Current Atherosclerosis Reports

, Volume 10, Issue 5, pp 377–385

Is it LDL particle size or number that correlates with risk for cardiovascular disease?



The role of low-density lipoprotein cholesterol (LDL-C) in the pathogenesis of cardiovascular disease (CVD) and the clinical benefit of lowering LDL-C in high-risk patients is well established. What remains controversial is whether we are using the best measure(s) of LDL characteristics to identify all individuals who are at CVD risk or if they would benefit from specific therapies. Despite the successful LDL-C reduction trials, substantial numbers of patients continue to have clinical events in the treatment groups. The size of LDL particles and assessment of the number of LDL particles (LDL-Num) have been suggested as a more reliable method of atherogenicity. Each LDL particle has one apoprotein B-100 measure attached; therefore, determination of whole plasma apoprotein B can be considered the best measure of LDL-Num. Because the cholesterol content per LDL particle exhibits large interindividual variation, the information provided by LDL-C and LDL-Num is not equivalent. Individuals with the same level of LDL-C may have higher or lower numbers of LDL particles and, as a result, may differ in terms of absolute CVD risk. LDL particle size and number provide independent measures of atherogenicity and are strong predictors of CVD.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Superko HR, Krauss RM: Coronary artery disease regression. Convincing evidence for the benefit of aggressive lipoprotein management. Circulation 1994, 90:1056–1069.PubMedGoogle Scholar
  2. 2.
    MAAS Investigators: Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet 1994, 344:633–638.CrossRefGoogle Scholar
  3. 3.
    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.PubMedCrossRefGoogle Scholar
  4. 4.
    Waters D, Higginson L, Gladstone P, et al.: Effects of cholesterol lowering on the progression of coronary atherosclerosis in women: a Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) substudy. Circulation 1995, 92:2404–2410.PubMedGoogle Scholar
  5. 5.
    Jukema JW, Bruschke VG, van Boven AJ, et al., for the REGRESS Study Group: Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995, 91:2528–2540.PubMedGoogle Scholar
  6. 6.
    Miller BD, Alderman EL, Haskell WL, et al.: Predominance of dense low-density lipoprotein particles predicts angiographic benefit of therapy in the Stanford Coronary Risk Intervention Project (SCRIP). Circulation 1996, 94:2146–2153.PubMedGoogle Scholar
  7. 7.
    Mack WJ, Krauss RM, Hodis HN: Lipoprotein subclasses in the Monitored Atherosclerosis Regression Study (MARS). Treatment effects and relation to coronary angiographic progression. Arterioscler Thromb Vasc Biol 1996, 16:697–704.PubMedGoogle Scholar
  8. 8.
    Watts GF, Mandalia S, Brunt JH, et al.: Independent associations between plasma lipoprotein subfraction levels and the course of coronary artery disease in the St. Thomas’ Atherosclerosis Regression Study (STARS). Metabolism 1993, 42:1461–1467.PubMedCrossRefGoogle Scholar
  9. 9.
    Zambon A, Hokanson JE, Brown BG, Brunzell JD: Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density. Circulation 1999, 99:1959–1964.PubMedGoogle Scholar
  10. 10.
    Gofman JW, Young W, Tandy R: Ischemic heart disease, atherosclerosis, and longevity. Circulation 1966, 34:679–697.PubMedGoogle Scholar
  11. 11.
    Krauss RM: Heterogeneity of plasma low-density lipoproteins and atherosclerosis risk. Curr Opin Lipidol 1994, 5:339–349.PubMedCrossRefGoogle Scholar
  12. 12.
    Krauss RM: Atherogenicity of triglyceride-rich lipoproteins. Am J Cardiol 1998, 81:13B–17B.PubMedCrossRefGoogle Scholar
  13. 13.
    Superko HR: What can we learn about dense low density lipoprotein and lipoprotein particles from clinical trials? Current Opin Lipidol 1996, 7:363–368.CrossRefGoogle Scholar
  14. 14.
    Nishina PM, Johnson JP, Naggert JK, Krauss RM: Linkage of atherogenic lipoprotein phenotype to the low-density lipoprotein receptor locus on the short arm of chromosome 19. Proc Natl Acad Sci U S A 1992, 89:708–712.PubMedCrossRefGoogle Scholar
  15. 15.
