Effect of various regimens of vitamin B<sub>6</sub> and folic acid on mild hyperhomocysteinaemia in vascular patients

Franken, D. G.; Boers, G.H.J.; Blom, Henk J.; Trijbels, J. M. F.

doi:10.1007/bf00735426

Cited by 52 publications

(25 citation statements)

References 7 publications

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Section: Discussioncontrasting

confidence: 76%

“…These data contrast with uncontrolled reports, [22][23][24] and our earlier randomized, placebo-controlled 2ϫ2 factorial study in renal transplant recipients, 25 demonstrating that vitamin B 6 treatment could significantly reduce mean post-methionine load increases in tHcy levels. However, in all these previous reports, [22][23][24][25] subjects had lower mean plasma pyridoxal 5Ј-phosphate status, and/or significantly greater mean post-methionine load increases in their tHcy levels, at baseline. In conjunction with the current null findings, the aggregate data [22][23][24][25] suggest that vitamin B 6 treatment for the potential reduction of postmethionine load tHcy levels may only be effective when vitamin B 6 status is marginal, emphasizing the role of vitamin B 6 as a cofactor, not a substrate, for cystathionine beta synthase in the transsulfuration pathway.…”

Section: Discussioncontrasting

confidence: 76%

“…However, in all these previous reports, [22][23][24][25] subjects had lower mean plasma pyridoxal 5Ј-phosphate status, and/or significantly greater mean post-methionine load increases in their tHcy levels, at baseline. In conjunction with the current null findings, the aggregate data [22][23][24][25] suggest that vitamin B 6 treatment for the potential reduction of postmethionine load tHcy levels may only be effective when vitamin B 6 status is marginal, emphasizing the role of vitamin B 6 as a cofactor, not a substrate, for cystathionine beta synthase in the transsulfuration pathway. 26 Including the current report, two controlled total homocysteine-lowering treatment studies have been completed in the United States and Canada among coronary artery disease (CAD) patient populations chronically exposed to a background of folic acid fortified cereal grain flour.…”

Section: Discussionmentioning

confidence: 72%

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Total Homocysteine Lowering Treatment Among Coronary Artery Disease Patients in the Era of Folic Acid-Fortified Cereal Grain Flour

Bostom

Jacques

Liaugaudas

et al. 2002

ATVB

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Abstract-The prevalence of deficient plasma folate status and elevated total plasma levels of homocysteine (tHcy), have been dramatically reduced after fortification of all enriched cereal grain flour products with folic acid at 140 g/100 g flour. Against this new background fortification, we evaluated the tHcy-lowering efficacy of pharmacological dose, folic acid-based vitamin B supplementation among stable coronary artery disease (CAD) patients. Using a 2ϫ2 factorial design, 131 stable CAD patients (mean age 60.1 years; 29.8% women) were randomly assigned to receive a combination of folic acid 2.5 mg/d, riboflavin 5 mg/d, ϩ B 12 0.4 mg/d, or placebo, with or without vitamin B 6 50 mg/d, for 12 weeks of treatment. ANCOVA adjusted for baseline fasting tHcy levels revealed only very modest (ie, Ϸ1.0 mol/L), albeit statistically significant (PϽ0.05), reductions in mean fasting tHcy levels afforded by the folic acid-containing treatments. Additional analyses indicated that none of the treatments provided a statistically significant reduction in the 2-hour post-methionine increase in tHcy levels, relative to placebo treatment. CAD patients exposed to cereal grain flour products fortified with folic acid who receive high-dose, folic acid-containing vitamin B regimens, experience only very modest reductions in their mean fasting plasma tHcy levels. [1][2][3][4][5] and elevated fasting total plasma levels of the putatively atherothrombotic 6 sulfur amino acid homocysteine (tHcy), 1,4,5 have been dramatically reduced since the recent advent of United States 7 and Canadian 8 initiatives to fortify all enriched cereal grain flour products with physiological amounts (ie, 140 g/100 g flour) of folic acid. Presently, there are three large, randomized, controlled trials of tHcy-lowering for the potential reduction of arteriosclerotic cardiovascular disease outcomes ongoing in the United States and Canada. 9 The considerable (nutritional) biochemical effects 1-5 of cereal grain flour fortification with folic acid could substantially reduce the statistical power of these ongoing cardiovascular disease prevention studies. All three trials assume the patient groups assigned to active treatment will achieve the same mean tHcy-lowering treatment effects (ie, a mean reductions of Ϸ33%, or 4 to 6 mo/L) previously reported 10 in the absence of the large potential background effect of folic acid-fortified cereal grain flour. We re-examined this assumption by evaluating the tHcy-lowering efficacy of pharmacological dose, folic acid-based vitamin B supplementation among stable coronary artery disease (CAD) patients chronically exposed to cereal grain flour products fortified with folic acid at 140 g/100 g flour. MethodsThe institutional review board at Memorial Hospital of Rhode Island (Pawtucket, RI) approved the study protocol, and all participants provided written, informed consent. Study participants were 267 stable CAD patients (ie, they were at least 3 months post-myocardial infarction or coronary angioplasty and/or at least 6 mon...

