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Thromb Haemost 2000; 84(01): 27-31
DOI: 10.1055/s-0037-1613962
Commentary
Schattauer GmbH

Homocysteine as a Risk Factor for Restenosis after Coronary Angioplasty

Hiroyuki Morita
1   From the Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Japan
,
Hiroki Kurihara
1   From the Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Japan
,
Tomoyuki Kuwaki
2   Department of Physiology, Faculty of Medicine, Chiba University, Chiba, Japan
,
Chikuma Hamada
3   Department of Pharmacoepidemiology, Graduate School of Medicine, University of Tokyo, Japan
,
Masao Kitaoka
4   Sakakibara Heart Institute, Tokyo, Japan
,
Shin Suzuki
4   Sakakibara Heart Institute, Tokyo, Japan
,
Yoshio Yazaki
5   The Hospital International Medical Center of Japan, Tokyo, Japan
,
Ryozo Nagai
1   From the Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Japan
› Author AffiliationsThis work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan; the Japan Cardiovascular Research Foundation; TMFC; the Suzuken Memorial Foundation; the Ryoichi Naito Foundation for Medical Research; the Tokyo Biochemical Research Foundation; and the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to H. Kurihara); and by the Japan Heart Foundation; a Pfizer Pharmaceuticals Grant for Research on Coronary Artery Disease; a Research Grant of the Tokyo Hypertension Conference; and a Research Grant of Sankyo Foundation of Life Science (to H. Morita).
Further Information

Publication History

Received 03 November 1999

Accepted after resubmission 29 February 2000

Publication Date:
10 December 2017 (online)

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Summary

We examined the relationship between plasma homocysteine levels and restenosis after PTCA (Percutaneous transluminal coronary angioplasty) to investigate whether plasma homocysteine levels can be a predictor of restenosis after PTCA. One hundred and twelve male patients who have undergone a successful elective PTCA were consecutively enrolled and plasma homocysteine levels were measured at the time of follow-up angiography. Plasma homocysteine levels in patients with restenosis were significantly higher than those in patients without restenosis (15.0 ± 3.9 vs. 13 ± 2.9 µmol/L; P = 0.011). The difference was augmented when diabetic patients were selectively studied. The comparison between restenosis group and non-restenosis group indicated the threshold effect of hyperhomocysteinemia. These results suggest that plasma homocysteine is a potential risk factor of restenosis after PTCA, and therapeutic strategy targeted against hyperhomocysteinemia may be beneficial for preventing restenosis.

