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Low-density lipoprotein particle number and risk for cardiovascular disease

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Abstract

The key role played by low-density lipoprotein (LDL) particles in the pathogenesis of coronary heart disease (CHD) is well accepted, as is the benefit of lowering LDL in high-risk patients. What remains controversial is whether we are using the best measure(s) of LDL to identify all individuals who would benefit from therapy. Many studies have shown that, at a given level of LDL cholesterol, individuals with predominantly small LDL particles (pattern B) experience greater CHD risk than those with larger-size LDL. However, it is not clear from this observation that small LDL particles are inherently more atherogenic than large ones because, at a given level of LDL cholesterol, individuals with small LDL have more LDL particles in total. The phenotype of small LDL particle size co-segregates with a cluster of metabolic factors, including elevated triglycerides and reduced HDL cholesterol, and in multivariate analyses has generally been found not to be independently associated with CHD risk. In contrast, LDL particle number measured by nuclear magnetic resonance has consistently been shown to be a strong, independent predictor of CHD.

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References and Recommended Reading

  1. Otvos JD, Jeyarajah EJ, Cromwell WC: Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002, 90(Suppl): 22i-29i.

    Article  PubMed  CAS  Google Scholar 

  2. Otvos J: Measurement of triglyceride rich lipoproteins by nuclear magnetic resonance spectroscopy. Clin Cardiol 1999, 22(suppl 6): II21-II27.

    PubMed  CAS  Google Scholar 

  3. Packard CJ: Understanding coronary heart disease as a consequence of defective regulation of apolipoprotein B metabolism. Curr Opin Lipidol 1999, 10: 237–244.

    Article  PubMed  CAS  Google Scholar 

  4. Krauss RM: Heterogeneity of plasma low-density lipoproteins and atherosclerosis risk. Curr Opin Lipidol 1994, 5: 339–349.

    Article  PubMed  CAS  Google Scholar 

  5. Austin MA: Triglyceride, small, dense low-density lipoprotein, and the atherogenic lipoprotein phenotype. Curr Atheroscler Rep 2000, 2: 200–207.

    Article  PubMed  CAS  Google Scholar 

  6. Berneis KK, Krauss RM: Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res 2002, 43: 1363–1379.

    Article  PubMed  CAS  Google Scholar 

  7. Lamarche B, Lemieux I, Despres JP: The small, dense LDL phenotype and the risk of coronary heart disease: epidemiology, pathophysiology, and therapeutic aspects. Diabetes Metab 1999, 25: 199–211.

    PubMed  CAS  Google Scholar 

  8. McNamara JR, Campos H, Ordovas JM, et al.: Effect of gender, age, and lipid status on low density lipoprotein subfraction distribution. Results of the Framingham Offspring Study. Arteriosclerosis 1987, 7: 483–490.

    PubMed  CAS  Google Scholar 

  9. 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.

    PubMed  CAS  Google Scholar 

  10. Reaven GM, Chen YD, Jeppesen J, et al.: Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles. J Clin Invest 1993, 92: 141–146.

    Article  PubMed  CAS  Google Scholar 

  11. Fisher WR: Heterogeneity of plasma low density lipoproteins manifestations of the physiologic phenomenon in man. Metabolism 1983, 32: 283–291.

    Article  PubMed  CAS  Google Scholar 

  12. Crouse JR, Parks JS, Schey HM, Kahl FR: Studies of low density lipoprotein molecular weight in human beings with coronary artery disease. J Lipid Res 1985, 26: 566–574.

    PubMed  CAS  Google Scholar 

  13. Austin MA, Breslow JL, Hennekens CH, et al.: Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 1988, 260: 1917–1921.

    Article  PubMed  CAS  Google Scholar 

  14. Griffin B, Caslake M, Yip B, et al.: Rapid isolation of low density lipoprotein (LDL) subfractions from plasma by density gradient ultracentrifugation. Atherosclerosis 1990, 83: 59–67.

