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Thromb Haemost 2000; 83(03): 397-403
DOI: 10.1055/s-0037-1613826
Review Article
Schattauer GmbH

Fibrinolytic Proteins and Progression of Coronary Artery Disease in Relation to Gemfibrozil Therapy

Anders Hamsten
1   From the King Gustaf V Research Institute, Karolinska Institute, Stockholm, Sweden
,
Mikko Syvänne
2   From the Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
,
Angela Silveira
1   From the King Gustaf V Research Institute, Karolinska Institute, Stockholm, Sweden
,
Le-Anh Luong
3   From the Division of Cardiovascular Genetics, Department of Medicine, University College London Medical School, London, United Kingdom
,
Markku S. Nieminen
2   From the Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
,
Steve Humphries
3   From the Division of Cardiovascular Genetics, Department of Medicine, University College London Medical School, London, United Kingdom
,
M. Heikki Frick
2   From the Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
,
Marja-Riitta Taskinen
3   From the Division of Cardiovascular Genetics, Department of Medicine, University College London Medical School, London, United Kingdom
› Author Affiliations
Further Information

Publication History

Received 23 April 1999

Accepted after resubmission 10 November 1999

Publication Date:
14 December 2017 (online)

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Summary

Impaired fibrinolytic function, mainly due to increased plasma plasminogen activator inhibitor-1 (PAI-1) activity, is common in patients with manifest coronary artery disease (CAD) and a predictor of recurrent cardiovascular events. We investigated the relationships of plasma tissue-type plasminogen activator (tPA) and PAI-1 antigen levels, plasma PAI-1 activity and PAI 4/5-guanosine (4G/5G) genotype to CAD progression in 203 middle-aged men participating in the Lopid Coronary Angiography Trial (LOCAT).

A higher tPA antigen concentration, whether baseline or on-trial, was associated with a more severe global angiographic response (p < 0.05), an association mainly accounted for by progression of diffuse lesions in graft-affected segments (change in per-patient means of average diameters of segments haemodynamically related to bypass grafts). Plasma PAI-1 activity and mass concentration and 4G/5G PAI-1 genotype were unrelated to angiographic outcome measurements. tPA and PAI-1 antigen increased significantly in the gemfibrozil group (+11.3% and + 16.4%, respectively, p < 0.001), whereas there was no treatment effect on PAI-1 activity (median change 0.0%).

It is concluded that fibrinolytic function does not substantially influence progression of CAD as assessed by angiography in middle-aged men. Furthermore, pronounced long-term lowering of serum triglycerides by gemfibrozil treatment does not significantly affect the plasma PAI-1 activity level but increases the plasma tPA and PAI-1 antigen concentrations.

Key words

Atherosclerosis - thrombosis - gemfibrozil - coronary artery disease - angiography - fibrinolysis - lipoproteins
 

