Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide and small dense low-density lipoprotein (sdLDL) has been suggested to be a potential risk factor for cardiovascular disease (CVD). We reviewed published studies on formation and measurement of sdLDL, as well as relationship between LDL subfractions and CVD. sdLDL particle formation is highly dependent on triglycerides (TG) levels, and the physicochemical properties of sdLDL particles provide a potential for increased atherogenicity. Various conditions (e.g. hypertriglyceridemia, diabetes mellitus, metabolic syndrome, chronic renal failure and HIV infections) with increased cardiometabolic risk are associated with increased sdLDLs. Most studies suggest that sdLDL particles are associated with increased prevalence of clinical and subclinical CVDs, as well as non-coronary forms of atherosclerosis. Moreover, LDL size seems to be an important determinant of the progression of CVD. Therapeutic modulation (mostly fibrates, but also some statins, as well as niacin and thiazolidinediones) of small LDL size, number and distribution may decrease CVD risk. However, no definitive causal relationship is yet established, probably due to the close association between sdLDL and triglycerides and other risk factors.
Figures and Tables
Fig. 1
Formation of small, dense low-density lipoprotein (LDL) particles. Two steps are involved in the formation of small, dense LDL particles. The first is lipid transfer mediated by cholesterol ester transfer protein (CETP); the second is lipid hydrolysis by lipoprotein lipase (LPL) and hepatic lipase (HL). B=apoB100; CE=cholesterol ester; Tg=triglyceride; VLDL=very-low-density lipoprotein. Modified from Sniderman et al.88
![jla-1-1-g001](/upload/SynapseData/ArticleImage/0211jla/jla-1-1-g001.jpg)
References
1. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet. 1997; 349:1269–1276.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
2. Executive Summary of The 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). JAMA. 2001; 285:2486–2497.
3. Steinberg D, Glass CK, Witztum JL. Evidence mandating earlier and more aggressive treatment of hypercholesterolemia. Circulation. 2008; 118:672–677.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
4. Kannel WB. Range of serum cholesterol values in the population developing coronary artery disease. Am J Cardiol. 1995; 76:69C–77C.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
5. Chapman J. Beyond LDL-cholesterol reduction: the way ahead in managing dyslipidaemia. Eur Heart J. 2005; 7:Suppl. F56–F62.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
6. Packard CJ, Shepherd J. Lipoprotein heterogeneity and apolipoprotein B metabolism. Arterioscler Thromb Vasc Biol. 1997; 17:3542–3556.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
7. Austin MA, Talmud PJ, Luong LA, Haddad L, Day IN, Newman B, Edwards KL, Krauss RM, Humphries SE. Candidate-gene studies of the atherogenic lipoprotein phenotype: a sib-pair linkage analysis of DZ women twins. Am J Hum Genet. 1998; 62:406–419.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
8. 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.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
9. Campos H, Blijlevens E, McNamara JR, Ordovas JM, Posner BM, Wilson PW, Castelli WP, Schaefer EJ. LDL particle size distribution. Results from the Framingham Offspring Study. Arterioscler Thromb. 1992; 12:1410–1419.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
10. Selby JV, Austin MA, Newman B, Zhang D, Quesenberry CP Jr, Mayer EJ, Krauss RM. LDL subclass phenotypes and the insulin resistance syndrome in women. Circulation. 1993; 88:381–387.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
11. Packard CJ. Triacylglycerol-rich lipoproteins and the generation of small, dense low-density lipoprotein. Biochem Soc Trans. 2003; 31:1066–1069.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
12. Packard CJ, Demant T, Stewart JP, Bedford D, Caslake MJ, Schwertfeger G, Bedynek A, Shepherd J, Seidel D. Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions. J Lipid Res. 2000; 41:305–318.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
13. Hirano T, Ito Y, Yoshino G. Measurement of small dense low-density lipoprotein particles. J Atheroscler Thromb. 2005; 12:67–72.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
14. Otvos JD, Jeyarajah EJ, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol. 2002; 90:22i–29i.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
15. Nichols AV, Krauss RM, Musliner TA. Nondenaturing polyacrylamide gradient gel electrophoresis. Methods Enzymol. 1986; 128:417–431.
