ROLE OF HYPERHOMOCYSTEINEMIA IN ATHEROSCLEROTIC DISEASE AND ITS IMPLICATION FOR CLINICAL NUTRITION
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Published:
Dec 31, 2019
Keywords:
Homocysteine; Homocysteinemia; Atherosclerosis; Cardiovascular diseases; Vitamin B
Main Article Content
Abstract
Atherosclerosis is an initiation process in pathogenesis of many atherosclerotic diseases, such as heart attack, stroke, hypertension and peripheral vascular disease. There are two majors of risk factor involving in atherogenesis, including non-modifiable risk factors (e.g. age, ethnicity, genetic) and modifiable risk factors (e.g. dietary habit, alcohol drinking, smoking, some health conditions as obesity, dyslipidemia, hypertension, and hyperhomocysteinemia). Many observational studies have been reporting the positive association between homocysteine level and cardiovascular events. In the present, investigators have focused on homocysteine in human body, which has been revealed as an independent risk factor for atherosclerosis. Previous studies investigated how homocysteine induce vascular dysfunction via different mechanisms. Moreover, implication for clinical nutritional researches were applied by using folate vitamin B6 and vitamin B12 supplementation for manipulating homocysteine level and delayed progression of cardiovascular events. Therefore, this review article aims to provide and comprehend the possible mechanisms of atherogenesis through hyperhomocysteinemia. In addition, effect of vitamin B supplementation on homocysteine level and cardiovascular events were also reviewed and criticized in this article. WธรThisธ
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How to Cite
1.
Lainumngen N. ROLE OF HYPERHOMOCYSTEINEMIA IN ATHEROSCLEROTIC DISEASE AND ITS IMPLICATION FOR CLINICAL NUTRITION. crmj [internet]. 2019 Dec. 31 [cited 2025 Dec. 12];11(2):106-1. available from: https://he01.tci-thaijo.org/index.php/crmjournal/article/view/203788
Section
Review Article
References
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Williams KT, Schalinske KL. Homocysteine metabolism and its relation to health and disease. Biofactora. 2010;36(1):19-24.
Wierzbicki AS. Homocysteine and cardiovascular disease: a review of the evidence. Diab Vasc Dis Res. 2007; 4(2):143-50.
Falk E. Pathogenesis of Atherosclerosis. J Am Coll Cardiol. 2006; 47: C7-12.
Wang C, Han L, Wu Q, Zhuo R, Liu K, Zhao J, et al. Association between homocysteine and incidence of ischemic stroke in subjects with essential hypertension: a matched case-control study. Clin Exp Hypertens. 2015; 37: 557-62.
Zhang Z, Fang X, Hua Y, Liu B, Ji X, Tang Z, et al. Combined Effect of Hyperhomocysteinemia and Hypertension on the Presence of Early Carotid Artery Atherosclerosis. J Stroke Cerebrovasc Dis. 2016; 25: 1254-62.
Liu J, Liu H, Zhao Y, Zhou Y, Li L, Wang H. Relationship between cardio-ankle vascular index and homocysteine in hypertension subjects with hyperhomocysteinemia. Clin Exp Hypertens. 2016; 38: 652-7.
Wilcken D, Wang XL, Adachi T, Hara H, Duarte N, Green K, et al. Relationship between Homocysteine and Superoxide Dismutase in Homocystiuria. Possible relevance to cardiovascular risk. Aterioscler Thromb Vas Biol. 2000; 20: 1199-1202.
Handy DE, Zhang Y, Loscalzo J. Homocysteine Down-regulates Cellular Glutathione Peroxidase (GPx1) by Decreasing Translation. J Biol Chem. 2005; 280:15518-25.
Celik N, Vurmaz A, Kahraman A. Protective effect of quercetin on homocysteine-induce oxidative stress. Nutrition. 2016:1-6.
Dayal S, Lentz SR. ADMA and hyperhomocysteinemia. Vasc Med. 2005; 10:s27-s33.
Yucel H, Ozaydin M, Dogan A, Erdogan D, Turkey Y, Ceyhan BM, et al. Plasma concentrations of asymmetric dimethylarginine, nitric oxide and homocysteine in patients with slow coronary flow. Scand J Clin Lab Invest. 2012; 72: 495-500.
