Manfredi Rizzo Kaspar Berneis

Manfredi Rizzo1 and Kaspar Berneis2, 1Department of Clinical Medicine and Emerging Diseases, University of Palermo, Via del Vespro, 141, 90127, Palermo, Italy, Tel: +39 (091) 6552945, Fax: +39 (091) 6552982, E-mail: mrizzo@unipa.it, 2Clinics for Endocrinology, Diabetes & Clinical Nutrition, University Hospital Zurich, Switzerland, Tel. and Fax: + 41 (44) 2553585, E-mail: Kaspar.Berneis@usz.ch In the past few years several expert groups have suggested somewhat different diagnostic criteria to be used in clinical practice to identify patients with metabolic syndrome, As recently stated by the joint American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement on “Diagnosis and Management of the Metabolic Syndrome” III [1], all the proposed classifications have in common the concept that the metabolic syndrome represents a constellation of interrelated risk factors of metabolic origin (“metabolic risk factors”) that appear to directly promote the development of atherosclerotic cardiovascular disease. These metabolic risk factors include elevated blood pressure, elevated plasma glucose and atherogenic dyslipidemia, which consists of an aggregation of lipoprotein abnormalities including elevated plasma triglyceride levels, increased small, dense low density lipoproteins (LDL), and reduced high density lipoproteins (HDL) cholesterol concentrations.

This form of dyslipidemia, also known as “atherogenic lipoprotein phenotype” or “lipid triad” represents a partially heritable trait and is associated with increased cardiovascular risk [2-4]. It has been suggested that the clinical importance of the atherogenic lipoprotein phenotype probably exceeds that of LDL-cholesterol, because many more patients with coronary artery disease are found to have this trait compared to those with hypercholesterolaemia [5,6]. LDL comprises multiple distinct subclasses that differ in size, density, physicochemical composition, metabolic behavior and atherogenicity. There are at least four major subspecies of LDL, e.g. large LDL-I, medium LDL-II, small LDL-III, and very small LDL-IV [7] and, based on measurement of peak particle diameter or ultracentrifugal density, individuals generally cluster into two broad subgroups, the majority with a predominance of larger LDL (LDL pattern A) and a minority with a higher proportion of smaller particles (LDL pattern B) [7,8]. Small, dense LDL are associated with increased risk for cardiovascular disease and diabetes mellitus [reviewed in 9] and their predominance has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III [10].

Beyond the atherogenic lipoprotein phenotype, small, dense LDL may be even independently associated with the metabolic syndrome. Hulthe et al. [11] assessed the prevalence of metabolic syndrome in a population-based sample of clinically 58 years old healthy men, using the WHO definition [12]. The authors found that LDL size was significantly smaller in subjects with the metabolic syndrome, in relation to those without it. In addition, they found that subjects with pattern B had significantly higher mean values for body mass index, blood pressures, heart rate, serum cholesterol, triglyceride levels, and plasma insulin and lower HDL levels compared to subjects with pattern A. Subjects with pattern B also had higher prevalence of moderate to large plaques in the carotid artery compared to subjects with pattern A. Interestingly, decreasing LDL peak particle size was significantly associated with increasing IMT of the common carotid artery, the carotid artery bulb, and the common femoral artery. There was a statistically significant association between plaque occurrence and size and LDL peak particle diameter in both carotid and femoral arteries.

However, Haffner et al. had already shown in 1995 that LDL size is decreased in subjects with multiple metabolic disorders. Since no exact definition was available at that time regarding the metabolic syndrome, the authors [13] examined the association of LDL size and pattern to specific insulin, proinsulin, increased triglyceride, decreased HDL, hypertension, and impaired glucose tolerance in 488 non-diabetic subjects. They found that LDL size decreased with increasing number of the metabolic disorders described above (zero 262.6 +/- 9.4; one 257.0 +/- 9.3; two 256.4 +/- 9.4; three 249.0 +/- 9.1; and four 244.9 +/- 9.0 angstrom). These results were similar in subjects of different gender and ethnicity. Notably, the association between LDL size and the number of metabolic disorders remained statistically significant, even after adjustment for obesity, body fat distribution, gender, ethnicity, and proinsulin and insulin concentrations. Other studies [14,15] have more recently indirectly assessed levels of small, dense LDL in subjects with the metabolic syndrome, using recent evidences that support the use of the triglyceride/HDL-cholesterol ratio for the prediction of LDL pattern B [16,17]. Many issues on the accuracy may be questioned, but this indirect measure holds the great advantage of being inexpensive as well as easily used in routine practice.

In summary, LDL size and subclasses may show specific alterations in patients with the metabolic syndrome that probably significantly increase their cardiovascular risk; however, so far it has not been recommended by the international scientific societies to incorporate LDL size measurements in treatment plans, when hypolipidemic therapies are implemented. It is known that the therapeutic modulation of HDL-cholesterol and triglyceride concentrations significantly reduce cardiovascular risk [10] and lipid-lowering agents are also effective in increasing LDL size by reducing levels of small, dense LDL, but strong differences have been noticed among the different molecules [18,19]. Measurements beyond traditional lipids, such as the presence of small, dense LDL in patients with the metabolic syndrome, may help to identify cardiovascular risk subgroups. In addition, it might be possible in the future to individualize hypolipidemic treatments if more than the traditional lipids are taken into account. LDL size measurements in particular may help to assess cardiovascular risk within the metabolic syndrome and adapt the treatment goals thereafter [20].

References

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