The Significance of LDL Heterogeneity in the Metabolic Syndrome

Manfredi Rizzo¹ and Kaspar Berneis²,
¹ Department 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
² Clinics for Endocrinology, Diabetes & Clinical Nutrition, University Hospital Zurich, Switzerland, Tel. and Fax: + 41 (44) 2553585, E-mail: Kaspar.Berneis@usz.ch

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 hypercholesterolemia [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-year-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

1. Grundy SM, Cleeman JI, Daniels SR, et al.; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735-52.
   
2. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 1990;82:495-506.
   
3. Krauss RM. Dietary and genetic probes of atherogenic dyslipidemia. Arterioscler Thromb Vasc Biol 2005;25:2265-72.
   
4. Rizzo M, Berneis K. Lipid triad or atherogenic lipoprotein phenotype: a role in cardiovascular prevention? J Atheroscl Thromb 2005;12:237-39.
   
5. Sattar N, Petrie JR, Jaap AJ. The atherogenic lipoprotein phenotype and vascular endothelial dysfunction. Atherosclerosis 1998;138:229-35.
   
6. Superko HR. Beyond LDL cholesterol reduction. Circulation 1996;94:2351-54.
   
7. Krauss RM, Burke DJ. Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res 1982;23:97-104.
   
8. Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res 2002;43:1363-79.
   
9. Rizzo M, Berneis K. Low-density-lipoproteins size and cardiovascular risk assessment QJM - Int J Med 2006;99:1-14.
   
10. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-421.
    
11. Hulthe J, Bokemark L, Wikstrand J, Fagerberg B. The metabolic syndrome, LDL particle size, and atherosclerosis: the Atherosclerosis and Insulin Resistance (AIR) study. Arterioscler Thromb Vasc Biol 2000;20:2140-47.
    
12. World Health Organization: Definition, Diagnosis, and Classification of Diabetes Mellitus and its Complications: Report of a WHO Consultation. Geneva, World Health Org, 1999.
    
13. Haffner SM, Mykkanen L, Robbins D, et al. A preponderance of small dense LDL is associated with specific insulin, proinsulin and the components of the insulin resistance syndrome in non-diabetic subjects. Diabetologia 1995;38:1328-36.
    
14. Garin MC, Kalix B, Morabia A, James RW. Small, dense lipoprotein particles and reduced paraoxonase-1 in patients with the metabolic syndrome. J Clin Endocrinol Metab 2005;90:2264-69.
    
15. Slapikas R, Luksiene D, Slapikiene B, Babarskiene MR, Grybauskiene R, Linoniene L. Prevalence of cardiovascular risk factors in coronary heart disease patients with different low-density lipoprotein phenotypes. Medicina (Kaunas) 2005;41:925-31.
    
16. Hanak V, Munoz J, Teague J, Stanley A Jr, Bittner V. Accuracy of the triglyceride to high-density lipoprotein cholesterol ratio for prediction of the low-density lipoprotein phenotype B. Am J Cardiol 2004;94:219-22.
    
17. McLaughlin T, Reaven G, Abbasi F, et al. Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? Am J Cardiol 2005;96:399-404.
    
18. Rizzo M, Berneis K. The clinical relevance of low-density-lipoproteins size modulation by statins. Cardiovasc Drug Ther 2006;20:205-17.
    
19. Backes JM, Gibson CA. Effect of lipid-lowering drug therapy on small-dense low-density lipoprotein. Ann Pharmacother 2005;39:523-26.
    
20. Rizzo M, Berneis K. Small, dense low-density-lipoproteins and the metabolic syndrome. Diabetes Metab Res Rev 2007;23:14-20.