16. Hirano T, Ito Y, Saegusa H, Yoshino G. A novel and simple method for quantification of small, dense LDL. J Lipid Res. 2003; 44:2193–2201.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
17. Hoefner DM, Hodel SD, O'Brien JF, Branum EL, Sun D, Meissner I, McConnell JP. Development of a rapid, quantitative method for LDL subfractionation with use of the Quantimetrix Lipoprint LDL System. Clin Chem. 2001; 47:266–274.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
18. Maruyama C, Imamura K, Teramoto T. Assessment of LDL particle size by triglyceride/HDL-cholesterol ratio in non-diabetic, healthy subjects without prominent hyperlipidemia. J Atheroscler Thromb. 2003; 10:186–191.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
19. Anber V, Millar JS, McConnell M, Shepherd J, Packard CJ. Interaction of very-low-density, intermediate-density, and low-density lipoproteins with human arterial wall proteoglycans. Arterioscler Thromb Vasc Biol. 1997; 17:2507–2514.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
20. Nielsen LB. Transfer of low density lipoprotein into the arterial wall and risk of atherosclerosis. Atherosclerosis. 1996; 123:1–15.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
21. Krauss RM. Atherogenic lipoprotein phenotype and diet-gene interactions. J Nutr. 2001; 131:340S–343S.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
22. Galeano NF, Al-Haideri M, Keyserman F, Rumsey SC, Deckelbaum RJ. Small dense low density lipoprotein has increased affinity for LDL receptor-independent cell surface binding sites: a potential mechanism for increased atherogenicity. J Lipid Res. 1998; 39:1263–1273.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
23. Toyota Y, Yamamura T, Miyake Y, Yamamoto A. Low density lipoprotein (LDL) binding affinity for the LDL receptor in hyperlipoproteinemia. Atherosclerosis. 1999; 147:77–86.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
24. Rizzo M, Berneis K. Should we measure routinely the LDL peak particle size? Int J Cardiol. 2006; 107:166–170.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
25. Maki KC, Davidson MH, Marx P, Cyrowski MS, Maki A. Association between elevated plasma fibrinogen and the small, dense low-density lipoprotein phenotype among postmenopausal women. Am J Cardiol. 2000; 85:451–456.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
26. Festa A, D'Agostino R Jr, Mykkanen L, Tracy R, Howard BV, Haffner SM. Low-density lipoprotein particle size is inversely related to plasminogen activator inhibitor-1 levels. The Insulin Resistance Atherosclerosis Study. Arterioscler Thromb Vasc Biol. 1999; 19:605–610.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
27. Krauss RM. Dietary and genetic probes of atherogenic dyslipidemia. Arterioscler Thromb Vasc Biol. 2005; 25:2265–2272.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
28. Blackburn P, Cote M, Lamarche B, Couillard C, Pascot A, Tremblay A, Bergeron J, Lemieux I, Despres JP. Impact of postprandial variation in triglyceridemia on low-density lipoprotein particle size. Metabolism. 2003; 52:1379–1386.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
29. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993; 16:434–444.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
30. Consensus development conference on the diagnosis of coronary heart disease in people with diabetes: 10-11 February 1998, Miami, Florida. American Diabetes Association. Diabetes Care. 1998; 21:1551–1559.
31. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001; 24:683–689.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
32. Watson KE, Horowitz BN, Matson G. Lipid abnormalities in insulin resistant states. Rev Cardiovasc Med. 2003; 4:228–236.
