Plasma Total Homocysteine and its Relationship with Cardiovascular Disease

Authors

  • D. Obersby University of West London
  • D.C. Chappell University of West London
  • A.A. Tsiami University of West London

DOI:

https://doi.org/10.6000/1929-5634.2013.02.04.2

Keywords:

Hyperhomocysteinemia, cardiovascular disease, metabolism, diet, lifestyle

Abstract

Aims: The specific aim of this review was to compile the first systematic review of systematic reviews and meta-analyses from a range of studies that evaluates the evidence that elevated homocysteine may be a risk factor for CVD.

Data Synthesis: 379 entries were identified by initial screening using set criteria revealing eleven meta-analyses, one systematic review, two systematic reviews/meta-analyses and ten other studies, between 1994 and 2013.These studies compared homocysteine levels and its relationship with twelve different types of CVD chronic conditions. Final methodological quality assessment was conducted independently using the instrument AMSTAR for the systematic reviews and meta-analyses. The remaining studies were assessed using data extraction tools from JBI QARI, Appendix 2 & 4 packages.

Conclusions: From the selected studies, 82.8% of the CVD conditions demonstrated that epidemiologic and clinical data strongly indicated that elevated homocysteine levels is a risk factor for primary CVD. 71.4% of the CVD conditions demonstrated that plasma tHcy can be employed as an independent biomarker. Despite 46.2% of the CVD conditions finding that reducing plasma tHcy lowers the risk of many CVD events, it remains unclear whether the reduction in plasma tHcy will reduce the risk of some CVD events; it is therefore considered prudent to take precautionary measures to aim for normal levels of homocysteine to avoid the risk of developing or exacerbating CVD. Moreover, it was shown that levels of homocysteine can be profoundly affected by diet, supplementation and lifestyle.

The present study will help to clarify the present scientific understanding of this subject.

