doi: 10.1161/CIRCULATIONAHA.105.573923
(Circulation. 2005;112:e307-e311.)
© 2005 American Heart Association, Inc.
Clinician Update |
Homocysteine and Its Effects on In-Stent Restenosis
From the Division of Cardiology, "Federico II" University, Naples, Italy (G.D.L., M.C.); the Division of Cardiology, San Luca Hospital, Vallo della Lucania, Italy (G.D.L., G.G.); the Division of Cardiology, Isala Klinieken, "De Weezenlanden" Hospital, Zwolle, The Netherlands (G.D.L., H.S.); and Kardiologische Praxis at Klinikum "Links der Weser," Heart Center Bremen, Bremen, Germany (H.L.).
Correspondence to Dr Giuseppe De Luca, Division of Cardiology "Federico II" University Via A. Pansini, 5 80131 Naples, Italy. E-mail p.de_luca{at}libero.it
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Introduction |
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 Top Introduction Underlying Cause of...Homocysteine and In-Stent...Summary and RecommendationsReferences |
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Despite the significant reduction in restenosis observed with the use of bare metal stents,1,2 results are still unsatisfactory for high-risk subsets of patients, such as those with diabetes, long lesions, small vessels, bifurcations, and restenotic lesions,3,4 with a restenosis rate up to 30% to 50%. Mounting interest emerged about hyperhomocystinemia as an independent risk factor for atherothrombotic disease,5–9 and several experimental studies have shown that it may affect in-stent restenosis.10–12
Homocysteine is an intermediary amino acid formed by the conversion of methionine to cysteine (Figure 1). Normal homocysteine plasma levels range between 5 and 15 µmol/L, and hyperhomocystinemia levels have been classified as moderate (15 to 30 µmol/L), intermediate (30 to 100 µmol/L), or severe (>100 µmol/L).13 However, normal basal homocysteine does not exclude an abnormality of this metabolic pathway. Such subtle abnormalities can potentially be uncovered by the use of methionine-load test.14
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Severe hyperhomocystinemia is a rare genetic disorder characterized by marked elevations in plasma and urine homocysteine concentrations that are associated with osteoporosis, ocular abnormalities, developmental delay, thromboembolic disease, and severe premature atherosclerosis. Less marked elevations in plasma homocysteine (15 to 30 µmol/L) are much more common, occurring in 5% to 7% of the population.14
An example of a patient with mild hyperhomocystinemia is a 50-year-old man who was hospitalized for non–ST-segment elevation myocardial infarction. There were no major risk factors for coronary artery disease. Angiography showed a long subocclusive stenosis (>50 mm) in the proximal-mid right coronary artery. The patient underwent stent implantation of the right coronary artery. After 5 months, he was rehospitalized for new-onset angina. Repeat angiography showed a significant in-stent restenosis. Homocysteine was screened and found mildly elevated (22.1 µg/dL). Two major questions might emerge from this clinical case: (1) Was restenosis due to mildly elevated homocysteine? (2) Would in-stent restenosis have been prevented by homocysteine-lowering therapy?
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Underlying Cause of Hyperhomocystinemia |
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TopIntroductionUnderlying Cause of...Homocysteine and In-Stent...Summary and RecommendationsReferences |
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Two major pathways may be identified in the metabolism of homocysteine: transsulfuration and remethylation (Figure 1), with the involvement of several vitamins. Elevations in the plasma homocysteine concentration (Table) are mostly due to conditions described as follow.
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1. Genetic Defects in the Metabolic Enzymes
A thermolabile variant of methylene tetrahydrofolate reductase (MTHFR) with reduced enzymatic activity (T mutation) is the most common form of genetic hyperhomocysteinemia.15 The responsible gene is relatively common in the population (estimated to be between 5% to 14%).16,17 Homozygosity for the thermolabile variant of MTHFR (TT genotype) is a common cause of mildly elevated plasma homocysteine levels in the general population.17,18
2. Nutritional Deficiencies in Vitamin Cofactors
Elevated homocysteine may be a consequence of deficiency of folate, vitamin B6, and/or vitamin B12.6 In fact, these vitamins are major determinants of the homocysteine concentration.
