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Thursday, January 5, 2017

PART II HOMOCISTEYNEANEMIA TREATMENT

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'via Blog this'The use of vitamin therapy for the primary prevention of cognitive decline has produced conflicting results. In the Folic Acid and Carotid Intima-Media Thickness (FACIT) study, a double blinded, randomized placebo-controlled trial from the Netherlands suggested that in healthy individuals between 50-70 years old with homocysteine concentrations of 11–14 μmol/L, daily supplementation with 800 μg of folic acid improved memory, information processing speed, and sensorimotor speed as compared to placebo (75); however, a similarly designed trial by McMahon and colleagues (20) drew different conclusions. In this study, 276 healthy subjects >65 years old with plasma homocysteine levels >13 μmol/L received placebo or daily vitamin therapy with folate (1000 μg), vitamin B12 (500 μg) and B6 (10 mg). No improvement in cognitive function was detected over a 2 year period, despite a 26% (4.4 μmol/L) decrease in homocysteine levels after vitamin therapy. There are several possible reasons to explain the failure of homocysteine level reduction to improve cognitive function or decrease progression of AD. First, decreasing circulating homocysteine levels addresses only one of several pro-inflammatory mechanisms identified to promote oxidant stress and decrease the threshold for neurotoxicity. Second, randomized clinical trials in this arena have included patients with only mildly elevated homocysteine levels. The role of homocysteine reduction in patients with more robustly elevated homocysteine levels for both primary prevention and therapeutic treatment of dementia has not yet been conducted. Finally, elevated homocysteine levels may be a marker of other processes more closely associated with the neurotoxicity of dementia. For example, the transulfuration pathway facilitates metabolism of homocysteine to the antioxidant glutathione. An abnormally reciprocal relationship between homocysteine and glutathione has been observed in neurodegenerative diseases, raising the possibility that increased homocysteine levels in dementia reflect impaired transulfuration, and are in actuality a surrogate for decreased cellular concentrations of neuroprotective antioxidants (76). Homocysteine and hip fractures Hip fractures are a major cause of morbidity and mortality in elderly patients, and account for a substantial portion of annual health care-related costs in the U.S. (77). Spondylo-epimetaphyseal dysplasia, characterized by accelerated skeletal growth, osteopenia, and elongation of the appendicular skeleton (78), is a clinical feature of homocystinuria. Homocysteine-induced collagen-crosslinking dysregulation and Type I collagen fibril enlargement have been suggested as possible mechanisms to explain the pathogenesis of bone disease in patients with homocystinuria (79). Several prospective, observational studies have established that hyperhomocysteinemia is an independent risk factor for osteoporotic fractures in elderly men and women. For example, data from the Rotterdam study demonstrated an association between circulating homocysteine levels and the risk of incident osteoporotic fracture in 2,406 subjects > 55 years of age (RR=1.4 per 1 SD increase in the natural-log–transformed homocysteine level, 95 % CI, 1.2 to 1.6) (80). Furthermore, data from the Framingham Heart Study cohort suggest that, compared to individuals with normal or low-normal homocysteine levels, moderate elevations in homocysteine (>20 μmol/L for men and >18 μmol/L for woman) confer a sizeable risk increase for bone fracture (4.1-fold men, 1.9 fold for women) (81). The effect of vitamin therapy on decreasing hip fracture rates in patients with moderately elevated homocysteine concentrations was tested in a randomized controlled trial of 628 post-stroke, osteoporitc patients in Japan (mean=19.9 μmol/L) (21). Post-stroke patients were selected because hemiplegia significantly increases the incidence of bone fractures in the affected limb. Therapy with 5 mg of folate and 1,500 μg of methylcobalamin resulted