Download PDF
Thromb Haemost 2023; 123(03): 270-282
DOI: 10.1055/a-1952-1946
Review Article

Hyperhomocysteinemia in Cardiovascular Diseases: Revisiting Observational Studies and Clinical Trials

Jean-Louis Guéant‡   *
1   Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, Departments of Hepato-Gastroenterology and Molecular Medicine, University Hospital of Nancy, F-54000 Nancy, France
2   Reference Centre for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, F-54000 Nancy, France
3   INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, F-54000 Nancy, France
,
Rosa-Maria Guéant-Rodriguez‡   *
1   Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, Departments of Hepato-Gastroenterology and Molecular Medicine, University Hospital of Nancy, F-54000 Nancy, France
2   Reference Centre for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, F-54000 Nancy, France
3   INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, F-54000 Nancy, France
,
Abderrahim Oussalah
1   Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, Departments of Hepato-Gastroenterology and Molecular Medicine, University Hospital of Nancy, F-54000 Nancy, France
2   Reference Centre for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, F-54000 Nancy, France
3   INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, F-54000 Nancy, France
,
Stéphane Zuily
4   Vascular Medicine Division and Regional Competence Center for Rare Auto-Immune Diseases, INSERM UMR_S 1116 DCAC and CHRU-Nancy, Université de Lorraine, F-54000 Nancy, France
,
Irwin Rosenberg
5   Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, United States
› Author Affiliations Funding This work was financed by FHU ARRIMAGE, CHRU of Nancy and University of Lorraine, the AGIR grant of Université de Lorraine and CHRU of Nancy, and the French PIA project “Lorraine Université d'Excellence,” reference ANR-15-IDEX-04-LUE.
› Further Information
    Permissions and Reprints


Abstract

Thromboembolic manifestations are relatively frequent in patients with intermediate/severe hyperhomocysteinemia (>30 µmol/L) related to inherited disorders and deficiencies in vitamin B12 and folate. In contrast, moderate hyperhomocysteinemia (15–30 µmol/L) is a modest predictor of cardiovascular risk. The recognition of homocysteine as a cardiovascular risk factor has been challenged by some but not all randomized clinical trials. We reviewed the main data of this controversy and formulated conclusions to be translated in clinical practice.

Homocysteine-lowering trials have been performed in cardiovascular subjects with moderate but not intermediate/severe hyperhomocysteinemia despite the dose–effect risk association. The first meta-analyses found no benefit and led cardiology societies not recommending homocysteine in the assessment of cardiovascular risk. This guideline challenged the need to diagnose and treat the nutritional and genetic causes of intermediate/major hyperhomocysteinemia and was not revised when larger meta-analyses concluded to a reduced risk of stroke. In a recent observational study, 84% of consecutive cardiovascular patients assessed for homocysteine had intermediate or major hyperhomocysteinemia, which was properly assessed in only half of the cases and related to B12 and/or folate deficiency and Addison/Biermer disease in 55% of these cases.

In conclusion, revisiting observational studies and clinical trials suggests that cardiovascular patients should be screened for hyperhomocysteinemia, when no other risk factor is found. Patients with intermediate/major hyperhomocysteinemia should be properly assessed and treated for B vitamin deficiencies and inherited disorders according to current guidelines. Further trials are needed to assess the effect of lowering homocysteine according to hyperhomocysteinemia categories at baseline.

Keywords

homocysteine - vascular risk - cardiovascular disease - vitamin B12 deficiency - folate deficiency - one-carbon metabolism

Author Contributions

J.-L.G. and R.-M.G.-R. conducted research, analyzed data, performed statistical analysis, wrote the manuscript, and had primary responsibility for the final content. A.O. conducted research, performed analyses, analyzed data, and revised the manuscript. S.Z. and I.R. conducted research, analyzed data, and revised the manuscript.


* These authors contributed equally to this work.


