Triglycerides and atherogenic lipoproteins: rationale for lipid management

  • Ronald M. Krauss
    Requests for reprints should be addressed to Ronald M. Krauss, MD, Donner Laboratory, Room 465, E.O. Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720
    Donner Laboratory, Lawrence Berkeley National Laboratory, University of California, Berkeley, California, USA
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      Epidemiologic and clinical studies have demonstrated a relation between plasma triglyceride levels and risk of coronary artery disease and an amplification of risk with combined elevations of triglyceride and low-density lipoprotein (LDL) cholesterol. In patients with coronary disease, angiographic progression and clinical events have been correlated with concentrations of smaller very-low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL), consistent with evidence for enhanced atherogenicity of lipolytic products of triglyceride-rich lipoprotein metabolism, including postprandial lipoproteins. IDL levels also have been shown to be strongly and independently predictive of progression of carotid artery intimal–medial thickness, a measure of early atherogenesis that is related to coronary disease risk. Although there is evidence that these triglyceride-rich lipoprotein species may have direct atherogenic effects, other lipoprotein changes associated with altered triglyceride metabolism may be of particular importance in the development of coronary artery disease. These include reductions in high-density lipoprotein (HDL) and increases in small, dense LDL particles (LDL subclass pattern B). Because of the strong interrelations among elevated triglyceride, reduced HDL, and small dense LDL, it is difficult to use statistical techniques to determine the independent contributions of these traits to coronary disease risk. Based on their biologic properties, it is likely that each are involved in multiple steps of the disease process. Moreover, this cluster of lipoprotein changes is associated with other conditions that can promote vascular disease, including increases in coagulation factors and reduced insulin sensitivity. Analyses from intervention trials in patients with coronary disease have indicated that measurement of plasma triglyceride and LDL particle distributions can be of value in predicting the benefits of specific lipid-altering therapies on disease progression.
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        • Hokanson J.E.
        • Austin M.A.
        Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level.
        J Cardiovasc Risk. 1996; 3: 213-219
        • Assmann G.
        • Shulte H.
        Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience).
        Am J Cardiol. 1992; 70: 733-737
        • Stampfer M.J.
        • Krauss R.M.
        • 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
        • Manninen V.
        • Tenkanen L.
        • Koskinen P.
        • et al.
        Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study.
        Circulation. 1991; 85: 37-45
        • Genest Jr, J.J.
        • Martin-Munley S.S.
        • McNamara J.R.
        • et al.
        Familial lipoprotein disorders in patients with premature coronary artery disease.
        Circulation. 1992; 85: 2025-2033
        • Lindgren F.T.
        • Elliott H.A.
        • Gofman J.W.
        The ultracentrifugal characterization and isolation of human blood lipids and liporoteins, with applications to the study of atherosclerosis.
        J Phys Colloid Chem. 1951; 55: 80-93
        • Steiner G.
        • Schwartz L.
        • Shumak S.
        • Poapst M.
        The association of increased levels of intermediate-density lipoproteins with smoking and coronary artery disease.
        Circulation. 1987; 75: 124-130
        • Krauss R.M.
        • Lindgren F.T.
        • Williams P.T.
        • et al.
        Intermediate-density lipoproteins and progression of coronary artery disease in hypercholesterolaemic men.
        Lancet. 1987; ii: 62-66
        • Phillips N.R.
        • Waters D.
        • Havel R.J.
        Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events.
        Circulation. 1993; 88: 2762-2770
        • Mack W.J.
        • Krauss R.M.
        • Hodis H.N.
        Lipoprotein subclasses in the Monitored Atherosclerosis Regression Study (MARS).
        Arterioscler Thromb Vasc Biol. 1996; 16: 697-704
        • Hodis H.N.
        • Mack W.J.
        • Dunn M.
        • et al.
        Intermediate-density lipoproteins and progression of carotid arterial wall intima-media thickness.
        Circulation. 1997; 95: 2022-2026
        • Rapp J.H.
        • Lespine A.
        • Hamilton R.L.
        • et al.
        Triglyceride-rich lipoproteins isolated by selected-affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque.
        Arterioscler Thromb. 1994; 14: 1767-1774
        • Gianturco S.H.
        • Bradley W.A.
