Heterogeneity Of Atherogenic Lipoproteins

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The pathogenesis of dyslipidemia revolves around the metabolism of lipoproteins. Comprising proteins and lipids (cholesterol, triglycerides [TGs], and phospholipids), lipoproteins are the vehicles for lipid transport. The proteins associated with a lipoprotein are known as apolipoproteins, and each atherogenic lipoprotein contains a single protein designated apolipoprotein B (apoB). Lipoprotein metabolism is largely governed by apolipoproteins, which operate as cofactors for enzymes, interact with cell-membrane receptors, and provide a structural framework for lipoproteins. Several lipoproteins are associated with atherosclerosis to varying degrees. The best established is low-density lipoprotein (LDL), which is also typically the most abundant atherogenic lipoprotein. Several other lipoproteins promote atherosclerosis, including very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and lipoprotein(a) (Lp[a]). By contrast, high-density lipoprotein (HDL) appears to protect against atherosclerosis.

It is well established that the cholesterol content of LDL (LDL-cholesterol [LDL-C]) is a risk factor for atherosclerotic cardiovascular disease (ASCVD), and therapy that lowers LDL-C limits ASCVD events. This paradigm has spawned clinical guidelines that set convenient targets for LDL lowering (1-8). Yet many patients continue to have events despite reaching LDL-C targets, and many who have low LDL-C at baseline present with ASCVD events. Several studies suggest that even patients with "optimal" LDL-C levels benefit from lipid-lowering therapy. These observations have led to a search for other biomarkers that might predict risk of ASCVD events and, in particular, markers that refine the ability to forecast risk from atherogenic lipoproteins. Responding to these concerns, the Adult Treatment Panel III (ATP-III) proposed two important clinical tools to identify patients whose risk may be underestimated by traditional markers (1). First, it adopted a treatment goal based on non-HDL-C in patients with hypertriglyceridemia. Second, it emphasized the diagnosis of metabolic syndrome (1). Both conditions are associated with deleterious LDL abnormalities that are not detectable by estimating LDL-C content. This situation highlights an important limitation to using LDL cholesterol as a risk marker: this presumes that all LDL particles are uniformly atherogenic.

In fact, LDL is heterogeneous regarding size and density, which leads to important variability in the atherogenicity of these lipoproteins. The small, dense variety of LDL is thought to be especially atherogenic (9), owing to increased residence time in the circulation, reduced LDL receptor binding, heightened potential for oxidation, enhanced penetration ofthe artery intima, and increased retention therein (9). Elevated levels of TGs promote a shift to the small, dense form of LDL. The common association ofhigh TGs, low HDL-C, and small, dense LDL is variably known as atherogenic dyslipidemia, the atherogenic lipoprotein phenotype, or simply the lipid triad, and itself may be considered an associated risk factor for ASCVD (1). This triad correlates with several metabolic abnormalities, including renal disease, metabolic syndrome, insulin resistance, and type 2 diabetes (1). Because there is no intervention that selectively improves small, dense LDL without affecting other lipoprotein fractions, it will be very difficult to prove that therapeutic intervention that targets small, dense LDL specifically reduces risk.

In some circumstances, it may be helpful to know whether a patient has increased levels of small, dense LDL because the finding is an important clue that the usual marker of LDL atherogenicity, LDL-C, may be leading to an underestimation ofrisk (10). There are several commercially available techniques that measure the size of LDL. These include analytic

Table 1

Common Pitfalls Associated With LDL Cholesterol

Circumstances in which lipoproteins in general may not reflect a patient's usual level (1)

Acute illness Acute coronary syndrome Cerebrovascular accident Surgery Infection Recent weight loss Change in usual diet Pregnancy

Circumstances in which LDL-C approximation may not reflect a patient's LDL-C

Frederickson class I, III, or V hyperlipoproteinemia (11)

Presence of chylomicrons (11)

Approximated LDL-C < 120 mg/dL (comparable with measured LDL-C < 130 mg/dL) (26) Approximated LDL-C within 11 mg/dL of 100 mg/dL goal, within 15 mg/dL of 130 mg/dL

goal, or within 18 mg/dL of 160 mg/dL goal (assuming two samples) (12) Fewer than two samples available for interpretation (12) Diabetes (17) Liver disease (20)

Nephrotic syndrome (21) or chronic renal insufficiency (22,23) Hormone replacement therapy (24,25)

ultracentrifugation, gradient gel electrophoresis, nuclear magnetic resonance (NMR) spectroscopy, and equilibrium density gradient ultracentrifugation (9). (See part I of the appendix.)

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