responsible for the strong predilection for certain sites (e.g. at
the low-shear side of the origin of arteries branching from
the aorta). The injury may initially be undetectable morphologi-
cally, but results in focal endothelial dysfunction. Blood
monocytes adhere to adhesion molecules expressed by injured
endothelium and migrate into the vessel wall, where they
become macrophages. These possess receptors for oxidized
(but not native) LDL, which they ingest to become ‘foam cells’.
Lesions become infiltrated with extracellular as well as
intracellular cholesterol. Lymphocytes and platelets adhere to
the injured intima and secrete growth factors and cytokines,
which cause migration, proliferation and differentiation of
vascular smooth muscle cells and fibroblasts from the under-
lying media and adventitia. These processes result in the for-
mation of fibro-fatty plaques.
Atheromatous lesions are not necessarily irreversible.
Cholesterol is mobilized from tissues in the form of HDL
particles. These are not atherogenic – indeed, epidemiological
studies have identified HDL as being strongly negatively correl-
ated with coronary heart disease. There is a close relationship
between an apolipoprotein, apo(a), and plasminogen, linking
atherogenesis to thrombosis. Apo(a) is present in a lipoprotein
known as Lp(a). The plasma concentration of Lp(a) varies over
a 100-fold range and is strongly genetically determined. Most
drugs have little effect (nicotinic acid is an exception). Apo(a)
contains multiple repeats of one of the kringles of plasminogen
(a kringle is a doughnut-shaped loop of amino acids held
together by three internal disulphide bonds). This leads to inter-
ference by Lp(a) with the function of plasminogen, which is the
precursor of the endogenous fibrinolytic plasmin, and hence to
a predisposition to thrombosis on atheromatous plaques.
PREVENTION OF ATHEROMA
Modifiable risk factors are potentially susceptible to therapeutic
intervention. These include smoking, obesity, sedentary habits,
dyslipidaemia, glucose intolerance (Chapter 37) and hyperten-
sion (Chapter 28). Disappointingly hopes, based on epidemio-
logical observations, that hormone replacement treatment of
post-menopausal women (Chapter 41) would prevent athero-
matous disease were disproved by randomized controlled trials
(Figure 27.4).SMOKINGCigarette smoking (Chapter 53) is a strong risk factor for vas-
cular disease. It causes vasoconstriction via activation of the
sympathetic nervous system and platelet activation/aggrega-
tion with a consequent increase in thromboxane A 2 biosynthe-
sis (see Figure 27.2), although the precise mechanism whereby
smoking promotes atheroma is unknown. Stopping smoking
is of substantial and rapid benefit. Smoking is addictive and
attempts to give up are often unsuccessful. The use of nico-
tine,bupropionandvarenicline(partial agonist at the nico-
tinic receptor) in conjunction with counselling in smoking
cessation programmes are covered in Chapter 53.DIET AND EXERCISEObesity is increasingly common and is a strong risk factor,
partly via its associations with hypertension, diabetes and
dyslipidaemia. Treatment (Chapter 34) is notoriously difficult.
Sedentary habit is a risk factor and regular exercise reduces
cardiovascular risk, partly by reducing resting systolic blood
pressure and increasing HDL.DYSLIPIDAEMIAMost patients with dyslipidaemia have a combination of
genetic and dietary factors. Secondary forms of dyslipidaemia
are listed in Table 27.1. Reducing the total plasma cholesterol
concentration reduces the risk of coronary heart disease and
can cause regression of atheroma. Dietary advice focuses on
reducing saturated fat and correcting obesity rather than
reducing cholesterol intake per se. In people without clinical
evidence of atheromatous disease, the decision as to whether
to initiate drug treatment at any given level of serum lipids
should be informed by the risk of coronary events. This is cal-
culated from cardiovascular risk prediction charts (e.g. at the
back of the British National Formulary) or algorithms or cal-
culators available on--line, e.g. via the British Hypertension
Society website (www.bhsoc.org/Cardiovascular_Risk_Charts_
and_Calculators.stm). An approach to therapy is summarized in
Figure 27.5.PREVENTION OFATHEROMA 179Key points
Atherogenesis- Endothelial injury initiates the process. The distribution
of lesions is influenced by turbulence (e.g. at branch
points) in the arterial circulation. - Monocytes in the blood bind to ICAM/integrin
receptors on injured endothelium and migrate into the
vessel wall, where they become macrophages. - LDL is oxidized by free radicals generated by activated
cells (including macrophages and endothelial cells).
Oxidized LDL is taken into macrophages via scavenger
receptors. - This sets up a chronic inflammatory process in which
chemical messengers are released by lipid-laden
macrophages (‘foam cells’), T-lymphocytes and
platelets. These interleukins and growth factors cause
the migration and proliferation of vascular smooth
muscle cells and fibroblasts, which form a fibro-fatty
plaque. - Cigarette smoking promotes several of these processes
(e.g. platelet aggregation). - If the plaque ruptures, thrombosis occurs on the
subendothelium, and may occlude the vessel, causing
stroke, myocardial infarction, etc., depending on the
anatomical location.