Should we measure routinely the LDL peak particle size?

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Abstract

Low density lipoproteins (LDL) do not show in humans a normal distribution and comprise two different main fractions: large, buoyant (phenotype pattern A) and small, dense (phenotype pattern B) particles, that differ not only in size and density but also in physicochemical composition, metabolic behaviour and atherogenicity. The prevalence of small, dense LDL changes with age (30–35% in adult men, 5–10% in men < 20 years and in pre-menopausal women, 15–25% in postmenopausal women) and is genetically influenced, with a heritability ranging from 35% to 45%. Small, dense LDL correlate negatively with plasma HDL levels and positively with plasma triglyceride levels and are associated with the metabolic syndrome and with increased risk for cardiovascular disease and diabetes mellitus. LDL size seems also to be an important predictor of cardiovascular events and progression of coronary artery disease and the predominance of small dense LDL has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III. In addition, patients with acute myocardial infarction show an early reduction of LDL size, which persists during hospitalization and seems to precede all other plasma lipoprotein modifications. However, it is still on debate whether to measure the LDL size routinely and in which categories of patients. Since the therapeutic modulation of small, dense LDL particles is of great benefit in reducing the atherosclerotic risk, the LDL size measurement should be extended to patients at high risk of coronary artery disease as much as possible.

Introduction

It is commonly accepted today that apolipoprotein B particles do not comprise a population with continuously variable size, but multiple subclasses with discrete size and density, different physicochemical composition and different metabolic behaviour [1], [2]. Based on their peculiar appearance in analytical ultracentrifugation and gradient gel electrophoresis, distinct subclasses of very low density lipoprotein, intermediate density lipoprotein and low density lipoprotein (LDL) particles have been defined [1].

Regarding LDLs, peak size of these particles in humans does not show a normal, but a bimodal distribution and can be separated into a buoyant and a dense phenotype. These phenotypes have been assigned as pattern A when large LDLs and pattern B when smaller LDL particles predominate. LDL size correlates positively with plasma HDL levels and negatively with plasma triglyceride levels [3] and the combination of small dense LDL, decreased high density lipoprotein (HDL)-cholesterol and increased triglycerides has been defined as the atherogenic lipoprotein phenotype [1], [4] (Fig. 1).

The prevalence of small, dense LDL is 30–35% in adult men, 5–10% in men < 20 years and in pre-menopausal women, and 15–25% in postmenopausal women. It has been shown that LDL size is genetically influenced with a heritability ranging from 35% to 45% based on an autosomal dominant or codominant model with varying additive and polygenic effects. Thus, genetic and environmental factors influence the expression of this phenotype [5].

However, the formation of small, dense LDL particles is mostly observed in the presence of a hypertriglyceridemic state. Indeed, hypertriglyceridemia from a variety of causes is associated with an increased exchange of triglycerides from triglyceride-rich lipoproteins to LDL and HDL particles in exchange of cholesteryl esters through the action of the cholesteryl ester transfer protein. This phenomenon results in the generation of very low density lipoprotein particles enriched in cholesteryl esters and to smaller, triglyceride-rich LDL and HDL particles. These smaller lipoproteins are good substrates for hepatic lipase [6], [7], [8], [9] which has a higher binding affinity for small lipoproteins (Fig. 2).

Therefore, the lipolysis of the triglycerides in these LDL particles will lead to the formation of highly atherogenic small, dense, cholesteryl ester-depleted LDL particles. In type 2 diabetic patients, it has been demonstrated that cholesteryl ester transfer protein contributes significantly to the increased levels of small dense LDL by preferential cholesteryl ester transfer from HDL to small dense LDL, as well as through an indirect mechanism involving enhanced cholesteryl ester transfer from HDL to very low density lipoproteins [10], [11].

Particle size distribution of plasma LDL subfractions is determined by 2–16% gradient gel electrophoresis at 10 °C using a Tris (0.09 M)–boric acid (0.08 M)–Na2 EDTA (0.003 M) buffer (pH 8.3). Plasma is adjusted to 20% sucrose, and 3 to 10 μL is applied to the gel. Potentials are set at 40 mV (15 min), 80 mV (15 min), and 125 mV (24 h). Gels are fixed and stained for lipids in a solution containing oil red O in 60% ethanol at 55 °C, for proteins in a solution containing 0.1% Coomassie brilliant blue R-250, 50% ethanol and 9% acetic acid and then scanned at 530 nm with a transidyne densitometer. Molecular diameters are determined on the basis of migration distance by comparison with standards of known diameter [5], [9].