Zhang F, Li X, Dong Q, Wang Y, Zhang H. Risk of acute cerebral infarction and plasma asymmetrical dimethylarginine and homocysteine levels: a clinical correlation analysis of Chinese population. J Stroke Cerebrovasc Dis. 2014; 23: 2225-32.
Li H, Lewis A, Brodsky S, Rieger R, Iden C, Goligorsky MS. Homocysteine induces 3-hydroxyl-3-methylglutaryl coenzyme a reductase in vascular endothelial cells: a mechanism for development of atherosclerosis? Circulation. 2002; 105(9): 1037-43.
Chen C, Halkos ME, Surowiec SM, Conklin BS, Lin PH, Lumsden AB. Effects of homocysteine on smooth muscle cell proliferation in both cell culture and artery perfusion culture models. J Surg Res 2000; 88(1): 26-33.
Woo DK, Dudrick SJ, Sumpio BE. Homocysteine stimulates MAP kinase in bovine aortic smooth muscle cells. Surgery. 2000; 128(1): 59-66.
Davi G, Patrono C. Platelet Activation and Atherothrombosis. N Engl J Med. 2007; 357: 2482-94.
Bianca R, Mitidieri E, Minno M, Kirkby NS, Warner TD, Minno GD, et al. Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia. Proc Nati Acad Sci USA. 2013; 110: 15812-7.
Davi G, Minno GD, Coppola A, Andria G, Cerbone AM, Madonna P, et al. Oxidative stress and platelet activation in homozygous homocystinuria. Circulation. 2001; 104: 1124-8.
Jacovina AT, Deora AB, Ling Q, Broekman MJ, Almeida D, Greenberg CB, et al. Homocysteine inhibits neoangiogenesis in mice through blockade of annexin A2-dependent fibrinolysis. J Clin Invest. 2009; 119: 3384-94.
Iqbal MP, Lindblad BS, Mehboobali N, Yusuf FA, Khan AH, Iqbal SP. Folic acid and vitamin B6 defeciencies related hyperhomocysteinemia in apparently healthy Pakistani adults; is mass micronutrient supplementation indicated in this population? J Coll Physicians Surq Pak. 2009; 19: 308-312.
Choi SH, Choi-Kwon S, Kim Ms, Kim JS. Poor nutrition and alcohol consumption are related to high serum homocysteine level at post-stroke. Nutr Res Pract. 2015; 9: 503-10.
Maruyama K, Eshak ES, Kinuta M, Nagao M, Cui R, Imana H, et al. Association between vitamin B group supplementation with changes in % flow-mediated dilation and plasma homocysteine levels: a randomized controlled trial. J Clin Biochem Nutr. 2019; 64(3): 243-9.
Christen WG, Cook NR, Van Denburgh M, Zaharris E, Albert CM, Manson JF. Effect of combined treatment with folic acid, vitaminB6 and vitaminB12 on plasma biomarkers of inflammation and endothelial dysfunction in women. J Am Heart Assoc. 2018; 7(11): e008517.
Menzel D, Haller H, Wilhelm M, Robenek H. L-arginine and B vitamins improve endothelial function in subjects with mild to moderate blood pressure elevation. Eur J Nutr. 2018; 57(2): 557-68.
Huo Y, Li J, Qin X, Huang Y, Wang X, Gottesman RF, et al. 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): 1325-35.
Wang L, Hongtian L, Zhou Y, Jin L, Liu J. Low-dose B vitamins supplementation ameliorates cardiovascular risk: a double-blind randomized controlled trial in healthy Chinese elderly. Eur J Clin Nutr. 2015; 54: 455-64.
Van SC, Enneman AW, Swart KM, Van JP, Ham AC, Brouwer-Brolsma EM, 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: 1897-906.
Durga J, Bots ML, Schouten EG, Grobbee DE, Kok FJ, Verhoef P. Effect of 3 y of folic acid supplementation on the progression of carotid intima-media thickness and carotid arterial stiffness in older adults. Am J Clin Nutr. 2011; 93: 941-9.
Hankey GJ, Eikelboom JW, Baker RI, Gelavis A, Hickling SC, Jamrozik K, et al. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomized, double blind, parallel, placebo-controlled trial. Lancet Neurol. 2010; 9: 855-65.
Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, 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: 2027-36.
Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006; 354(15): 1567-77.
Zhang C, Wang ZY, Qin YY, Yu FF, Zhou YH. Association between B vitamins supplementation and risk of cardiovascular outcomes: a cumulative meta-analysis of randomized controlled trials. PLoS One. 2014; 9(9): e107060.
Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37485 individuals. Arch Intern Med. 2010; 170(18): 1622-31.
Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice. Atherosclerosis. 2016; 252: 207-74.
Jelingers PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, et al. American association of clinical endocrinologists and American college of endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017; 23: 1-87.
Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 guidelines for the early management of patients with acute ischemic stroke. Stroke. 2018; 49: e46-110.
Yakub M, Moti N, Parveen S, Chaudhry B, Azam I, Iqbal MP. Polymorphisms in MTHFR, MS and CBS genes and homocysteine levels in a Pakistani population. PLos One. 2012; 7(3): e33222.
Yang X, Zhang M, Song R, Liu C, Huo Y, Qian G, et al. The modifying effect of the MTHFR genotype on the association between folic acid supplementation and pulse wave velocity: finding from the CSPPT. 2018; 36(6): e12473.
Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation. 2019; 139(10):e56-e528.
Williams KT, Schalinske KL. Homocysteine metabolism and its relation to health and disease. Biofactora. 2010;36(1):19-24.
Wierzbicki AS. Homocysteine and cardiovascular disease: a review of the evidence. Diab Vasc Dis Res. 2007; 4(2):143-50.
Falk E. Pathogenesis of Atherosclerosis. J Am Coll Cardiol. 2006; 47: C7-12.
Wang C, Han L, Wu Q, Zhuo R, Liu K, Zhao J, et al. Association between homocysteine and incidence of ischemic stroke in subjects with essential hypertension: a matched case-control study. Clin Exp Hypertens. 2015; 37: 557-62.
Zhang Z, Fang X, Hua Y, Liu B, Ji X, Tang Z, et al. Combined Effect of Hyperhomocysteinemia and Hypertension on the Presence of Early Carotid Artery Atherosclerosis. J Stroke Cerebrovasc Dis. 2016; 25: 1254-62.
Liu J, Liu H, Zhao Y, Zhou Y, Li L, Wang H. Relationship between cardio-ankle vascular index and homocysteine in hypertension subjects with hyperhomocysteinemia. Clin Exp Hypertens. 2016; 38: 652-7.
Wilcken D, Wang XL, Adachi T, Hara H, Duarte N, Green K, et al. Relationship between Homocysteine and Superoxide Dismutase in Homocystiuria. Possible relevance to cardiovascular risk. Aterioscler Thromb Vas Biol. 2000; 20: 1199-1202.
Handy DE, Zhang Y, Loscalzo J. Homocysteine Down-regulates Cellular Glutathione Peroxidase (GPx1) by Decreasing Translation. J Biol Chem. 2005; 280:15518-25.
Celik N, Vurmaz A, Kahraman A. Protective effect of quercetin on homocysteine-induce oxidative stress. Nutrition. 2016:1-6.
Dayal S, Lentz SR. ADMA and hyperhomocysteinemia. Vasc Med. 2005; 10:s27-s33.
Yucel H, Ozaydin M, Dogan A, Erdogan D, Turkey Y, Ceyhan BM, et al. Plasma concentrations of asymmetric dimethylarginine, nitric oxide and homocysteine in patients with slow coronary flow. Scand J Clin Lab Invest. 2012; 72: 495-500.
Zhang F, Li X, Dong Q, Wang Y, Zhang H. Risk of acute cerebral infarction and plasma asymmetrical dimethylarginine and homocysteine levels: a clinical correlation analysis of Chinese population. J Stroke Cerebrovasc Dis. 2014; 23: 2225-32.
Li H, Lewis A, Brodsky S, Rieger R, Iden C, Goligorsky MS. Homocysteine induces 3-hydroxyl-3-methylglutaryl coenzyme a reductase in vascular endothelial cells: a mechanism for development of atherosclerosis? Circulation. 2002; 105(9): 1037-43.
Chen C, Halkos ME, Surowiec SM, Conklin BS, Lin PH, Lumsden AB. Effects of homocysteine on smooth muscle cell proliferation in both cell culture and artery perfusion culture models. J Surg Res 2000; 88(1): 26-33.
Woo DK, Dudrick SJ, Sumpio BE. Homocysteine stimulates MAP kinase in bovine aortic smooth muscle cells. Surgery. 2000; 128(1): 59-66.
