Homocysteine and Its Effects on In-Stent Restenosis
2005; Lippincott Williams & Wilkins; Volume: 112; Issue: 19 Linguagem: Inglês
10.1161/circulationaha.105.573923
ISSN1524-4539
AutoresGiuseppe De Luca, Harry Suryapranata, G. De Gregorio, Helmut W. Lange, Massimo Chiariello,
Tópico(s)Cardiac Valve Diseases and Treatments
ResumoHomeCirculationVol. 112, No. 19Homocysteine and Its Effects on In-Stent Restenosis Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBHomocysteine and Its Effects on In-Stent Restenosis Giuseppe De Luca, MD, PhD, Harry Suryapranata, MD, PhD, Giovanni Gregorio, MD, Helmut Lange, MD, PhD and Massimo Chiariello, MD, PhD Giuseppe De LucaGiuseppe De Luca 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.). , Harry SuryapranataHarry Suryapranata 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.). , Giovanni GregorioGiovanni Gregorio 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.). , Helmut LangeHelmut Lange 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.). and Massimo ChiarielloMassimo Chiariello 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.). Originally published8 Nov 2005https://doi.org/10.1161/CIRCULATIONAHA.105.573923Circulation. 2005;112:e307–e311Despite 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.10–12Homocysteine 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.14Download figureDownload PowerPointFigure 1. Graph shows vitamin coenzymes and substrates involved in homocysteine metabolism. THF indicates tetrahydrofolate; VIT B2, riboflavin; VIT B6, vitamin B6; VIT B12, methyl cobalamin; DMG, dimethylglycine; MS, methionine synthase; MTHFR, methylene tetrahydrofolate reductase; CS, cystathionine-beta synthase; CL, cystathionine-gamma-lyase; and BHMT, betaine homocysteine methyl transferase.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.14An 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?Underlying Cause of HyperhomocystinemiaTwo 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. Causes of HyperhomocystinemiaGenetic defects (methylenetetrahydrofolate reductase)Deficiency of folic acid, vitamin B12, or vitamin B6HypothyroidismPsoriasisSystemic lupus erythematosusRenal failureHyperproliferative disordersLate-stage diabetesMedications (methotrexate, trimethoprim, anticonvulsant inducers, cholestyramine, nitrous oxide, niacin, theophilline, L-DOPA, androgens, aminoglutethimide, cyclosporine A, fibrates, diuretics).1. Genetic Defects in the Metabolic EnzymesA 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.17,182. Nutritional Deficiencies in Vitamin CofactorsElevated 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.Homocysteine and In-Stent RestenosisExperimental EvidenceHistopathologic 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.23Clinical EvidenceDespite 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). Download figureDownload PowerPointFigure 2. Pooled data of clinical trials evaluating the relation between homocysteine and in-stent restenosis (odds ratios and 95% confidence intervals). The size of the data markers (squares) is approximately proportional to the sample size. *Defined as basal homocysteine ≥15 μmol/L.Pharmacological InterventionVitamin 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.35Summary and RecommendationsMild 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 T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002; 288: 2023–2031.CrossrefMedlineGoogle Scholar9 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.CrossrefMedlineGoogle Scholar10 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.CrossrefMedlineGoogle Scholar11 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.CrossrefMedlineGoogle Scholar12 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.MedlineGoogle Scholar13 Kang SS, Wong PW, Malinow MR. Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr. 1992; 12: 279–298.CrossrefMedlineGoogle Scholar14 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.CrossrefMedlineGoogle Scholar15 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.MedlineGoogle Scholar16 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.MedlineGoogle Scholar17 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.CrossrefMedlineGoogle Scholar18 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.CrossrefMedlineGoogle Scholar19 McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969; 56: 111–128.MedlineGoogle Scholar20 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.CrossrefMedlineGoogle Scholar21 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.CrossrefMedlineGoogle Scholar22 Majors A, Ehrhart LA, Pezacka EH. Homocysteine as a risk factor for vascular disease: enhanced collagen production and accumulation by smooth muscle cells. 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Relation of homocysteine, vitamin B(12), and folate to coronary in-stent restenosis. Am J Cardiol. 2002; 89: 495–499.CrossrefMedlineGoogle Scholar27 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.CrossrefMedlineGoogle Scholar28 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.CrossrefMedlineGoogle Scholar29 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.CrossrefMedlineGoogle Scholar30 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.CrossrefMedlineGoogle Scholar31 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.CrossrefMedlineGoogle Scholar32 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.MedlineGoogle Scholar33 Glynn S, Albanes D. 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Lancet. 2004; 364: 1519–1521.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Nardin M, Verdoia M, Gioscia R, Negro F and De Luca G (2021) Impact of renin angiotensin system inhibitors on homocysteine levels and platelets reactivity in patients on dual antiplatelet therapy, Nutrition, Metabolism and Cardiovascular Diseases, 10.1016/j.numecd.2020.12.004, 31:4, (1276-1285), Online publication date: 1-Apr-2021. Barbieri L, Verdoia M, Schaffer A, Niccoli G, Perrone-Filardi P, Bellomo G, Marino P, Suryapranata H and Luca G (2014) Elevated Homocysteine and the Risk of Contrast-Induced Nephropathy, Angiology, 10.1177/0003319714533401, 66:4, (333-338), Online publication date: 1-Apr-2015. de Franciscis S, De Sarro G, Longo P, Buffone G, Molinari V, Stillitano D, Gallelli L and Serra R (2013) Hyperhomocysteinaemia and chronic venous ulcers, International Wound Journal, 10.1111/iwj.12042, 12:1, (22-26), Online publication date: 1-Feb-2015. 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Guo J, Gao Y, Ahmed M, Dong P, Gao Y, Gong Z, Liu J, Mao Y, Yue Z, Zheng Q, Li J, Rong J, Zhou Y, An M, Gu L and Zhang J (2022) Serum Homocysteine Level Predictive Capability for Severity of Restenosis Post Percutaneous Coronary Intervention, Frontiers in Pharmacology, 10.3389/fphar.2022.816059, 13 November 8, 2005Vol 112, Issue 19 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.105.573923PMID: 16275872 Originally publishedNovember 8, 2005 PDF download Advertisement SubjectsCatheter-Based Coronary and Valvular InterventionsChronic Ischemic Heart Disease
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