Apolipoprotein (apo) B-100 is an apolipoprotein found in LDL, VLDL, and IDL. It serves as the ligand for the hepatic LDL receptor.
Partly because apo B-100 occurs as a single molecule in an LDL particle, a plasma apo B-100 measurement is a more accurate indicator of LDL particle number than is the LDL-C level when the triglyceride value is normal. An apo B-100 value that is elevated in disproportion to the LDL-C suggests the presence of hyperbetalipoproteinemia, particularly if the triglycerides are not elevated. The relative risk of CAD is increased approximately 2-fold in the setting of elevated apo B-100 but is not additive if LDL-C is also elevated.
Apolipoprotein (apo) E, a component of other lipoproteins, regulates an array of processes that affect plasma cholesterol homeostasis, including hepatic extraction of plasma cholesterol and intestinal absorption of dietary fat. Variations in the sequence of its constituent amino acids yield three apo E isoforms:
Relative to apo E3, apo E4 promotes increases in the plasma levels of LDL-C and LDL particle number as well as the absorption of dietary fat by the gut. On the other hand, it also promotes a marked reduction of LDL-C in response to a low-fat diet.
The E4 isoform is also associated with the development of Alzheimer's disease in individuals with a family history of the disease.
In contrast to the apo E4 isoform, apo E2 promotes a reduction of LDL-C, inhibits gut absorption of dietary fat, and renders the lipoprotein profile relatively insensitive to the amount of dietary fat intake.
In the presence of moderate or greater dietary fat intake, the apo E2 isoform actually poses a lower risk of CAD than does the E3 isoform. However, in the presence of a low-fat diet, the E2 isoform promotes a rise in plasma triglycerides and impairs reverse cholesterol transport, yielding an increase in CAD risk.
An individual inherits one of six permanent isoform patterns that reflect combinations of the alleles coding for apo E.
In the general U.S. population, the descending order of frequency for these six apo E isoform patterns is
To different degrees the E4/E4 and E4/E3 patterns are associated with elevated LDL-C and marked reduction of LDL-C in response to a low-fat diet.
Neither the E2/E3 nor the E2/2 patterns are independently associated with an abnormal lipoprotein metabolism. However, apo E2/E2 can produce type III hyperlipoproteinemia in the presence of certain additional risk factors, including obesity, diabetes, and familial combined hyperlipidemia.
In individuals with the E2/E4 pattern, the two abnormal isoforms tend to counteract each other, and the effect of the pattern on the lipoprotein varies with individuals, but LDL-C reduction in response to a low-fat diet is likely to be pronounced.
Assuming a moderate intake of dietary fat, the order of descending CAD risk for the six apo E isoform patterns is
Since the apo E isoform pattern is genetically fixed, it need be determined only once.
Chlamydia pneumoniae (Cp), an obligate intracellular pathogen that is established as a common cause of pneumonia, is suspected of contributing to atherosclerosis partly because a high proportion of patients with CAD are seropositive for Cp infection and Cp is often found at atherosclerotic arterial sites.
In CAD (coronary artery disease) patients, an elevated Cp titer was reported to increase the risk of experiencing a cardiovascular event 3- to 4-fold.
It is hypothesized that Cp stimulates the transformation of macrophages into lipid-rich foam cells. Antibacterial therapy with Azithromycin (Biaxin) after myocardial infarction (heart attack) in patients with high Cp titers was found to significantly reduce the incidence of CAD events.
Familial combined hyperlipidemia (FCH) involves elevations of both LDL-C and triglycerides with documentation of either elevation in at least one first-degree relative. The probability of expression in a sibling or offspring is 50%. Concurrent elevation of LDL-C and triglycerides is typical but is not an essential diagnostic criterion. FCH signifies a 3- to 4-fold risk of an ischemic cardiac event.
Familial defective apolipoprotein (apo) B is an uncommon inherited disorder in which a defect of the apo B-100 component of the LDL particle reduces binding of the particle to the hepatic LDL receptor, resulting in a total cholesterol >350 mg/dl and an LDL-C of 270-370 mg/dl. The triglyceride level is often normal.
HDL gradient gel electrophoresis (HDL-GGE) is used to determine HDL subclass distribution. It separates HDL particles according to size, measures the optical density of the size-determined particle groupings, and mathematically translates these measurements into mass distributions for the HDL subclasses.
Of all commercially available methods for determining HDL subclass distribution, HDL-GGE claims the most favorable documented comparison with analytic ultracentrifugation, a research-only tool that is considered the gold standard for such determination
Of the five HDL subtypes, HDL2b is the most active in reverse cholesterol transport, mediating the transfer of cholesterol from within the arterial wall to the liver.
