Plasminogen activator inhibitor-1 and outcome after femoropopliteal angioplasty: analysis of genotype and plasma levels

Wolfgang Mlekusch; Martin Schillinger; Markus Exner; Schila Sabeti; Christine Mannhalter; Erich Minar; Oswald Wagner

doi:10.1160/TH03-03-0159

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 90(04): 717-723
DOI: 10.1160/TH03-03-0159

Vascular Development and Vessel Remodelling

Schattauer GmbH

Plasminogen activator inhibitor-1 and outcome after femoropopliteal angioplasty: analysis of genotype and plasma levels

Authors

Wolfgang Mlekusch

¹Department of Angiology Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
Martin Schillinger

¹Department of Angiology Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
Markus Exner

²Department of Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
Schila Sabeti

¹Department of Angiology Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
Christine Mannhalter

²Department of Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
Erich Minar

¹Department of Angiology Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria
Oswald Wagner

²Department of Medical and Chemical Laboratory Diagnostics, University of Vienna, Medical School, Vienna, Austria

Abstract

Summary

Plasminogen activator inhibitor-1 (PAI-1) is suggested to be involved in the pathophysiology of early thrombosis and late restenosis after percutaneous transluminal angioplasty (PTA). The role of the PAI-1 promoter genotype in this context is indeterminate. We investigated the association of the (4G/5G) polymorphism at nucleotide position (–675) in the PAI-1 gene promoter, PAI-1 plasma levels, and postangioplasty outcome after femoropopliteal PTA.

We studied 251 consecutive patients who underwent femoropopliteal PTA. In a subgroup of 86 patients PAI-1 plasma levels at baseline,8,24 and 48 hours postintervention were measured and correlated to the genotype. Patients were followed for early thrombosis and the late restenosis (≥50%) within 12 months. Multivariate Cox proportional hazards analysis was performed to assess the association between the PAI-1 genotype and PTA failure.

Results show that the PAI-1 genotype was neither associated with PAI-1 plasma levels (p=0.40) nor the change of PAI-1 from baseline to 8 (p=0.39), 24 (p=0.86) and 48 hours (p=0.89). Three out of 35 homozygous (4G/4G) patients (9%) had early thrombotic reocclusions, compared to two out of 153 heterozygous (4G/5G) patients (1%) and none of the 63 homozygous (5G/5G) patients (p=0.007). Restenosis after median 5 months (interquartile range 3 to 9) was found in 117 patients (42%), without significant association between the PAI-1 genotype and late postangioplasty failure (Log Rank p=0.95).

We can conclude that carriers of the 4G allele exhibited a higher frequency of early thrombotic reocclusions after percutaneous angioplasty. However, the PAI-1 gene promoter polymorphism (4G/5G) was not associated with PAI-1 plasma levels or late postangioplasty restenosis.