in an absolute risk reduction for fracture of 7.1% (95% CI, 3.6%-10.8%), with a number needed to treat to prevent one fracture was 14 (95% CI, 9-28). The 4.5% fracture rate observed in the placebo group, however, is several fold higher than the predicted fracture rate in an age- and sex- cohort of normal controls, which has led some to argue against the application of these findings to routine clinical practice. The benefit of vitamin therapy for fracture risk has not been reproduced in mildly hyperhomocysteinemic individuals (<15 μmol/L) without a stroke history (82). In addition, vitamin therapy does not appear to influence measures of bone turnover in healthy, elderly individuals, although its effect in hyperhomocysteinemics is unknown (83). Thus, at this time, vitamin therapy may be useful for the prevention of fractures in certain high risk patients, but there are insufficient data to support its use in primary prevention of fractures in elderly individuals with mildly elevated homocysteine levels. Go to: CONCLUSIONS Data from randomized clinical trials have been unable to translate convincingly homocysteine lowering into improved clinical outcome for the secondary prevention of cardiovascular disease or in the prevention or treatment of dementia-type disorders. Vitamin therapy may decrease the risk of osteoporosis-induced bone fracture in selected, high risk patients. Thus, although the efficacy of combined folic acid, B6-, and B12-vitamin supplementation in decreasing circulating homocysteine levels is not in dispute, identification of patients who are most likely to benefit from this treatment is a subject of continued investigation. Most randomized intervention trials published to date have studied groups with only mildly elevated homocysteine levels, thus targeting clinical entities for which the attributable risk of homocysteine is unknown or is likely small compared to other factors. Importantly, the role of vitamin therapy has not been tested in key patient groups for which it may prove useful, such as in the primary prevention of coronary artery disease, or in the prevention of other, homocysteine-associated disease in patients with moderately or severely elevated homocysteine levels. Go to: SUMMARY POINTS Epidemiologic reports have established that elevated levels of homocysteine are an independent risk factor for atherothrombotic cardiovascular disease, stroke, cognitive impairment, and osteoporosis-induced bone fracture. Oxidation of homocysteine promotes reactive oxygen species formation that may impair vascular function via decreased bioavailable nitric oxide levels, depletion of nitric oxide synthase cofactors, or impairment of normal antioxidant enzyme function. Homocysteine overexcitation of N-methyl-d-aspartate receptors in the central nervous system may promote reactive oxygen species formation to induce synaptic failure in brain tissue. Randomized clinical trials have shown that oral supplementation with the combination of folic acid, B6-, and B12-vitmains substantially lowers circulating homocysteine levels, but does not appear to improve outcome in the secondary prevention of cardiovascular disease or dementia. Combination vitamin therapy may a have a role in preventing osteoporosis-induced bone fractures in selected, high risk patients. The diverse biologic effects of folic acid include indirectly increasing asymmetrical dimethylarginine (ADMA) levels, a molecule associated with impaired vascular function. Go to: FUTURE ISSUES Can a clinically salient proatherogenic homocysteine concentration threshold be identified for improved targeting of individuals who may benefit from combination B-vitamin therapy? Are derivative species of homocysteine oxidation, such as thiolactone, superior to total homocysteine as a measure of cardiovascular risk? Does homocysteine level lowering have a role in decreasing vascular event rates or delaying hemodialysis in patients with mild to intermediately decreased creatinine clearance? Go to: ACKNOWLEDGEMENTS We gratefully acknowledge Ms. Stephanie Tribuna for assistance in the preparation of this manuscript. Disclaimer: The project described was supported by Award Numbers: HL 61795, HL 58976, N01 HV 28178, and P01 HL 81587 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Go to: LITERATURE CITED 1. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. J. Am. Med. Assoc. 1995;74:1049–57. [PubMed] 2. Homocysteine Studies Collaboration Homocysteine and risk of ischemic heart disease and stroke; a meta-analysis. J. Am. Med. Assoc. 2002;288:2015–22. [PubMed] 3. Handy DE, Zhang Y, Loscalzo J. Homocysteine down-regulates cellular glutathione peroxidase (GPx1) by decreasing translation. J. Biol. Chem. 2005;280:15518–25. [PubMed] 4. Zhou J, Werstuck GH, Lhoták S, de Koning AB, Sood SK, et al. Association of multiple cellular stress pathways with accelerated atherosclerosis in hyperhomocysteinemic apolipoprotein E-deficient mice. Circulation. 2004;110:207–13. [PubMed] 5. Eberhardt RT, Forgione MA, Cap A, Leopold JA, Rudd MA, et al. Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J. Clin. Invest. 2000;106:483–491. [PMC free article] [PubMed] 6. Loscalzo J. Homocysteine and dementias. N. Engl. J. Med. 2002;346:466–8. [PubMed] 7. Seshardi S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N. Engl. J. Med. 2002;346:476–83. [PubMed] 8. McCully KS. Homocysteine, vitamins, and vascular disease prevention. Am. J. Clin. Nutr. 2007;86:1563S–8S. [PubMed] 9. Brazionis L, Rowley K, Sr, Itsiopoulos C, Harper CA, O'Dea K. Homocysteine and diabetic retinopathy. Diab. Care. 2008;31:50–6. [PubMed] 10. Agulló-Ortuño MT, Albaladejo MD, Parra S, Rodríguez-Manotas M, Fenollar M, et al. Plasmatic homocysteine concentration and its relationship with complications associated to diabetes mellitus. Clin. Chim. Acta. 2002;326:105–12. [PubMed] 11. Herrmann W, Herrmann M, Joseph J, Tyagi SC. The role of hyperhomocysteinemia as well as folate, vitamin B(6) and B(12) deficiencies in osteoporosis: a systematic review. Clin. Chem. Lab. Med. 2007;45:1621–32. [PubMed] 12. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N. Engl. J. Med. 1999;340:1449–54. [PubMed] 13. MRC Vitamin Study Research Group Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131–7. [PubMed] 14. Refsum H, Ueland PM, Nygård O, Vollset SE. Homocysteine and cardiovascular disease. Annu. Rev. Med. 1998;49:31–62. [PubMed] 15. Graham IM, Daly LE, Refsum HM, Robinson K, Brattström LE, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. J. Am. Med. Assoc. 1997;277:1775–81. [PubMed] 16. Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N. Eng. J. Med. 1997;337:23–36. [PubMed] 17. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N. Engl. J. Med. 2006;355:2631–9. [PubMed] 18. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br. Med. J. 2002;325:1202–9. [PMC free article] [PubMed] 19. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, et al. Lowering Homocysteine in Patients With Ischemic Stroke to Prevent Recurrent Stroke, Myocardial Infarction, and Death: The Vitamin Intervention for Stroke Prevention (VISP) Randomized Controlled Trial. J. Am. Med. Assoc. 2004;291:565–75. [PubMed] 20. McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, et al. A controlled trial of homocysteine lowering and cognitive performance. N. Engl. J. Med. 2006;354:2764–72. [PubMed] 21. Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. J. Am. Med. Assoc. 2005;293:1082–8. [PubMed] 22. Maron BA, Loscalzo J. Should hyperhomocysteinemia be treated in patients with atherosclerotic disease? Curr. Atheroscler. Rep. 2007;9:375–83. [PubMed] 23. Weiss N, Keller C, Hoffmann U, Loscalzo J. Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia. Vasc. Med. 2003;7:227–239. [PubMed] 24. Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J. Clin. Invest. 1996;98:5–7. [PMC free article] [PubMed] 25. Lubos E, Loscalzo J, Handy DE. Homocysteine and glutathione peroxidase-1. Antioxid Redox Signal. 2007;9:1923–40. [PubMed] 26. Rounds S, Yee WL, Dawicki DD, Harrington E, Parks N. Mechanism of extracellular ATP- and adenosine-induced apoptosis of cultured pulmonary artery endothelial cells. Am. J. Physiol. 1998;275:L379–388. [PubMed] 27. Welch GN, Upchurch GR, Jr, Farivar RS, Pigazzi A, Vu K, et al. Homocysteine-induced nitric oxide production in vascular-smooth muscle cells by NF-kB-dependent transcriptional activation of Nos2. Proc. Assoc. Am. Physiol. 