A low prevalence in mass of HDL2b among the HDL subtypes is a potent predictor of the presence or development of symptomatic CAD and of arteriographic progression of CAD.
HDL2b typically accounts for about a third of total HDL mass in healthy premenopausal women and about a fifth of HDL in middle-aged men without CAD.
A low HDL2b prevalence is frequently, but not invariably, associated with the atherogenic lipoprotein profile and diabetes. It is not precluded by a high HDL or HDL-C level.
Effective treatment for increasing HDL2b includes exercise, fat-weight loss, niacin, fibric-acid derivatives in patients with elevated triglycerides, and hormone replacement therapy in postmenopausal women.
Homocysteine is a byproduct of the metabolism of the amino acid methionine. Homocysteinemia generally results from an inherited heterozygous disorder of the metabolism of homocysteine.
It stands in contrast to homozygous homocysteinemia, which is marked by higher serum levels of total homocysteine and associated with homocysteinuria and an array of serious clinical disorders that develop in childhood, including neurologic and skeletal impairment.
The mean fasting level of total plasma homocysteine in a study of a healthy population was 8 nm/ml.
A homocysteine >14 nm/mg signifies an independent increase in the risk of CAD, with a twofold increase in risk at >20 nm/ml. Elevated homocysteine is a potent mortality predictor in patients with established CAD.
The incidence of hyperhomocysteinemia (elevated blood homocysteine) is:
The known or presumed atherogenic effects of excess homocysteine include:
The expression of heterozygous hyperhomocysteinemia often depends on low serum levels of:
so dietary modification and/or vitamin supplementation often constitute adequate therapy. Niacin therapy often increases plasma homocysteine.
Hyper-apo-beta-lipo-proteinemia, which is found in more than 50% of the CAD population, signifies an apo-lipoprotein (apo B-100 or apo B) value that is disproportionately high for the companion LDL-C value.
Partly because each LDL particle carries one molecule of apo B, the apo B level indicates the LDL particle number more reliably than the does the level of LDL-C.
Hyperapobetalipoproteinemia resembles both the atherogenic lipoprotein profile and familial combined hyperlipidemia in that it is marked by a predominance of small, dense particles within the LDL family, an independent indicator of CAD risk.
Hypo-alpha-lipo-proteinemia, which is found in less than 10% of the general population and about 20% of patients with CAD, is an inherited metabolic disorder that results in low HDL.
It often exists independently of other lipid disorders, whereas most cases of low HDL are secondary to other problems, including elevated triglycerides, lipoprotein particle metabolism that produces the atherogenic lipoprotein profile (LDL subclass pattern B), or unfavorable lifestyle factors.
As with secondary forms of low HDL, hypoalphalipoproteinemia signifies a 2- to 3-fold elevated risk of CAD.
Hygienic measures, such as exercise and smoking cessation, are at best modestly effective against hypoalphalipoproteinemia.
The most effective treatments are niacin and, for postmenopausal women, estrogen therapy, but failure is common even with these methods. In cases of refractory hypoalphalipoproteinemia, aggressive efforts to optimize other risk factors are warranted.
LDL gradient gel electrophoresis (LDL-GGE) is used to determine LDL subclass distribution. It separates LDL particles according to size, measures the optical density of the size-determined particle groupings, and mathematically translates these measurements into mass distributions for the LDL subclasses.
Of all commercially available methods for determining LDL class distribution, LDL-GGE claims the most favorable documented comparison with analytic ultracentrifugation, a research-only tool that is considered the gold standard for such determination.
This is the LDL particle size (in Angstroms = 10-8 cm) represented by largest accumulation of particle-specific LDL mass distributions.
In general, peak particle diameters (PPDs) of <257Å indicate LDL subclass Pattern B and >263Å indicates LDL subclass Pattern A, with intermediate PPDs indicating subclass pattern I.
However, the PPD is a less reliable indicator of these clinically important patterns if its mass peak is closely rivaled by that of at least one additional particle diameter. This situation would be graphically represented as multiple peaks on LDL gradient gel electrophoresis, which is used to determine LDL subclass pattern.
LDL particles are conventionally subclassified into 7 size ranges, which, in order of descending size, are designated I, IIa, IIb, IIIa, IIIb, IVa, and IVb.
On LDL gradient gel electrophoreses, which is used to determine the clinically important LDL subclass patterns, these size classes have counterpart regions of particle distribution that are identified by the corresponding Roman numerals.
Particles that are relative small and dense distribute in regions IIIa and IIIb, and it is been shown that the percentage of LDL mass distribution in a combination of these two regions is a reliable indicator of clinically significant subclass pattern.
