Increased ApoB in Small Dense LDL Particles Predicts Premature Coronary Artery Disease
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动脉硬化血栓血管生物学 2005年第3期
From the Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle.
Correspondence to John D. Brunzell, University of Washington, Division of Metabolism, Endocrinology, and Nutrition, Seattle, WA 98195-6426. E-mail brunzell@u.washington.edu
The relation between plasma lipoproteins and atherosclerosis has evolved over the past fifty years. Serum cholesterol levels were shown to be associated with coronary artery disease (CAD) in familial hypercholesterolemia in the early 20th century (see Frederickson1). This cholesterol was determined to be in a particular lipoprotein class2 now termed low-density lipoprotein (LDL) cholesterol.3 LDL cholesterol has been shown to predict premature CAD in many studies,4 and a reduction in LDL cholesterol with statin therapy has been shown to decrease CAD events by up to 50% in primary5 and in secondary6 intervention trials. The National Cholesterol Education Program Adult Treatment Panel7 initially based recommendations for therapy to prevent CAD on LDL cholesterol levels. Later the measurement of HDL cholesterol was added to estimate risk.8
See page 553
Because treatment for LDL cholesterol levels only decreases the risk for premature CAD by about half, other lipoprotein factors have been sought to explain the additional risk. Plasma triglyceride levels are associated with CAD, independently of LDL and HDL cholesterol levels.9 Hypertriglyceridemia also has been associated with small dense LDL particles.1,10
Studies of the heterogeneity of LDL particles and their number have suggested that small dense LDL and increased number of LDL particles, as reflected by increased apoB, are specific components of LDL important in the risk for premature CAD. Several studies noted heterogeneity of LDL particles with apoB enrichment of LDL in hypertriglyceridemic individuals.11–13 Total apoB levels were then noted to be elevated in individuals with atherosclerosis.14,15 Hyperapobetalipoproteinemia, an elevated LDL apoB with small cholesterol-poor LDL particles, was also reported in individuals with CAD.16,17 A number of prospective studies18–20 demonstrated that small LDL particles predicted CAD. The Interheart Study of 15 000 individuals in 52 countries found that the apoB/Apo AI ratio was a major predictor of CAD in men and women in all parts of the world.21
In the 13-year follow-up of the Quebec Cardiovascular Study (in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology), the Laval University group report that small LDL are a strong and independent predictor of CAD, particularly in the first 7 years of follow-up.22 They report that big LDL particles at baseline were not predictors of future CAD events. This implies that much of the association of LDL cholesterol with premature CAD is due to the small dense LDL component. These were studies of 2072 men 46 to 75 years of age chosen to represent the male population in Quebec City. No women were involved with the study, and individuals with high levels of big buoyant LDL particles with familial hypercholesterolemia would be uncommon. In the Quebec Cardiovascular Study they found that particle number, as determined by plasma apoB levels, was an important codeterminate of risk. It cannot be said that large buoyant LDL are never a risk for CAD, eg, when present in excess numbers of particles. Individuals with familial hypercholesterolemia have increased numbers of LDL particles of large size, which together account for the very high levels of LDL cholesterol seen with an early onset of CAD.
Who are these individuals with increased numbers (elevated apoB) of small dense LDL particles23? These individuals tend to be centrally obese, to have hypertriglyceridemia with low HDL cholesterol, and occur in familial clusters.24 NCEP-ATP III25 has attempted to include these individuals in a risk stratification plan by incorporating the metabolic syndrome into the guidelines with LDL and HDL cholesterol.26 It is clear that individuals with the metabolic syndrome who have type 2 diabetes27 and those with familial combined hyperlipidemia28,29 are at increased risk for premature CAD. However, the risk for those individuals with the metabolic syndrome with normal fasting apoB and glucose levels is unknown at this time.24 Because the metabolic syndrome encompasses such a large proportion of adults, this is a question that needs to be addressed.