Supplementary Material



Publication History

Received: 27 June 2022

Accepted: 28 September 2022

Accepted Manuscript online:
28 September 2022

Article published online:
31 December 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 World Health Organization Global Status Report on Noncommunicable Diseases 2014. Geneva: World Health Organization; 2014
    Google Scholar
  • 2 Yusuf S, Hawken S, Ounpuu S. et al; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364 (9438): 937-952
    CrossrefPubMedGoogle Scholar
  • 3 Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993; 270 (22) 2693-2698
    CrossrefPubMedGoogle Scholar
  • 4 Jakubowski H. Homocysteine modification in protein structure/function and human disease. Physiol Rev 2019; 99 (01) 555-604
    CrossrefPubMedGoogle Scholar
  • 5 Green R, Allen LH, Bjorke-Monsen AL. et al. Vitamin B12 deficiency. Nat Rev Dis Primers 2017; 3: 17040
    CrossrefPubMedGoogle Scholar
  • 6 McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969; 56 (01) 111-128
    PubMedGoogle Scholar
  • 7 Huemer M, Diodato D, Martinelli D. et al; EHOD consortium. Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: data from the E-HOD registry. J Inherit Metab Dis 2019; 42 (02) 333-352
    CrossrefPubMedGoogle Scholar
  • 8 Lenti MV, Miceli E, Corazza GR, Di Sabatino A. Editorial: determinants of diagnostic delay in autoimmune atrophic gastritis-a salutary lesson. Authors' reply. Aliment Pharmacol Ther 2019; 50 (04) 459-460
    CrossrefPubMedGoogle Scholar
  • 9 Esse R, Barroso M, Tavares de Almeida I, Castro R. The contribution of homocysteine metabolism disruption to endothelial dysfunction: state-of-the-art. Int J Mol Sci 2019; 20 (04) E867
    CrossrefPubMedGoogle Scholar
  • 10 Balint B, Jepchumba VK, Guéant JL, Guéant-Rodriguez RM. Mechanisms of homocysteine-induced damage to the endothelial, medial and adventitial layers of the arterial wall. Biochimie 2020; 173: 100-106
    CrossrefPubMedGoogle Scholar
  • 11 Balint B, Hergalant S, Camadro JM. et al. Fetal programming by methyl donor deficiency produces pathological remodeling of the ascending aorta. Arterioscler Thromb Vasc Biol 2021; 41 (06) 1928-1941
    CrossrefPubMedGoogle Scholar
  • 12 Undas A, Brozek J, Szczeklik A. Homocysteine and thrombosis: from basic science to clinical evidence. Thromb Haemost 2005; 94 (05) 907-915
    PubMedGoogle Scholar
  • 13 Fryer RH, Wilson BD, Gubler DB, Fitzgerald LA, Rodgers GM. Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb 1993; 13 (09) 1327-1333
    CrossrefPubMedGoogle Scholar
  • 14 Marcucci R, Prisco D, Brunelli T. et al. Tissue factor and homocysteine levels in ischemic heart disease are associated with angiographically documented clinical recurrences after coronary angioplasty. Thromb Haemost 2000; 83 (06) 826-832
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Al-Obaidi MK, Stubbs PJ, Collinson P, Conroy R, Graham I, Noble MI. Elevated homocysteine levels are associated with increased ischemic myocardial injury in acute coronary syndromes. J Am Coll Cardiol 2000; 36 (04) 1217-1222
    CrossrefPubMedGoogle Scholar
  • 16 Lentz SR, Sadler JE. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 1991; 88 (06) 1906-1914
    CrossrefPubMedGoogle Scholar
  • 17 Hayashi T, Honda G, Suzuki K. An atherogenic stimulus homocysteine inhibits cofactor activity of thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial cells. Blood 1992; 79 (11) 2930-2936
    CrossrefPubMedGoogle Scholar
  • 18 Lentz SR, Sobey CG, Piegors DJ. et al. Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest 1996; 98 (01) 24-29
