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C HAPTER 36 / Lipid Management and Cardiovascular Disease 827
Production of apo A-I is higher in women than in men and is in- those who are Caucasian or from other Asian populations. 57 Epi-
creased by exercise training, alcohol consumption, and estrogen demiology studies suggest that Lp(a) levels above 25 to 30 mg/dL
administration. 21 Premenopausal women have more than three constitute CVD risk, further, it is estimated that 37% of those at
times the concentration of HDL 2 than do men. Studies have also high risk of CVD have elevated levels of Lp(a). 55 Currently only
suggested that HDL may act as an antioxidant, preventing the ox- one therapeutic agent, niacin, lowers Lp(a) levels. A more com-
idation of LDL. 45,46 plete understanding of the mechanisms by which Lp(a) influences
atherosclerosis and the effect of apo(a) size is needed. Like Lp(a),
there are a number of emerging lipid risk factors that may further
LDL VARIANTS explain the relationship of dyslipidemia to coronary heart disease
(CHD) (Table 36-3).
LDL Particle Size
Mounting evidence suggests that the size of the LDL particle plays Lipoprotein-Associated
an important role in its atherogenicity. Particle size is determined Phospholipase A (Lp-PLA )
by flotation rates after ultracentrifugation procedures. LDL can be 2 2
separated into a small dense LDL particle (phenotype B) and a The search for biomarkers that identify those at risk for CVD has
A
larger less dense LDL particle (phenotype A). 48 Clinical trial evi- led to interest in Lp-PLA 2 , an enzyme that hydrolyzes lipids and
dence suggests that people with a predominance of small dense preferentially oxidized LDL thereby triggering inflammatory
LDL particles have a higher incidence of CVD and more acceler- processes. 58 It is known that Lp-PLA 2 is produced by
ated progression of coronary lesions. 49 The exact mechanism of macrophages (prominent in the inflammatory atherosclerotic
the negative influence of the small dense LDL particle is not com- process) and mainly carried in circulation bound to LDL choles-
pletely understood. One possible explanation is that the smaller terol. Clinical trial studies have observed a positive but inconsis-
denser particles have a greater ability to penetrate the endothelial tent association between elevated Lp-PLA 2 and risk of CVD and
space and participate fully in the subendothelial atherosclerotic stroke. 58 A cut-point of 235 ng/mL or more (greater than the
process. Small LDL particles also appear to be more susceptible to 50th percentile from population studies) has been suggested as a
oxidation than larger LDL particles. 50 In addition, the small level indicative of risk for CVD. 59
dense LDL particle is most commonly found in conjunction with
a constellation of other factors, including hypertriglyceridemia,
low HDL cholesterol, and insulin resistance. 51 CHOLESTEROL AND
Research also suggests that it is possible to increase (alter) the ENDOTHELIAL FUNCTION
size of the LDL particle to the larger (phenotype A) size by re-
ducing triglycerides and normalizing insulin sensitivity. In addi- Serum cholesterol levels and diets high in saturated fat have been
tion, lipid-lowering drugs such as bile acid-binding resins, niacin, associated with impairments in endothelial functioning. The en-
and the fibrates are reported to alter particle size favorably. 48 dothelium acts to regulate vascular tone, platelet adhesion, throm-
bosis, and growth factors. 60 Studies have demonstrated that ele-
Oxidized LDL vated cholesterol results in a reduced vasodilation response.
Furthermore, when cholesterol is lowered, vasodilation responses
Ongoing research in lipid metabolism is investigating the issue of improve. 61
oxidation. Molecular biologists have established that modified or Elevated cholesterol also increases platelet aggregation and
oxidized LDL is taken up more rapidly in vitro by monocytes and monocyte adhesion, factors that lead to thrombus formation and
macrophages than is native LDL. 52 It has also been shown that plaque rupture. 62 Continuing research suggests that the lipids in-
Lp(a) is a primary carrier of oxidized LDL and account for the re- fluence a variety of endothelial responses that appear to contribute
lationship between elevated Lp(a) and atherosclerosis. 53 to the atherosclerotic process.
Oxidized LDL has been found to be cytotoxic, and it is postu-
lated that this facilitates endothelial injury, leading to the devel-
opment of fatty streaks and atherosclerotic lesions. Oxidative in- DYSLIPIDEMIC DISORDERS
hibitors can block the modification of LDL to an oxidized form.
Studies are ongoing in this area but a clear understanding of oxi-
dized lipids and CVD remains elusive. 54 Although the metabolic processes related to blood lipids are com-
plex and influenced by both genetic and environmental factors,
the management of dyslipidemia has been well characterized. Na-
The Role of Lp(a)
tional recommendations have been developed on the basis of the
Genetic researchers investigating variant LDL particles uncovered scientific evidence and taking into account the need for both pri-
a lipoprotein, Lp(a), that is similar to LDL with each particle mary and secondary prevention of CVD. 2,3 In general, lipid dis-
linked to a molecule of the atherogenic apo B-100 in a 1:1 ratio. 55 orders can be characterized by the specific lipid abnormalities ob-
The attached protein, apolipoprotein(a) (apo[a]) is unique and is served (see Table 36-3).
similar in DNA sequence to plasminogen, a substance that breaks
up blood clots Recent prospective studies and meta-analysis have
found elevated levels of Lp(a) are independent predictors of CVD. HYPERCHOLESTEROLEMIA
Lp(a) has also been detected in atherosclerotic plaques. 56 Lp(a)
levels vary inversely to the size of the apo(a) protein. Those who Hypercholesterolemia is the most common dyslipidemia and, in
are Black and South Asian have higher Lp(a) levels compared with most people, decreased LDL clearance is responsible for the