Keywords

Homocysteine - PTCA - restenosis - risk factor
 

  • References

  • 1 Serruys PW, Luijten HE, Beatt KJ, Geuskens R, de Feyter PJ, van den Brand M, Reiber JH, ten Katen HJ, van Es GA, Hugenholtz PG. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. Circulation 1988; 77: 361-71.
    CrossrefPubMedGoogle Scholar
  • 2 Faxon DP, Currier JW. Prevention of post-PTCA restenosis. Ann NY Acad Sci 1995; 748: 419-28.
    PubMedGoogle Scholar
  • 3 Currier JW, Faxon DP. Restenosis after percutaneous transluminal coronary angioplasty. Have we been aiming at the wrong target?. J Am Coll Cardiol 1995; 25: 516-20.
    CrossrefPubMedGoogle Scholar
  • 4 The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336: 1689-96.
    CrossrefPubMedGoogle Scholar
  • 5 Tardif JC, Cote G, Lesperance J, Bourassa M, Lambert J, Doucet S, Bilodeau L, Nattel S, de Guise P. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. Multivitamins and Probucol Study Group. N Engl J Med 1997; 337: 365-72.
    CrossrefPubMedGoogle Scholar
  • 6 Yokoi H, Daida H, Kuwabara Y, Nishikawa H, Takatsu F, Tomihara H, Nakata Y, Kutsumi Y, Ohshima S, Nishiyama S, Seki A, Kato K, Nishimura S, Kanoh T, Yamaguchi H. Effectiveness of an antioxidant in preventing restenosis after percutaneous transluminal coronary angioplasty: the Probucol Angioplasty Restenosis Trial. J Am Coll Cardiol 1997; 30: 855-62.
    CrossrefPubMedGoogle Scholar
  • 7 Tsuchikane E, Fukuhara A, Kobayashi T, Kirino M, Yamasaki K, Kobayashi T, Izumi M, Otsuji S, Tateyama H, Sakurai M, Awata N. Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty. Circulation 1999; 100: 21-6.
    CrossrefPubMedGoogle Scholar
  • 8 Kanzaki H, Miyazaki S, Noguchi T, Yasuda S, Sumida H, Daikoku S, Morii I, Itoh A, Goto Y, Nonogi H. Influence of calcium antagonists on long-term survival of patients treated with coronary angioplasty. Jpn Heart J 1999; 40: 11-21.
    CrossrefPubMedGoogle Scholar
  • 9 Mudd SH, Levy HL, Skovby F. Disorders of transulfuration. In: Scriver C, Beandet AL, Sly WS, Valle D. The metabolic basis of inherited disease. 6th ed.. Vol. 1. New York: McGraw-Hill; 1989: 693-734.
    Google Scholar
  • 10 Malinow MR, Kang SS, Taylor LM, Wong PWK, Coull B, Inahara T, Mukerjee D, Sexton G, Upson B. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation 1989; 79: 1180-8.
    CrossrefPubMedGoogle Scholar
  • 11 Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324: 1149-55.
    CrossrefPubMedGoogle Scholar
  • 12 Selhub J, Jacques PF, Bostom AG, D’Agostino RB, Wilson PW, Belanger AJ, O’Leary DH, Wolf PA, Schaefer EJ, Rosenberg IH. Association between plasma homocysteine concentrations and extracranial carotidartery stenosis. N Engl J Med 1995; 332: 286-91.
    CrossrefPubMedGoogle Scholar
  • 13 den Heijer M, Koster T, Blom HJ, Bos GMJ, Briet E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759-62.
    CrossrefPubMedGoogle Scholar
  • 14 Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992; 268: 877-81.
    CrossrefPubMedGoogle Scholar
  • 15 Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GH, Bromberg IL, Cerone R, Fowler B, Grobe H, Schmidt H, Schweitzer L. The natural history of homocystinuria due to cystathionine f3-synthase deficiency. Am J Hum Genet 1985; 37: 1-31.
    PubMedGoogle Scholar
  • 16 Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995; 346: 1395-8.
    CrossrefPubMedGoogle Scholar
  • 17 Coull BM, Malinow MR, Beamer N, Sexton G, Nordt F, de Garmo P. Elevated plasma homocyst(e)ine concentration as a possible independent risk factor for stroke. Stroke 1990; 21: 572-6.
    CrossrefPubMedGoogle Scholar
  • 18 Morita H, Taguchi J, Kurihara H, Kitaoka M, Kaneda H, Kurihara Y, Maemura K, Shindo T, Minamino T, Ohno M, Yamaoki K, Ogasawara K, Aizawa T, Suzuki S, Yazaki Y. Genetic polymorphism of 5, 10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation 1997; 95: 2032-6.
    CrossrefPubMedGoogle Scholar
  • 19 Morita H, Kurihara H, Tsubaki S, Sugiyama T, Hamada C, Kurihara Y, Shindo T, Oh-hashi Y, Kitamura K, Yazaki Y. Methylenetetrahydrofolate reductase gene polymorphism and ischemic stroke in Japanese. Arterioscler Thromb Vasc Biol 1998; 18: 1465-9.
    CrossrefPubMedGoogle Scholar
  • 20 Morita H, Kurihara H, Taguchi J, Ohno M, Yazaki Y. ACE and MTHFR gene polymorphisms: genetic coronary risk factors relating to different aspects of pathophysiology. Thromb Haemost 1998; 80: 200-1.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Morita H, Kurihara H, Sugiyama T, Hamada C, Kurihara Y, Shindo T, Oh-hashi Y, Yazaki Y. Polymorphism of the methionine synthase gene: association with homocysteine metabolism and late-onset vascular diseases in the Japanese population. Arterioscler Thromb Vasc Biol 1999; 19: 298-302.
    CrossrefPubMedGoogle Scholar
  • 22 Kluijtmans LA, van den Heuvel LP, Boers GH, Frosst P, Stevens EM, van Oost BA, den Heijer M, Trijbels FJ, Rozen R, Blom HJ. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996; 58: 35-41.