  • References

  • 1 Wiman B, Hamsten A. Impaired fibrinolysis and risk of thromboembolism. Prog Cardiovasc Dis 1991; 34: 179-92.
    CrossrefPubMedSearch in Google Scholar
  • 2 Hamsten A, de Faire U, Walldius G, Dahlén G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; ii: 3-9.
    PubMedSearch in Google Scholar
  • 3 Cortellaro M, Cofrancesco E, Boschetti C, Mussoni L, Donati MB, Cardillo M, Catalano M, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, Pozzoli E, Turri M. Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients. A case-control study. The PLAT Group. Arterioscler Thromb 1993; 13: 1412-7.
    CrossrefPubMedSearch in Google Scholar
  • 4 Malmberg K, Båvenholm P, Hamsten A. Clinical and biochemical factors associated with the prognosis after myocardial infarction at a young age. J Am Coll Cardiol 1994; 24: 592-9.
    CrossrefPubMedSearch in Google Scholar
  • 5 Juhan-Vague I, Pyke SD, Alessi MC, Jespersen J, Haverkate F, Thompson SG. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation 1996; 94: 2057-63.
    CrossrefPubMedSearch in Google Scholar
  • 6 Schneiderman J, Sawdey MS, Keeton MR, Bordin GM, Bernstein EF, Dilley RB, Loskutoff DJ. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci USA 1992; 89: 6998-7002.
    CrossrefPubMedSearch in Google Scholar
  • 7 Lupu F, Bergonzelli GE, Heim DA, Cousin E, Genton CY, Bachmann F, Kruithof EK. Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb 1993; 13: 1090-100.
    CrossrefPubMedSearch in Google Scholar
  • 8 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. New Engl J Med 1985; 313: 1557-63.
    CrossrefPubMedSearch in Google Scholar
  • 9 Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis. Diabetologia 1991; 34: 457-62.
    CrossrefPubMedSearch in Google Scholar
  • 10 Olofsson BO, Dahlén G, Nilsson TK. Evidence for increased levels of plasminogen activator inhibitor and tissue plasminogen activator in plasma of patients with angiographically verified coronary artery disease. Eur Heart J 1989; 10: 77-82.
    CrossrefPubMedSearch in Google Scholar
  • 11 Jansson JH, Nilsson TK, Olofsson BO. Tissue plasminogen activator and other risk factors as predictors of cardiovascular events in patients with severe angina pectoris. Eur Heart J 1991; 12: 157-61.
    CrossrefPubMedSearch in Google Scholar
  • 12 Jansson J-H, Olofsson B-O, Nilsson TK. Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease. A 7-year follow-up. Circulation 1993; 88 (part 1): 2030-4.
    CrossrefPubMedSearch in Google Scholar
  • 13 Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. for the ECAT Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635-41.
    CrossrefPubMedSearch in Google Scholar
  • 14 Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165-8.
    CrossrefPubMedSearch in Google Scholar
  • 15 Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268: 10739-45.
    PubMedSearch in Google Scholar
  • 16 Eriksson P, Kallin B, Van’t Hooft FM, Båvenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92: 1851-5.
    CrossrefPubMedSearch in Google Scholar
  • 17 Eriksson P, Nilsson L, Karpe F, Hamsten A. Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridaemia. Arterioscler Thromb Vasc Biol 1998; 18: 20-26.
    CrossrefPubMedSearch in Google Scholar
  • 18 Syvänne M, Taskinen M-R, Nieminen MS, Manninen V, Kesäniemi YA, Pasternack A, Nawrocki JW, Haber H, Frick MH. A study to determine the response of coronary atherosclerosis to raising low high density lipoprotein cholesterol with a fibric-acid derivative in men after coronary bypass surgery. The rationale, design and baseline characteristics of the LOCAT study. Lopid Coronary Angiography Trial. Controlled Clin Trials 1997; 18: 93-119.
    CrossrefPubMedSearch in Google Scholar
  • 19 Frick MH, Syvänne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, Kesäniemi YA, Pasternack A, Taskinen M-R. for the Lopid Coronary Angiography Trial (LOCAT) Study Group. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Circulation 1997; 96: 2137-43.
    CrossrefPubMedSearch in Google Scholar
  • 20 Syvänne M, Nieminen MS, Frick MH, Kauma H, Majahalme S, Virtanen V, Kesäniemi YA, Pasternack A, Ehnholm C, Taskinen M-R. for the LOCAT study group. Associations between lipoproteins and the progression of coronary and vein-graft atherosclerosis in a controlled trial with gemfibrozil in men with low baseline levels of HDL cholesterol. Circulation 1998; 98: 1993-9.
    CrossrefPubMedSearch in Google Scholar
