Reduction of homocysteine levels in coronary artery disease by low-dose folic acid combined with vitamins B6 and B12

Lobo, Arlene; Naso, Arabi; Arheart, Kristopher L.; Kruger, Warren D.; Abou-Ghazala, Tariq; Alsous, Fadi; Nahlawi, Maher; Gupta, Anjan; Moustapha, Ali; Lente, Frederick Van; Jacobsen, Donald W.; Robinson, Killian

doi:10.1016/s0002-9149(98)01041-8

Cited by 85 publications

(42 citation statements)

References 26 publications

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“…It is important to stress that plasma folate levels observed in this study cannot be achieved by dietary fortification with folic acid (up to 0.665 mg/d) 21 or low-dose (0.4 mg) folic acid supplementation. 5 Plausible mechanisms exist Figure 2. Time course of plasma folate after first dose of placebo or folic acid (5 mg) and after 6 weeks of treatment (meanϮSEM).…”

Section: Discussionmentioning

confidence: 99%

“…The homocysteinereducing effect of folic acid in CAD is maximal at 0.4 mg in patients with normal renal function. 5 However, if homocysteine lowering is not the major mechanism of benefit of high-dose folic acid, on-going outcome studies with moderate doses of folate in patients with cardiovascular disease (0.8 to 2.5 mg) 26 may not reveal benefit despite lowering homocysteine. This may reflect the lower doses of folate used, and this point should be borne in mind when interpreting the results of these studies.…”

Section: Implications Of the Studymentioning

confidence: 99%

“…Folic acid reduces total plasma homocysteine by 25% 4 and is maximally achieved by doses of 0.4 to 0.5 mg daily. 4,5 This has led to the proposal that folic acid treatment may reduce cardiovascular risk by reducing tHcy.…”

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confidence: 99%

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Folic Acid Improves Endothelial Function in Coronary Artery Disease via Mechanisms Largely Independent of Homocysteine Lowering

et al. 2002

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Background-Homocysteine is a risk factor for coronary artery disease (CAD), although a causal relation remains to be proven. The importance of determining direct causality rests in the fact that plasma homocysteine can be safely and inexpensively reduced by 25% with folic acid. This reduction is maximally achieved by doses of 0.4 mg/d. High-dose folic acid (5 mg/d) improves endothelial function in CAD, although the mechanism is controversial. It has been proposed that improvement occurs through reduction in total (tHcy) or free (non-protein bound) homocysteine (fHcy). We investigated the effects of folic acid on endothelial function before a change in homocysteine in patients with CAD. Methods and Results-A randomized, placebo-controlled study of folic acid (5 mg/d) for 6 weeks was undertaken in 33 patients. Endothelial function, assessed by flow-mediated dilatation (FMD), was measured before, at 2 and 4 hours after the first dose of folic acid, and after 6 weeks of treatment. Plasma folate increased markedly by 1 hour (200 compared with 25.8 nmol/L; PϽ0.001). FMD improved at 2 hours (83 compared with 47 m; PϽ0.001) and was largely complete by 4 hours (101 compared with 51 m; PϽ0.001). tHcy did not significantly differ acutely (4-hour tHcy, 9.56 compared with 9.79 mol/L; PϭNS). fHcy did not differ at 3 hours but was slightly reduced at 4 hours (1.55 compared with 1.78 mol/L; Pϭ0.02). FMD improvement did not correlate with reductions in either fHcy or tHcy at any time. Conclusions-These data suggest that folic acid improves endothelial function in CAD acutely by a mechanism largely independent of homocysteine.

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Section: Discussionmentioning

confidence: 99%

Section: Implications Of the Studymentioning

confidence: 99%

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Folic Acid Improves Endothelial Function in Coronary Artery Disease via Mechanisms Largely Independent of Homocysteine Lowering

et al. 2002

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“…BH 4 is an essential cofactor for eNOS, and its depletion results in uncoupling of eNOS activity and a switch from production of NO, from L-arginine, to generation of superoxide. 41 5-MTHF is essential in the redox cycling of the inactive quinonoid BH 2 (qBH 2 ) back to the active form, BH 4 . 42 Furthermore, oral BH 4 supplementation can improve endothelial function in CAD.…”

Section: Doshi Et Al Folate Improves Endothelial Function In Cadmentioning

confidence: 99%

“…3 This effect occurs despite normal plasma folate and can be achieved by folic acid in doses of 400 g to 5 mg/d. 3,4 This has led to the proposal that folic acid treatment may reduce cardiovascular risk by reducing tHcy.…”

mentioning

confidence: 99%

Folate Improves Endothelial Function in Coronary Artery Disease

Doshi

McDowell

Moat

et al. 2001

ATVB

219

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Abstract-Homocysteine is a risk factor for coronary artery disease (CAD). Folic acid lowers homocysteine and may improve endothelial function in CAD, although the mechanism is unclear. We investigated the effect of folic acid on endothelial function, homocysteine, and oxidative stress in patients with CAD. We also examined the acute effect of 5-methyltetrahydrofolate (5-MTHF), the principal circulating folate, on endothelial function in vivo and on intracellular superoxide in cultured endothelial cells. A randomized crossover study of folic acid (5 mg daily) for 6 weeks was undertaken in 52 patients with CAD. Ten further patients were given intra-arterial 5-MTHF. Endothelial function was assessed by flow-mediated dilatation (FMD). Folic acid increased plasma folate (PϽ0.001), lowered homocysteine by 19% (PϽ0.001), and improved FMD (PϽ0.001). FMD improvement did not correlate with homocysteine reduction. Malondialdehyde and total plasma antioxidant capacity, markers of oxidative stress, were unchanged. 5-MTHF acutely improved FMD (PϽ0.001) without altering homocysteine (Pϭ0.47). In vitro, 5-MTHF abolished homocysteineinduced intracellular superoxide increase (PϽ0.001); this effect was also observed with folic acid and tetrahydrobiopterin. Our data support the beneficial effect of folic acid on endothelial function in CAD but suggest that the mechanism is independent of homocysteine. Reduction of intracellular endothelial superoxide may have contributed to the effect.

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