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Homocysteine and In-Stent Restenosis |
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TopIntroductionUnderlying Cause of...Homocysteine and In-Stent...Summary and RecommendationsReferences |
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Experimental Evidence
Histopathologic hallmarks of atherothrombosis related to elevated homocysteine levels include intimal thickening, elastic lamina disruption, smooth muscle hypertrophy, platelet accumulation, and the formation of platelet-enriched occlusive thrombi.11,19,20 Several studies have demonstrated the involvement of homocysteine in the process of in-stent restenosis. Three mechanisms have been proposed: (1) leukocyte recruitment by upregulation of monocyte chemoattractant protein-1 and interleukin-8 expression and secretion21; (2) increased smooth muscle cell proliferation and enhanced collagen production22; and (3) marked platelet accumulation due to either direct proaggregatory effects of homocysteine or an impairment in endothelium-mediated platelet inhibition.23
Clinical Evidence
Despite the potential involvement of hyperhomocystinemia in the restenotic process suggested by experimental studies,10–12,20–23 almost all available clinical trials have shown that hyperhomocystinemia is not associated with in-stent restenosis.24–29 One study was conducted by Kosokabe et al,24 who in 67 patients analyzed the impact of MTHFR genotypes and levels of homocysteine on in-stent restenosis evaluated by intravascular ultrasound. Even though neointimal hyperplasia was related to MTHFR genotypes, no relation to plasma homocysteine levels was observed. Several additional studies25–29 have investigated the relation between homocysteine, genotypes of MTHFR, vitamins (levels of B6, B12, and folate), and angiographic restenosis after stent implantation, confirming the absence of any relation between hyperhomocystinemia and restenosis.
Figure 2 shows the pooled data of larger trials (>100 patients) evaluating the relation between homocysteine and in-stent restenosis in patients undergoing planned angiographic follow-up.25,26,28,29 In a total of 1429 patients studied, 383 (26.8%) had hyperhomocystinemia (defined according to a threshold of 15 µmol/L) that was not associated with higher rates of in-stent restenosis (29.0% versus 29.5%; odds ratio 0.91, 95% confidence interval 0.70 to 1.18; P=0.47).
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Pharmacological Intervention
Vitamin administration (a combination of folic acid, vitamins B6, and B12) has been shown to reduce homocysteine levels.30 So far, only 2 randomized studies have investigated the impact of homocysteine-lowering therapy on restenosis after coronary angioplasty and stent implantation. Schnyder and colleagues31 compared placebo with a daily administration of folic acid (1.0 mg), vitamin B12 (400 µg), and vitamin B6 (10 mg) in 205 patients (56% of whom received stent implantation). They found that vitamin therapy was most beneficial in patients treated with balloon angioplasty and in those patients with small vessels, whereas a nonsignificant reduction in restenosis was observed in patients treated with stenting (20.6% versus 29.9%, P=0.32). In a larger study that enrolled 636 patients undergoing stent implantation, Lange and colleagues29 randomly assigned patients to placebo or folates. The folate treatment consisted of an intravenous bolus of folic acid (1.0 mg), vitamin B6 (5.0 mg), and vitamin B12 (1.0 mg) followed by daily oral administration of folic acid (1.2 mg), vitamin B6 (48.0 mg), and vitamin B12 (60 µg) for 6 months. They found a paradoxical harmful effect, with higher restenosis rates associated with folates (34.5% versus 26.5%, P=0.05), particularly in patients with homocysteine levels in the normal range (<15 µmol/L) (36.2% versus 25.3%, P=0.02), whereas slight benefits were observed in patients with elevated homocysteine (27.2% versus 31.7%, P=NS). The observed deleterious effects of homocysteine-lowering therapy after coronary stenting may be due to the fact that folate plays a crucial role in the synthesis of DNA and RNA through the formation of 1-carbon units that are needed for the synthesis of purine and pyrimidine.32 The administration of high doses of folate significantly promoted the growth of neointimal cells by providing larger amounts of biochemical precursors for cell duplication.33 Furthermore, by decreasing homocysteine, folate can improve the availability of methyl groups for DNA-methylation,34 which may favor endothelial growth.35
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Summary and Recommendations |
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TopIntroductionUnderlying Cause of...Homocysteine and In-Stent...Summary and RecommendationsReferences |
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Mild hyperhomocystinemia does not appear to be a major determinant of in-stent restenosis. It does appear, however, to be an independent risk factor for cerebrovascular, peripheral vascular, and coronary heart disease and for venous thromboembolic disease.5–9 Several randomized clinical trials are underway to address the effect of folate, vitamin B6, and vitamin B12 supplementation on cardiovascular disease. Until complete results of these studies become available, screening for hyperhomocystinemia in patients undergoing coronary stenting is only recommended in the case of premature atherosclerotic disease (patients <45 years of age), when there is a paucity of more conventional risk factors, and in patients with a history of unexplained venous thrombosis. However, it should be remembered that homocysteine-lowering therapy might have a deleterious effect in patients treated with stent implantation, with paradoxically more neointimal proliferation and in-stent restenosis, particularly in patients with a homocysteine level within the normal range. Additional studies are needed to investigate the impact of moderate to severe hyperhomocystinemia and vitamin therapy on restenosis in the era of drug-eluting stents.36 In fact, the vast majority of patients included in randomized trials had homocysteine levels that were within the normal range or were mildly elevated, whereas patients with moderate to severe hyperhomocystinemia might be at higher risk for restenosis and subacute thrombosis, particularly in case of delayed reendothelialization observed with drug-eluting stents.37,38 Until these data become available, vitamin therapy cannot be recommended.