    CrossrefPubMedGoogle Scholar
  • 19 Dayal S, Bottiglieri T, Arning E. et al. Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine beta-synthase-deficient mice. Circ Res 2001; 88 (11) 1203-1209
    CrossrefPubMedGoogle Scholar
  • 20 Cella G, Burlina A, Sbarai A. et al. Tissue factor pathway inhibitor levels in patients with homocystinuria. Thromb Res 2000; 98 (05) 375-381
    CrossrefPubMedGoogle Scholar
  • 21 Piazza F, Galimberti G, Conti E. et al. Increased tissue factor pathway inhibitor and homocysteine in Alzheimer's disease. Neurobiol Aging 2012; 33 (02) 226-233
    CrossrefPubMedGoogle Scholar
  • 22 Sauls DL, Wolberg AS, Hoffman M. Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability: implications for the mechanism of thrombosis in hyperhomocysteinemia. J Thromb Haemost 2003; 1 (02) 300-306
    CrossrefPubMedGoogle Scholar
  • 23 Tofler GH, D'Agostino RB, Jacques PF. et al. Association between increased homocysteine levels and impaired fibrinolytic potential: potential mechanism for cardiovascular risk. Thromb Haemost 2002; 88 (05) 799-804
    PubMedGoogle Scholar
  • 24 Hajjar KA. Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 1993; 91 (06) 2873-2879
    CrossrefPubMedGoogle Scholar
  • 25 Sikora M, Marczak Ł, Kubalska J, Graban A, Jakubowski H. Identification of N-homocysteinylation sites in plasma proteins. Amino Acids 2014; 46 (01) 235-244
    CrossrefPubMedGoogle Scholar
  • 26 Sauls DL, Lockhart E, Warren ME, Lenkowski A, Wilhelm SE, Hoffman M. Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia. Biochemistry 2006; 45 (08) 2480-2487
    CrossrefPubMedGoogle Scholar
  • 27 Gurda D, Handschuh L, Kotkowiak W, Jakubowski H. Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells. Amino Acids 2015; 47 (07) 1319-1339
    CrossrefPubMedGoogle Scholar
  • 28 Borowczyk K, Wróblewski J, Suliburska J, Akahoshi N, Ishii I, Jakubowski H. Mutations in homocysteine metabolism genes increase keratin N-homocysteinylation and damage in mice. Int J Genomics 2018; 2018: 7570850
    CrossrefPubMedGoogle Scholar
  • 29 Jakubowski H, Zhang L, Bardeguez A, Aviv A. Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis. Circ Res 2000; 87 (01) 45-51
    CrossrefPubMedGoogle Scholar
  • 30 Domagała TB, Łacinski M, Trzeciak WH, Mackness B, Mackness MI, Jakubowski H. The correlation of homocysteine-thiolactonase activity of the paraoxonase (PON1) protein with coronary heart disease status. Cell Mol Biol 2006; 52 (05) 4-10
    PubMedGoogle Scholar
  • 31 Koubaa N, Nakbi A, Hammami S. et al. Association of homocysteine thiolactonase activity and PON1 polymorphisms with the severity of acute coronary syndrome. Clin Biochem 2009; 42 (09) 771-776
    CrossrefPubMedGoogle Scholar
  • 32 Guéant-Rodriguez RM, Spada R, Moreno-Garcia M. et al. Homocysteine is a determinant of ApoA-I and both are associated with ankle brachial index, in an ambulatory elderly population. Atherosclerosis 2011; 214 (02) 480-485
    CrossrefPubMedGoogle Scholar
  • 33 Davì G, Di Minno G, Coppola A. et al. Oxidative stress and platelet activation in homozygous homocystinuria. Circulation 2001; 104 (10) 1124-1128
    CrossrefPubMedGoogle Scholar
  • 34 Durand P, Lussier-Cacan S, Blache D. Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. FASEB J 1997; 11 (13) 1157-1168
    CrossrefPubMedGoogle Scholar
  • 35 Domagala TB, Undas A, Sydor WJ, Szczeklik A. Thrombin formation in platelet-rich plasma after oral methionine loading: preliminary report. Thromb Res 2002; 105 (06) 503-506
    CrossrefPubMedGoogle Scholar