    Zhao XQ, Kosinski AS, Barnhart HX, et al.: Prediction of native coronary artery disease progression following PTCA or CABG in the Emory Angioplasty Versus Surgery Trial. Med Sci Monit 2003, 9:48–54.Google Scholar
  16. 16.
    Superko HR, McGovern ME, Raul E, Garrett B: Differential effect of two nicotinic acid preparations on low-density lipoprotein subclass distribution in patients classified as low-density lipoprotein pattern A, B, or I. Am J Cardiol 2004, 94:588–594.PubMedCrossRefGoogle Scholar
  17. 17.
    Superko HR, King S 3rd: Lipid management to reduce cardiovascular risk: a new strategy is required. Circulation 2008, 117:560–568.PubMedCrossRefGoogle Scholar
  18. 18.
    Fless GM, Rolih CA, Scanu AM: Heterogeneity of human plasma lipoprotein (a). Isolation and characterization of the lipoprotein subspecies and their apoproteins. J Biol Chem 1984, 259:11470–11478.PubMedGoogle Scholar
  19. 19.
    Friedewald WT, Levy RI, Fredrickson DS: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972, 18:499–502.PubMedGoogle Scholar
  20. 20.
    Phillips NR, Waters D, Havel RJ: Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events. Circulation 1993, 88:2762–2770.PubMedGoogle Scholar
  21. 21.
    Nauck M, Warnick GR, Rifai N: Methods for measurement of LDL-cholesterol: a critical assessment of direct measurement by homogeneous assays versus calculation. Clin Chem 2002, 48:236–254.PubMedGoogle Scholar
  22. 22.
    Nichols AV, Krauss RM, Musliner TA: Nondenaturing polyacrylamide gradient gel electrophoresis. Methods Enzymol 1986, 128:417–431.PubMedCrossRefGoogle Scholar
  23. 23.
    Krauss RM, Burke DJ: Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res 1982, 23:97–104.PubMedGoogle Scholar
  24. 24.
    Austin MA, Breslow JL, Hennekens CH, et al.: Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 1988, 260:1917–1921.PubMedCrossRefGoogle Scholar
  25. 25.
    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.PubMedCrossRefGoogle Scholar
  26. 26.
    Blake GJ, Otvos JD, Rifai N, Ridker PM: Low-density lipoprotein particle concentration, and size as determined by nuclear magnetic resonance spectroscopy as predictors of cardiovascular disease in women. Circulation 2002, 106:1930–1937.PubMedCrossRefGoogle Scholar
  27. 27.
    St-Pierre AC, Ruel IL, Cantin B, et al.: Comparison of various electrophoretic characteristics of LDL particles and their relationship to the risk of ischemic heart disease. Circulation 2001, 104:2295–2299.PubMedCrossRefGoogle Scholar
  28. 28.
    Stampfer MJ, Krauss RM, Ma J, et al.: A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA 1996, 276:882–888.PubMedCrossRefGoogle Scholar
  29. 29.
    Cromwell WC, Otvos JD: Low-density lipoprotein particle number and risk of cardiovascular disease. Curr Atheroscler Rep 2004, 6:381–387.PubMedCrossRefGoogle Scholar
  30. 30.
    Superko HR: Small, dense, low-density lipoprotein and atherosclerosis. Curr Atheroscler Rep 2000, 2:226–231.PubMedCrossRefGoogle Scholar
  31. 31.
    Lamarche B, Tchernof A, Moorjani S, et al.: 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.PubMedGoogle Scholar
  32. 32.
    Kulkarni KR, Garber DW, Marcovina SM, Segrest JP: Quantification of cholesterol in all lipoprotein classes by VAP II method. J Lipid Res 1994, 35:159–168.PubMedGoogle Scholar
  33. 33.
    Otvos JD, Jeyarajah EJ, Bennett DW, Krauss RM: Development of a proton nuclear magnetic resonance spectroscopic method for determining plasma lipoprotein concentrations and subspecies distributions from a single, rapid measurement. Clin Chem 1992, 38:1632–1638.PubMedGoogle Scholar
  34. 34.
