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Semin Thromb Hemost 2000; 26(5): 513-520
DOI: 10.1055/s-2000-13207
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Lipoproteins and the Endothelium: Insights from Clinical Research

Klaus A. Dugi1 , Daniel J. Rader2
  • 1Department of Internal Medicine I, Endocrinology and Metabolism, Heidelberg University, Heidelberg, Germany
  • 2University of Pennsylvania Medical Center, Philadelphia, Pennsylvania
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Publication History

Publication Date:
31 December 2000 (online)

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ABSTRACT

Elevated plasma levels of atherogenic lipoproteins such as low-density lipoprotein (LDL) and remnant lipoproteins and low levels of HDL cholesterol constitute major risk factors for the development of atherothrombotic disease. In addition to their role in the initiation and propagation of atherosclerosis, hyperlipidemia also causes endothelial dysfunction. In addition, hyperlipidemia has an influence on thrombosis by modulating levels of prothrombotic and fibrinolytic factors, thus promoting the final step in the atherosclerotic process, vascular occlusion. In the last 5 years, randomized, prospective, placebo-controlled studies aimed at reducing plasma levels of atherogenic lipoproteins have demonstrated a significant effect on cardiovascular morbidity and all-cause mortality in both primary and secondary prevention. Although the mechanisms underlying the clinical benefit of lipid-lowering therapy remain uncertain, the lowering of lipids has been associated with improved endothelial function and a less thrombotic state, two factors that could play a role in the benefit of lipid lowering. This review focuses on recent clinical research related to the impact of lipoproteins and lipid-lowering therapy on endothelial function and plasma levels of prothrombotic and fibrinolytic factors.

KEYWORD

Atherothrombotic disease - endothelial dysfunction - hyperlipidemia - statins - treatment