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Section: Discussioncontrasting

confidence: 76%

Section: Discussioncontrasting

confidence: 76%

Section: Discussionmentioning

confidence: 72%

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Total Homocysteine Lowering Treatment Among Coronary Artery Disease Patients in the Era of Folic Acid-Fortified Cereal Grain Flour

Bostom

Jacques

Liaugaudas

et al. 2002

ATVB

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“…In patients with residual CBS activity (between 0% and 2% of normal), approximately half of the cases of homozygous homocystinuria, pyridoxine treatment can decrease the hyperhomocysteinemia. Treatment by folates and betaine combined with a lowmethionine diet is effective in vitamin B 6 nonresponders (Franken et al, 1994). However, betaine treatment may have some disadvantages because of an increase in methionine that is not found with folic acid treatment.…”

Section: Genetic Factorsmentioning

confidence: 99%

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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“…11 Folate, as well as vitamin B6 status, 9,11 are significant predictors of PML tHcy. These vitamin effects in humans are at variance with the idea, based on enzymological data, 5 animal, 12 and human studies, 6 that PML tHcy is determined by the activity of vitamin B6-dependent enzyme, cystathionine ␤-synthase, whereas the folate-dependent homocysteine remethylation regulates basal tHcy.…”

mentioning

confidence: 98%

Betaine as a Determinant of Postmethionine Load Total Plasma Homocysteine Before and After B-Vitamin Supplementation

Holm

Bleie

Ueland

et al. 2004

ATVB

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Objective-Betaine is a substrate in the betaine-homocysteine methyltransferase reaction, converting homocysteine to methionine. There are only sparse data on plasma betaine as a determinant of the plasma total homocysteine (tHcy) concentration. Methods and Results-Ninety patients undergoing coronary angiography were randomized into 4 groups administered oral: (1) folic acid (0.8 mg), vitamin B12 (0.4 mg), and vitamin B6 (40 mg); (2) folic acid and vitamin B12; (3) vitamin B6 alone; or (4) placebo. Nonfasting blood samples were collected at baseline and 3, 14, and 28 days and 3, 6, and 12 months after treatment start. A 4-hour methionine-loading test (0.1 g/kg) was performed at baseline and after 3 months. At baseline, median (interquartile range) plasma betaine was 36.9 mol/L (range: 30.3 to 46.8) and was increased by 15% after methionine loading. The postmethionine load (PML) increase in tHcy was inversely related to plasma betaine (␤ϭϪ0.29, Pϭ0.02) and even more strongly to PML betaine (␤ϭϪ0.47, PϽ0.001). After 3 months of intervention, the relation between the PML increase in tHcy and PML betaine was weakened (␤ϭϪ0.33, Pϭ0.007). Conclusions-Plasma

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Effect of various regimens of vitamin B₆ and folic acid on mild hyperhomocysteinaemia in vascular patients

Cited by 52 publications

References 7 publications

Total Homocysteine Lowering Treatment Among Coronary Artery Disease Patients in the Era of Folic Acid-Fortified Cereal Grain Flour

Total Homocysteine Lowering Treatment Among Coronary Artery Disease Patients in the Era of Folic Acid-Fortified Cereal Grain Flour

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Betaine as a Determinant of Postmethionine Load Total Plasma Homocysteine Before and After B-Vitamin Supplementation

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Effect of various regimens of vitamin B6 and folic acid on mild hyperhomocysteinaemia in vascular patients

Cited by 52 publications

References 7 publications

Total Homocysteine Lowering Treatment Among Coronary Artery Disease Patients in the Era of Folic Acid-Fortified Cereal Grain Flour

Total Homocysteine Lowering Treatment Among Coronary Artery Disease Patients in the Era of Folic Acid-Fortified Cereal Grain Flour

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Betaine as a Determinant of Postmethionine Load Total Plasma Homocysteine Before and After B-Vitamin Supplementation

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Effect of various regimens of vitamin B₆ and folic acid on mild hyperhomocysteinaemia in vascular patients