    Article  PubMed  CAS  Google Scholar 

  15. Tornvall P, Karpe F, Carlson L, Hamsten A: Relationship of low density lipoprotein subfractions to angiographically defined coronary artery disease in young survivors of myocardial infarction. Atherosclerosis 1991, 90: 67–80.

    Article  PubMed  CAS  Google Scholar 

  16. Campos H, Genest J Jr, Blijlevens E, et al.: Low density lipoprotein particle size and coronary artery disease. Arterioscler Thromb 1992, 12: 187–195.

    PubMed  CAS  Google Scholar 

  17. Coresh J, Kwiterovich P Jr, Smith H, Bachorik P: Association of plasma triglyceride and LDL particle diameter, density and chemical composition with premature coronary artery disease in men and women. J Lipid Res 1993, 34: 1687–1697.

    PubMed  CAS  Google Scholar 

  18. Griffin BA, Freeman DJ, Tait GW, et al.: Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart disease risk. Atherosclerosis 1994, 106: 241–253.

    Article  PubMed  CAS  Google Scholar 

  19. Campos H, Roederer GO, Lussier-Cacan S, et al.: Predominance of large LDL and reduced HDL2 cholesterol in normolipidemic men with coronary artery disease. Arterioscler Thromb Vasc Biol 1995, 15: 1043–1048.

    PubMed  CAS  Google Scholar 

  20. Sherrard B, Simpson H, Cameron J, et al.: LDL particle size in subjects with previously unsuspected coronary heart disease: relationship with other cardiovascular risk markers. Atherosclerosis 1996, 126: 277–287.

    Article  PubMed  CAS  Google Scholar 

  21. Rajman I, Kendall MJ, Cramb R, et al.: Investigation of low density lipoprotein subfractions as a coronary risk factor in normotriglyceridaemic men. Atherosclerosis 1996, 125: 231–242.

    Article  PubMed  CAS  Google Scholar 

  22. Wahi S, Gatzka CD, Sherrard B, et al.: Risk factors for coronary heart disease in a population with a high prevalence of obesity and diabetes: a case-control study of the Polynesian population of Western Samoa. J Cardiovasc Risk 1997, 55: 173–178.

    Article  Google Scholar 

  23. Slyper AH, Zvereva S, Schectman G, et al.: Lowdensity lipoprotein particle size is not a discriminating marker for atherogenic risk in male offspring of parents with early coronary artery disease. Metabolism 1997, 46: 954–958.

    Article  PubMed  CAS  Google Scholar 

  24. Freedman DS, Otvos JD, Jeyarajah EJ, et al.: Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectroscopy to coronary artery disease. Arterioscler Thromb Vasc Biol 1998, 18: 1046–1053.

    PubMed  CAS  Google Scholar 

  25. Erbey JR, Robbins D, Forrest KY, Orchard TJ: Low-density lipoprotein particle size and coronary artery disease in a childhood-onset type 1 diabetes population. Metabolism 1999, 48: 531–534.

    Article  PubMed  CAS  Google Scholar 

  26. Kamigaki AS, Siscovick DS, Schwartz SM, et al.: Low density lipoprotein particle size and risk of early-onset myocardial infarction in women. Am J Epidemiol 2001, 153: 939–945.

    Article  PubMed  CAS  Google Scholar 

  27. Koba S, Hirano T, Kondo T, et al.: 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.

    Article  PubMed  CAS  Google Scholar 

  28. Gardner CD, Fortmann SP, Krauss RM: Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women [see comments]. JAMA 1996, 276: 875–881.

    Article  PubMed  CAS  Google Scholar 

  29. Stampfer MJ, Krauss RM, Ma J, et al.: A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction [see comments]. JAMA 1996, 276: 882–888.

    Article  PubMed  CAS  Google Scholar 

  30. Lamarche B, Tchernof A, Moorjani S, et al.: Small, dense lowdensity lipoprotein particles as a predictor of risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Circulation 1997, 95: 69–75.