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Acknowledgments |
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We are indebted to W. Koch, MD, M.N. Zairis, MD, and D. Genser, MD for their support in providing additional data.
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References |
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1. Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P. A comparison of balloon expandable stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med. 1994; 331: 489–495.
2. Suryapranata H, van’t Hof AW, Hoorntje JC, de Boer MJ, Zijlstra F. Randomized comparison of coronary stenting with balloon angioplasty in selected patients with acute myocardial infarction. Circulation. 1998; 97: 2502–2505.
3. Elezi S, Kastrati A, Pache J, Wehinger A, Hadamitzky M, Dirschinger J, Neumann FJ, Schomig A. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol. 1998; 32: 1866–1873.
4. Agostoni P, Biondi-Zoccai GG, Gasparini GL, Anselmi M, Morando G, Turri M, Abbate A, McFadden EP, Vassanelli C, Zardini P, Colombo A, Serruys PW. Is bare-metal stenting superior to balloon angioplasty for small vessel coronary artery disease? Evidence from a meta-analysis of randomized trials. Eur Heart J. 2005; 26: 881–889.
5. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002; 288: 2015–2022.
6. Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, Hennekens C, Stampfer MJ. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA. 1998; 279: 359–364.
7. Boers GH, Smals AG, Trijbels FJ, Fowler B, Bakkeren JA, Schoonderwaldt HC, Kleijer WJ, Kloppenborg PW. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med. 1985; 313: 709–715.[Abstract]
8. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG, MTHFR Studies Collaboration Group. MTHFR 677C–>T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002; 288: 2023–2031.
9. den Heijer M, Koster T, Blom HJ, Bos GM, Briet E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med. 1996; 334: 759–762.
10. Morita H, Kurihara H, Yoshida S, Saito Y, Shindo T, Oh-Hashi Y, Kurihara Y, Yazaki Y, Nagai R. Diet-induced hyperhomocysteinemia exacerbates neointima formation in rat carotid arteries after balloon injury. Circulation. 2001; 103: 133–139.
11. Tsai JC, 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 U S A. 1994; 91: 6369–6373.
12. Cook JW, Malinow MR, Moneta GL, Taylor LM, Orloff SL. Neointimal hyperplasia in balloon-injured rat carotid arteries: the influence of hyperhomocysteinemia. J Vasc Surg. 2002; 35: 158–165.[Medline] [Order article via Infotrieve]
13. Kang SS, Wong PW, Malinow MR. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr. 1992; 12: 279–298.[CrossRef][Medline] [Order article via Infotrieve]
14. van der Griend R, Haas FJ, Duran M, Biesma DH, Meuwissen OJ, Banga JD. Methionine loading test is necessary for detection of hyperhomocysteinemia. J Lab Clin Med. 1998; 132: 67–72.[CrossRef][Medline] [Order article via Infotrieve]
15. Ueland PM, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med. 1989; 114: 473–501.[Medline] [Order article via Infotrieve]
16. Kang SS, Wong PW, Susmano A, Sora J, Norusis M, Ruggie N. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet. 1991; 48: 536–545.[Medline] [Order article via Infotrieve]
17. Guttormsen AB, Ueland PM, Nesthus I, Nygard O, Schneede J, Vollset SE, Refsum H. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (
40 micromol/liter): the Hordaland Homocysteine Study. J Clin Invest. 1996; 98: 2174–2183.[Medline]
[Order article via Infotrieve]
18. Kluijtmans LA, Young IS, Boreham CA, Murray L, McMaster D, McNulty H, Strain JJ, McPartlin J, Scott JM, Whitehead AS. Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults. Blood. 2003; 101: 2483–2488.
19. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969; 56: 111–128.[Medline] [Order article via Infotrieve]
20. Harker LA, Ross R, Slichter SJ, Scott CR. Homocystine-induced arteriosclerosis: the role of endothelial cell injury and platelet response in its genesis. J Clin Invest. 1976; 58: 731–741.[Medline] [Order article via Infotrieve]
21. Poddar R, Sivasubramanian N, DiBello PM, Robinson K, Jacobsen DW. Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells: implications for vascular disease. Circulation. 2001; 103: 2717–2723.
22. Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease: enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol. 1997; 17: 2074–2081.
23. McCully KS, Carvalho AC. Homocysteine thiolactone, N-homocysteine thiolactonyl retinamide, and platelet aggregation. Res Commun Chem Pathol Pharmacol. 1987; 56: 349–360.[Medline] [Order article via Infotrieve]
24. Kosokabe T, Okumura K, Sone T, Kondo J, Tsuboi H, Mukawa H, Tomida T, Suzuki T, Kamiya H, Matsui H, Hayakawa T. Relation of a common methylenetetrahydrofolate reductase mutation and plasma homocysteine with intimal hyperplasia after coronary stenting. Circulation. 2001; 103: 2048–2054.
25. Koch W, Ndrepepa G, Mehilli J, Braun S, Burghartz M, Lengnick H, Kolling K, Schomig A, Kastrati A. Homocysteine status and polymorphisms of methylenetetrahydrofolate reductase are not associated with restenosis after stenting in coronary arteries. Arterioscler Thromb Vasc Biol. 2003; 23: 2229–2234.
26. Genser D, Prachar H, Hauer R, Halbmayer WM, Mlczoch J, Elmadfa I. Relation of homocysteine, vitamin B(12), and folate to coronary in-stent restenosis. Am J Cardiol. 2002; 89: 495–499.[CrossRef][Medline] [Order article via Infotrieve]
27. Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Association of plasma homocysteine with restenosis after percutaneous coronary angioplasty. Eur Heart J. 2002; 23: 726–733.
28. Zairis MN, Ambrose JA, Manousakis SJ, Stefanidis AS, Papadaki OA, Bilianou HI, DeVoe MC, Fakiolas CN, Pissimissis EG, Olympios CD, Foussas SG, Global Evaluation of New Events and Restenosis After Stent Implantation Study Group. The impact of plasma levels of C-reactive protein, lipoprotein (a) and homocysteine on the long-term prognosis after successful coronary stenting: the Global Evaluation of New Events and Restenosis After Stent Implantation Study. J Am Coll Cardiol. 2002; 40: 1375–1382.
29. Lange H, Suryapranata H, De Luca G, Borner C, Dille J, Kallmayer K, Pasalary MN, Scherer E, Dambrink JH. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med. 2004; 350: 2673–2681.
30. Verhaar MC, Wever RM, Kastelein JJ, van Loon D, Milstien S, Koomans HA, Rabelink TJ. Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia: a randomized placebo-controlled trial. Circulation. 1999; 100: 335–338.
31. Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, Meier B, Turi ZG, Hess OM. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med. 2001; 345: 1593–1600.
32. Scott J, Weir D. The methyl folate trap: a physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anemia. Lancet. 1981; 2: 337–340.[Medline] [Order article via Infotrieve]
33. Glynn S, Albanes D. Folate and cancer: a review of the literature. Nutr Cancer. 1994; 22: 103–119.
34. Ingrosso D, Cimmino A, Perna AF, Masella L, De Santo NG, De Bonis ML, Vacca M, D’Esposito M, D’Urso M, Galletti P, Zappia V. Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet. 2003; 36: 1693–1699.
35. 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: 25380–25385.
36. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME, TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med. 2004; 350: 221–231.
37. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005; 293: 2126–2130.
38. McFadden EP, Stabile E, Regar E, Cheneau E, Ong AT, Kinnaird T, Suddath WO, Weissman NJ, Torguson R, Kent KM, Pichard AD, Satler LF, Waksman R, Serruys PW. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet. 2004; 364: 1519–1521.[CrossRef][Medline] [Order article via Infotrieve]
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