LDL-C or apoB as the Best Target for Reducing Coronary Heart Disease

Should Apob be Implemented into Clinical Practice?

Helena Vaverkova


Clin Lipidology. 2011;6(1):35-48. 

In This Article

Pathophysiological Background

Atherogenic lipoprotein particles can vary considerably in their cholesterol content, but each particle contains only one molecule of apoB-100 (or simply apoB). As a result, serum concentration of apoB is a better marker of atherogenic lipoprotein particle numbers than both LDL-C and non-HDL-C. Especially in subjects with a large number of cholesterol-depleted sdLDL, LDL-C underestimates the number of LDL particles the most (Figure 1). Subjects with insulin resistance, metabolic syndrome and diabetes, in addition to increased prevalence of sdLDL, also have a multiplication of other potentially atherogenic lipoprotein particles rich in TGs, namely VLDL and their remnants IDL, which are not contained within the LDL-C parameter.

Figure 1.

LDL-C most underestimates the number of LDL particles in subjects with a prevalence of cholesterol-depleted small dense LDL. The LDL-C concentration is equal in both (A) and (B). However, as all LDL particles contain only one molecule of apoB, the concentration of apoB is much higher in the case of prevalence of cholesterol-depleted sdLDL (B) than in the case of prevalence of cholesterol rich lbLDL (A).
CH: Cholesterol content of LDL particles; lbLDL: Large buoyant LDL; sdLDL: Small dense LDL.

In contrast with this, the concentration of apoB is a reliable marker of the number of all potentially atherogenic particles because all these lipoprotein particles (VLDL, IDL, LDL [including sdLDL] and Lp[a]) contain only one molecule of apoB-100 and various amounts of cholesterol (Figure 2).[7] Each chylomicron and chylomicron remnant contains one molecule of apoB-48. Clinical assays measure both apoB-100 and apoB-48. Thus, the apoB concentration also represents chylomicrons and their remnants. Nevertheless, with the exception of rare type III hyperlipoproteinemia and extremely rare type I hyperlipoproteinemia, there are so few chylomicron particles compared with even VLDL particles that they do not significantly influence total plasma apoB levels.

Figure 2.

Schematic view of atherogenic lipoprotein particles. (A) Non-HDL-C is the cholesterol content of all atherogenic LP particles (LDL + IDL + VLDL + Lp[a]). (B) All atherogenic lipoprotein particles contain only one molecule of apoB. Thus, apoB concentration represents the number of all atherogenic lipoprotein particles (LDL + IDL + VLDL + Lp[a]).
CH: Cholesterol content of lipoprotein particles; LP: Lipoprotein.

In normotriglyceridemic subjects, more than 90% of apoB is carried in LDL particles and even in hypertriglyceridemic subjects, most of the apoB is associated with LDL. Thus, apoB may also be a good surrogate for LDL particle concentration.

This concept is further supported by the findings of Cromwell et al., who measured lipoprotein particle numbers by the nuclear magnetic resonance (NMR) method.[10] In this study, VLDL particles represented only a small fraction (~5%) of the total number of atherogenic VLDL plus LDL particles. Even when TG levels are significantly elevated, VLDL particle numbers are only modestly elevated because the excess of TGs is predominantly carried in large VLDL particles that are relatively few in number.[11] Furthermore, in terms of the percentage of total atherogenic particles, VLDL particle levels are not very different in persons with high TG levels because these individuals also typically have elevated numbers of sdLDL.[10]

All apoB-containing species appear to be atherogenic to a greater or lesser extent, but larger apoB-carrying particles, such as VLDL, may be less atherogenic than the smaller LDL particles.

Small dense LDL particles are probably more atherogenic than large buoyant LDL as they enter the artery wall much more easily and are not well recognized by LDL receptors and thus remain longer in the subendothelial space, where they undergo modification and induce inflammation (reviewed in[12]). Modification affects the structure of apoB-100 so that it becomes a ligand for the scavenger receptors of monocytes or macrophages. Cholesterol then accumulates in the cytoplasm of macrophages to form foam cells, which is the characteristic feature of all stages of atherosclerosis.

Furthermore, experimental studies demonstrated that apoB, by highly specific interaction with proteoglycans, leads to entrapment and retention of lipoprotein particles in the artery wall, where they become oxidized or otherwise modified.[13,14] Thus, it is apoB and not the cholesterol content of the lipoprotein particle that leads to the initiation of atherosclerotic processes and subsequent deposition of cholesterol in the artery wall.

The greater atherogenicity of sdLDL particles in comparison with large buoyant LDL is supported by findings from the Quebec Cardiovascular Study that confirmed that a greater proportion of sdLDL at baseline was a strong and independent predictor of CHD in the first 7 years of follow-up.[15] By contrast, an elevated concentration of large LDL was a poor predictor of CHD in this study and seemed to be paradoxically associated with a low CHD risk.[15]

Similarly, Koba et al. demonstrated that both male and female CHD patients had significantly smaller LDL particles, higher sdLDL-C concentrations and lower large LDL-C concentrations than the control subjects.[16] In this study, sdLDL-C levels were more powerful than LDL-C levels for the determination of severe stable CHD.

On the other hand, Jungner et al. demonstrated in an updated analysis of the Apolipoprotein-Related Mortality Risk Study (AMORIS) that LDL size, as reflected by the LDL-C:apoB ratio, did not add predictive power to apoB (as a marker of atherogenic particle numbers) in the prediction of the risk of fatal myocardial infarction (MI) in a large Swedish cohort.[17]

Non-HDL-C (i.e., total cholesterol minus HDL-C) was suggested by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III to be another parameter that reflects cholesterol transported in all potentially atherogenic particles (VLVL, IDL, LDL [including sdLDL] and Lp[a]) (Figure 2).[1,18] Nevertheless, discrepancies in cholesterol content in various lipoprotein species produce discordance in the levels of non-HDL-C and apoB, which results in differences in the accuracy with which they measure the number of atherogenic particles.[19] In this respect, apoB is a better marker of atherogenic particle numbers than non-HDL-C.

On the basis of a high correlation, non-HDL-C and apoB have been suggested to be of equivalent value for clinical practice. However, in dyslipidemic patients, especially those with more severe hypertriglyceridemia, both correlation and concordance are low (in type III and V hyperlipoproteinemia) or only fair (in type IV hyperlipoproteinemia).[20] It follows that correlation is not sufficient as a sole judge of the equivalence of laboratory parameters.


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