  • 21 Lamlum H, Luong L-A, Green F, Humphries S, Henney AM. Fluorescencebased PCR detection of single base insertion/deletion polymorphisms in stromelysin and plasminogen activator inhibitor-1 genes. Biotechniques. in press.
    PubMed
  • 22 Syvänne M, Nieminen MS, Frick MH. Accuracy and precision of quantitative arteriography in the evaluation of coronary artery disease after coronary bypass surgery. A validation study. Int J Cardiac Imaging 1994; 10: 243-52.
    CrossrefPubMedSearch in Google Scholar
  • 23 Reiber JHC, van der Zwet PMJ, von Land CD, Koning G, van Meurs B, Buis B, van Voorthuisen AE. Quantitative coronary angiography equipment and technical requirements. In: Reiber JHC, Serruys PW. Advances in Quantitative Coronary Arteriography. Dordrecht: Kluwer Academic Publishers; 1993: 75-111.
    Search in Google Scholar
  • 24 Eliasson M, Evrin P-E, Lundblad D, Asplund K, Rånby M. Influence of gender, age and sampling time on plasma fibrinolytic variables and fibrinogen. Fibrinolysis 1993; 07: 316-23.
    PubMedSearch in Google Scholar
  • 25 Dawson S, Henney A. The status of PAI-1 as a risk factor for arterial and thrombotic disease: a review. Atherosclerosis 1992; 95: 105-17.
    CrossrefPubMedSearch in Google Scholar
  • 26 Stiko-Rahm A, Wiman B, Hamsten A, Nilsson J. Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. Arteriosclerosis 1990; 10: 1067-73.
    CrossrefPubMedSearch in Google Scholar
  • 27 Mussoni L, Mannucci L, Sirtori M, Camera M, Maderna P, Sironi L, Tremoli E. Hypertriglyceridemia and regulation of fibrinolytic activity. Arterioscler Thromb 1992; 12: 19-27.
    CrossrefPubMedSearch in Google Scholar
  • 28 Avellone G, Di Garbo V, Cordova R, Panno AV, Ranelli G, de Simone R, Bompiani GD. Fibrinolytic effect of gemfibrozil versus placebo administration in response to venous occlusion. Fibrinolysis 1993; 07: 416-21.
    PubMedSearch in Google Scholar
  • 29 Andersen P, Smith P, Seljeflot I, Brataker S, Arnesen H. Effects of gemfibrozil on lipids and haemostasis after myocardial infarction. Thromb Haemost 1990; 63: 174-7.
    Thieme ConnectPubMedSearch in Google Scholar
  • 30 Keber I, Lavre J, Suc S, Keber D. The decrease of plasminogen activator inhibitor after normalization of triglycerides during treatment with fibrates. Fibrinolysis 1994; 08: 57-9.
    PubMedSearch in Google Scholar
  • 31 Bröijersen A, Eriksson M, Wiman B, Angelin B, Hjemdahl P. Gemfibrozil treatment of combined hyperlipoproteinemia. No improvement of fibrinolysis despite marked reduction of plasma triglyceride levels. Arterioscler Thromb Vasc Biol 1996; 16: 511-6.
    CrossrefPubMedSearch in Google Scholar
  • 32 Kockx M, de Maat MPM, Knipscheer HC, Kastelein JJP, Kluft C, Princen HMG, Kooistra T. Effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor-1 and fibrinogen in hyperlipidaemic patients. Thromb Haemost 1997; 78: 1167-72.
    Thieme ConnectPubMedSearch in Google Scholar
  • 33 Fujii S, Sobel BE. Direct effects of gemfibrozil on the fibrinolytic system. Diminution of synthesis of plasminogen activator inhibitor type I.. Circulation 1992; 85: 1888-93.
    CrossrefPubMedSearch in Google Scholar
  • 34 Arts J, Kockx M, Princen HMG, Kooistra T. Studies on the mechanism of fibrate-inhibited expression of plasminogen activator inhibitor-1 in cultured hepatocytes from cynomolgus monkey. Arterioscler Thromb Vasc Biol 1997; 17: 26-32.
    CrossrefPubMedSearch in Google Scholar
  • 35 Nilsson L, Takemura T, Eriksson P, Hamsten A. Effects of fibrate compounds on expression of plasminogen activator inhibitor-1 by cultured endothelial cells. Arterioscler Thromb Vasc Biol 1999; 19: 1577-1581.
    CrossrefPubMedSearch in Google Scholar
  • 36 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 tissuetype plasminogen activator release from endothelial cells. Circ Res 1993; 73: 335-343.
    CrossrefPubMedSearch in Google Scholar
  • 37 Levin EG, Miles LA, Fless GM, Scanu AM, Baynham P, Curtiss LK, Plow EF. Lipoproteins inhibit the secretion of tissue plasminogen activator from human endothelial cells. Arterioscler Thromb 1994; 14: 438-42.
    CrossrefPubMedSearch in Google Scholar
  • 38 Juhan-Vague I, Alessi MC, Joly P, Thirion X, Vague P, Declerck PJ, Serradimigni A, Collen D. Plasma plasminogen activator inhibitor 1 in angina pectoris. Influence of plasma insulin and acute-phase response. Arteriosclerosis 1989; 09: 362-7.
    CrossrefPubMedSearch in Google Scholar
  • 39 Nguyen ND, Ghaddar H, Stinson V, Chambless LE, Wu KK. ARIC hemostasis study: IV. Intraindividual variability and reliability of hemostatic factors. Thromb Haemost 1995; 73: 256-60.
    Thieme ConnectPubMedSearch in Google Scholar