Perhaps it is time to add the measurement of plasma apoB levels to the standard lipid profile to find those individuals with the metabolic syndrome at high CAD risk. An apoB/AI ratio could be measured as in the Interheart Study,21 or apoB levels and determination of LDL size (or density) could be measured as in the Quebec Cardiovascular Study. If one has a standard lipid profile, the LDL cholesterol level in the context of the plasma apoB level can be used to determine the presence or absence of small dense LDL particles. It is expected that the apoB level would help to assess the risk of CAD due to small dense LDL particles in those who have borderline levels of LDL cholesterol in a primary prevention program. A normogram for apoB levels by age and sex has been generated from the NHANES III data set.24
References
Frederickson DS, Levy RI, Lees RS. Fat transport in lipoproteins: an integrated approach to mechanisms and disorders. N Engl J Med. 1967; 276: 215–225.
Gofman JW, Rubin L, Mcginley JP, Jones HB. Hyperlipoproteinemia. Am J Med. 1954; 17: 514–520.
Havel FJ, Eder HA, Bragdon JH. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955; 34: 1345–1353.
Kannel WB, Garcia MJ, McNamara PM, Pearson G. Serum lipid precursors of coronary heart disease. Human Pathol. 1971; 2: 129–151.
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995; 333: 1301–1307.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383–1389.
Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med. 1988; 148: 36–69.
Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993; 269: 3009–3014.
Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996; 3: 213–219.
Krauss RM, Burke DJ. Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res. 1982; 23: 97–104.
Lees RS. Immunoassay of plasma low-density lipoproteins. Science. 1970; 169: 493–495.
Schonfeld G, Lees RS, George PK, Pfleger B. Assay of total plasma apolipoprotein B concentration in human subjects. J Clin Invest. 1974; 53: 1458–1467.
Fisher WR. Heterogeneity of plasma low density lipoproteins manifestations of the physiologic phenomenon in man. Metabolism. 1983; 32: 283–291.
Avogaro P, Beittolo BJ, Cuzzolato G, Quinci GB, Belussi F. Plasma level of lipoprotein A-1 and apolipoprotein B in human atherosclerosis. Artery. 1978; 4: 385–394.
Vergani C, Trovato G, Dioguardi N. Serum total lipids, lipoproteins, cholesterol, apoproteins A and B in cardiovascular disease. Clin Chim Acta. 1978; 87: 127–133.
Sniderman A, Shapuiro S, Marpole D, Skinner B, Teng B, Kwiterovich PO Jr. Association of coronary atherosclerosis with hyperapobetalipoproteinemia (increased protein but normal cholesterol levels in human plasma low density (beta) lipoproteins). Proc Natl Acad Sci U S A. 1980; 77: 604–608.
Sniderman AD, Wolfson C, Teng B, Franklin FA, Bachorik PS, Kwiterovich PO Jr. Association of hyperapobetalipoproteinemia with endogenous hypertriglyceridemia and atherosclerosis. Ann Intern Med. 1982; 97: 833–839.
Austin M, Breslow J, Hennekens C, Buring J, Willett W, Krauss R. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA. 1988; 260: 1917–1921.
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.
Lamarche B, Tchernof A, Moorjani S, Camtin B, Dagenais G, Lupien P, Despres J-P. Small, dense low-density 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.
Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, Mcqueen M, Budaj A, Pais P, Varigos J, Lisheng L. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART STUDY): case-control study. Lancet. 2004; 364: 937–952.
St-Pierre AC, Cantin B, Dagenais GR, Mauriege P, Bernard PM, Despres JP, Lamarche B. 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.
Brunzell JD, Sniderman AD, Albers JJ, Kwiterovich PO. Apoproteins B and A-1 and coronary artery disease in humans. Arteriosclerosis. 1984; 4: 79–83.
Carr MC, Brunzell JD. Abdominal Obesity and Dyslipidemia in the Metabolic Syndrome: Importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk. J Clin Endocrinol Metab. 2004; 89: 2601–2607.
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.
Grundy S. Low-density lipoprotein, non–high-density lipoprotein, and apolipoprotein b as targets of lipid-lowering therapy. Circulation. 2002; 106: 2526–2529.
Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003; 52: 1210–1214.
Austin M, McKnight B, Edwards K, Bradley C, McNeely M, Psaty B, Brunzell JD. Cardiovascular disease mortality in familial forms of hypertriglyceridemia: a 20-year prospective study. Circulation. 2000; 101: 2777–2782.