        Lipoprotein-mediated cellular mechanisms for atherogenesis in hypertriglyceridemia.
        Semin Thromb Hemost. 1988; 14: 165-169
        • Chung B.H.
        • Segrest J.P.
        Cytotoxicity of remnants of triglyceride-rich lipoproteins.
        Adv Exp Med Biol. 1991; 285: 341-351
        • Chung B.H.
        • Tallis G.
        • Yalamoori V.
        • et al.
        Liposome-like particles isolated from human atherosclerotic plaques are structurally and compositionally similar to surface remnants of triglyceride-rich lipoproteins.
        Arterioscler Thromb. 1994; 14: 622-635
        • Rutledge J.C.
        • Woo M.M.
        • Rezai A.A.
        • et al.
        Lipoprotein lipase increases lipoprotein binding to the artery wall and increases endothelial layer permeability by formation of lipolysis products.
        Circ Res. 1997; 80: 819-828
        • Benlian P.
        • Hayden M.R.
        Premature atherosclerosis in familial chylomicronemia.
        N Engl J Med. 1997; 336 (Letter): 1027
        • Patsch J.R.
        • Miesenböck G.
        • Hopferwieser T.
        • et al.
        Relation of triglyceride metabolism and coronary artery disease.
        Arterioscler Thromb. 1992; 12: 1336-1345
        • Sharrett A.R.
        • Chambless L.E.
        • Heiss G.
        • et al.
        Association of postprandial triglyceride and retinyl palmitate responses with asymptomatic carotid artery atherosclerosis in middle-aged men and women.
        Arterioscler Thromb Vasc Biol. 1995; 15: 2122-2129
        • Nordestgaard B.G.
        • Lewis B.
        Intermediate density lipoprotein levels are strong predictors of the extent of aortic atherosclerosis severity in the St. Thomas’s Hospital rabbit strain.
        Atherosclerosis. 1991; 87: 39-46
        • Masucci-Magoulas L.
        • Goldberg I.J.
        • Bisgaier C.L.
        • et al.
        A mouse model with features of familial combined hyperlipidemia.
        Science. 1997; 275: 391-394
        • Grundy S.M.
        Small LDL, atherogenic dyslipidemia, and the metabolic syndrome.
        Circulation. 1997; 95: 1-4
        • Reaven G.M.
        Syndrome X.
        J Intern Med. 1994; 236: 13-22
        • Byberg L.
        • Siegbahn A.
        • Berglund L.
        • et al.
        Plasminogen activator inhibitor-1 activity is independently related to both insulin sensitivity and serum triglycerides in 70-year-old men.
        Arterioscler Thromb Vasc Biol. 1998; 18: 258-264
        • Xu N.
        • Dahlback B.
        • Ohlin A.K.
        • Nilsson A.
        Association of vitamin K-dependent coagulation proteins and C4b binding protein with triglyceride-rich lipoproteins of human plasma.
        Arterioscler Thromb Vasc Biol. 1998; 18: 33-39
        • Hodis H.N.
        • Mack W.J.
        • Azen S.P.
        • et al.
        Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin.
        Circulation. 1994; 90: 42-49
        • Krauss R.M.
        Heterogeneity of plasma low-density lipoproteins and atherosclerosis risk.
        Curr Opin Lipidol. 1994; 5: 339-349
        • Austin M.A.
        • Breslow J.L.
        • Hennekens C.H.
        • et al.
        Low-density lipoprotein subclass patterns and risk of myocardial infarction.
        JAMA. 1988; 260: 1917-1921
        • Gardner C.D.
        • Fortmann S.P.
        • Krauss R.M.
        Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.
        JAMA. 1996; 276: 875-881
        • 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.
        Circulation. 1997; 95: 69-75
        • 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
        • Anber V.
        • Griffin B.A.
        • McConnell M.
        • et al.
        Influence of plasma lipid and LDL-subfraction profile on the interaction between low density lipoprotein with human arterial wall proteoglycans.
        Atherosclerosis. 1996; 124: 261-271
        • Tribble D.L.
        Lipoprotein oxidation in dyslipidemia.
        Curr Opin Lipidol. 1995; 6: 196-208
        • Miller B.D.
        • Alderman E.L.
        • Haskell W.L.
        • 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