    Mueller O, Chang E, Deng D, et al.; PROCAM Study: Risk prediction for myocardial infarction using microfluidic high density lipoprotein (HDL) sub-fractionation is independent of HDL-cholesterol. Clin Chem Lab 2008, 46:490–498.CrossRefGoogle Scholar
  35. 35.
    Sniderman AD, Furberg CD, Keech A, et al.: Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet 2003, 361:777–780.PubMedCrossRefGoogle Scholar
  36. 36.
    Berneis KK, Krauss RM: Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res 2002, 43:1363–1379.PubMedCrossRefGoogle Scholar
  37. 37.
    Austin MA, King MC, Vranizan JM, Krauss RM: Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease risk. Circulation 1990, 82:495–506.PubMedGoogle Scholar
  38. 38.
    Sacks FM, Campos H: Clinical review 163: cardiovascular endocrinology: low-density lipoprotein size and cardiovascular disease: a reappraisal. J Clin Endocrinol Metab 2003, 88:4525–4532.PubMedCrossRefGoogle Scholar
  39. 39.
    Lamarche B, Lewis GF: Atherosclerosis prevention for the next decade: risk assessment beyond low density lipoprotein cholesterol. Can J Cardiol 1998, 14:841–851.PubMedGoogle Scholar
  40. 40.
    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, 106:3143–3421.Google Scholar
  41. 41.
    Austin MA, Rodriguez BL, McKnight B, et al.: 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.PubMedCrossRefGoogle Scholar
  42. 42.
    Rizzo M, Berneis K: Low-density lipoprotein size and cardiovascular risk assessment. Q J Med 2006, 99:1–14.Google Scholar
  43. 43.
    Björnheden T, Babyi A, Bondjers G, Wiklund O: Accumulation of lipoprotein fractions and subfractions in the arterial wall, determined in an in vitro perfusion system. Atherosclerosis 1996, 123:43–56.PubMedCrossRefGoogle Scholar
  44. 44.
    Weisser B, Locher R, de Graaf J, et al.: Low density lipoprotein subfractions increase thromboxane formation in endothelial cells. Biochem Biophys Res Commun 1993, 192:1245–1250.PubMedCrossRefGoogle Scholar
  45. 45.
    Tertov VV, Sobenin IA, Gabbasov ZA, et al.: Multiple-modified desialylated low density lipoproteins that cause intracellular lipid accumulation. Isolation, fractionation and characterization. Lab Invest 1992, 67:665–675.PubMedGoogle Scholar
  46. 46.
    Woodman RJ, Watts GF, Playford DA, et al.: Oxidized LDL and small LDL particle size are independently predictive of a selective defect in microcirculatory endothelial function in type 2 diabetes. Diabetes Obes Metab 2005, 7:612–617.PubMedCrossRefGoogle Scholar
  47. 47.
    Superko HR, Berneis KK, Williams PT, et al.: Gemfibrozil reduces small low-density lipoprotein more in normolipemic subjects classified as low-density lipoprotein pattern B compared with pattern A. Am J Cardiology 2005, 96:1266–1272.CrossRefGoogle Scholar
  48. 48.
    Ruotolo G, Ericsson CG, Tettamanti C, et al.: Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT). J Am Coll Cardiol 1998, 32:1648–1656.PubMedCrossRefGoogle Scholar
  49. 49.
    Mykkänen L, Kuusisto J, Haffner SM, et al.: LDL size and risk of coronary heart disease in elderly men and women. Arterioscler Thromb Vasc Biol 1999, 19:2742–2748.PubMedGoogle Scholar
  50. 50.
    Campos H, Moye LA, Glasser SP, et al.: Low-density lipoprotein size, pravastatin treatment, and coronary events. JAMA 2001, 286:1468–1474.PubMedCrossRefGoogle Scholar
  51. 51.
    Vakkilainen J, Pajukanta P, Cantor RM, et al.: Genetic influences contributing to LDL particle size in familial combined hyperlipidaemia. Eur J Hum Genet 2002, 10:547–552.PubMedCrossRefGoogle Scholar
  52. 52.