Ayyobi A, McGladdery SH, McNeely MJ, Austin MA, Motulsky AG, Brunzell JD. Small, dense LDL and elevated apolipoprotein B are the common characteristics for the three major lipid phenotypes of familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol. 2003; 23: 1289–1294.(John D. Brunzell)
Correspondence to John D. Brunzell, University of Washington, Division of Metabolism, Endocrinology, and Nutrition, Seattle, WA 98195-6426. E-mail brunzell@u.washington.edu
The relation between plasma lipoproteins and atherosclerosis has evolved over the past fifty years. Serum cholesterol levels were shown to be associated with coronary artery disease (CAD) in familial hypercholesterolemia in the early 20th century (see Frederickson1). This cholesterol was determined to be in a particular lipoprotein class2 now termed low-density lipoprotein (LDL) cholesterol.3 LDL cholesterol has been shown to predict premature CAD in many studies,4 and a reduction in LDL cholesterol with statin therapy has been shown to decrease CAD events by up to 50% in primary5 and in secondary6 intervention trials. The National Cholesterol Education Program Adult Treatment Panel7 initially based recommendations for therapy to prevent CAD on LDL cholesterol levels. Later the measurement of HDL cholesterol was added to estimate risk.8
See page 553
Because treatment for LDL cholesterol levels only decreases the risk for premature CAD by about half, other lipoprotein factors have been sought to explain the additional risk. Plasma triglyceride levels are associated with CAD, independently of LDL and HDL cholesterol levels.9 Hypertriglyceridemia also has been associated with small dense LDL particles.1,10
Studies of the heterogeneity of LDL particles and their number have suggested that small dense LDL and increased number of LDL particles, as reflected by increased apoB, are specific components of LDL important in the risk for premature CAD. Several studies noted heterogeneity of LDL particles with apoB enrichment of LDL in hypertriglyceridemic individuals.11–13 Total apoB levels were then noted to be elevated in individuals with atherosclerosis.14,15 Hyperapobetalipoproteinemia, an elevated LDL apoB with small cholesterol-poor LDL particles, was also reported in individuals with CAD.16,17 A number of prospective studies18–20 demonstrated that small LDL particles predicted CAD. The Interheart Study of 15 000 individuals in 52 countries found that the apoB/Apo AI ratio was a major predictor of CAD in men and women in all parts of the world.21
In the 13-year follow-up of the Quebec Cardiovascular Study (in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology), the Laval University group report that small LDL are a strong and independent predictor of CAD, particularly in the first 7 years of follow-up.22 They report that big LDL particles at baseline were not predictors of future CAD events. This implies that much of the association of LDL cholesterol with premature CAD is due to the small dense LDL component. These were studies of 2072 men 46 to 75 years of age chosen to represent the male population in Quebec City. No women were involved with the study, and individuals with high levels of big buoyant LDL particles with familial hypercholesterolemia would be uncommon. In the Quebec Cardiovascular Study they found that particle number, as determined by plasma apoB levels, was an important codeterminate of risk. It cannot be said that large buoyant LDL are never a risk for CAD, eg, when present in excess numbers of particles. Individuals with familial hypercholesterolemia have increased numbers of LDL particles of large size, which together account for the very high levels of LDL cholesterol seen with an early onset of CAD.
Who are these individuals with increased numbers (elevated apoB) of small dense LDL particles23? These individuals tend to be centrally obese, to have hypertriglyceridemia with low HDL cholesterol, and occur in familial clusters.24 NCEP-ATP III25 has attempted to include these individuals in a risk stratification plan by incorporating the metabolic syndrome into the guidelines with LDL and HDL cholesterol.26 It is clear that individuals with the metabolic syndrome who have type 2 diabetes27 and those with familial combined hyperlipidemia28,29 are at increased risk for premature CAD. However, the risk for those individuals with the metabolic syndrome with normal fasting apoB and glucose levels is unknown at this time.24 Because the metabolic syndrome encompasses such a large proportion of adults, this is a question that needs to be addressed.
Perhaps it is time to add the measurement of plasma apoB levels to the standard lipid profile to find those individuals with the metabolic syndrome at high CAD risk. An apoB/AI ratio could be measured as in the Interheart Study,21 or apoB levels and determination of LDL size (or density) could be measured as in the Quebec Cardiovascular Study. If one has a standard lipid profile, the LDL cholesterol level in the context of the plasma apoB level can be used to determine the presence or absence of small dense LDL particles. It is expected that the apoB level would help to assess the risk of CAD due to small dense LDL particles in those who have borderline levels of LDL cholesterol in a primary prevention program. A normogram for apoB levels by age and sex has been generated from the NHANES III data set.24
References
Frederickson DS, Levy RI, Lees RS. Fat transport in lipoproteins: an integrated approach to mechanisms and disorders. N Engl J Med. 1967; 276: 215–225.
