Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery

disease.

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Rader DJ, Hoeg JM, Brewer HB Jr

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Ann Intern Med. 1994;120(12):1012.

PURPOSE: To review current knowledge of apolipoprotein quantitation used in the clinical management
of persons with or at risk for the development of premature coronary artery disease.DATA SOURCES:
The English-language literature was analyzed using MEDLINE (1975 to 1993) with key words
"apolipoproteins," "quantitation," and "coronary artery disease." Article bibliographies were also
reviewed to obtain additional references.STUDY SELECTION: Published, peer-reviewed retrospective and
prospective studies relevant to the association of plasma apolipoprotein levels with coronary artery
disease in humans.DATA SYNTHESIS: Most studies concerned apolipoprotein A-I (apo A-I),
apolipoprotein B (apo B), and lipoprotein(a) [Lp(a)].

In retrospective cross-sectional studies, apo A-l levels were not substantially more
predictive of coronary artery disease than were high-density lipoprotein (HDL)
cholesterol levels. In contrast, levels of apo B and Lp(a) were often more strongly
associated with coronary artery disease than were traditional lipid
measurements. In studies of the relation between apolipoprotein levels in
children and premature coronary artery disease in their parents, Lp(a) levels, but
not apo A-l and apo B levels, were consistently predictive of familial coronary
artery disease. Prospective studies have yielded variable results for all three
apolipoproteins. Low apo A-l levels were consistently associated with coronary
artery disease in six prospective studies but were not more predictive than HDL
levels. Apolipoprotein B levels were strongly associated with coronary artery
disease in four of five prospective studies but were more predictive of coronary
artery disease than were total cholesterol levels in only two of the four studies.
Lipoprotein(a) levels were strongly associated with coronary artery disease in five
of seven prospective studies but were not associated in two of the four largest
studies.
CONCLUSIONS: Too few large prospective studies of apolipoprotein quantitation
using validated assay methods, both in general unselected populations and in
subgroups of persons with premature coronary artery disease or family histories
of premature coronary artery disease, are available to make definitive
recommendations concerning clinical utility. The data do not support use of
apolipoprotein quantitation as a screening tool to predict coronary artery disease
risk in the general population. However, the data suggest that quantitation of apo
B and Lp(a) may be indicated in subgroups of persons with premature coronary
artery disease or with family histories of premature coronary artery disease. In
these persons, an increased apo B or Lp(a) level or both could be a clinical
indication for more aggressive treatment of low-density lipoprotein cholesterol.
Triglycerides and cholesterol are transported by chylomicrons and remnant
lipoproteins from the intestine and by VLDL and LDL from the liver (white arrows).
ApoA-1 is synthesized by the liver and, after interaction with ABCA1, is secreted
into plasma as lipid-poor apoA-1 (yellow arrow). In reverse cholesterol transport,
newly synthesized lipid-poor apoA-1 interacts with ABCA1, removing excess
cellular cholesterol and forming pre-beta-HDL (green arrow). Pre-beta-HDL is
converted into mature alpha-HDL by LCAT (black arrow). HDL-C is returned to the
liver through two pathways: selective uptake of cholesterol by the hepatic SR-B1
(blue arrow), or the transfer of cholesteryl ester by CETP to VLDL-LDL, with uptake
by the liver through the LDL receptor (red arrows). Short-term HDL therapy to
increase the HDL level and potentially provide protection against cardiovascular
events can be achieved with the infusion of complexes consisting of apoA-1
Milano and phospholipids. Long-term increases in the HDL level and reductions in
the LDL level result from the partial inhibition of CETP.
HDL: high density lipoprotein; VLDL: very low density lipoprotein; LDL: low density
lipoprotein; ApoA-1: apolipoprotein A-1; ABCA1: ATP-binding cassette transporter
1; LCAT: lecithin-cholesterol acyltransferase; SR-B1: scavenger receptor, class B,
type I; CETP: cholesteryl ester transfer protein; FC: free cholesterol; PL:
phsopholipids; LRP: LDL-related protein; LPL: lipoprotein lipase.
The apo E locus contributes to determining the variation in plasma cholesterol
levels of healthy and diseased populations. It also influences the expression of
hyperlipidemia and appears to modulate the susceptibility to atherosclerosis in a
complex multifactorial interaction. There is evidence that the presence of apo E2
is protective, whereas that of apo E4 predisposes to coronary artery disease. The
burden of proof, however, lies on future, well-designed clinical trials and
prospective studies. The study of the biological significance of the apo E
polymorphism in humans has emphasized the importance of gene-gene and gene-
environment interactions in the pathogenesis of hyperlipidemia and
atherosclerosis. The apo E polymorphism involves the coding region of the apo E
gene and results in alterations of the gene product which, in turn, either directly
or secondarily affect the metabolic fate of the lipoprotein particles. Rapid
advances in knowledge over the last decade have provided a metabolic
explanation for the observation of the opposite effects of the epsilon 4 and the
epsilon 2 alleles on lipoprotein levels. Apo E2 has lower receptor binding affinity
which results in delayed clearance of apo E2-bearing lipoprotein particles from
plasma. Apo E4 is distributed differently from apo E3 between VLDL and HDL, is
degraded more rapidly than apo E3, and may enhance the catabolism of E4-
bearing particles, leading to other alterations in lipoprotein metabolism which
result in elevated levels of LDL. In view of the significant opposite impacts of the
epsilon 4 and the epsilon 2 alleles on plasma LDL cholesterol concentrations, it is
evident that determination of the apo E phenotype will becomea useful adjunct
to the assessment of the cardiovascular risk profile of an individual. In addition,
the relationship between the epsilon 2 allele and type III hyperlipoproteinemia
provides a valuable model for the study of complex genetic interactions in the
pathogenesis of hyperlipidemia. The further study of apo E and its interactions
shows great promise for a deeper comprehension of the pathogenesis of
atherosclerosis.
The molecular mechanisms regulating the amount of dietary cholesterol retained
in the body as well as the body's ability to selectively exclude other dietary sterols
are poorly understood. Studies of the rare autosomal recessively inherited
disease sitosterolemia (OMIM 210250) may shed some light on these processes.
Patients suffering from this disease appear to hyperabsorb both cholesterol and
plant sterols from the intestine. Additionally, there is failure of the liver's ability to
preferentially and rapidly excrete these non-cholesterol sterols into bile.
Consequently, people who suffer from this disease have very elevated plasma
plant sterol levels and develop tendon and tuberous xanthomas, accelerated
atherosclerosis, and premature coronary artery disease. Identification of this gene
defect may therefore throw light on regulation of net dietary cholesterol
absorption and lead to an advancement in the management of this important
cardiovascular risk factor. By studying 10 well-characterized families with this
disorder, we have localized the genetic defect to chromosome 2p21, between
microsatellite markers D2S1788 and D2S1352

