DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

884 Tangier disease, a genetic disorder characterized by
extremely low levels of HDL and cholesterol accumulation
in the liver, spleen, tonsils, and neurons of peripheral
nerves. Transgenic animals overexpressing ABCA1
in the liver and macrophages have elevated plasma levels
of HDL and apoA-I and reduced susceptibility to
atherosclerosis (Van Eck et al., 2006).
After free cholesterol is acquired by the pre-β1
HDL, it is esterified by lecithin:cholesterol acyltransferase.
The newly esterified and nonpolar cholesterol
moves into the core of the discoidal HDL. As the cholesteryl
ester content increases, the HDL particle
becomes spherical and less dense. These newly formed
spherical HDL particles (HDL 3
) further enlarge by
accepting more free cholesterol, which is in turn esterified
by lecithin:cholesterol acyltransferase. In this way,
HDL 3
are converted to HDL 2
, which are larger and less
dense than HDL 3
.
As the cholesteryl ester content of the HDL 2
increases, the cholesteryl esters of these particles begin
to be exchanged for triglycerides derived from any of
the triglyceride-containing lipoproteins (chylomicrons,
VLDL, remnant lipoproteins, and LDL). This exchange
is mediated by the cholesteryl ester transfer protein
(CETP), and in humans accounts for the removal of
about two-thirds of the cholesterol associated with
HDL. The transferred cholesterol subsequently is
metabolized as part of the lipoprotein into which it was
transferred. Treatments that target CETP and the ABC
transporters have yielded equivocal results in humans.
While CETP inhibitors effectively reduce LDL, they
also appear to paradoxically increase the frequency of
adverse cardiovascular events (angina, revascularization,
myocardial infarction, heart failure, and death)
(Tall, 2007; Tall et al, 2008).
The triglyceride that is transferred into HDL 2
is
hydrolyzed in the liver by HL, a process that regenerates
smaller, spherical HDL 3
particles that recirculate and
acquire additional free cholesterol from tissues containing
excess free cholesterol. HL activity is regulated and
modulates HDL-C levels. Both androgens and estrogens
affect HL gene expression, but with opposite effects.
Androgens increase HL activity, which accounts for the
lower HDL-C values observed in men than in women.
Estrogens reduce HL activity, but their impact on HDL-C
levels in women is substantially less than that of androgens
on HDL-C levels in men. HL appears to have a
pivotal role in regulating HDLC levels, as HL activity is
increased in many patients with low HDL-C levels.
HDL are protective lipoproteins that decrease the
risk of CHD; thus, high levels of HDL are desirable.
This protective effect may result from the participation
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
of HDL in reverse cholesterol transport, the process by
which excess cholesterol is acquired from cells and
transferred to the liver for excretion. HDL also may
protect against atherogenesis by mechanisms not
directly related to reverse cholesterol transport. These
functions include putative anti-inflammatory, antioxidative,
platelet anti-aggregatory, anticoagulant, and
profibrinolytic activities (deGoma et al., 2008).
Lipoprotein(a). Lipoprotein(a) [Lp(a)] is composed of
an LDL particle that has a second apoprotein in addition
to apoB-100 (Mahley et al., 2008). The second
apoprotein, apo(a), is attached to apoB-100 by at least
one disulfide bond and does not function as a lipidbinding
apoprotein. Apo(a) of Lp(a) is structurally
related to plasminogen and appears to be atherogenic
by interfering with fibrinolysis of thrombi on the surfaces
of plaques.
HYPERLIPIDEMIA AND
ATHEROSCLEROSIS
Despite a 59% decline in the death rate from CHD
between 1950 and 1999, deaths from CVD accounted
for 36.3% of the 2.4 million deaths in the U.S. during
2004. Most of these deaths were caused by atherosclerosis,
which is responsible for more deaths than cancer,
accidents, chronic lung disease, and diabetes combined.
Two-thirds of atherosclerosis deaths were due to CHD.
About 82% of CHD deaths occurred in individuals >65
years of age. Among the 18% dying prematurely (<65
years), 80% died during their first CHD event. Among
those dying of sudden cardiac death, 50% of the men
and 64% of the women had previously been asymptomatic
(American Heart Association, 2003).
These statistics illustrate the importance of identifying
and managing risk factors for CHD. The major
conventional risk factors are elevated LDL-C, reduced
HDL-C, cigarette smoking, hypertension, type 2 diabetes
mellitus, advancing age, and a family history of premature
CHD events (men <55 years; women <65 years) in
a first-degree relative. Control of the modifiable risk
factors is especially important in preventing premature
CHD. Observational studies suggest that modifiable
risk factors account for 85% of excess risk (risk over
and above that of individuals with optimal risk-factor
profiles) for premature CHD. The presence of one or
more conventional risk factors in 90% of patients with
CHD belies claims that a large percentage of CHD is
not attributable to conventional risk factors. When total
cholesterol levels are below 160 mg/dL, CHD risk is
markedly attenuated, even in the presence of additional