Gofman JW, Rubin L, Mcginley JP, Jones HB. Hyperlipoproteinemia. Am J Med. 1954; 17: 514–520.
Havel FJ, Eder HA, Bragdon JH. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955; 34: 1345–1353.
Kannel WB, Garcia MJ, McNamara PM, Pearson G. Serum lipid precursors of coronary heart disease. Human Pathol. 1971; 2: 129–151.
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995; 333: 1301–1307.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383–1389.
Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med. 1988; 148: 36–69.
Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993; 269: 3009–3014.
Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996; 3: 213–219.
Krauss RM, Burke DJ. Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res. 1982; 23: 97–104.
Lees RS. Immunoassay of plasma low-density lipoproteins. Science. 1970; 169: 493–495.
Schonfeld G, Lees RS, George PK, Pfleger B. Assay of total plasma apolipoprotein B concentration in human subjects. J Clin Invest. 1974; 53: 1458–1467.
Fisher WR. Heterogeneity of plasma low density lipoproteins manifestations of the physiologic phenomenon in man. Metabolism. 1983; 32: 283–291.
Avogaro P, Beittolo BJ, Cuzzolato G, Quinci GB, Belussi F. Plasma level of lipoprotein A-1 and apolipoprotein B in human atherosclerosis. Artery. 1978; 4: 385–394.
Vergani C, Trovato G, Dioguardi N. Serum total lipids, lipoproteins, cholesterol, apoproteins A and B in cardiovascular disease. Clin Chim Acta. 1978; 87: 127–133.
Sniderman A, Shapuiro S, Marpole D, Skinner B, Teng B, Kwiterovich PO Jr. Association of coronary atherosclerosis with hyperapobetalipoproteinemia (increased protein but normal cholesterol levels in human plasma low density (beta) lipoproteins). Proc Natl Acad Sci U S A. 1980; 77: 604–608.
Sniderman AD, Wolfson C, Teng B, Franklin FA, Bachorik PS, Kwiterovich PO Jr. Association of hyperapobetalipoproteinemia with endogenous hypertriglyceridemia and atherosclerosis. Ann Intern Med. 1982; 97: 833–839.
Austin M, Breslow J, Hennekens C, Buring J, Willett W, Krauss R. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA. 1988; 260: 1917–1921.
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.
Lamarche B, Tchernof A, Moorjani S, Camtin B, Dagenais G, Lupien P, Despres J-P. Small, dense low-density 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.
Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, Mcqueen M, Budaj A, Pais P, Varigos J, Lisheng L. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART STUDY): case-control study. Lancet. 2004; 364: 937–952.
St-Pierre AC, Cantin B, Dagenais GR, Mauriege P, Bernard PM, Despres JP, Lamarche B. 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.
Brunzell JD, Sniderman AD, Albers JJ, Kwiterovich PO. Apoproteins B and A-1 and coronary artery disease in humans. Arteriosclerosis. 1984; 4: 79–83.
Carr MC, Brunzell JD. Abdominal Obesity and Dyslipidemia in the Metabolic Syndrome: Importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk. J Clin Endocrinol Metab. 2004; 89: 2601–2607.
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.
Grundy S. Low-density lipoprotein, non–high-density lipoprotein, and apolipoprotein b as targets of lipid-lowering therapy. Circulation. 2002; 106: 2526–2529.
Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003; 52: 1210–1214.
Austin M, McKnight B, Edwards K, Bradley C, McNeely M, Psaty B, Brunzell JD. Cardiovascular disease mortality in familial forms of hypertriglyceridemia: a 20-year prospective study. Circulation. 2000; 101: 2777–2782.
Ayyobi A, McGladdery SH, McNeely MJ, Austin MA, Motulsky AG, Brunzell JD. Small, dense LDL and elevated apolipoprotein B are the common characteristics for the three major lipid phenotypes of familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol. 2003; 23: 1289–1294.(John D. Brunzell)