Resistance to diet-induced hypercholesterolemia and gallstone formation in

ACAT2-deficient mice.
 
The importance of cholesterol ester synthesis by acyl CoA:cholesterol
acyltransferase (ACAT) enzymes in intestinal and hepatic cholesterol metabolism
has been unclear. We now demonstrate that ACAT2 is the major ACAT in mouse
small intestine and liver, and suggest that ACAT2 deficiency has profound effects
on cholesterol metabolism in mice fed a cholesterol-rich diet, including complete
resistance to diet-induced hypercholesterolemia and cholesterol gallstone
formation. The underlying mechanism involves the lack of cholesterol ester
synthesis in the intestine and a resultant reduced capacity to absorb cholesterol.
Our results indicate that ACAT2 has an important role in the response to dietary
cholesterol, and suggest that ACAT2 inhibition may be a useful strategy for
treating hypercholesterolemia or cholesterol gallstones.
AD
Gladstone Institute of Cardiovascular Disease, P.O. Box 419100, San Francisco,
California 94141-9100, USA.
Effect of ACAT inhibition on the progression of coronary atherosclerosis.
BACKGROUND: The enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT)
esterifies cholesterol in a variety of tissues. In some animal models, ACAT
inhibitors have antiatherosclerotic effects.METHODS: We performed intravascular
ultrasonography in 408 patients with angiographically documented coronary
disease. All patients received usual care for secondary prevention, including
statins, if indicated. Patients were randomly assigned to receive the ACAT
inhibitor pactimibe (100 mg per day) or matching placebo. Ultrasonography was
repeated after 18 months to measure the progression of atherosclerosis.RESULTS:
The primary efficacy variable analyzing the progression of atherosclerosis--the
change in percent atheroma volume--was similar in the pactimibe and placebo
groups (0.69 percent and 0.59 percent, respectively; P=0.77). However, both
secondary efficacy variables assessed by means of intravascular ultrasonography
showed unfavorable effects of pactimibe treatment. As compared with baseline
values, the normalized total atheroma volume showed significant regression in
the placebo group (-5.6 mm3, P=0.001) but not in the pactimibe group (-1.3 mm3,
P=0.39; P=0.03 for the comparison between groups). The atheroma volume in the
most diseased 10-mm subsegment regressed by 3.2 mm3 in the placebo group, as
compared with a decrease of 1.3 mm3 in the pactimibe group (P=0.01). The
combined incidence of adverse cardiovascular outcomes was similar in the two
groups (P=0.53).CONCLUSIONS: For patients with coronary disease, treatment
with an ACAT inhibitor did not improve the primary efficacy variable (percent
atheroma volume) and adversely affected two major secondary efficacy measures
assessed by intravascular ultrasonography. ACAT inhibition is not an effective
strategy for limiting atherosclerosis and may promote atherogenesis.
(ClinicalTrials.gov number, NCT00268515.)