33. Tan KC, Cooper MB, Ling KL, Griffin BA, Freeman DJ, Packard CJ, Shepherd J, Hales CN, Betteridge DJ. Fasting and postprandial determinants for the occurrence of small dense LDL species in non-insulin-dependent diabetic patients with and without hypertriglyceridaemia: the involvement of insulin, insulin precursor species and insulin resistance. Atherosclerosis. 1995; 113:273–287.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
34. Siegel RD, Cupples A, Schaefer EJ, Wilson PW. Lipoproteins, apolipoproteins, and low-density lipoprotein size among diabetics in the Framingham offspring study. Metabolism. 1996; 45:1267–1272.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
35. Taskinen MR. LDL-cholesterol, HDL-cholesterol or triglycerides--which is the culprit? Diabetes Res Clin Pract. 2003; 61:Suppl 1. S19–S26.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
36. Kolovou GD, Anagnostopoulou KK, Cokkinos DV. Pathophysiology of dyslipidaemia in the metabolic syndrome. Postgrad Med J. 2005; 81:358–366.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
37. Gazi I, Tsimihodimos V, Filippatos T, Bairaktari E, Tselepis AD, Elisaf M. Concentration and relative distribution of low-density lipoprotein subfractions in patients with metabolic syndrome defined according to the National Cholesterol Education Program criteria. Metabolism. 2006; 55:885–891.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
38. Suh S, Park HD, Kim SW, Bae JC, Tan AH, Chung HS, Hur KY, Kim JH, Kim KW, Lee MK. Smaller Mean LDL Particle Size and Higher Proportion of Small Dense LDL in Korean Type 2 Diabetic Patients. Diabetes Metab J. 2011; 35:536–542.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
39. Miller WM, Nori-Janosz KE, Lillystone M, Yanez J, McCullough PA. Obesity and lipids. Curr Cardiol Rep. 2005; 7:465–470.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
40. Gazi IF, Filippatos TD, Tsimihodimos V, Saougos VG, Liberopoulos EN, Mikhailidis DP, Tselepis AD, Elisaf M. The hypertriglyceridemic waist phenotype is a predictor of elevated levels of small, dense LDL cholesterol. Lipids. 2006; 41:647–654.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
41. Carr MC, Hokanson JE, Zambon A, Deeb SS, Barrett PH, Purnell JQ, Brunzell JD. The contribution of intra-abdominal fat to gender differences in hepatic lipase activity and low/high density lipoprotein heterogeneity. J Clin Endocrinol Metab. 2001; 86:2831–2837.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
42. Bioletto S, Golay A, Munger R, Kalix B, James RW. Acute hyperinsulinemia and very-low-density and low-density lipoprotein subfractions in obese subjects. Am J Clin Nutr. 2000; 71:443–449.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
43. Hyre AD, Fox CS, Astor BC, Cohen AJ, Muntner P. The impact of reclassifying moderate CKD as a coronary heart disease risk equivalent on the number of US adults recommended lipid-lowering treatment. Am J Kidney Dis. 2007; 49:37–45.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
44. Wanner C, Krane V. Uremia-specific alterations in lipid metabolism. Blood Purif. 2002; 20:451–453.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
45. Quaschning T, Krane V, Metzger T, Wanner C. Abnormalities in uremic lipoprotein metabolism and its impact on cardiovascular disease. Am J Kidney Dis. 2001; 38:S14–S19.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
46. Glass TR, Ungsedhapand C, Wolbers M, Weber R, Vernazza PL, Rickenbach M, Furrer H, Bernasconi E, Cavassini M, Hirschel B, Battegay M, Bucher HC. Prevalence of risk factors for cardiovascular disease in HIV-infected patients over time: the Swiss HIV Cohort Study. HIV Med. 2006; 7:404–410.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
47. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D, Bax J, Vahanian A, Auricchio A, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Filippatos G, Funck-Brentano C, Hasdai D, Hoes A, Kearney P, Knuuti J, Kolh P, McDonagh T, Moulin C, Poldermans D, Popescu BA, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vardas P, Widimsky P, Windecker S, Berkenboom G, De Graaf J, Descamps O, Gotcheva N, Griffith K, Guida GF, Gulec S, Henkin Y, Huber K, Kesaniemi YA, Lekakis J, Manolis AJ, Marques-Vidal P, Masana L, McMurray J, Mendes M, Pagava Z, Pedersen T, Prescott E, Rato Q, Rosano G, Sans S, Stalenhoef A, Tokgozoglu L, Viigimaa M, Wittekoek ME, Zamorano JL. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011; 32:1769–1818.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
48. Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WC, Krauss RM. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA. 1988; 260:1917–1921.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
