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chapter20
Lipids ill: Plasma Lipoproteins
of 100 mg/dL, whereas children of comparable age in the
U.S.A. have a value of 185 mg/dL.
Epidemiological studies have established that reduc-
tion in plasma total cholesterol levels reduces the risk
of coronary heart disease (CHD). For example, when the
bile acid sequestrant cholestyramine was used to reduce
plasma cholesterol levels in a randomized, double-blind
study, a 19% reduction in CHD risk was associated with
each decrement of
8
% in total plasma cholesterol levels.
The incidence of CHD in men who experienced a fall
of 25% in total plasma cholesterol was half that of men
who remained at pretreatment levels. Several studies show
that therapy with cholesterol-reducing HMG-CoA reduc-
tase inhibitors (called statins) in patients with coronary
artery disease and elevated cholesterol levels reduces both
fatal and nonfatal heart attacks. Cardiovascular benefits
from statin therapy have been observed even among pa-
tients with “normal” cholesterol levels. These data and
the significant decreases in CHD mortality in industrial-
ized nations in recent years, which were accompanied by
declines in total plasma cholesterol levels, suggest that
although a large fraction of an individual’s plasma choles-
terol level may be genetically determined, sociocultural
determinants can strongly influence susceptibility to heart
disease.
The relationship between the development of prema-
ture CHD and LDL cholesterol is well established. Recent
analyses of epidemiological data have suggested an in-
verse correlation between HDL cholesterol and prema-
ture CHD. At any given level of LDL cholesterol, the
probability of CHD increases as the level of HDL choles-
terol decreases. These observations suggest that a lowered
HDL cholesterol level (or HDL deficiency) is an inde-
pendent risk factor for premature CHD. In one study of
men aged 50-69, the prevalence (number of cases per
1000 persons) of CHD at plasma HDL cholesterol lev-
els of < 25, 25-34, 35^14, and 45-54 mg/dL was 180,
123.6, 94.6, and 77.9, respectively. The cardioprotective
effect of HDL cholesterol may involve removal of choles-
terol from the peripheral tissues and its transport to the
liver for removal. As discussed earlier, the efflux of
cholesterol from peripheral cells is mediated by ABC1-
transporter 1. Defects and polymorphisms of this protein
are determining factors in the plasma HDL cholesterol lev-
els. In animal studies it has been shown that regulation and
expression of the ABC1 protein play a significant role in
cholesterol efflux and reverse cholesterol transport. Fur-
thermore the ABC1 protein present in the intestinal cell
membrane mediates the cholesterol efflux into the lumen,
thus preventing cholesterol absorption. Potential mecha-
nisms of the antiatherogenic effects of HDL cholesterol
include:
1. Inhibition of conversion of LDL to oxidized LDL
which is preferentially taken up by the tissue
macrophages,
2. The prevention of adhesion of monocytes to the
endothelium, and
3. The prolongation of the half-life of prostacyclin
produced by endothelial cells to promote vasodilatory
effects.
The inhibition of LDL oxidation by HDL has been at-
tributed to both an HDL-associated, calcium-dependent
enzyme known as paraoxonase, and to a phospholipid
fraction. HDL cholesterol and triacylglycerol levels are in-
versely correlated across various populations. Decreased
HDL levels are associated with male sex, obesity, phys-
ical inactivity, cigarette smoking, and hypertriacylglyc-
erolemia. Increased HDL levels are associated with female
sex and vigorous exercise undertaken regularly (e.g., run-
ning). The incidence of atherosclerosis in premenopausal
women is significantly lower than in men. This difference
has been attributed to estrogen. In fact, in postmenopausal
women with a decline in estrogen levels, the risk of ather-
sclerosis rises and this risk can be reduced with estrogen
therapy. The atheroprotective effect of estrogen involves
both rapid effects (nongenomic) and long-term effects (ge-
nomic). The direct effects of estrogen on endothelial cells
and smooth muscle cells of blood vessels include vasodi-
lation and inhibition of response to vascular injury. The
vasodilation has been attributed to the production of nitric
oxide and prostacyclin in the blood vessel. The long-term
effects of estrogen involve changes in gene expression me-
diated by estrogen receptors that are ligand-activated tran-
scription factors (Chapter 34).
Several parameters are affected by estrogen. Some of
these include changes in the serum lipid concentration,
coagulation and fibrinolytic systems, and antioxidant sys-
tems. Estrogen in women lowers total serum cholesterol,
LDL cholesterol levels, and Lp(a) concentrations and ele-
vates HDL cholesterol. These effects of estrogen on serum
lipoproteins are largely due to estrogen-mediated effects
of the expression of apolipoprotein genes in the liver. Pro-
gesterone can blunt estrogen’s effect on serum lipid lev-
els. In addition to environmental factors, genetic factors
influence HDL levels. The familial aggregation of CHD
is well recognized, and children of CHD patients have
lower HDL concentations. The approach taken in the man-
agement of individuals with low HDL cholesterol level
(Table 20-6) is similar to that of patients in whom LDL
cholesterol levels are high (discussed later). First, it is es-
sential to exclude secondary causes of lipid abnormalities,
which include acute illness, chronic diseases, and some
commonly prescribed drugs (Table 20-7). Second, it is