    Wallenfeldt K, Bokemark L, Wikstrand J, et al.: Apolipoprotein B/apolipoprotein A-I in relation to the metabolic syndrome and change in carotid artery intima-media thickness during 3 years in middle-aged men. Stroke 2004, 35:2248–2252.PubMedCrossRefGoogle Scholar
  53. 53.
    van Tits LJ, Smilde TJ, van Wissen S, et al.: Effects of atorvastatin and simvastatin on low-density lipoprotein subfraction profile, low-density lipoprotein oxidizability, and antibodies to oxidized low-density lipoprotein in relation to carotid intima media thickness in familial hypercholesterolemia. J Invest Med 2004, 52:177–184.CrossRefGoogle Scholar
  54. 54.
    Kuller L, Arnold A, Tracy R, et al.: Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 2002, 22:1175–1180.PubMedCrossRefGoogle Scholar
  55. 55.
    El Harchaoui K, van der Steeg WA, Stroes ES, et al.: Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol 2007, 49:547–553.PubMedCrossRefGoogle Scholar
  56. 56.
    Cullen P: Evidence that triglycerides are an independent coronary heart disease risk factor. Am J Cardiol 2000, 86:943–949.PubMedCrossRefGoogle Scholar
  57. 57.
    Gazi IF, Tsimihodimos V, Tselepis AD, et al.: Clinical importance and therapeutic modulation of small dense low-density lipoprotein particles. Expert Opin Biol Ther 2007, 7:53–72.PubMedCrossRefGoogle Scholar
  58. 58.
    Lada AT, Rudel LL: Associations of low density lipoprotein particle composition with atherogenicity. Curr Opin Lipidol 2004, 15:19–24.PubMedCrossRefGoogle Scholar
  59. 59.
    Otvos JD, Collins D, Freedman DS, et al.: Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation 2006, 113:1556–1563.PubMedCrossRefGoogle Scholar
  60. 60.
    St-Pierre AC, Cantin B, Dagenais GR, et al.: Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Quebec Cardiovascular Study. Arterioscler Thromb Vasc Biol 2005, 25:553–559.PubMedCrossRefGoogle Scholar
  61. 61.
    Williams PT, Superko HR, Haskell WL, et al.: Smallest LDL particles are most strongly related to coronary disease. Arterioscler Thromb Vasc Biol 2003, 23:314–321.PubMedCrossRefGoogle Scholar
  62. 62.
    Sniderman AD, Bergeron J, Frohlich J: Apolipoprotein B versus lipoprotein lipids: vital lessons from the AFCAPS/TexCAPS trial. CMAJ 2001, 164:44–47.PubMedGoogle Scholar
  63. 63.
    Durrington PN: Can measurement of apolipoprotein B replace the lipid profile in the follow-up of patients with lipoprotein disorders? Clin Chem 2002, 48:401–402.PubMedGoogle Scholar
  64. 64.
    Marcovina SM, Albers JJ, Henderson LO, Hannon WH: International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. III. Comparability of apolipoprotein A-I values by use of international reference material. Clin Chem 1993, 39:773–781.PubMedGoogle Scholar
  65. 65.
    Kwiterovich PO: HyperapoB: a pleiotropic phenotype characterized by dense low-density lipoproteins and associated with coronary artery disease. Clin Chem 1988, 34:B71–B77.PubMedGoogle Scholar
  66. 66.
    Rader DJ, Hoeg JM, Brewer HB Jr: Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease. Ann Intern Med 1994, 120:1012–1025.PubMedGoogle Scholar
  67. 67.
    Otvos JD, Jeyarajah EJ, Cromwell WC: Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002, 90:22i–29i.PubMedCrossRefGoogle Scholar
  68. 68.
    Kathiresan S, Otvos JD, Sullivan LM, et al.: Increased small low-density lipoprotein particle number. A prominent feature of the metabolic syndrome in the Framingham Heart Study. Circulation 2006, 113:20–29.PubMedCrossRefGoogle Scholar
  69. 69.
    Superko HR, Chronos NA: Hypercholesterolemia and dyslipidemia. Issues for clinicians. Curr Treat Options Cardiovasc Med 2004, 5:35–50.CrossRefGoogle Scholar
  70. 70.
    Superko HR: Lipoprotein subclasses and atherosclerosis. Front Biosci 2001, 6:D355–D365.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  1. 1.Center for Genomics and Human HealthSaint Joseph’s Translational Research InstituteAtlantaUSA

Personalised recommendations