49. Campos H, Genest JJ Jr, Blijlevens E, McNamara JR, Jenner JL, Ordovas JM, Wilson PW, Schaefer EJ. Low density lipoprotein particle size and coronary artery disease. Arterioscler Thromb. 1992; 12:187–195.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
50. Coresh J, Kwiterovich PO Jr, Smith HH, Bachorik PS. Association of plasma triglyceride concentration and LDL particle diameter, density, and chemical composition with premature coronary artery disease in men and women. J Lipid Res. 1993; 34:1687–1697.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
51. Tornvall P, Karpe F, Carlson LA, Hamsten A. Relationships of low density lipoprotein subfractions to angiographically defined coronary artery disease in young survivors of myocardial infarction. Atherosclerosis. 1991; 90:67–80.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
52. Koba S, Hirano T, Kondo T, Shibata M, Suzuki H, Murakami M, Geshi E, Katagiri T. Significance of small dense low-density lipoproteins and other risk factors in patients with various types of coronary heart disease. Am Heart J. 2002; 144:1026–1035.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
53. Yoon Y, Song J, Park HD, Park KU, Kim JQ. Significance of small dense low-density lipoproteins as coronary risk factor in diabetic and non-diabetic Korean populations. Clin Chem Lab Med. 2005; 43:431–437.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
54. Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA. 1996; 276:875–881.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
55. Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres JP. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Circulation. 1997; 95:69–75.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
56. Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG, Sacks FM, Hennekens CH. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA. 1996; 276:882–888.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
57. Austin MA, Rodriguez BL, McKnight B, McNeely MJ, Edwards KL, Curb JD, Sharp DS. Low-density lipoprotein particle size, triglycerides, and high-density lipoprotein cholesterol as risk factors for coronary heart disease in older Japanese-American men. Am J Cardiol. 2000; 86:412–416.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
58. Koba S, Hirano T, Ito Y, Tsunoda F, Yokota Y, Ban Y, Iso Y, Suzuki H, Katagiri T. Significance of small dense low-density lipoprotein-cholesterol concentrations in relation to the severity of coronary heart diseases. Atherosclerosis. 2006; 189:206–214.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
59. Rosenson RS, Otvos JD, Freedman DS. Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) trial. Am J Cardiol. 2002; 90:89–94.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
60. Kwon SW, Yoon SJ, Kang TS, Kwon HM, Kim JH, Rhee J, Lee SJ, Park JK, Lim JY, Yoon YW, Hong BK. Significance of small dense low-density lipoprotein as a risk factor for coronary artery disease and acute coronary syndrome. Yonsei Med J. 2006; 47:405–414.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
61. Koba S, Hirano T, Yoshino G, Sakai K, Sakaue T, Adachi M, Katagiri T. Remarkably high prevalence of small dense low-density lipoprotein in Japanese men with coronary artery disease, irrespective of the presence of diabetes. Atherosclerosis. 2002; 160:249–256.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
62. Ip S, Lichtenstein AH, Chung M, Lau J, Balk EM. Systematic review: association of low-density lipoprotein subfractions with cardiovascular outcomes. Ann Intern Med. 2009; 150:474–484.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
63. Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum JL. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008; 31:811–822.
64. Milionis HJ, Liberopoulos E, Goudevenos J, Bairaktari ET, Seferiadis K, Elisaf MS. Risk factors for first-ever acute ischemic non-embolic stroke in elderly individuals. Int J Cardiol. 2005; 99:269–275.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
65. Rizzo M, Berneis K, Corrado E, Novo S. The significance of low-density-lipoproteins size in vascular diseases. Int Angiol. 2006; 25:4–9.
66. Hallman DM, Brown SA, Ballantyne CM, Sharrett AR, Boerwinkle E. Relationship between low-density lipoprotein subclasses and asymptomatic atherosclerosis in subjects from the Atherosclerosis Risk in Communities (ARIC) Study. Biomarkers. 2004; 9:190–202.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
67. Watanabe T, Koba S, Kawamura M, Itokawa M, Idei T, Nakagawa Y, Iguchi T, Katagiri T. Small dense low-density lipoprotein and carotid atherosclerosis in relation to vascular dementia. Metabolism. 2004; 53:476–482.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
68. Skoglund-Andersson C, Tang R, Bond MG, de Faire U, Hamsten A, Karpe F. LDL particle size distribution is associated with carotid intima-media thickness in healthy 50-year-old men. Arterioscler Thromb Vasc Biol. 1999; 19:2422–2430.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