1998;110:22–31. [PubMed] 28. Finkelstein JD. Methionine metabolism in mammals. J. Nutr. Biochem. 1990;1:228–237. [PubMed] 29. Qi Z, Hoffman G, Kurtycz D, Yu J. Prevalence of the C677T substitution of the methylenetetrahydrofolate reductase (MTHFR) gene in Wisconsin. Genet. Med. 2003;5:458–9. [PubMed] 30. Malinow R, Bostom AG, Krauss RM. Homocyst(e)ine, Diet, and Cardiovascular Diseases:A Statement for Healthcare Professionals From the Nutrition Committee, American Heart Association. Circulation. 1999;99:178–82. [PubMed] 31. Kolling K, Ndrepepa G, Koch W, Braun S, Mehilli J, et al. Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms, plasma homocysteine, folate, and vitamin B12 levels and the extent of coronary artery disease. Am. J. Cardiol. 2004;93:1201–06. [PubMed] 32. Garovic-Kocic V, Rosenblatt DS. Methionine auxotrophy in inborn errors of cobalamin metabolism. Clin. Invest. Med. 1995;15:395–400. [PubMed] 33. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N. Engl. J. Med. 1998;338:1042–50. [PubMed] 34. Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle DL, editors. The metabolic and molecular bases of inherited disease. 1. Vol. 7. McGraw-Hill; New York: 1995. pp. 1279–327. 35. Mandel H, Brenner B, Berant M, Rosenberg N, Lanir N, et al. Coexistence of hereditary homocystinuria and factor V Leiden--effect on thrombosis. N. Engl. J. Med. 1996;334:763–8. [PubMed] 36. McCully KS. Vascular pathology of homocysteine-emia: implications for the pathogenesis of arteriosclerosis. Am. J. Pathol. 1969;56:111–28. [PMC free article] [PubMed] 37. Hiltunen MO, Yia-herttuala S. DNA methylation, smooth muscle cells, and atherogenesis. Arterioscler. Thromb. Vasc. Biol. 2003;23:1750–53. [PubMed] 38. Babior BM, Bunn FH. Meagaloblastic anemias. In: Kasper D, Braunwald E, Fauci A, Hauser S, Longo D, Jameson L, editors. Harrison's Principles of Internal Medicine. 16th edition McGraw-Hill; New York: 2005. pp. 601–7. 39. Kim YI. Folic acid fortification and supplementation--good for some but not so good for others. Nutr. Rev. 2007;65:504–11. [PubMed] 40. Andrès E, Affenberger S, Vinzio S, Kurtz JE, Noel E, et al. Food-cobalamin malabsorption in elderly patients: clinical manifestations and treatment. Am. J. Med. 2005;118:1154–9. [PubMed] 41. Lindenbaum J, Rosenberg IH, Wilson PWF, Stabler S, Allen RH. Prevalence of cobalamin deficiency in the Framingham elderly population. Am. J. Clin. Nutr. 1994;60:2–11. [PubMed] 42. Shane B, Stokstad EL. Vitamin B12-folate interrelationships. Annu. Rev. Nutr. 1985;5:115–41. [PubMed] 43. Cravo ML, Glória LM, Selhub J, Nadeau MR, Camilo ME, et al. Hyperhomocysteinemia in chronic alcoholism: correlation with folate, vitamin B12, and vitamin B6 status. Am. J. Clin. Nutr. 1996;63:220–4. [PubMed] 44. Cravo ML, Camilo ME. Hyperhomocysteinemia in chronic alcoholism: relations to folic acid and vitamins B(6) and B(12) status. Nutrition. 2000;16:296–302. [PubMed] 45. Hron G, Lombardi R, Eichinger S, Lecchi A, Kyrle PA, et al. Low vitamin B --------- The use of vitamin therapy for the primary prevention of cognitive decline has produced conflicting results. In the Folic Acid and Carotid Intima-Media Thickness (FACIT) study, a double blinded, randomized placebo-controlled trial from the Netherlands suggested that in healthy individuals between 50-70 years old with homocysteine concentrations of 11–14 μmol/L, daily supplementation with 800 μg of folic acid improved memory, information processing speed, and sensorimotor speed as compared to placebo (75); however, a similarly designed trial by McMahon and colleagues (20) drew different conclusions. In this study, 276 healthy subjects >65 years old with plasma homocysteine levels >13 μmol/L received placebo or daily vitamin therapy with folate (1000 μg), vitamin B12 (500 μg) and B6 (10 mg). No improvement in cognitive function was detected over a 2 year period, despite a 26% (4.4 μmol/L) decrease in homocysteine levels after vitamin therapy. There are several possible reasons to explain the failure of homocysteine level reduction to improve cognitive function or decrease progression of AD. First, decreasing circulating