Author Biographies

D. Obersby, University of West London

School of Psychology, Social Work and Human Sciences, Paragon House

D.C. Chappell, University of West London

School of Psychology, Social Work and Human Sciences, Paragon House

A.A. Tsiami, University of West London

School of Psychology, Social Work and Human Sciences, Paragon House

References

[1] Herrmann W, Obeid R, Schorr H, et al. The usefulness of holotranscobalamin in predicting vitamin B12 status in different clinical settings. Cur Drug Meta 2005; 6: 47-53.
http://dx.doi.org/10.2174/1389200052997384
[2] Ravaglia G, Forti P, Maioli F, et al. Apolipoprotein E e4 allele affects risk of hyperhomocysteinemia in the elderly. Am J Clin Nutr 2006; 84: 473-1480.
[3] Refsum H, Smith AD, Ueland PM, et al. Facts and recommendations about total homocysteine determinations: ‘An Expert Opinion’. Clin Chem 2004; 50: 3-32.
http://dx.doi.org/10.1373/clinchem.2003.021634
[4] Mudd SH, Finkelstein JD, Refsum D, et al. Homocysteine and its disulfide derivatives: a suggested consensus terminology. Arts, Throm Vas Bio 2000; 20: 1704-1706.
http://dx.doi.org/10.1161/01.ATV.20.7.1704
[5] Wilcken DE, Wilcken B. The natural history of vascular disease in homocystinuria and the effects of treatment. J Inhere Metab Dis 1997; 20: 295-300.
http://dx.doi.org/10.1023/A:1005373209964
[6] McNulty H, McKinley MC, Wilson B, et al. Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements. Am J Clin Nutr 2002; 76: 436-41.
[7] Jacques PF, Rosenberg IH, Rogers G, et al. Serum total homocysteine concentrations in adolescent and adult Americans: results from the Third National Health and Nutrition Examination Survey. Am J Clin Nutr 1999; 69: 482-489.
[8] Tallova J, Tomandl J, Bicikova M, et al. Changes of plasma total homocysteine levels during the menstrual cycle. Eur J Clin Invest 1999; 29: 1041-1044.
http://dx.doi.org/10.1046/j.1365-2362.1999.00572.x
[9] Obersby D, Chappell DC, Dunnett A, et al. Plasma total homocysteine status of vegetarians compared with omnivores: a systematic review and meta-analysis. Brit J Nutr 2013; 109: 785-794.
http://dx.doi.org/10.1017/S000711451200520X
[10] Tice JA, Ross E, Coxson PG Cost-effectiveness of vitamin therapy to lower plasma homocysteine levels for prevention of coronary heart disease: effect of grain fortification and beyond. J Am Med Ass 2001; 286: 936-943.
http://dx.doi.org/10.1001/jama.286.8.936
[11] Selhub J, Jacques P, Rosenberg IH, Rogers G, et al. Serum total homocysteine concentrations in the Third National Health and Nutrition Examination Survey (1991-1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann Inter Med 1999; 131: 331-339.
http://dx.doi.org/10.7326/0003-4819-131-5-199909070-00003
[12] Yang Q, Botto LD, Erickson JD, et al. Improvement in stroke mortality in Canada and the United States 1990 to 2002. Circulation 2006; 113: 1335-1343.
http://dx.doi.org/10.1161/CIRCULATIONAHA.105.570846
[13] Morita H. Homocysteine is particularly harmful to arteries in the presence of high salt intake. Diet-induced mild hyperhomocysteinemia and increased salt intake diminish vascular endothelial function in a synergistic manner. J Hyper 2002; 20: 55-62.
http://dx.doi.org/10.1097/00004872-200201000-00009
[14] Fleming RM. The effect of high, moderate and low-fat diets on weight loss and cardiovascular disease risk factors. Prev Cardio 2002; 5: 110-118.
http://dx.doi.org/10.1111/j.1520-037X.2002.01231.x
[15] Millian NS, Garrow TA. Human betaine-homocysteine methyltransferase is a zinc metalloenzyme. Arc Biochem and Biophys 1998; 356: 93-98.
http://dx.doi.org/10.1006/abbi.1998.0757
[16] Olthof MR. Consumption of high doses of chlorogenic acid present in coffee or black tea increases plasma total homocysteine concentrations in humans. J Clin Nutr 2001; 73(3): 532-538.
[17] Bleich K, Bleich K, Kropp S, et al. Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: a contradiction to the ‘French Paradox’? Alco, Alcoholism 2001; 36 (3): 189-192.
http://dx.doi.org/10.1093/alcalc/36.3.189
[18] de Oliveira AC, Suchecki D, Cohen S, et al. Acute stresser-selactive effect on plasma total homocysteine concentration in rats. Pharm Biochem Behaviour 2004; 77: 268-273.
[19] Stein JH. Smoking cessation, but not smoking reduction, reduces plasma homocysteine levels. Clin Cardio 2002; 25: 23-26.
http://dx.doi.org/10.1002/clc.4950250107
[20] Refsum H, Ueland PM, Nygard O, et al. Homocysteine and cardiovascular disease. Ann Rev Med 1998; 49: 31-62.