Assignment of LDL subclass phenotypes is based on particle diameter of the major plasma LDL peak: LDL phenotype A (lager, more buoyant LDL) is defined as an LDL subclass pattern with the major gradient gel peak at a particle diameter of 258.4 Å or greater, whereas the major peak of LDL phenotype B (small, dense LDL) is at a particle diameter of less than 258.4 Å [5], [9].

The presence of small, dense LDL has been associated with an approximately three-fold increased risk for coronary artery disease [12] and many studies suggested for LDL size even a predictive role [13], [14], [15], [16], [17], [18].

Several reasons have been suggested for atherogenicity of small dense LDL. First, smaller, denser LDLs are taken up more easily by arterial tissue than larger LDLs [19], suggesting greater transendothelial transport of smaller particles. In addition, smaller LDL particles may also have decreased receptor-mediated uptake and increased proteoglycan binding [20]. Sialic acid, maybe for its exposure at the LDL surface, plays a determinant role in the in vitro association of LDL with the polyanionic proteoglycans [21] and the sialic acid content of LDL particles of pattern B subjects is reduced. Further it has been shown that oxidative susceptibility increases and antioxidant concentrations decrease with decreasing LDL size [22]. Altered properties of the surface lipid layer associated with reduced content of free cholesterol and increased content of polyunsaturated fatty acids might contribute to enhanced oxidative susceptibility of small dense LDL.

Recently [23] we have chosen the model of apoB transgenic mice to evaluate the kinetic behaviour of human LDL particles of different size in vivo in a genetically homogeneous recipient avoiding other metabolic differences that could influence LDL metabolism. We found that small LDL particles have intrinsic features that lead to retarded metabolism and decreased intra-extravascular equilibration compared to medium sized LDL; these properties could contribute to greater atherogenicity of small dense LDL.

Acute myocardial infarction is accompanied by profound plasma lipid and lipoprotein modifications that have a great clinical relevance since they must be taken into account in making therapeutic decisions [24].

The common lipid alterations observed during the acute phase include a rise of triglyceride levels and a fall of total, LDL- and HDL-cholesterol concentrations [25], [26], [27]. These lipoprotein modifications may be linked to other changes occurring in lipid metabolism during the acute phase of myocardial infarction: either up- or down-regulation of cholesterol synthesis, an increased LDL-receptor activity and an impairment of lypolitic enzymes [28], [29], [30], [31]. Also glucose metabolism is severely impaired [32].

Therefore, the acute myocardial infarction and the atherogenic lipoprotein phenotype seem to share a similar array of interrelated metabolic aberrations, including increased levels of triglyceride-rich lipoproteins, reduced levels of HDL and a relative resistance to insulin-mediated glucose uptake. However, despite a number of data regarding the modifications of total plasma lipoprotein fractions during a myocardial infarction, it is less defined whether or not also the LDL peak particle size is modified by the acute phase and therefore the best time to measure it [25], [26], [27].

We recently found in a group of subjects admitted to hospital for a myocardial infarction, and followed until the discharge and three months after the event, that the reduction of LDL peak particle size is premature and persists during the hospitalisation, with a significant increase 3 months after the myocardial infarction [33]. In addition, the timing of these changes seems to precede those of all other lipoproteins.

We speculated on the mechanisms underlying these LDL size modifications. Since the cholesterol synthesis and/or the receptor-mediated catabolism is known to not affect the LDL size [34], its early reduction may be linked to the action of lipases (in particular hepatic lipase), which are depressed in myocardial infarction, leading to the increase of triglyceride concentrations and to the reduction of HDL-cholesterol levels [30].

Therefore, we suggest that the evaluation of the LDL peak particle size should be extended to patients with acute myocardial infarction as more as possible [33].

Section snippets

Conclusions

Genetic and environmental factors influence the expression of small, dense LDL which is not completely independent of traditional lipids and, in fact, correlates negatively with plasma HDL concentrations and positively with plasma triglyceride levels. Small, dense LDLs are associated with the metabolic syndrome and with increased risk for cardiovascular disease and diabetes mellitus. LDL size seems also to be an important predictor of cardiovascular events and progression of coronary artery

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