(Circulation. 1995;92:698-699.)
© 1995 American Heart Association, Inc.
Articles |
Lipid Lowering and Enhancement of Fibrinolysis With Niacin
From the Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, O&N, Leuven, Belgium.
Correspondence to Désiré Collen, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, O&N, Herestraat 49, B-3000, Leuven, Belgium. E-mail Desire.Collen@med.kuleuven.ac.bc.
Key Words: fibrinolysis • editorials • lipids
 |
Introduction |
|---|
 Top Introduction References |
|---|
Several controlled trials in patients with atherosclerotic heart disease have demonstrated that a 30% to 40% reduction in low-density lipoprotein (LDL) cholesterol levels is associated not only with a moderate reduction of angiographic progression but, importantly, also with an impressive reduction of ischemic clinical events,1 suggesting that intensive lipid lowering may stabilize existing lesions. Atherosclerotic plaque rupture occurs primarily at the site of unstable, lipid-rich areas2 where infiltrated macrophages facilitate matrix degradation,3 activate the extrinsic pathway of blood coagulation through tissue factor expression, and inhibit fibrinolysis via increased plasminogen activator inhibitor type 1 (PAI-1) synthesis.4
LDL cholesterol levels are, however, only weak predictors of the progression of atherosclerotic disease.5 Their inherent susceptibility to oxidative modification may constitute a more important pathogenic mechanism.6 Oxidized LDL may facilitate atherogenesis by enhancing monocyte/macrophage adhesion and foam cell generation; inducing smooth muscle cell migration, proliferation, and foam cell generation; enhancing platelet adhesion and aggregation; initiating thrombosis; and impairing vasodilation (reviewed in Reference 7). Patients with hypertension, obesity, hypertriglyceridemia, depressed high-density lipoprotein (HDL) cholesterol levels and insulin resistance, for example, have increased levels of small, dense LDL particles with a pronounced predisposition to oxidative modification,8 whereas elevated levels of oxidatively modified LDL have also been demonstrated in the plasma of patients with acute myocardial infarction.9
Deficient fibrinolytic capacity, eg, due to increased PAI-1 levels or reduced levels of tissue-type plasminogen activator (TPA), predisposes patients to thrombotic events.10 Ischemic heart disease, angina pectoris, and recurrent myocardial infarction are indeed associated with increased levels of PAI-1.11 Oxidized LDL may reduce the fibrinolytic capacity of endothelium by stimulating the synthesis of PAI-1 and by inhibiting the synthesis of TPA.12
Defective fibrinolysis may also play a role in the
early stages of the atherosclerotic process (reviewed in Reference 10).
Elevated levels of both PAI-1 and 
2-antiplasmin and
decreased levels of TPA have been detected in both the intima and the
media of atherosclerotic arterial
segments.13
Treatment with niacin not only induces a significant reduction of LDL cholesterol and triglyceride levels and an increase of HDL cholesterol but also converts easily oxidized small, dense LDL particles to larger, buoyant, oxidation-resistant particles.8 Thus, both modulation of the lipoprotein profile and inhibition of the oxidation of LDL may contribute to the decreased mortality of patients with ischemic heart disease in secondary prevention trials.14 Niacin also reduces the level of lipoprotein(a) that may be atherogenic via inhibition of fibrinolysis in the arterial wall.14
In this issue of Circulation, Brown et al15 demonstrate that niacin not only decreased the constitutive synthesis of PAI-1 by Hep G2 cells but also attenuated the induction of PAI-1 synthesis by transforming growth factor-ß1. It was concluded that niacin may potentiate fibrinolysis, thereby reducing the induction of atherothrombosis by clot-associated mitogens. The modulation of PAI-1 synthesis appears to be unrelated to triggers such as (1) oxidized LDL that may be produced by activated endothelium and/or activated platelets, (2) interleukin-1 that may be produced by infiltrating leukocytes, or (3) platelet-derived growth factor that may be produced by activated platelets and/or infiltrated macrophages. Provided this phenomenon also occurs in vascular smooth muscle and/or endothelial cells, it might constitute an alternative pathway for pharmacological interference with atherogenesis.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
|
TopIntroductionReferences |
|---|
1. Paterson RW, Paat JJ, Steele GH, Hathaway SC, Won JG. Impact of intensive lipid modulation on angiographically defined coronary disease: clinical implications. South Med J. 1994;87:236-242. [Medline] [Order article via Infotrieve]
2. Fuster V, Badimon JJ, Badimon L. Clinical-pathological correlations of coronary disease progression and regression. Circulation. 1992;86(suppl 6):III-1-III-11.
3. Shingu M, Isayama T, Yasutake C, Naono T, Nobunaga N, Tomari K, Horie K, Goto Y. Role of oxygen radicals and IL-6 in IL-1-dependent cartilage matrix degradation. Inflammation. 1994;18:613-623. [Medline] [Order article via Infotrieve]
4. Salgado A, Boueda JC, Monasterio J, Segura RM, Mourelle M, Gomez-Jimenel J, Peracaula R. Inflammatory mediators and their influence on haemostasis. Haemostasis. 1994;24:132-138. [Medline] [Order article via Infotrieve]
5.
Buring JE, O'Connor GT, Goldhaber SZ, Rosner B,
Herbert PN, Blum CB, Breslow JL, Hennekens CH. Decreased HDL2
and HDL3 cholesterol, apo A-I and apo A-II in increased
risk of myocardial infarction.
Circulation. 1992;85:22-29.
6. O'Keefe JH Jr, Lavie CJ Jr, McCallister BD. Insights into the pathogenesis and prevention of coronary artery disease. Mayo Clin Proc. 1995;70:69-79. [Abstract]
7. Holvoet P, Collen D. Oxidized lipoproteins in atherosclerosis and thrombosis. FASEB J. 1994;8:1279-1284. [Abstract]
8. Chait A, Brazg RL, Tribble DL, Kraus RM. Susceptibility of small dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, type B. Am J Med. 1993;94:350-356. [Medline] [Order article via Infotrieve]
9. Holvoet P, Perez G, Zhao Z, Brouwers E, Bernar H, Collen D. Malondialdehyde-modified low density lipoproteins in patients with atherosclerotic disease. J Clin Invest. 1995;95:2611-2619.
10. Wiman B, Hamsten A. Impaired fibrinolysis and risk of thromboembolism. Prog Cardiovasc Dis. 1991;34:179-192. [Medline] [Order article via Infotrieve]
11. Hamsten A, de Faire U, Walldius G, Dahlen G, Szasmosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987;2:3-9. [Medline] [Order article via Infotrieve]
12.
Kugiyama K, Sakamoto T, Misumi I, Sugiyama S, Ohgushi
M, Ogawa H, Horiguchi M, Yasue H. Transferable lipids in
oxidized low-density lipoprotein stimulate plasminogen
activator inhibitor-1 and inhibit tissue-type
plasminogen activator release from
endothelial cells. Circ
Res. 1993;73:335-343.
13. Robbie LA, Booth NA, Brown PAJ, Croll AM, Bennett WJ. Localization and quantitation of proteins of the fibrinolytic system in normal and atherosclerotic vessels. Fibrinolysis. 1994;8(suppl 1):253-262.
14. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W, for the Coronary Drug Project Research Group. Fifteen year mortality in coronary drug project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-1255. [Abstract]
15.
Brown SL, Sobel BE, Fujii S. Attenuation of the
synthesis of plasminogen activator
inhibitor type-1 by niacin: a potential link between lipid
lowering and fibrinolysis.
Circulation. 1995;92:767-772.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||