Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease.

Kang, Seok Seon; Passen, Edward; Ruggie, Neal; Wong, Paul; Sora, H.

doi:10.1161/01.cir.88.4.1463

Cited by 338 publications

(278 citation statements)

References 37 publications

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“…Similar to the thermostable mutations of MTHFR, a treatment with methionine and/or betaine should be effective in patients bearing these genetic abnormalities. The C677T mutation of the MTHFR gene, which leads to the synthesis of a thermolabile form of MTHFR that is responsible for 50% of the MTHFR activity, has a homozygosity prevalence, which may vary between 1.4% and 15% in the population, according to geographic area (D'Angelo and Frosst et al, 1995;Kang et al, 1993;Kluijtmans et al, 1996). In homozygous individuals, this autosomal recessive mutation provokes a moderate hyperhomocysteinemia that can be treated with a folic acid supplement.…”

Section: Genetic Factorsmentioning

confidence: 99%

“…The pioneer work of Wilcken and Wilcken (1976) showed an abnormal increase in homocysteine after an oral methionine load in patients with coronary artery disease. A prevalence of partial CBS and MTHFR inherited defects is observed in patients suffering from cardiovascular disease (Clarke et al, 1991;Kang et al, 1993). Numerous retrospective case-controlled Mansoor et al, 1995;Pancharuniti et al, 1994;Verhoef et al, 1994) and some prospective nested case-controlled studies (Arnesen et al, 1995;den Heijer et al, 1996;Stampfer et al, 1992) established the link between hyperhomocysteinemia and occlusive coronary artery (Arnesen et al, 1995;Pancharuniti et al, 1994;Stampfer et al, 1992), cerebrovascular Verhoef et al, 1994), and peripheral vascular (Mansoor et al, 1995) diseases, as well as venous thrombosis (also reviewed in Refsum et al, 1998).…”

Section: Hyperhomocysteinemia and Vascular Pathologiesmentioning

confidence: 99%

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Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

232

147

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SUMMARY:Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N 5,10 -methylenetetrahydrofolate reductase, and vitamin B 6 deficiency, perhaps associated with cystathionine ␤-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease. (Lab Invest 2001, 81:645-672).C ardiovascular diseases remain the leading cause of mortality in Western populations. Hyperlipoproteinemia, hypertension, diabetes, obesity, and tobacco smoking are the main risk factors for atherosclerosis and its thrombotic complications. However, these factors alone cannot account for all of the deaths caused by vascular pathologies.As early as 1969, clinical studies conducted in homocystinuric children revealed the importance of severe hyperhomocysteinemia in premature development of atherosclerosis and thromboembolism (McCully, 1983). According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine, which can be precisely quantitated by high performance liquid chromatography (HPLC), raise the risk for cardiovascular disease 2-fold, after adjusting for classic risk factors. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia. However, results from prospective studies are inconsistent. Additionally, molecular mechanisms underlying hyperhomocysteinemia-induced vascular diseas...

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Section: Genetic Factorsmentioning

confidence: 99%

Section: Hyperhomocysteinemia and Vascular Pathologiesmentioning

confidence: 99%

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

232

147

View full text Add to dashboard Cite

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“…Patients with coronary artery disease had significantly higher fasting plasma homocysteine levels in 22 out of 27 studies 29,30 with a risk ratio of 1.2 to 10.9 after adjusting for other risk factors. Two metaanalyses of retrospective studies confirm these findings [22][23][24][25][26][27][28][29][30][31] . Homocysteine may be considered a risk factor, as may smoking 32,33 , hypertension [32][33][34] , dyslipidemia 31,35,36 , and hyperglycemia 37 ; it seems, however, to be an independent factor 38,39 .…”

Section: Discussionmentioning

confidence: 81%

“…Some medications, such as niacin, methotrexate, and phenytoin, may also increase homocysteine levels [20][21][22][23] . Ethnic differences have been reported to interfere with the homocysteine levels, which are lower in black individuals as compared with Caucasian and Asian individuals [24][25][26][27][28][29][30][31][32][33] .…”

Section: Discussionmentioning

confidence: 99%

“…Approximately 30 studies have compared the homocysteine levels of patients with coronary artery disease and those of control groups with no disease 27,28 . Patients with coronary artery disease had significantly higher fasting plasma homocysteine levels in 22 out of 27 studies 29,30 with a risk ratio of 1.2 to 10.9 after adjusting for other risk factors.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of Plasma Homocysteine Levels in Patients with Unstable Angina

Tavares¹,

D’Almeida²,

Diniz³

et al. 2002

Arq. Bras. Cardiol.

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Hyperhomocysteinemia and Atherosclerotic Vascular Disease

Stein¹,

McBride²

1998

Arch Intern Med

134

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Hyperhomocysteinemia has recently been identified as an important risk factor for atherosclerotic vascular disease. This article reviews homocysteine metabolism, causes of hyperhomocysteinemia, the pathophysiological findings of this disorder, and epidemiological studies of homocysteine and vascular disease. Screening for hyperhomocysteinemia should be considered for patients at high risk for vascular disease or abnormalities of homocysteine metabolism. For primary prevention of vascular disease, treatment of patients with homocysteine levels of 14 micromol/L or higher should be considered. For secondary prevention, treatment of patients with homocysteine levels of 11 micromol/L or higher should be considered. Treatment is most conveniently administered as a folic acid supplement (400-1000 microg) and a high-potency multivitamin that contains at least 400 microg of folate. Higher doses of folic acid and cyanocobalamin supplements may be required in some patients. Until prospective clinical trial data become available, these conservative recommendations provide a safe, effective, and evidence-based approach to the diagnosis, evaluation, and management of patients with hyperhomocysteinemia.

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Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease.

Cited by 338 publications

References 37 publications

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Analysis of Plasma Homocysteine Levels in Patients with Unstable Angina

Hyperhomocysteinemia and Atherosclerotic Vascular Disease

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