  • 36 Wu X, Zhang L, Miao Y. et al. Homocysteine causes vascular endothelial dysfunction by disrupting endoplasmic reticulum redox homeostasis. Redox Biol 2019; 20: 46-59
    CrossrefPubMedGoogle Scholar
  • 37 Chan SH, Hung CH, Shih JY. et al. Exercise intervention attenuates hyperhomocysteinemia-induced aortic endothelial oxidative injury by regulating SIRT1 through mitigating NADPH oxidase/LOX-1 signaling. Redox Biol 2018; 14: 116-125
    CrossrefPubMedGoogle Scholar
  • 38 Szabo C. Hydrogen sulfide, an enhancer of vascular nitric oxide signaling: mechanisms and implications. Am J Physiol Cell Physiol 2017; 312 (01) C3-C15
    CrossrefPubMedGoogle Scholar
  • 39 Zhao Z, Liu X, Shi S. et al. Exogenous hydrogen sulfide protects from endothelial cell damage, platelet activation, and neutrophils extracellular traps formation in hyperhomocysteinemia rats. Exp Cell Res 2018; 370 (02) 434-443
    CrossrefPubMedGoogle Scholar
  • 40 Xue H, Zhou S, Xiao L, Guo Q, Liu S, Wu Y. Hydrogen sulfide improves the endothelial dysfunction in renovascular hypertensive rats. Physiol Res 2015; 64 (05) 663-672
    CrossrefPubMedGoogle Scholar
  • 41 Paganelli F, Mottola G, Fromonot J. et al. Hyperhomocysteinemia and cardiovascular disease: is the adenosinergic system the missing link?. Int J Mol Sci 2021; 22 (04) 1690
    CrossrefPubMedGoogle Scholar
  • 42 Perła-Kaján J, Jakubowski H. Dysregulation of epigenetic mechanisms of gene expression in the pathologies of hyperhomocysteinemia. Int J Mol Sci 2019; 20 (13) E3140
    CrossrefPubMedGoogle Scholar
  • 43 Panayiotou AG, Nicolaides AN, Griffin M. et al. Leukocyte telomere length is associated with measures of subclinical atherosclerosis. Atherosclerosis 2010; 211 (01) 176-181
    CrossrefPubMedGoogle Scholar
  • 44 Lubec B, Labudova O, Hoeger H. et al. Homocysteine increases cyclin-dependent kinase in aortic rat tissue. Circulation 1996; 94 (10) 2620-2625
    CrossrefPubMedGoogle Scholar
  • 45 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 (10) 2074-2081
    CrossrefPubMedGoogle Scholar
  • 46 Ovechkin AV, Tyagi N, Sen U. et al. 3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice. Am J Physiol Lung Cell Mol Physiol 2006; 291 (05) L905-L911
    CrossrefPubMedGoogle Scholar
  • 47 Sun Z. Aging, arterial stiffness, and hypertension. Hypertension 2015; 65 (02) 252-256
    CrossrefPubMedGoogle Scholar
  • 48 Hofmann MA, Lalla E, Lu Y. et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest 2001; 107 (06) 675-683
    CrossrefPubMedGoogle Scholar
  • 49 Li Z, Kosgei VJ, Bison A. et al. Programming by methyl donor deficiency during pregnancy and lactation produces cardiomyopathy in adult rats subjected to high fat diet. Mol Nutr Food Res 2021; 65 (13) e2100065
    CrossrefPubMedGoogle Scholar
  • 50 Liu Z, Luo H, Zhang L. et al. Hyperhomocysteinemia exaggerates adventitial inflammation and angiotensin II-induced abdominal aortic aneurysm in mice. Circ Res 2012; 111 (10) 1261-1273
    CrossrefPubMedGoogle Scholar
  • 51 Yao D, Sun NL. Hyperhomocysteinemia accelerates collagen accumulation in the adventitia of balloon-injured rat carotid arteries via angiotensin II type 1 receptor. Int J Mol Sci 2014; 15 (11) 19487-19498
    CrossrefPubMedGoogle Scholar
  • 52 Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002; 288 (16) 2015-2022
    CrossrefPubMedGoogle Scholar
  • 53 Zhu M, Mao M, Lou X. Elevated homocysteine level and prognosis in patients with acute coronary syndrome: a meta-analysis. Biomarkers 2019; 24 (04) 309-316
    CrossrefPubMedGoogle Scholar
  • 54 Aday AW, Duran EK, Van Denburgh M. et al. Homocysteine is associated with future venous thromboembolism in 2 prospective cohorts of women. Arterioscler Thromb Vasc Biol 2021; 41 (07) 2215-2224