    PubMed  CAS  Google Scholar 

  31. Mykkanen 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.

    PubMed  CAS  Google Scholar 

  32. 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.

    Article  PubMed  CAS  Google Scholar 

  33. Campos H, Moye LA, Glasser SP, et al.: Low-density lipoprotein size, pravastatin treatment, and coronary events. JAMA 2001, 286: 1468–1474.

    Article  PubMed  CAS  Google Scholar 

  34. Blake GJ, Otvos JD, Rifai N, Ridker PM: LDL particle concentration and size as determined by NMR spectroscopy as predictors of cardiovascular disease in women. Circulation 2002, 106: 1930–1937.

    Article  PubMed  CAS  Google Scholar 

  35. 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.

    Article  PubMed  CAS  Google Scholar 

  36. 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. Circulation 1996, 94: 2146–2153.

    PubMed  CAS  Google Scholar 

  37. 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.

    Article  PubMed  CAS  Google Scholar 

  38. Zambon A, Hokanson JE, Brown BG, Brunzell JB: Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density. Circulation 1999, 99: 1959–1964.

    PubMed  CAS  Google Scholar 

  39. Campos H, Moye LA, Glasser SP, et al.: Low-density lipoprotein size, pravastatin treatment, and coronary events. JAMA 2001, 286: 1468–1474.

    Article  PubMed  CAS  Google Scholar 

  40. 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.

    Article  PubMed  CAS  Google Scholar 

  41. Vakkilainen J, Steiner G, Ansquer JC, et al.: Relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary artery disease: the Diabetes Atherosclerosis Intervention Study (DAIS). Circulation 2003, 107: 1733–1737.

    Article  PubMed  Google Scholar 

  42. Rader DJ, Hoeg JM, Brewer HB: Quantitation of plasma apolipoproteins in the primary and secondary prevention of coronary artery disease. Ann Intern Med 1994, 120: 1012–1025.

    PubMed  CAS  Google Scholar 

  43. 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.

    Article  PubMed  CAS  Google Scholar 

  44. Sharrett AR, Ballantyne CM, Coady SA, et al.: Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions. The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001, 104: 1108–1113.

    Article  PubMed  CAS  Google Scholar 

  45. Otvos JD: Measurement of lipoprotein subclass profiles by nuclear magnetic resonance spectroscopy. In Handbook of Lipoprotein Testing. Edited by Rifai N, Warnick GR, Dominiczak MH. Washington, DC: AACC Press; 2000:609–623.

    Google Scholar 

  46. Otvos JD, Freedman DS, Pegus C, et al.: LDL and HDL particle subclasses are independent predictors of cardiovascular events in the Veteran Affairs HDL Intervention Trial (VA-HIT). Paper presented at American Heart Association Scientific Sessions, Chicago, IL, 2002.

  47. 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.

  48. Otvos JD: Why cholesterol measurements may be misleading about lipoprotein levels and cardiovascular disease risk—clinical implications of lipoprotein quantification using NMR spectroscopy. J Lab Med 2002, 26: 544–550.

    CAS  Google Scholar 

  49. Garvey WT, Kwon S, Zheng D, et al.: The effects of insulin resistance and type 2 diabetes mellitus on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes 2003, 52: 453–462.

    Article  PubMed  CAS  Google Scholar 

  50. Otvos J, Cromwell W, Shalaurova I, et al.: LDL particles, but not LDL cholesterol, are highly elevated in the metabolic syndrome—results from the Framingham Offspring Study [abstract]. Circulation 2003, 108:IV-740.

    Google Scholar 

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Cromwell, W.C., Otvos, J.D. Low-density lipoprotein particle number and risk for cardiovascular disease. Curr Atheroscler Rep 6, 381–387 (2004). https://doi.org/10.1007/s11883-004-0050-5

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