http://dx.doi.org/10.1146/annurev.med.49.1.31
[21] Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Eng J Med 1998; 338: 1042-1050.
http://dx.doi.org/10.1056/NEJM199804093381507
[22] Khandanpour N, Loke YK, Meyer PJ, Armon MP. Homocysteine and peripheral arterial disease: a systematic review and meta-analysis. Eur J Vascular Endovas Surg 2009; 38: 316-322.
http://dx.doi.org/10.1016/j.ejvs.2009.05.007
[23] Ford ES, Smith SJ, Stroup D, et al. Homocysteine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies. Inter J Epidem 2002; 31: 59-70.
http://dx.doi.org/10.1093/ije/31.1.59
[24] Humphrey LL, Fu R, Rogers K, et al. Homocysteine level and coronary heart disease: a systematic review and meta-analysis. Mayo Clinic Proc 2008; 83: 1203-1212.
http://dx.doi.org/10.4065/83.11.1203
[25] Ueland PM, Refsum H, Beresford M, et al. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr 2000; 72: 324-332.
[26] Malinow MR, Boston AG, Krauss RM. Homocysteine, diet and cardiovascular disease. Circulation 1999; 99: 178-182.
http://dx.doi.org/10.1161/01.CIR.99.1.178
[27] Ubbink JB. What is a desirable homocysteine level? Carmel R Jacobsen, D. W eds. Homocysteine in health and disease. Cambridge, Cambridge University Press 2001.
[28] Stanger O, Herrmann W, Pietrzik K, et al. Homocysteine [German, Austrian and Swiss Homocysteine Society]: Consensus paper on the rational clinical use of homocysteine, folic acid and B vitamins in cardiovascular and thrombotic disease: Guidelines and recommendations. Clin Chem Lab Me 2003; 41: 1392-1403.
http://dx.doi.org/10.1515/CCLM.2003.214
[29] Robinson K, Miller DP, van Lente F, et al. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation 1995; 92: 2825-2830.
http://dx.doi.org/10.1161/01.CIR.92.10.2825
[30] Guttormsen AB, Ueland PM, Suarstad E, et al. Kinetic basis of hyperhomocysteinemia in patients with chronic renal failure. Kidney Intl 1997; 52: 59-62.
http://dx.doi.org/10.1038/ki.1997.359
[31] Arnadottir M, Hultberg B, Nilsson-Ehle P, et al. The effect of reduced glomerular filtration rate on plasma total homocysteine concentration. Scand J Clin Invest 1996; 56: 41-46.
http://dx.doi.org/10.3109/00365519609088586
[32] McCully KS. Chemical pathology of homocysteine ‘I. Atherogenesis’. Ann Clin Lab Science 1993; 23: 477-493.
[33] Naruszewicz M, Mirkiewicz E, Olszewski AJ, et al. Thiolation of low density lipoprotein by homocysteine thiolactone causes increased aggregation and interaction with cultured macrophages. Nutr Metab Cardio Dis 1994; 4: 70-77.
[34] Wald NJ, Watt HC, Law MR. Homocysteine and ischaemic heart disease. Arch Inter Med 1998; 158: 862-867.
http://dx.doi.org/10.1001/archinte.158.8.862
[35] George NW, Joseph L. Homocysteine and atherothrombosis. N Eng J Med 1998; 338: 1042-1049.
http://dx.doi.org/10.1056/NEJM199804093381507
[36] McCully KS. The biomedical significance of homocysteine. J Scientific Explore 2001; 15: 5-20.
[37] Fruchart JC, Nierman MC, Stroes ESG, et al. New risk factors for atherosclerosis and patient risk assessment. Circulation 2004; 109: 1115-1119.
http://dx.doi.org/10.1161/01.CIR.0000131513.33892.5b
[38] Harker LA, Slichter SJ, Scott C, et al. Homocysteinemia: vascular injury and arterial thrombosis. N Eng J Med 1984; 291: 537-543.
http://dx.doi.org/10.1056/NEJM197409122911101
[39] Altura BM. Sudden-death ischemic heart disease and dietary magnesium intake: Is the target site coronary vascular smooth muscle? Med Hypotheses 1979; 8: 843-848.
http://dx.doi.org/10.1016/0306-9877(79)90074-4
[40] Altura BT, Altura BM. Magnesium in cardiovascular biology. Scientific American May/June 1995; 28-36.
[41] Li W, Zheng T, Wang J, et al. Homocysteine results in magnesium depletion from vascular smooth muscle. J Neuroscience 1999; 274: 83-86.
[42] Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Brit Med J 2002; 325: 1202.
http://dx.doi.org/10.1136/bmj.325.7374.1202
[43] Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. J Am Med Ass 1995; 274: 1049-1057.
http://dx.doi.org/10.1001/jama.1995.03530130055028
[44] Eikelboom JM, Lonn E, Genest J, et al. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Inter Med 1999; 131: 363-375.
http://dx.doi.org/10.7326/0003-4819-131-5-199909070-00008
[45] Brattstrom L, Wilcken DEL. Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr 2000; 72: 315-323.
[46] Ray JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Inter Med 1998; 158: 2101-6.