REFERENCES

  • 1 Stamler J, Wentworth D, Neaton J D. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded?.  <~>Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA . 1986;  256 2823-2828
    CrossrefPubMedSearch in Google Scholar
  • 2 Genest J J, McNamara J R, Salem D N, Schaefer E J. Prevalence of risk factors in men with premature coronary artery disease.  Am J Cardiol . 1991;  67 1185-1189
    CrossrefPubMedSearch in Google Scholar
  • 3 Gordon T, Castelli W P, Hjortland M C, Kannel W B, Dawber T R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study.  Am J Med . 1977;  62 707-714
    CrossrefPubMedSearch in Google Scholar
  • 4 Miller G J, Miller N E. Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease.  Lancet . 1975;  1 16-19
    PubMedSearch in Google Scholar
  • 5 Krauss R M, Lindgren F T, Williams P T. Intermediate-density lipoproteins and progression of coronary artery disease in hypercholesterolaemic men.  Lancet . 1987;  2 62-66
    PubMedSearch in Google Scholar
  • 6 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
    PubMedSearch in Google Scholar
  • 7 Kugiyama K, Doi H, Takazoe K. Remnant lipoprotein levels in fasting serum predict coronary events in patients with coronary artery disease. Improvement of endothelial vasomotor dysfunction by treatment with alpha-tocopherol in patients with high remnant lipoproteins levels.  J Am Coll Cardiol . 1999;  33 1512-1518
    CrossrefPubMedSearch in Google Scholar
  • 8 Miller N E, Hammett F, Saltissi S. Relation of angiographically defined coronary artery disease to plasma lipoprotein subfractions and apolipoproteins.  Br Med J (Clin Res Ed) . 1981;  282 1741-1744
    PubMedSearch in Google Scholar
  • 9 Ballantyne F C, Clark R S, Simpson H S, Ballantyne D. High density and low density lipoprotein subfractions in survivors of myocardial infarction and in control subjects.  Metabolism . 1982;  31 433-437
    CrossrefPubMedSearch in Google Scholar
  • 10 Puchois P, Kandoussi A, Fievet P. Apolipoprotein A-I containing lipoproteins in coronary artery disease.  Atherosclerosis . 1987;  68 35-40
    PubMedSearch in Google Scholar
  • 11 Lamarche B, Tchernof A, Moorjani S. 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
    PubMedSearch in Google Scholar
  • 12 Stampfer M J, Krauss R M, Ma J. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.  JAMA . 1996;  276 882-888
    CrossrefPubMedSearch in Google Scholar
  • 13 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
    CrossrefPubMedSearch in Google Scholar
  • 14 Quyyumi A A. Endothelial function in health and disease: New insights into the genesis of cardiovascular disease.  Am J Med . 1998;  105 32S-39S
    PubMedSearch in Google Scholar
  • 15 Vogel R A. Coronary risk factors, endothelial function, and atherosclerosis: A review.  Clin Cardiol . 1997;  20 426-432
    CrossrefPubMedSearch in Google Scholar
  • 16 Playford D A, Watts G F. Special article: Non-invasive measurement of endothelial function.  Clin Exp Pharmacol Physiol . 1998;  25 640-643
    PubMedSearch in Google Scholar
  • 17 Pitkanen O P, Raitakari O T, Niinikoski H. Coronary flow reserve is impaired in young men with familial hypercholesterolemia.  J Am Coll Cardiol . 1996;  28 1705-1711
    CrossrefPubMedSearch in Google Scholar
  • 18 Yokoyama I, Murakami T, Ohtake T. Reduced coronary flow reserve in familial hypercholesterolemia.  J Nucl Med . 1996;  37 1937-1942
    PubMedSearch in Google Scholar
  • 19 Drexler H, Zeiher A M, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by l-arginine.  Lancet . 1991;  338 1546-1550
    CrossrefPubMedSearch in Google Scholar
  • 20 Chowienczyk P J, Watts G F, Cockcroft J R, Ritter J M. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia.  Lancet . 1992;  340 1430-1432
    CrossrefPubMedSearch in Google Scholar
  • 21 Zeiher A M, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension.  J Clin Invest . 1993;  92 652-662
    CrossrefPubMedSearch in Google Scholar
  • 22 Seiler C, Hess O M, Buechi M, Suter T M, Krayenbuehl H P. Influence of serum cholesterol and other coronary risk factors on vasomotion of angiographically normal coronary arteries.  Circulation . 1993;  88 2139-2148
    PubMedSearch in Google Scholar
  • 23 Yokoyama I, Ohtake T, Momomura S. Reduced coronary flow reserve in hypercholesterolemic patients without overt coronary stenosis.  Circulation . 1996;  94 3232-3238
    PubMedSearch in Google Scholar
  • 24 Yokoyama I, Ohtake T, Momomura S. Impaired myocardial vasodilation during hyperemic stress with dipyridamole in hypertriglyceridemia.  J Am Coll Cardiol . 1998;  31 1568-1574
    CrossrefPubMedSearch in Google Scholar
  • 25 Yokoyama I, Ohtake T, Momomura S. Altered myocardial vasodilatation in patients with hypertriglyceridemia in anatomically normal coronary arteries.  Arterioscler Thromb Vasc Biol . 1998;  18 294-299
    PubMedSearch in Google Scholar
  • 26 Doi H, Kugiyama K, Ohgushi M. Remnants of chylomicron and very low density lipoprotein impair endothelium-dependent vasorelaxation.  Atherosclerosis . 1998;  137 341-349
    CrossrefPubMedSearch in Google Scholar
  • 27 Kugiyama K, Doi H, Motoyama T. Association of remnant lipoprotein levels with impairment of endothelium-dependent vasomotor function in human coronary arteries.  Circulation . 1998;  97 2519-2526