homocysteine levels addresses only one of several pro-inflammatory mechanisms identified to promote oxidant stress and decrease the threshold for neurotoxicity. Second, randomized clinical trials in this arena have included patients with only mildly elevated homocysteine levels. The role of homocysteine reduction in patients with more robustly elevated homocysteine levels for both primary prevention and therapeutic treatment of dementia has not yet been conducted. Finally, elevated homocysteine levels may be a marker of other processes more closely associated with the neurotoxicity of dementia. For example, the transulfuration pathway facilitates metabolism of homocysteine to the antioxidant glutathione. An abnormally reciprocal relationship between homocysteine and glutathione has been observed in neurodegenerative diseases, raising the possibility that increased homocysteine levels in dementia reflect impaired transulfuration, and are in actuality a surrogate for decreased cellular concentrations of neuroprotective antioxidants (76). Homocysteine and hip fractures Hip fractures are a major cause of morbidity and mortality in elderly patients, and account for a substantial portion of annual health care-related costs in the U.S. (77). Spondylo-epimetaphyseal dysplasia, characterized by accelerated skeletal growth, osteopenia, and elongation of the appendicular skeleton (78), is a clinical feature of homocystinuria. Homocysteine-induced collagen-crosslinking dysregulation and Type I collagen fibril enlargement have been suggested as possible mechanisms to explain the pathogenesis of bone disease in patients with homocystinuria (79). Several prospective, observational studies have established that hyperhomocysteinemia is an independent risk factor for osteoporotic fractures in elderly men and women. For example, data from the Rotterdam study demonstrated an association between circulating homocysteine levels and the risk of incident osteoporotic fracture in 2,406 subjects > 55 years of age (RR=1.4 per 1 SD increase in the natural-log–transformed homocysteine level, 95 % CI, 1.2 to 1.6) (80). Furthermore, data from the Framingham Heart Study cohort suggest that, compared to individuals with normal or low-normal homocysteine levels, moderate elevations in homocysteine (>20 μmol/L for men and >18 μmol/L for woman) confer a sizeable risk increase for bone fracture (4.1-fold men, 1.9 fold for women) (81). The effect of vitamin therapy on decreasing hip fracture rates in patients with moderately elevated homocysteine concentrations was tested in a randomized controlled trial of 628 post-stroke, osteoporitc patients in Japan (mean=19.9 μmol/L) (21). Post-stroke patients were selected because hemiplegia significantly increases the incidence of bone fractures in the affected limb. Therapy with 5 mg of folate and 1,500 μg of methylcobalamin resulted in an absolute risk reduction for fracture of 7.1% (95% CI, 3.6%-10.8%), with a number needed to treat to prevent one fracture was 14 (95% CI, 9-28). The 4.5% fracture rate observed in the placebo group, however, is several fold higher than the predicted fracture rate in an age- and sex- cohort of normal controls, which has led some to argue against the application of these findings to routine clinical practice. The benefit of vitamin therapy for fracture risk has not been reproduced in mildly hyperhomocysteinemic individuals (<15 μmol/L) without a stroke history (82). In addition, vitamin therapy does not appear to influence measures of bone turnover in healthy, elderly individuals, although its effect in hyperhomocysteinemics is unknown (83). Thus, at this time, vitamin therapy may be useful for the prevention of fractures in certain high risk patients, but there are insufficient data to support its use in primary prevention of fractures in elderly individuals with mildly elevated homocysteine levels. Go to: CONCLUSIONS Data from randomized clinical trials have been unable to translate convincingly homocysteine lowering into improved clinical outcome for the secondary prevention of cardiovascular disease or in the prevention or treatment of dementia-type disorders. Vitamin therapy may decrease the