http://dx.doi.org/10.1001/archinte.158.19.2101
[47] Eichinger S, Stumpflen A, Hirschl M. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. J Throm Haemos 1998; 80: 566-9.
[48] Langman LJ, Ray JG, Evrovski J, et al. Hyperhomocysteinemia and the increased risk of venous thromboembolism. Arch Inter Med 2000; 160: 961-964.
http://dx.doi.org/10.1001/archinte.160.7.961
[49] Fry FH, Wilson BD, Gubler DB, et al. Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterios Throm Vasc Bio 1993; 13: 1327-1333.
http://dx.doi.org/10.1161/01.ATV.13.9.1327
[50] Fermo I, Vigano D’ Angelo S, Paroni R, et al. Prevalence of moderate hyperhomocysteinemia in patients with early-onset venous and arterial occlusive disease. Ann Inter Med 1995; 123: 747-753.
http://dx.doi.org/10.7326/0003-4819-123-10-199511150-00002
[51] JB1000308. Qualitative, meta-analysis of statistics assessments and review instruments. Joanna Briggs Inst 2011; 9: 104-121.
[52] Bautista LE, Arenas IA, Penuela A, et al. Total plasma homocysteine level and risk of cardiovascular disease: A meta-analysis of prospective cohort studies. J Clin Epidem 2002; 55: 882-887.
http://dx.doi.org/10.1016/S0895-4356(02)00434-1
[53] Tanne D, Haim M, Goldbourt U, et al. Prospective study of serum homocysteine and risk of ischemic stroke among patients with pre-existing coronary heart disease. Stroke 2003; 34: 632-636.
http://dx.doi.org/10.1161/01.STR.0000060203.58958.35
[54] The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. J Am Med Ass 2002; 288: 2015-2022.
http://dx.doi.org/10.1001/jama.288.16.2015
[55] Veeranna V, Zalawadiya SK, Niraj A, et al. Homocysteine and reclassification of cardiovascular disease risk. J Am Col Card Found 2011; 58: 1025-33.
http://dx.doi.org/10.1016/j.jacc.2011.05.028
[56] Pancharuniti N, Lewis CA, Sauberlich HE, et al. Plasma homocysteine, folate, and vitamin B12 concentrations and risk of early onset coronary artery disease. Am J Clin Nut 1994; 59: 940-8.
[57] Govindaraju V, Manjunath CN, Risk prediction-homocysteine in coronary heart disease. Ind J Clin Bio 2007; 22(1): 18-21.
http://dx.doi.org/10.1007/BF02912875
[58] Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007; 369: 1876-1882.
http://dx.doi.org/10.1016/S0140-6736(07)60854-X
[59] Verhoef P, Stampfer MJ, Buring JE, et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Am J Epidemiol 1996; 143(8): 845-59.
http://dx.doi.org/10.1093/oxfordjournals.aje.a008828
[60] de Bree A, van Mierlo LA, Draijer R. Folic acid improves vascular reactivity in humans: a meta-analysis of randomised controlled trials. Am J Clin Nutr 2007; 86: 610-617.
[61] McNulty H, Strain JJ, Pentieva K, et al. C1 metabolism and CVD outcomes in older adults. Proc Nutr Soc 2012; 71: 213-221.
http://dx.doi.org/10.1017/S0029665111003387
[62] The Heart Outcomes Prevention Evaluation (HOPE2) Investigators. Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease. N Eng J Med 2006; 354: 1567-1577.
http://dx.doi.org/10.1056/NEJMoa060900
[63] Clarke R, Halsey J, Lewington S, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality .Arch Inter Med 2010; 179: 1622-1631.
[64] Nygard O, Refsum H, Ueland PM, et al. Major lifestyle determinants of plasma total homocysteine distribution: ‘The Hordaland Homocysteine Study’. Am J Clin Nutr 1998; 67: 263-270
[65] Bazzano LA, Reynolds K, Holder KN, et al. Effect of folic acid supplementation on risk of cardiovascular disease. J Am Med Assoc 2006; 296: 2720-2726.
http://dx.doi.org/10.1001/jama.296.22.2720
[66] Bleie O. Studies on Homocysteine-lowering B-vitamin Therapy in patients with coronary artery disease. Dr.med dissertation, University of Bergen, Norway 2008.
[67] Clarke R, Bennett A, Parish S, et al. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. Plos Med 2012.
http://dx.doi.org/10.1371/journal.pmed.1001177
[68] Gravina-Taddei CF, Batlouni N, Sartesch C, et al. Hyperhomocysteinemia as a risk factor for coronary atherosclerotic diseases in the elderly. Arq Bras Cardiol 2005; 85(3): 1-11.
[69] Viera AJ, Garrett JM. Understanding inter-observer agreement: the Kappa statistic. Family Med 2005; 37: 360-3.
[70] Shea BJ, Hamel C, Wells GA, et al. AMSTAR is a reliable and valid measurement tool to assess the methodological quality of systematic reviews. J Epidem 2009; 62: 1013-1020.
http://dx.doi.org/10.1016/j.jclinepi.2008.10.009

Downloads

Published

2013-12-30

Issue

Section

Articles