    PubMedGoogle Scholar
  • 23 Gallagher PM, Meleady R, Shields DC, Tan KS, McMaster D, Rozen R, Evans A, Graham IM, Whitehead AS. Homocysteine and risk of premature coronary heart disease: Evidence for a common gene mutation. Circulation 1996; 94: 2154-8.
    CrossrefPubMedGoogle Scholar
  • 24 Kluijtmans LA, Kastelein JJ, Lindemans J, Boers GH, Heil SG, Bruschke VG, Jukema JW, van den Heuvel LP, Trijbels FJ, Boerma GJ, Verheugt FW, Willems F, Blom HJ. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation 1997; 96: 2573-7.
    CrossrefPubMedGoogle Scholar
  • 25 Harmon DL, Doyle RM, Meleady R, Doyle M, Shields DC, Barry R, Coakley D, Graham IM, Whitehead AS. Genetic analysis of the thermolabile variant of 5, 10-methylenetetrahydrofolate reductase as a risk factor for ischemic stroke. Arterioscler Thromb Vasc Biol 1999; 19: 208-11.
    CrossrefPubMedGoogle Scholar
  • 26 Wall RT, Harlan JM, Harker LA, Striker GE. Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res 1980; 18: 113-21.
    CrossrefPubMedGoogle Scholar
  • 27 Starkebaum G, Harlan JM. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 1986; 77: 1370-6.
    CrossrefPubMedGoogle Scholar
  • 28 Dudman NP, Hicks C, Lynch JF, Wilcken DE, Wang J. Homocysteine thiolactone disposal by human arterial endothelial cells and serum in vitro. Arterioscler Thromb 1991; 11: 663-70.
    CrossrefPubMedGoogle Scholar
  • 29 Tsai J-C, Perrella MA, Yoshizumi M, Hsieh CM, Haber E, Schlegel R, Lee ME. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci USA 1994; 91: 6369-73.
    CrossrefPubMedGoogle Scholar
  • 30 Tsai J-C, Wang H, Perrella MA, Yoshizumi M, Sibinga ES, Tan LC, Haber E, Chang TH-T, Schlegel R, Lee ME. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells. J Clin Invest 1996; 97: 146-53.
    CrossrefPubMedGoogle Scholar
  • 31 Wang H, Yoshizumi M, Lai K, Tsai JC, Perrella MA, Haber E, Lee ME. Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine. J Biol Chem 1997; 272: 25380-5.
    CrossrefPubMedGoogle Scholar
  • 32 Rodgers GM, Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 1986; 77: 1909-16.
    CrossrefPubMedGoogle Scholar
  • 33 Lentz SR, Sadler JE. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 1991; 88: 1906-14.
    CrossrefPubMedGoogle Scholar
  • 34 Rodgers GM, Conn MT. Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood 1990; 75: 895-901.
    PubMedGoogle Scholar
  • 35 Hajjar KA. Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 1993; 91: 2873-9.
    CrossrefPubMedGoogle Scholar
  • 36 Nishinaga M, Ozawa T, Shimada K. Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells. J Clin Invest 1993; 92: 1381-6.
    CrossrefPubMedGoogle Scholar
  • 37 Ryan TJ, Faxon DP, Gunnar RM, Kennedy JW, King III SB, Loop FD, Peterson KL, Reeves TJ, Williams DO, Winters Jr WL. Guidelines for percutaneous transluminal coronary angioplasty. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Percutaneous Transluminal Coronary Angioplasty). Circulation 1988; 78: 486-502.
    CrossrefPubMedGoogle Scholar
  • 38 Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1987; 422: 43-52.
    CrossrefPubMedGoogle Scholar
  • 39 SAS Institute, Inc. SAS/STAT User’s Guide, Version 6. 4th ed.. Vol 2. SAS Institute Inc; 1990
    Google Scholar
  • 40 Araki A, Sako Y, Ito H. Plasma homocysteine concentrations in Japanese patients with non-insulin-dependent diabetes mellitus: effect of parenteral methylcobalamin treatment. Atherosclerosis 1993; 103: 149-57.
    CrossrefPubMedGoogle Scholar
  • 41 Hoogeveen EK, Kostense PJ, Beks PJ, Mackaay AJ, Jakobs C, Bouter LM, Heine RJ, Stehouwer CD. Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study. Arterioscler Thromb Vasc Biol 1998; 18: 133-8.
    CrossrefPubMedGoogle Scholar
  • 42 Harker LA, Ross R, Slichter SJ, Scott R. Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis. J Clin Invest 1976; 58: 731-41.
    CrossrefPubMedGoogle Scholar
  • 43 Steele PM, Chesebro JH, Stanson AW, Holmes Jr DR, Dewanjee MK, Badimon L, Fuster V. Balloon angioplasty. Natural history of the pathophysiological response to injury in a pig model. Circ Res 1985; 57: 105-12.
    CrossrefPubMedGoogle Scholar
  • 44 Voutilainen S, Morrow JD, Roberts II LJ, Alfthan G, Alho H, Nyyssonen K, Salonen JT. Enhanced in vivo lipid peroxidation at elevated plasma total homocysteine levels. Arterioscler Thromb Vasc Biol 1999; 19: 1263-6.
    CrossrefPubMedGoogle Scholar
  • 45 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-9.
    CrossrefPubMedGoogle Scholar
  • 46 Bittl JA. Advances in coronary angioplasty. N Engl J Med 1996; 335: 1290-302.
    CrossrefPubMedGoogle Scholar
  • 47 Azar AJ, Detre K, Goldberg S, Kiemeneij F, Leon MB, Serruys PW. A meta-analysis on the clinical and angiographic outcomes of stents vs. PTCA in the different coronary vessel sizes in the BENESTENT-1 ans STRESS-1/2 trials. Circulation. 1995 92. Suppl I: I-475 (abstract).
    PubMedGoogle Scholar