    PubMedSearch in Google Scholar
  • 28 Chowienczyk P J, Watts G F, Wierzbicki A S. Preserved endothelial function in patients with severe hypertriglyceridemia and low functional lipoprotein lipase activity.  J Am Coll Cardiol . 1997;  29 964-968
    CrossrefPubMedSearch in Google Scholar
  • 29 Vogel R A, Corretti M C, Plotnick G D. Effect of a single high-fat meal on endothelial function in healthy subjects.  Am J Cardiol . 1997;  79 350-354
    CrossrefPubMedSearch in Google Scholar
  • 30 Hackman A, Abe Y, Insull Jr W. Levels of soluble cell adhesion molecules in patients with dyslipidemia.  Circulation . 1996;  93 1334-1338
    PubMedSearch in Google Scholar
  • 31 Toikka J O, Ahotupa M, Viikari J S. Constantly low HDL-cholesterol concentration relates to endothelial dysfunction and increased in vivo LDL-oxidation in healthy young men.  Atherosclerosis . 1999;  147 133-138
    CrossrefPubMedSearch in Google Scholar
  • 32 Zeiher A M, Schachlinger V, Hohnloser S H, Saurbier B, Just H. Coronary atherosclerotic wall thickening and vascular reactivity in humans. Elevated high-density lipoprotein levels ameliorate abnormal vasoconstriction in early atherosclerosis.  Circulation . 1994;  89 2525-2532
    PubMedSearch in Google Scholar
  • 33 Simpson H C, Mann J I, Meade T W. Hypertriglyceridaemia and hypercoagulability.  Lancet . 1983;  1 786-790
    PubMedSearch in Google Scholar
  • 34 Silveira A, Karpe F, Blombãck M. Activation of coagulation factor VII during alimentary lipemia.  Arterioscler Thromb . 1994;  14 60-69
    CrossrefPubMedSearch in Google Scholar
  • 35 Woodward M, Lowe G D, Rumley A. Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey. II. Relationships to cardiovascular risk factors and prevalent cardiovascular disease.  Br J Haematol . 1997;  97 785-797
    CrossrefPubMedSearch in Google Scholar
  • 36 Hamsten A, de Faire U, Walldius G. Plasminogen activator inhibitor in plasma: Risk factor for recurrent myocardial infarction.  Lancet . 1987;  2 3-9
    PubMedSearch in Google Scholar
  • 37 Hamsten A, Wiman B, de Faire U, Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction.  N Engl J Med . 1985;  313 1557-1563
    CrossrefPubMedSearch in Google Scholar
  • 38 Sandset P M, Lund H, Norseth J, Abildgaard U, Ose L. Treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors in hypercholesterolemia induces changes in the components of the extrinsic coagulation system.  Arterioscler Thromb . 1991;  11 138-145
    PubMedSearch in Google Scholar
  • 39 Hansen J B, Huseby N E, Sandset P M. Tissue-factor pathway inhibitor and lipoproteins. Evidence for association with and regulation by LDL in human plasma.  Arterioscler Thromb . 1994;  14 223-229
    PubMedSearch in Google Scholar
  • 40 Zitoun D, Bara L, Basdevant A, Samama M M. Levels of factor VIIc associated with decreased tissue factor pathway inhibitor and increased plasminogen activator inhibitor-1 in dyslipidemias.  Arterioscler Thromb Vasc Biol . 1996;  16 77-81
    CrossrefPubMedSearch in Google Scholar
  • 41 Carvalho A C, Colman R W, Lees R S. Platelet function in hyperlipoproteinemia.  N Engl J Med . 1974;  290 434-438
    CrossrefPubMedSearch in Google Scholar
  • 42 Aoki I, Aoki N, Kawano K. Platelet-dependent thrombin generation in patients with hyperlipidemia.  J Am Coll Cardiol . 1997;  30 91-96
    CrossrefPubMedSearch in Google Scholar
  • 43 Brunzell J D. Familial lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis af Inherited Disease New York: McGraw-Hill, 1995: 1913-1932
    Search in Google Scholar
  • 44 Benlian P, De Gennes L J, Foubert L. Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene [published erratum appears in N Engl J Med 1997;336:451].  N Engl J Med . 1996;  19 335:848-854
    PubMedSearch in Google Scholar
  • 45 The Scandinavian Simvastatin Survival Study (4S). Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: Lancet .  1994;  19 344:1383-1389
    PubMedSearch in Google Scholar
  • 46 Sacks F M, Pfeffer M A, Moye L A. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.  N Engl J Med . 1996;  335 1001-1009
    CrossrefPubMedSearch in Google Scholar
  • 47 The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.  N Engl J Med . 1998;  339 1349-1357
    CrossrefPubMedSearch in Google Scholar
  • 48 Shepherd J, Cobbe S M, Ford I. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.  N Engl J Med . 1995;  333(20) 1301-1307
    CrossrefPubMedSearch in Google Scholar
  • 49 Downs J R, Clearfield M, Weis S. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.  JAMA . 1998;  279 1615-1622
    CrossrefPubMedSearch in Google Scholar
  • 50 LaRosa J C, He J, Vupputuri S. Effect of statins on risk of coronary disease: A meta-analysis of randomized controlled trials.  JAMA . 1999;  282 2340-2346
    CrossrefPubMedSearch in Google Scholar
  • 51 Rubins H B, Robins S J, Collins D. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.  N Engl J Med . 1999;  341 410-418
    CrossrefPubMedSearch in Google Scholar
  • 52 Harrison D G, Armstrong M L, Freiman P C, Heistad D D. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis.  J Clin Invest . 1987;  80 1808-1811
    PubMedSearch in Google Scholar
  • 53 Leung W H, Lau C P, Wong C K. Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolaemic patients.  Lancet . 1993;  341 1496-1500