risk of osteoporosis-induced bone fracture in selected, high risk patients. Thus, although the efficacy of combined folic acid, B6-, and B12-vitamin supplementation in decreasing circulating homocysteine levels is not in dispute, identification of patients who are most likely to benefit from this treatment is a subject of continued investigation. Most randomized intervention trials published to date have studied groups with only mildly elevated homocysteine levels, thus targeting clinical entities for which the attributable risk of homocysteine is unknown or is likely small compared to other factors. Importantly, the role of vitamin therapy has not been tested in key patient groups for which it may prove useful, such as in the primary prevention of coronary artery disease, or in the prevention of other, homocysteine-associated disease in patients with moderately or severely elevated homocysteine levels. Go to: SUMMARY POINTS Epidemiologic reports have established that elevated levels of homocysteine are an independent risk factor for atherothrombotic cardiovascular disease, stroke, cognitive impairment, and osteoporosis-induced bone fracture. Oxidation of homocysteine promotes reactive oxygen species formation that may impair vascular function via decreased bioavailable nitric oxide levels, depletion of nitric oxide synthase cofactors, or impairment of normal antioxidant enzyme function. Homocysteine overexcitation of N-methyl-d-aspartate receptors in the central nervous system may promote reactive oxygen species formation to induce synaptic failure in brain tissue. Randomized clinical trials have shown that oral supplementation with the combination of folic acid, B6-, and B12-vitmains substantially lowers circulating homocysteine levels, but does not appear to improve outcome in the secondary prevention of cardiovascular disease or dementia. Combination vitamin therapy may a have a role in preventing osteoporosis-induced bone fractures in selected, high risk patients. The diverse biologic effects of folic acid include indirectly increasing asymmetrical dimethylarginine (ADMA) levels, a molecule associated with impaired vascular function. Go to: FUTURE ISSUES Can a clinically salient proatherogenic homocysteine concentration threshold be identified for improved targeting of individuals who may benefit from combination B-vitamin therapy? Are derivative species of homocysteine oxidation, such as thiolactone, superior to total homocysteine as a measure of cardiovascular risk? Does homocysteine level lowering have a role in decreasing vascular event rates or delaying hemodialysis in patients with mild to intermediately decreased creatinine clearance? Go to: ACKNOWLEDGEMENTS We gratefully acknowledge Ms. Stephanie Tribuna for assistance in the preparation of this manuscript. Disclaimer: The project described was supported by Award Numbers: HL 61795, HL 58976, N01 HV 28178, and P01 HL 81587 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Go to: LITERATURE CITED 1. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. J. Am. Med. Assoc. 1995;74:1049–57. [PubMed] 2. Homocysteine Studies Collaboration Homocysteine and risk of ischemic heart disease and stroke; a meta-analysis. J. Am. Med. Assoc. 2002;288:2015–22. [PubMed] 3. Handy DE, Zhang Y, Loscalzo J. Homocysteine down-regulates cellular glutathione peroxidase (GPx1) by decreasing translation. J. Biol. Chem. 2005;280:15518–25. [PubMed] 4. Zhou J, Werstuck GH, Lhoták S, de Koning AB, Sood SK, et al. Association of multiple cellular stress pathways with accelerated atherosclerosis in hyperhomocysteinemic apolipoprotein E-deficient mice. Circulation. 2004;110:207–13. [PubMed] 5. Eberhardt RT, Forgione MA, Cap A, Leopold JA, Rudd MA, et al. Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J. Clin. Invest. 