    CrossrefPubMedGoogle Scholar
  • 55 Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337 (04) 230-236
    CrossrefPubMedGoogle Scholar
  • 56 Han L, Wu Q, Wang C. et al. Homocysteine, ischemic stroke, and coronary heart disease in hypertensive patients: a population-based, prospective cohort study. Stroke 2015; 46 (07) 1777-1786
    CrossrefPubMedGoogle Scholar
  • 57 Selhub J, Jacques PF, Bostom AG. et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995; 332 (05) 286-291
    CrossrefPubMedGoogle Scholar
  • 58 Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. J Thromb Haemost 2005; 3 (02) 292-299
    CrossrefPubMedGoogle Scholar
  • 59 Holmen M, Hvas A-M, Arendt JFH. Hyperhomocysteinemia and ischemic stroke: a potential dose-response association-a systematic review and meta-analysis. TH Open 2021; 5 (03) e420-e437
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 Wu X, Zhou Q, Chen Q. et al. Association of homocysteine level with risk of stroke: a dose-response meta-analysis of prospective cohort studies. Nutr Metab Cardiovasc Dis 2020; 30 (11) 1861-1869
    CrossrefPubMedGoogle Scholar
  • 61 Levy J, Rodriguez-Guéant R-M, Oussalah A. et al. Cardiovascular manifestations of intermediate and major hyperhomocysteinemia due to vitamin B12 and folate deficiency and/or inherited disorders of one-carbon metabolism: a 3.5-year retrospective cross-sectional study of consecutive patients. Am J Clin Nutr 2021; 113 (05) 1157-1167
    CrossrefPubMedGoogle Scholar
  • 62 Clarke R, Halsey J, Lewington S. et al; B-Vitamin Treatment Trialists' Collaboration. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 2010; 170 (18) 1622-1631
    CrossrefPubMedGoogle Scholar
  • 63 Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB. Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. J Am Heart Assoc 2016; 5 (08) e003768
    CrossrefPubMedGoogle Scholar
  • 64 Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev 2017; 8 (08) CD006612
    PubMedGoogle Scholar
  • 65 Liu Y, Tian T, Zhang H, Gao L, Zhou X. The effect of homocysteine-lowering therapy with folic acid on flow-mediated vasodilation in patients with coronary artery disease: a meta-analysis of randomized controlled trials. Atherosclerosis 2014; 235 (01) 31-35
    CrossrefPubMedGoogle Scholar
  • 66 Smith AD, Refsum H. Homocysteine - from disease biomarker to disease prevention. J Intern Med 2021; 290 (04) 826-854
    CrossrefPubMedGoogle Scholar
  • 67 Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E. Heart Outcomes Prevention Evaluation 2 Investigators. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke 2009; 40 (04) 1365-1372
    CrossrefPubMedGoogle Scholar
  • 68 Wald DS, Morris JK, Wald NJ. Reconciling the evidence on serum homocysteine and ischaemic heart disease: a meta-analysis. PLoS One 2011; 6 (02) e16473
    CrossrefPubMedGoogle Scholar
  • 69 Baker F, Picton D, Blackwood S. et al. Blinded comparison of folic acid and placebo in patients with ischaemic heart disease: an outcome trial. Circulation 2002; 106 (Suppl II): 741
    PubMedGoogle Scholar
  • 70 Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: effects on clinical outcomes. J Am Coll Cardiol 2003; 41 (12) 2105-2113
    CrossrefPubMedGoogle Scholar
  • 71 Liem AH, van Boven AJ, Veeger NJ. et al; Folic Acid on Risk Diminishment After Acute Myocarial Infarction Study Group. Efficacy of folic acid when added to statin therapy in patients with hypercholesterolemia following acute myocardial infarction: a randomised pilot trial. Int J Cardiol 2004; 93 (2–3): 175-179