Davi G, Patrono C. Platelet Activation and Atherothrombosis. N Engl J Med. 2007; 357: 2482-94.
Bianca R, Mitidieri E, Minno M, Kirkby NS, Warner TD, Minno GD, et al. Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia. Proc Nati Acad Sci USA. 2013; 110: 15812-7.
Davi G, Minno GD, Coppola A, Andria G, Cerbone AM, Madonna P, et al. Oxidative stress and platelet activation in homozygous homocystinuria. Circulation. 2001; 104: 1124-8.
Jacovina AT, Deora AB, Ling Q, Broekman MJ, Almeida D, Greenberg CB, et al. Homocysteine inhibits neoangiogenesis in mice through blockade of annexin A2-dependent fibrinolysis. J Clin Invest. 2009; 119: 3384-94.
Iqbal MP, Lindblad BS, Mehboobali N, Yusuf FA, Khan AH, Iqbal SP. Folic acid and vitamin B6 defeciencies related hyperhomocysteinemia in apparently healthy Pakistani adults; is mass micronutrient supplementation indicated in this population? J Coll Physicians Surq Pak. 2009; 19: 308-312.
Choi SH, Choi-Kwon S, Kim Ms, Kim JS. Poor nutrition and alcohol consumption are related to high serum homocysteine level at post-stroke. Nutr Res Pract. 2015; 9: 503-10.
Maruyama K, Eshak ES, Kinuta M, Nagao M, Cui R, Imana H, et al. Association between vitamin B group supplementation with changes in % flow-mediated dilation and plasma homocysteine levels: a randomized controlled trial. J Clin Biochem Nutr. 2019; 64(3): 243-9.
Christen WG, Cook NR, Van Denburgh M, Zaharris E, Albert CM, Manson JF. Effect of combined treatment with folic acid, vitaminB6 and vitaminB12 on plasma biomarkers of inflammation and endothelial dysfunction in women. J Am Heart Assoc. 2018; 7(11): e008517.
Menzel D, Haller H, Wilhelm M, Robenek H. L-arginine and B vitamins improve endothelial function in subjects with mild to moderate blood pressure elevation. Eur J Nutr. 2018; 57(2): 557-68.
Huo Y, Li J, Qin X, Huang Y, Wang X, Gottesman RF, et al. 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): 1325-35.
Wang L, Hongtian L, Zhou Y, Jin L, Liu J. Low-dose B vitamins supplementation ameliorates cardiovascular risk: a double-blind randomized controlled trial in healthy Chinese elderly. Eur J Clin Nutr. 2015; 54: 455-64.
Van SC, Enneman AW, Swart KM, Van JP, Ham AC, Brouwer-Brolsma EM, 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: 1897-906.
Durga J, Bots ML, Schouten EG, Grobbee DE, Kok FJ, Verhoef P. Effect of 3 y of folic acid supplementation on the progression of carotid intima-media thickness and carotid arterial stiffness in older adults. Am J Clin Nutr. 2011; 93: 941-9.
Hankey GJ, Eikelboom JW, Baker RI, Gelavis A, Hickling SC, Jamrozik K, et al. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomized, double blind, parallel, placebo-controlled trial. Lancet Neurol. 2010; 9: 855-65.
Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, 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: 2027-36.
Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006; 354(15): 1567-77.
Zhang C, Wang ZY, Qin YY, Yu FF, Zhou YH. Association between B vitamins supplementation and risk of cardiovascular outcomes: a cumulative meta-analysis of randomized controlled trials. PLoS One. 2014; 9(9): e107060.
Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37485 individuals. Arch Intern Med. 2010; 170(18): 1622-31.
Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice. Atherosclerosis. 2016; 252: 207-74.
Jelingers PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, et al. American association of clinical endocrinologists and American college of endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017; 23: 1-87.
Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 guidelines for the early management of patients with acute ischemic stroke. Stroke. 2018; 49: e46-110.
Yakub M, Moti N, Parveen S, Chaudhry B, Azam I, Iqbal MP. Polymorphisms in MTHFR, MS and CBS genes and homocysteine levels in a Pakistani population. PLos One. 2012; 7(3): e33222.
Yang X, Zhang M, Song R, Liu C, Huo Y, Qian G, et al. The modifying effect of the MTHFR genotype on the association between folic acid supplementation and pulse wave velocity: finding from the CSPPT. 2018; 36(6): e12473.
