Introduction to High-Density Lipoprotein, Dyslipidemia, and Coronary Heart Disease

  • Ernst J. Schaefer


Alterations in plasma lipoproteins are major risk factors for coronary heart disease caused by atherosclerosis. The purpose of this chapter is to provide the reader with an overview of lipids, lipoprotein composition, lipoprotein metabolism, and lipoprotein disorders, with particular relevance to coronary heart disease risk (CHD). This chapter will then provide a framework for the reader to understand the remaining chapters in this book which have a primary focus on high-density lipoproteins (HDLs). This chapter will also allow the reader to rapidly move from a rudimentary view of lipids to a more thorough understanding of HDL, dyslipidemia, and CHD. Both increased low-density lipoprotein (LDL) cholesterol (>160 mg/dl or 4.2 mmol/l) and decreased HDL cholesterol (<40 mg/dl or 1.0 mmol/l) have been associated with an increased CHD risk. Therapies lowering LDL cholesterol and/or raising HDL cholesterol have both been associated with decreased CHD risk. Markedly elevated triglycerides (>1,000 mg/dl or 11 mmol/l) can be associated with recurrent pancreatitis. In this chapter we cover lipoprotein composition, metabolism, and briefly review the rare lipoprotein disorders cerebrotendinous xanthomatosis, phytosterolemia, abetalipoproteinemia, hypobetalipoproteinemia, and lipoprotein lipase deficiency, as well as the more common disorders dysbetalipoproteinemia, dyslipidemia, combined hyperlipidemia, lipoprotein (a) excess, and familial hypercholesterolemia. Disorders of HDL metabolism are covered in other chapters in this book. The concluding chapter will summarize where we are with CHD risk assessment, lipid management, the current state of our knowledge about HDL metabolism, and therapies for the treatment of HDL deficiency.


