been damaged by oxidized LDL and other
toxic substances released by the foam cells. The cytokines act on the vascular
smooth muscle cells of the media, causing them to migrate into the intima,
to proliferate and to secrete abnormal amounts of collagen and other
connective tissue proteins. Over time, the intimal accumulation of smooth
muscle cells and connective tissue forms the fibrous cap on the inner arterial
wall. Underneath this, ongoing foam cell formation and deterioration forms a
layer of extracellular lipid (largely cholesterol and cholesteryl esters) and
cellular debris. Still viable foam cells often localize at the edges or
shoulders of the lesion. Underneath the lipid, the medial layer of smooth
muscle cells is weakened and atrophied.
Clinical consequences of advanced atherosclerosis
Atherosclerotic lesions are of most clinical consequence
when they occur in the coronary arteries. Lesions in which the fibrous cap
becomes thick tend to cause a significant stenosis, or narrowing of the
vascular lumen, which gradually comes to cause cardiac ischaemia, especially
when myocardial oxygen demand rises. This leads to stable or exertional
angina (see Chapter 39). Advanced plaques often have large areas of
endothelial denudation, which serve as sites for thrombus formation. In
addition, lipid and foam-cell-rich lesions are particularly unstable and prone
to tearing open. This plaque rupture may be favoured by the presence in
the lesion of T lymphocytes, as these produce interferon-γ which inhibits
matrix formation, and of macrophages, which produce proteases that degrade the
connective tissue matrix. Plaque rupture allows blood to enter the lesion,
causing thrombi to form on the surface and/or within the lesion, often
resulting in an acute coronary syndrome such as unstable angina (see Chapter
42) or myocardial infarction (see Chapter 43). Non-fatal chronic thrombi may
gradually be replaced by connective tissue and incorporated into the lesion, a
process termed organization. Atherosclerosis of cerebral arteries is the
major cause of stroke (cerebral infarction). Atherosclerotic stenosis of
the renal arteries causes about two-thirds of cases of renovascular
hypertension.