    CrossrefPubMedSearch in Google Scholar
  • 54 Seiler C, Suter T M, Hess O M. Exercise-induced vasomotion of angiographically normal and stenotic coronary arteries improves after cholesterol-lowering drug therapy with bezafibrate.  J Am Coll Cardiol . 1995;  26 1615-1622
    CrossrefPubMedSearch in Google Scholar
  • 55 Egashira K, Hirooka Y, Kai H. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia.  Circulation . 1994;  89 2519-2524
    PubMedSearch in Google Scholar
  • 56 Treasure C B, Klein J L, Weintraub W S. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease.  N Engl J Med . 1995;  332 481-487
    CrossrefPubMedSearch in Google Scholar
  • 57 Anderson T J, Meredith I T, Yeung A C. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.  N Engl J Med . 1995;  332 488-493
    CrossrefPubMedSearch in Google Scholar
  • 58 Stroes E S, Koomans H A, de Bruin W T, Rabelink T J. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication.  Lancet . 1995;  19 346:467-471
    PubMedSearch in Google Scholar
  • 59 Vogel R A, Corretti M C, Plotnick G D. Changes in flow-mediated brachial artery vasoactivity with lowering of desirable cholesterol levels in healthy middle-aged men.  Am J Cardiol . 1996;  77 37-40
    CrossrefPubMedSearch in Google Scholar
  • 60 van Boven J A, Jukema J W, Zwinderman A H. Reduction of transient myocardial ischemia with pravastatin in addition to the conventional treatment in patients with angina pectoris. REGRESS Study Group.  Circulation . 1996;  94 1503-1505
    PubMedSearch in Google Scholar
  • 61 Andrews T C, Raby K, Barry J. Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease.  Circulation . 1997;  95 324-328
    PubMedSearch in Google Scholar
  • 62 Baller D, Notohamiprodjo G, Gleichmann U. Improvement in coronary flow reserve determined by positron emission tomography after 6 months of cholesterol-lowering therapy in patients with early stages of coronary atherosclerosis.  Circulation . 1999;  99 2871-2875
    PubMedSearch in Google Scholar
  • 63 Huggins G S, Pasternak R C, Alpert N M, Fischman A J, Gewirtz H. Effects of short-term treatment of hyperlipidemia on coronary vasodilator function and myocardial perfusion in regions having substantial impairment of baseline dilator reverse.  Circulation . 1998;  98 1291-1296
    PubMedSearch in Google Scholar
  • 64 Pitt B, Waters D, Brown W V. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators.  N Engl J Med . 1999;  341 70-76
    CrossrefPubMedSearch in Google Scholar
  • 65 Gould K L, Martucci J P, Goldberg D I. Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease. A potential noninvasive marker of healing coronary endothelium.  Circulation . 1994;  89 1530-1538
    PubMedSearch in Google Scholar
  • 66 O'Driscoll G, Green D, Taylor R R. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month.  Circulation . 1997;  95 1126-1131
    PubMedSearch in Google Scholar
  • 67 Tamai O, Matsuoka H, Itabe H. Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans.  Circulation . 1997;  95 76-82
    PubMedSearch in Google Scholar
  • 68 Dupuis J, Tardif J C, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (reduction of cholesterol in ischemia and function of the endothelium) trial.  Circulation . 1999;  99 3227-3233
    PubMedSearch in Google Scholar
  • 69 Clarkson P, Adams M R, Powe A J. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults.  J Clin Invest . 1996;  97 1989-1994
    CrossrefPubMedSearch in Google Scholar
  • 70 Creager M A, Gallagher S J, Girerd X J. L-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans.  J Clin Invest . 1992;  90 1248-1253
    PubMedSearch in Google Scholar
  • 71 John S, Schlaich M, Langenfeld M. Increased bioavailability of nitric oxide after lipid-lowering therapy in hypercholesterolemic patients: A randomized, placebo-controlled, double-blind study.  Circulation . 1998;  98 211-216
    PubMedSearch in Google Scholar
  • 72 Laufs U, La F, Plutzky J, Liao J K. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors.  Circulation . 1998;  97 1129-1135
    CrossrefPubMedSearch in Google Scholar
  • 73 Branchi A, Rovellini A, Sommariva D, Gugliandolo A G, Fasoli A. Effect of three fibrate derivatives and of two HMG-CoA reductase inhibitors on plasma fibrinogen level in patients with primary hypercholesterolemia.  Thromb Haemost . 1993;  70 241-243
    PubMedSearch in Google Scholar
  • 74 Marais A D, Firth J C, Bateman M E. Atorvastatin: An effective lipid-modifying agent in familial hypercholesterolemia.  Arterioscler Thromb Vasc Biol . 1997;  17 1527-1531
    PubMedSearch in Google Scholar
  • 75 Davidson M, McKenney J, Stein E. Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia. Atorvastatin Study Group I.  Am J Cardiol . 1997;  79 1475-1481
    CrossrefPubMedSearch in Google Scholar
  • 76 Wierzbicki A S, Lumb P J, Semra Y K, Crook M A. Effect of atorvastatin on plasma fibrinogen [letter].  Lancet . 1998;  351 569-570
    CrossrefPubMedSearch in Google Scholar
  • 77 Rosenson R S, Tangney C C. Antiatherothrombotic properties of statins: Implications for cardiovascular event reduction.  JAMA . 1998;  279 1643-1650
    CrossrefPubMedSearch in Google Scholar
  • 78 Lacoste L, Lam J Y, Hung J. Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction.  Circulation . 1995;  92 3172-3177
    PubMedSearch in Google Scholar