69. Berneis K, Jeanneret C, Muser J, Felix B, Miserez AR. Low-density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes. Metabolism. 2005; 54:227–234.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
70. Lee W, Min WK, Chun S, Jang S, Kim JQ, Lee DH, Park JY, Park H, Son JE. Low-density lipoprotein subclass and its correlating factors in diabetics. Clin Biochem. 2003; 36:657–661.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
71. Park JS, Park J, Kim CS, Cho MH, Kim HJ, Kim JH, Ahn CW, Kim KR, Cha BS, Lim SK, Lee HC. Relationship of low-density lipoprotein particle size to insulin resistance and intima-media thickness in nondiabetic Koreans. Metabolism. 2006; 55:1610–1615.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
72. Yeo Y, Byun SW, Lee JY, Min WK, Park JS, Kim SB. Lack of association between small dense low-density lipoprotein levels and coronary artery disease in chronic hemodialysis patients. Am J Nephrol. 2009; 30:310–314.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
73. Rizzo M, Rini GB, Berneis K. The clinical relevance of LDL size and subclasses modulation in patients with type-2 diabetes. Exp Clin Endocrinol Diabetes. 2007; 115:477–482.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
74. Yuan JN, Tsai MY, Hegland J, Hunninghake DB. Effects of fluvastatin (XU 62-320), an HMG-CoA reductase inhibitor, on the distribution and composition of low density lipoprotein subspecies in humans. Atherosclerosis. 1991; 87:147–157.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
75. Marz W, Scharnagl H, Abletshauser C, Hoffmann MM, Berg A, Keul J, Wieland H, Baumstark MW. Fluvastatin lowers atherogenic dense low-density lipoproteins in postmenopausal women with the atherogenic lipoprotein phenotype. Circulation. 2001; 103:1942–1948.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
76. Yoshino G, Hirano T, Kazumi T, Takemoto M, Ohashi N. Fluvastatin increases LDL particle size and reduces oxidative stress in patients with hyperlipidemia. J Atheroscler Thromb. 2003; 10:343–347.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
77. Shimabukuro M, Higa N, Asahi T, Oshiro Y, Takasu N. Fluvastatin improves endothelial dysfunction in overweight postmenopausal women through small dense low-density lipoprotein reduction. Metabolism. 2004; 53:733–739.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
78. Caslake MJ, Stewart G, Day SP, Daly E, McTaggart F, Chapman MJ, Durrington P, Laggner P, Mackness M, Pears J, Packard CJ. Phenotype-dependent and -independent actions of rosuvastatin on atherogenic lipoprotein subfractions in hyperlipidaemia. Atherosclerosis. 2003; 171:245–253.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
79. Tsimihodimos V, Miltiadous G, Daskalopoulou SS, Mikhailidis DP, Elisaf MS. Fenofibrate: metabolic and pleiotropic effects. Curr Vasc Pharmacol. 2005; 3:87–98.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
80. Rizzo M, Berneis K. Low-density lipoprotein size and cardiovascular risk assessment. QJM. 2006; 99:1–14.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
81. Ikewaki K, Tohyama J, Nakata Y, Wakikawa T, Kido T, Mochizuki S. Fenofibrate effectively reduces remnants, and small dense LDL, and increases HDL particle number in hypertriglyceridemic men - a nuclear magnetic resonance study. J Atheroscler Thromb. 2004; 11:278–285.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
82. Badiou S, Merle De Boever C, Dupuy AM, Baillat V, Cristol JP, Reynes J. Fenofibrate improves the atherogenic lipid profile and enhances LDL resistance to oxidation in HIV-positive adults. Atherosclerosis. 2004; 172:273–279.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
83. Deighan CJ, Caslake MJ, McConnell M, Boulton-Jones JM, Packard CJ. Comparative effects of cerivastatin and fenofibrate on the atherogenic lipoprotein phenotype in proteinuric renal disease. J Am Soc Nephrol. 2001; 12:341–348.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
84. Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, Ganda OP, Rosenson RS, Buse JB, Robertson DD, Sheehan JP. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial. Arch Intern Med. 2002; 162:1568–1576.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
85. McKenney JM, McCormick LS, Schaefer EJ, Black DM, Watkins ML. Effect of niacin and atorvastatin on lipoprotein subclasses in patients with atherogenic dyslipidemia. Am J Cardiol. 2001; 88:270–274.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)
86. Parhofer KG, Otto C, Geiss HC, Laubach E, Goke B. Effect of pioglitazone on lipids in well controlled patients with diabetes mellitus type 2 -- results of a pilot study. Exp Clin Endocrinol Diabetes. 2005; 113:49–52.
![crossref](/image/icon/bnr_ref_cross.gif)
![crossref](/image/icon/bnr_ref_cross.gif)