2000;106:483–491. [PMC free article] [PubMed] 6. Loscalzo J. Homocysteine and dementias. N. Engl. J. Med. 2002;346:466–8. [PubMed] 7. Seshardi S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N. Engl. J. Med. 2002;346:476–83. [PubMed] 8. McCully KS. Homocysteine, vitamins, and vascular disease prevention. Am. J. Clin. Nutr. 2007;86:1563S–8S. [PubMed] 9. Brazionis L, Rowley K, Sr, Itsiopoulos C, Harper CA, O'Dea K. Homocysteine and diabetic retinopathy. Diab. Care. 2008;31:50–6. [PubMed] 10. Agulló-Ortuño MT, Albaladejo MD, Parra S, Rodríguez-Manotas M, Fenollar M, et al. Plasmatic homocysteine concentration and its relationship with complications associated to diabetes mellitus. Clin. Chim. Acta. 2002;326:105–12. [PubMed] 11. Herrmann W, Herrmann M, Joseph J, Tyagi SC. The role of hyperhomocysteinemia as well as folate, vitamin B(6) and B(12) deficiencies in osteoporosis: a systematic review. Clin. Chem. Lab. Med. 2007;45:1621–32. [PubMed] 12. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N. Engl. J. Med. 1999;340:1449–54. [PubMed] 13. MRC Vitamin Study Research Group Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131–7. [PubMed] 14. Refsum H, Ueland PM, Nygård O, Vollset SE. Homocysteine and cardiovascular disease. Annu. Rev. Med. 1998;49:31–62. [PubMed] 15. Graham IM, Daly LE, Refsum HM, Robinson K, Brattström LE, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. J. Am. Med. Assoc. 1997;277:1775–81. [PubMed] 16. Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N. Eng. J. Med. 1997;337:23–36. [PubMed] 17. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N. Engl. J. Med. 2006;355:2631–9. [PubMed] 18. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br. Med. J. 2002;325:1202–9. [PMC free article] [PubMed] 19. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, et al. Lowering Homocysteine in Patients With Ischemic Stroke to Prevent Recurrent Stroke, Myocardial Infarction, and Death: The Vitamin Intervention for Stroke Prevention (VISP) Randomized Controlled Trial. J. Am. Med. Assoc. 2004;291:565–75. [PubMed] 20. McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, et al. A controlled trial of homocysteine lowering and cognitive performance. N. Engl. J. Med. 2006;354:2764–72. [PubMed] 21. Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. J. Am. Med. Assoc. 2005;293:1082–8. [PubMed] 22. Maron BA, Loscalzo J. Should hyperhomocysteinemia be treated in patients with atherosclerotic disease? Curr. Atheroscler. Rep. 2007;9:375–83. [PubMed] 23. Weiss N, Keller C, Hoffmann U, Loscalzo J. Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia. Vasc. Med. 2003;7:227–239. [PubMed] 24. Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J. Clin. Invest. 1996;98:5–7. [PMC free article] [PubMed] 25. Lubos E, Loscalzo J, Handy DE. Homocysteine and glutathione peroxidase-1. Antioxid Redox Signal. 2007;9:1923–40. [PubMed] 26. Rounds S, Yee WL, Dawicki DD, Harrington E, Parks N. Mechanism of extracellular ATP- and adenosine-induced apoptosis of cultured pulmonary artery endothelial cells. Am. J. Physiol. 1998;275:L379–388. [PubMed] 27. Welch GN, Upchurch GR, Jr, Farivar RS, Pigazzi A, Vu K, et al. Homocysteine-induced nitric oxide production in vascular-smooth muscle cells by NF-kB-dependent transcriptional activation of Nos2. Proc. Assoc. Am. Physiol. 1998;110:22–31. [PubMed] 28. Finkelstein JD. Methionine metabolism in mammals. J. Nutr. Biochem. 1990;1:228–237. [PubMed] 29. Qi Z, Hoffman G, Kurtycz D, Yu J. Prevalence of the C677T substitution of the methylenetetrahydrofolate reductase (MTHFR) gene in Wisconsin. Genet. Med. 2003;5:458–9. [PubMed] 30. Malinow R, Bostom AG, Krauss RM. Homocyst(e)ine, Diet, and Cardiovascular Diseases:A Statement for Healthcare Professionals From the Nutrition Committee, American Heart Association. Circulation. 1999;99:178–82. [PubMed] 31. Kolling K, Ndrepepa G, Koch W, Braun S, Mehilli J, et al. Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms, plasma homocysteine, folate, and vitamin B12 levels and the extent of coronary artery disease. Am. J. Cardiol. 2004;93:1201–06. [PubMed] 32. Garovic-Kocic V, Rosenblatt DS. Methionine auxotrophy in inborn errors of cobalamin metabolism. Clin. Invest. Med. 1995;15:395–400. [PubMed] 33. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N. Engl. J. Med. 1998;338:1042–50. [PubMed] 34. Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle DL, editors. The metabolic and molecular bases of inherited disease. 1. Vol. 7. McGraw-Hill; New York: 1995. pp. 1279–327. 35. 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