Coronary Heart Disease Cholesteryl Ester Coronary Heart Disease Risk Cholesteryl Ester Transfer Protein Premature Coronary Heart Disease 
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  1. 1.
    Expert Panel (2001) 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 285:2486–2497CrossRefGoogle Scholar
  2. 2.
    Ingelsson E, Schaefer EJ, Contois JH, McNamara JR, Sullivan L, Keyes MJ, Pencina MJ, Schoonmaker C, Wilson PW, D’Agostino RB, Vasan RS (2007) Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 298:776–785CrossRefPubMedGoogle Scholar
  3. 3.
    Schaefer EJ (2002) E.V. McCollum Award Lecture: Lipoproteins, nutrition, and heart disease. Am J Clin Nutr 75:191–212PubMedGoogle Scholar
  4. 4.
    Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R (2005) Cholesterol Treatment Trialists Collaborators. Efficacy and safety of cholesterol-lowering treatment:prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins. Lancet 366:1267–1278CrossRefPubMedGoogle Scholar
  5. 5.
    Lamon-Fava S, Diffenderfer MR, Barrett PH, Buchsbaum A, Matthan NR, Lichtenstein AH, Dolnikowski GG, Horvath K, Asztalos BF, Zago V, Schaefer EJ (2007) Effects of different doses of atorvastatin on human apolipoprotein B-100, B-48, and A-I metabolism. J Lipid Res 48:1746–1753CrossRefPubMedGoogle Scholar
  6. 6.
    van Himbergen TM, Matthan NR, Resteghini NA, Otokozawa S, Ai M, Stein EA, Jones PH, Schaefer EJ (2009) Comparison of the effects of maximal dose atorvastatin and rosuvastatin therapy on cholesterol synthesis and absorption markers. J Lipid Res 50:730–739CrossRefPubMedGoogle Scholar
  7. 7.
    Lamon-Fava S, Schaefer EJ, Garuti R, Salen G, Calandra S (2002) Two novel mutations in the sterol 27-hydroxylase gene causing cerebrotendinous xanthomatosis. Clin Genet 61:185–191CrossRefPubMedGoogle Scholar
  8. 8.
    Keren Z, Falik-Zaccel TC (2009) Cerebrotendinous xanthomatosis (CTX), a treatable lipid storage disorder. Pediatr Endocrinol Rev 7:6–11PubMedGoogle Scholar
  9. 9.
    Genest JJ, Martin-Munley S, McNamara JR, Ordovas JM, Jenner J, Meyers R, Wilson PWF, Schaefer EJ (1992) Prevalence of familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 85:2025–2033PubMedGoogle Scholar
  10. 10.
    van Himbergen T, Otokozawa S, Matthan NR, Schaefer EJ, Buchsbaum A, Ai M, van Tits LJH, de Graaf J, Stalenhoef A (2009) Familial combined hyperlipidemia is associated with alterations in the cholesterol synthesis pathway. Arterioscler Thromb Vasc Biol (2010) 30:113–120.CrossRefPubMedGoogle Scholar
  11. 11.
    Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tezloff G, Iyer SP, Macquire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP (2004) Niemann-Pick C1 Like 1 protein is critical for intestinal absorption. Science 303:1201–1204CrossRefPubMedGoogle Scholar
  12. 12.
    Davis HR Jr, Basso F, Hoos LM, Tezloff G, Lally SM, Altmann SW (2008) Cholesterol homeostasis by the intestine: lessons from Niemann Pick C1 Like 1 (NPC1L1). Atheroscler Suppl 9:77–81CrossRefPubMedGoogle Scholar
  13. 13.
    Patel MD, Thompson PD (2006) Phytosterols and vascular disease. Atherosclerosis 186:12–19CrossRefPubMedGoogle Scholar
  14. 14.
    Matthan NB, Pencina M, Larocquw JM, Jacques PF, D’Agostino RB, Schaefer EJ, Lichtenstein AH (2009) Alterations in cholesterol absorption and synthesis characterize Framingham offspring study participants with coronary disease. J Lipid Res 50(9):1927–35CrossRefPubMedGoogle Scholar
  15. 15.
    Matthan NR, Restighini N, Robertson M, Ford I, Shepherd J, Packard C, Buckley BM, Jukema JW, Lichtenstein AH, Schaefer EJ (2009) Cholesterol absorption and synthesis in individuals with and without CHD events during pravastatin therapy: insights from the PROSPER Trial. J Lipid Res (2010) 51:202–209CrossRefGoogle Scholar
  16. 16.
    Sudhop T, Lutjohann D, Kodal A, Igel M, Tribble DL, Shah S, Perevozskaya I, von Bergmann K (2002) Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 106:1943–1948CrossRefPubMedGoogle Scholar
  17. 17.
    Pearson TA, Ballantyne CM, Veltri E, Shah A, Bird S, Lin J, Rosenberg E, Tershakovec AM (2009) Pooled analysis of effects on C reactive protein and low density lipoprotein cholesterol in placebo controlled trials of ezetimibe or ezetimibe added to baseline statin therapy. Am J Cardiol 103:369–374CrossRefPubMedGoogle Scholar
  18. 18.
    Ajees AA, Anantharamaiah GM, Mishra VK, Hussain MM, Murthy VK (2006) Crystal structure of human apolipoprotein A-I: insights into its protect effect against cardiovascular disease. Proc Natl Acad Sci USA 103:2136–2131CrossRefGoogle Scholar
  19. 19.
    Zamel R, Khan R, Pollex H, Hegele RA (2008) Abetalipoproteinemia: 2 case reports and literature review. Orphanet J Rare Dis 3:19–25CrossRefPubMedGoogle Scholar
  20. 20.
    Tarugi P, Averna M, DiLeo E, Cefalu AB, Noto D, Magnolo L, Cattin L, Bertolini S, Calandra S (2007) Molecular diagnosis of hypobetalipoproteinemia: an ENID review. Atherosclerosis 195:19–27CrossRefGoogle Scholar
  21. 21.
    Hegele RA, Pollex RL (2009) Hypobetalipoproteinemia: phenomics and genomics. Mol Cell Biochem 326:35–43CrossRefPubMedGoogle Scholar
  22. 22.
    Hegele RA, Joy T (2009) Novel LPL mutations associated with LPL deficiency: 2 case reports and a literature review. Can J Physiol Pharmacol 87:151–160CrossRefPubMedGoogle Scholar
  23. 23.
    Brom DJ, Byrne P, Jopnes S, Marais AD (2002) Dysbeta-lipoproteinemia: clinical and pathophysiologic features. S Afr Med J 92:892–897Google Scholar
  24. 24.
    Schaefer EJ, Gregg RE, Ghiselli G, Forte TM, Ordovas JM, Zech LA, Lindgren FT, Brewer HB Jr (1986) Familial apolipoprotein E deficiency. J Clin Invest 78:1206–1219CrossRefPubMedGoogle Scholar
  25. 25.
    Connelly PW, Hegele RA (1998) Hepatic lipase deficiency. Crit Rev Clin Lab Sci 35:547–572CrossRefPubMedGoogle Scholar
  26. 26.
    Deeb SS, Zambon A, Carr MC, Ayyobi AF, Brunzell JD (2003) Hepatic lipase and dyslipidemia:interactions among genetic variants, obesity, and diet. J Lipid Res 44:1279–1286CrossRefPubMedGoogle Scholar
  27. 27.
    Knopp RH, Paramsothy P, Atkinson B, Dowdy A (2008) Comprehensive lipid management versus aggressive LDL lowering to reduce cardiovascular risk. Am J Cardiol 101:48B-57BCrossRefPubMedGoogle Scholar
  28. 28.
    Sprecher DL, Hoeg JM, Schaefer EJ, Zech LA, Gregg RE, Lakatos E, Brewer HB Jr (1985) The association of LDL receptor activity, LDL cholesterol level, and clinical course in homozygous familial hypercholesterolemia. Metabolism 34:294–299CrossRefPubMedGoogle Scholar
  29. 29.
    Hobbs HH, Brown MJ, Goldstein JL (1992) Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1:445–466CrossRefPubMedGoogle Scholar
  30. 30.
    Farese RV Jr, Linton MF, Young SG (1992) Apolipoprotein B mutations affecting cholesterol levels. J Intern Med 231:643–652CrossRefPubMedGoogle Scholar
  31. 31.
    Schaefer EJ, Lamon-Fava S, Jenner JL, Ordovas JM, Davis CE, Lippel K, Levy RI (1994) Lipoprotein(a) levels predict coronary heart disease in the lipid research clinics coronary prevention trial. JAMA 271:999–1003CrossRefPubMedGoogle Scholar
  32. 32.
    Erqou S, Kaptoge S, Perry PC, DiAngelantino E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J; Emerging Risk Factors Collaboration (2009) Lipoprotein(a) as a risk factor coronary heart disease and stroke. JAMA 302:412–423CrossRefPubMedGoogle Scholar
  33. 33.
    Jenner JL, Seman LJ, Millar JS, Lamon-Fava S, Welty FK, Dolnikowski GG, Marcovina SM, Lichtenstein AH, Barrett PH, deLuca C, Schaefer EJ (2005) The metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein(a) in human beings. Metabolism 54:361–369CrossRefPubMedGoogle Scholar
  34. 34.
    Shlipak MG, Simon JA, Vittinghoff E, Lin F, Barrett-Connor E, Knopp RH, Levy RI, Hulley SB (2000) Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA 283:1845–1852CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Lipid Metabolism LaboratoryTufts UniversityBostonUSA

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