Keywords

Gene expression - intravascular devices - proteases/inhibitors - restenosis

Full Text

References

References
1 Kastrati A, Dirschinger J, Schomig A. Genetic risk factors and restenosis after percutaneous coronary interventions. Herz 2000; 25: 34-46.
2 Bauters C, Lamblin N, Amouyel P. Gene polymorphisms and outcome after coronary angioplasty. Curr Interv Cardiol Rep 2001; 3: 281-6.
3 Roguin A, Hochberg I, Nikolsky E.. et al. Haptoglobin phenotype as a predictor of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 2001; 87: 330-2.
4 Jukema JW, Kastelein JJ. Tailored therapy to fit individual profiles. Genetics and coronary artery disease. Ann N Y Acad Sci 2000; 902: 17-24.
5 Exner M, Schillinger M, Minar E. et al. Heme oxygenase-1 microsatellite gene promoter polymorphism is associated with restenosis after percutaneous transluminal angioplasty. J Endovasc Ther 2001; 8: 433-40.
6 Sawa H, Lundgren C, Sobel BE. et al. Increased intramural expression of plasmino-gen activator inhibitor type 1 after balloon injury: a potential progenitor of restenosis. J Am Coll Cardiol 1994; 24: 1742-8.
7 DeYoung MB, Tom C, Dichek DA. Plasmino-gen activator inhibitor type 1increases neointima formation in balloon-injured rat carotid arteries. Circulation 2001; 104: 1972-81.
8 Huber K, Jorg M, Probst P. et al. A decrease in plasminogen activator inhibitor-1 activity after successful percutaneous transluminal coronary angioplasty is associated with a significantly reduced risk for coronary restenosis. Thromb Haemost 1992; 67: 209-13.
9 Sakata K, Miura F, Sugino H. et al. Impaired fibrinolysis early after percutaneous transluminal coronary angioplasty is associated with restenosis. Am Heart J 1996; 131: 1-6.
10 Ishiwata S, Tukada T, Nakanishi S. et al. Postangioplasty restenosis: platelet activation and the coagulation-fibrinolysis system as possible factors in the pathogenesis of restenosis. Am Heart J 1997; 133: 387-92.
11 Gottsauner-Wolf M, Sochor H, Hornykewwycz S. et al. Predictive value of PAI-1 plasma activity and thallium perfusion imaging for restenosis after percutaneous transluminal angioplasty in clinically asymptomatic patients. Thromb Haemost 1999; 81: 522-6.
12 Roller E, Janisch S, Carroll V. et al. Changes in the fibrinolytic system in patients with peripheral arterial occlusive disease undergoing percutaneous transluminal angioplasty. Thromb Res 1999; 94: 241-7.
13 Strauss BH, Lau HK, Bowman KA. et al. Plasma urokinase antigen and plasminogen activator inhibitor 1 antigen levels predict angiographic coronary restenosis. Circulation 1999; 100: 1616-22.
14 Sartori MT, Vettor R, De Pergola G. et al. Role of the 4G/5G polymorphism of PAI-1 gene promoter on PAI-1 levels in obese patients: influence of fat distribution and insulin-resistance. Thromb Haemost 2001; 86: 1161-9.
15 Roest M, van der Shouw YT, Banga JD. et al. Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women. Circulation 2000; 101: 67-70.
16 Gardemann A, Lohre J, Katz N. et al. The 4G4G genotype of the plasminogen activator inhibitor 1 gene polymorphism is associated with coronary atherosclerosis in patients at high risk for this disease. Thromb Haemost 1999; 82: 1121-6.
17 Endler G, Lalouschke W, Exner M. et al. The 4G/4G genotype at nucleotide position –675 in the promoter region of plasmonigen activator inhibitor 1 (PAI-1) gene is less frequent in young patients with minor stroke than in controls. Br J Haematol 2000; 110: 469-71.
18 Ortlepp JR, Hofmann R, Killian A. et al. The 4G/5G promoter polymorphism of the plasminogen activator inhibitor-1 gene and late lumen loss after coronary stent placement in smoking and non-smoking patients. Clin Cardiol 2001; 24: 585-91.
19 Schillinger M, Exner M, Mlekusch W. et al. Vascular inflammation after femoropopliteal PTA: potential impact on restenosis. Radiology 2002; 225: 21-6.
20 Schillinger M, Haumer M, Schlerka G. et al. Restenosis after percutaneous transluminal angioplasty in patients with peripheral artery disease: the role of inflammation. J Endovasc Ther 2001; 8: 477-83.
21 Minar E, Pokrajac B, Ahmadi R. et al. Brachytherapy for prophylaxis of restenosis after long-segment femoropopliteal angioplasty: pilot study. Radiology 1998; 208: 173-9.
22 Ranke C, Creutzig A, Alexander K. Duplex scanning of the peripheral arteries: correlation of the peak velocity ratio with angiographic diameter reduction. Ultrasound Med Biol 1992; 18: 433-40.
23 Dawson S, Hamsten A, Wiman B. et al. Genetic variation at the plasminogen activator inhibitor-1 is associated with altered levels plasma plasminogen activator inhibitor-1 activity. Arterioscler Thromb 1991; 11: 183-90.
24 Brown NJ, Murphey LJ, Srikuma N. et al. Interactive effect of PAI-1 4G/5G genotype and salt intake on PAI-1 antigen. Arterioscler Thromb Vasc Biol 2001; 21: 1071-7.
25 Cesari M, Satori MT, Patrassi GM. et al. Determinants of plasma levels of plasminogen activator inhibitor 1: a study of normotensive twins. Arterioscler Thromb Vasc Biol 1999; 19: 316-20.
26 Margaglione M, Cappucci G, d´Addedda M. et al. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis: relation to environmental and genetic determinants. Arterioscler Thromb Vasc Biol 1998; 18: 562-7.
27 Burzotta F, Di CastelnuovoA, Amore C. et al. 4G/5G promoter PAI-1 gene polymorphism is associated with plasmatic PAI-1 activity in Italians: a model of gene-environmental interaction. Thromb Haemost 1998; 79: 354-8.
28 Henry M, Tregouet DA, Alessi MC. et al. Metabolic determinants are much more important that gene polymorphisms in determining the PAI-1 activity and antigen plasma concentrations: a family study with part of the Stanislas Cohort. Arterioscler Thromb Vasc Biol 1998; 18: 84-91.
29 Henry M, Chomiki N, Scarabin PY. et al. Five frequent polymorphisms of the PAI-1 gene: lack of association between genotypes, PAI activity, and triglyceride levels in a healthy population. Arterioscler Thromb Vasc Biol 1997; 17: 851-8.
30 Schillinger M, Exner M, Mlekusch W. et al. Heme oxygenase-1 genotype is a vascular anti-inflammatory factor after balloon angioplasty. J Endovasc Ther 2002; 9: 385-94.
31 Schillinger M, Exner M, Minar E. et al. Heme oxygenase-1 microsatellite gene promoter polymorphism is associated with restenosis after percutaneous transluminal angioplasty. Lancet. 2002. submitted
32 Exner M, Schillinger M, Minar E. Interleukin 6 genotype and restenosis after balloon angioplasty. Radiology. 2002. submitted
33 Nowak-Gottl U, Kotthoff S, Hagemeyer E. et al. Interaction of fibrinolysis and prothrom-boric risk factors in neonates, infants amd children with and without thromboembolism and underlying cardiac disease. A prospective Study. Thromb Res 2001; 103: 93-101.
34 Mikkelsson J, Perola M, Wartiovaara U. et al. Plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism, coronary thrombosis, and myocardial infarction in middle-aged Finnish men who died suddenly. Thromb Haemost 2000; 84: 78-82.
35 Gardemann A, Lohre J, Katz N. et al. The 4G4G genotype of the plasminogen activator inhibitor 4G/5G gene polymorphism is associated with coronary atherosclerosis in patients at high risk for this disease. Thromb Haemost 1999; 82: 1121-6.
36 Stegnar M, Uhrin P, Peternel P. et al. The 4G/5G sequence polymorphism in the promoter of plasminogen activator inhibitor-1 (PAI-1) gene: relationship to plasma PAI-1 level in venous thromboembolism. Thromb Haemost 1998; 79: 975-9.