    CrossrefPubMedGoogle Scholar
  • 72 Toole JF, Malinow MR, Chambless LE. 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. JAMA 2004; 291 (05) 565-575
    CrossrefPubMedGoogle Scholar
  • 73 Bønaa KH, Njølstad I, Ueland PM. et al; NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354 (15) 1578-1588
    CrossrefPubMedGoogle Scholar
  • 74 Lonn E, Yusuf S, Arnold MJ. et al; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354 (15) 1567-1577
    CrossrefPubMedGoogle Scholar
  • 75 Albert CM, Cook NR, Gaziano JM. et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA 2008; 299 (17) 2027-2036
    CrossrefPubMedGoogle Scholar
  • 76 Ebbing M, Bleie Ø, Ueland PM. et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA 2008; 300 (07) 795-804
    CrossrefPubMedGoogle Scholar
  • 77 Hodis HN, Mack WJ, Dustin L. et al; BVAIT Research Group. High-dose B vitamin supplementation and progression of subclinical atherosclerosis: a randomized controlled trial. Stroke 2009; 40 (03) 730-736
    CrossrefPubMedGoogle Scholar
  • 78 Armitage JM, Bowman L, Clarke RJ. et al; Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA 2010; 303 (24) 2486-2494
    CrossrefPubMedGoogle Scholar
  • 79 Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S. SU.FOL.OM3 Collaborative Group. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ 2010; 341: c6273
    CrossrefPubMedGoogle Scholar
  • 80 VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol 2010; 9 (09) 855-865
    CrossrefPubMedGoogle Scholar
  • 81 van Dijk SC, Enneman AW, Swart KM. et al. Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial. J Hypertens 2015; 33 (09) 1897-1906 , discussion 1906
    CrossrefPubMedGoogle Scholar
  • 82 Huo Y, Li J, Qin X. et al; CSPPT Investigators. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA 2015; 313 (13) 1325-1335
    CrossrefPubMedGoogle Scholar
  • 83 Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 2002; 288 (08) 973-979
    CrossrefPubMedGoogle Scholar
  • 84 Lange H, Suryapranata H, De Luca G. et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004; 350 (26) 2673-2681
    CrossrefPubMedGoogle Scholar
  • 85 Imasa MS, Gomez NT, Nevado Jr JB. Folic acid-based intervention in non-ST elevation acute coronary syndromes. Asian Cardiovasc Thorac Ann 2009; 17 (01) 13-21
    CrossrefPubMedGoogle Scholar
  • 86 Lamas GA, Boineau R, Goertz C. et al; TACT (Trial to Assess Chelation Therapy) Investigators. Oral high-dose multivitamins and minerals after myocardial infarction: a randomized trial. Ann Intern Med 2013; 159 (12) 797-805
    CrossrefPubMedGoogle Scholar
  • 87 Shu XJ, Li ZF, Chang YW, Liu SY, Wang WH. Effects of folic acid combined with vitamin B12 on DVT in patients with homocysteine cerebral infarction. Eur Rev Med Pharmacol Sci 2017; 21 (10) 2538-2544
    PubMedGoogle Scholar
  • 88 Huang X, Li Y, Li P. et al. Association between percent decline in serum total homocysteine and risk of first stroke. Neurology 2017; 89 (20) 2101-2107
    CrossrefPubMedGoogle Scholar
  • 89 Li C, Bu X, Liu Y. Effect of folic acid combined with pravastatin on arteriosclerosis in elderly hypertensive patients with lacunar infarction. Medicine (Baltimore) 2021; 100 (28) e26540
    CrossrefPubMedGoogle Scholar
  • 90 Oliai Araghi S, Kiefte-de Jong JC, van Dijk SC. et al. Long-term effects of folic acid and vitamin-B12 supplementation on fracture risk and cardiovascular disease: extended follow-up of the B-PROOF trial. Clin Nutr 2021; 40 (03) 1199-1206
    CrossrefPubMedGoogle Scholar