The mass distribution of IIIa + IIIb reliably indicates pattern A if <15%, pattern B if >25%, and pattern I if in between these two ranges.
LDL subclass pattern A is defined as a predominance of large and buoyant particles in the mass distribution of LDL; the size and density of LDL particles correlate inversely.
LDL subclass pattern B, which is characterized by a predominance of small, dense LDL particles, is associated with excess risk of CAD or its ischemic sequellae. Pattern A, on the other hand, is less dangerous and not as highly associated with excess risk. Pattern B converts to Pattern A through dietary, exercise and/or drug modifications. Pattern A simply become better Pattern A.
Low-density-lipoprotein (LDL) subclass pattern B, also referred to as the atherogenic lipoprotein profile or the small LDL trait, is defined as a predominance of small and dense particles in the mass distribution of LDL; the size and density of LDL particles correlate inversely.
A predominance of large and buoyant particles defines LDL subclass pattern A.
Compared to pattern A, pattern B signifies a 3- to 5-fold risk of CAD or its ischemic sequellae. It also predicts more rapid arteriographic progression of CAD.
Although part of the risk of LDL pattern B is explained by its frequent, though not invariable, association with such additional plasma risk-factor abnormalities as low levels of HDL-C, a low distribution of the HDL subfraction HDL2b, and elevations of triglycerides and fasting insulin, pattern B also independently signifies an approximate 3-fold elevation of risk.
This independent risk is attributed to an array of atherogenic traits that distinguish small LDL particles, including ease of passage through the intracellular spaces of the arterial endothelium and a high susceptibility to oxidative damage.
On the other hand, the presence of pattern B predicts a beneficial effect of antidyslipidemic treatment on both the lipoprotein profile and arteriographic CAD. LDL pattern B is a heritable trait determined by a dominant gene.
LDL subclass pattern I indicates a predominance of medium-sized particles in the mass distribution of LDL or similar prevalences of both large and small LDL particles. Thus, it indicates a particle distribution that falls between pattern A, in which large and buoyant particles predominate, and pattern B, in which small and dense particles predominate; the size and density of LDL particles correlate inversely.
Lipoprotein lipase (LPL) deficiency is an inherited impairment of the ability of LPL to hydrolyze the triglyceride in circulating particles of chylomicron, VLDL, and IDL, resulting in elevation of plasma triglycerides. The homozygous state of LPL deficiency, which occurs rarely, produces a triglyceride >1,000 mg/dl
Lipoprotein(a), or Lp(a), is a low-density-lipoprotein particle with an attached apolipoprotein (a), a protein structurally similar to plasminogen. It is one of a number of AGE products - advanced glycosylated (or glycated) end-products. Glyco-hemoglobin is another such example that is frequently followed in diabetics
An elevated Lp(a) is a potent risk factor for CAD.
An Lp(a) >30 mg/dl was found equivalent in risk to a total cholesterol >240 mg/dl or an HDL-C <25 mg/dl. It is an independent predictor of myocardial infarction (MI) in young men.
Its potency as a risk factor was reported to increase in the presence of other risk factors, particularly elevated LDL-C.
In women a Lp(a) >30 mg/dl is an independent predictor of MI, intermittent claudication, and cerebrovascular disease.
In women below 60 years of age the likelihood of having arteriographic CAD was 16.6-fold greater with:
than for those with:
Evidence that reduction of elevated Lp(a) reduces progression of arteriographic CAD or the risk of clinical events is only preliminary, but it has been found that reduction of a concomitant elevation in LDL-C can nullify the risk of progression that is conferred by elevated Lp(a).
Elevated Lp(a) may contribute to atherosclerosis by factors that include inhibition of thrombolysis and a high susceptibility to oxidation.
Type III hyperlipoproteinemia is a highly atherogenic disorder involving a marked plasma accumulation of VLDL that has undergone hydrolysis of its component triglycerides (remnant VLD).
The accumulation occurs partly because the apolipoprotein (apo) E component of larger lipoprotein particles is genetically defective in mediating the uptake and metabolism of these particles by the liver.
Although 90% of cases of type III hyperlipoproteinemia are traceable to the heterozygous state of the apo E2 isoform, only about 1% of individuals with the E2/E2 pattern have type III hyperlipoproteinemia.
Its clinical manifestation requires an additional contributor, such as familial combined hyperlipidemia, obesity, or diabetes. There are usually high levels of both triglyceride (400 to 800 mg/dl) and total cholesterol (300 to 600 mg/dl).
Weight loss and a reduction of dietary saturated fat often normalize the adverse lipid profile. Effective drugs include fibric-acid derivatives, the statins (Mevacor, Lipitor, etc), and nicotinic acid (Niacin - B3).