  • 91 Kotwal J, Kotwal A, Bhalla S, Singh PK, Nair V. Effectiveness of homocysteine lowering vitamins in prevention of thrombotic tendency at high altitude area: a randomized field trial. Thromb Res 2015; 136 (04) 758-762
    CrossrefPubMedGoogle Scholar
  • 92 Selhub J, Rosenberg IH. Excessive folic acid intake and relation to adverse health outcome. Biochimie 2016; 126: 71-78
    CrossrefPubMedGoogle Scholar
  • 93 Maruvada P, Stover PJ, Mason JB. et al. Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop. Am J Clin Nutr 2020; 112 (05) 1390-1403
    CrossrefPubMedGoogle Scholar
  • 94 Goff Jr DC, Lloyd-Jones DM, Bennett G. et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63 (25, Pt B): 2935-2959
    PubMedGoogle Scholar
  • 95 Perk J, De Backer G, Gohlke H. et al; European Association for Cardiovascular Prevention & Rehabilitation (EACPR), ESC Committee for Practice Guidelines (CPG). European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012; 33 (13) 1635-1701
    CrossrefPubMedGoogle Scholar
  • 96 Huemer M, Diodato D, Schwahn B. et al. Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. J Inherit Metab Dis 2017; 40 (01) 21-48
    CrossrefPubMedGoogle Scholar
  • 97 Guéant JL, Guéant-Rodriguez RM, Alpers DH. Vitamin B12 absorption and malabsorption. Vitam Horm 2022; 119: 241-274
    CrossrefPubMedGoogle Scholar
  • 98 Fousekis FS, Beka ET, Mitselos IV, Milionis H, Christodoulou DK. Thromboembolic complications and cardiovascular events associated with celiac disease. Ir J Med Sci 2021; 190 (01) 133-141
    CrossrefPubMedGoogle Scholar
  • 99 Visentin M, Diop-Bove N, Zhao R, Goldman ID. The intestinal absorption of folates. Annu Rev Physiol 2014; 76: 251-274
    CrossrefPubMedGoogle Scholar
  • 100 MacFarlane AJ. Hyperhomocysteinemia in patients with cardiovascular manifestations: to treat or not to treat. Am J Clin Nutr 2021; 113 (05) 1081-1082
    CrossrefPubMedGoogle Scholar
  • 101 Guéant JL, Candito M, Andres E, Van Obberghen E, Nicolas JP. Familial pernicious anaemia with hyperhomocysteinaemia in recurrent early pregnancy loss. Thromb Haemost 2004; 92 (05) 1147-1149
    PubMedGoogle Scholar
  • 102 Ammouri W, Tazi ZM, Harmouche H, Maamar M, Adnaoui M. Venous thromboembolism and hyperhomocysteinemia as first manifestation of pernicious anemia: a case series. J Med Case Reports 2017; 11 (01) 250
    CrossrefPubMedGoogle Scholar
  • 103 Venkatesh P, Shaikh N, Malmstrom MF, Kumar VR, Nour B. Portal, superior mesenteric and splenic vein thrombosis secondary to hyperhomocysteinemia with pernicious anemia: a case report. J Med Case Reports 2014; 8: 286
    CrossrefPubMedGoogle Scholar
  • 104 Fernández-Ruiz M, Alonso-Navas F, Muro E, Pérez-Carreras M. Portal and mesenteric vein thrombosis associated with hyperhomocysteinemia and pernicious anemia in a patient heterozygous for the MTHFR C677T mutation [in Spanish]. Med Clin (Barc) 2011; 136 (05) 225-226
    CrossrefPubMedGoogle Scholar
  • 105 Fernández-Miranda C, Yebra Yebra M, Ribera Casado C, Toledo Urgarte T, Martín Mola M, Gómez González P. Venous thromboembolism and hyperhomocysteinemia as first manifestation of pernicious anemia [in Spanish]. Rev Clin Esp 2005; 205 (10) 489-492
    PubMedGoogle Scholar
  • 106 Wiedemann A, Oussalah A, Lamireau N. et al. Clinical, phenotypic and genetic landscape of case reports with genetically proven inherited disorders of vitamin B12 metabolism: a meta-analysis. Cell Rep Med 2022; 3 (07) 100670
    CrossrefPubMedGoogle Scholar
  • 107 Morris AA, Kožich V, Santra S. et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis 2017; 40 (01) 49-74
    CrossrefPubMedGoogle Scholar