Effect of Folic Acid and Betaine Supplementation on Flow-Mediated Dilation: A Randomized, Controlled Study in Healthy Volunteers

Abstract

Objectives:We investigated whether lowering of fasting homocysteine concentrations, either with folic acid or with betaine supplementation, differentially affects vascular function, a surrogate marker for risk of cardiovascular disease, in healthy volunteers. As yet, it remains uncertain whether a high concentration of homocysteine itself or whether a low folate status—its main determinant—is involved in the pathogenesis of cardiovascular disease. To shed light on this issue, we performed this study.Design:This was a randomized, placebo-controlled, double-blind, crossover study.Setting:The study was performed at Wageningen University in Wageningen, the Netherlands.Participants:Participants were 39 apparently healthy men and women, aged 50–70 y.Interventions:Participants ingested 0.8 mg/d of folic acid, 6 g/d of betaine, and placebo for 6 wk each, with 6-wk washout in between.Outcome Measures:At the end of each supplementation period, plasma homocysteine concentrations and flow-mediated dilation (FMD) of the brachial artery were measured in duplicate.Results:Folic acid supplementation lowered fasting homocysteine by 20% (−2.0 μmol/l, 95% confidence interval [CI]: −2.3; −1.6), and betaine supplementation lowered fasting plasma homocysteine by 12% (−1.2 μmol/l; −1.6; −0.8) relative to placebo. Mean (± SD) FMD after placebo supplementation was 2.8 (± 1.8) FMD%. Supplementation with betaine or folic acid did not affect FMD relative to placebo; differences relative to placebo were −0.4 FMD% (95%CI, −1.2; 0.4) and −0.1 FMD% (−0.9; 0.7), respectively.Conclusions:Folic acid and betaine supplementation both did not improve vascular function in healthy volunteers, despite evident homocysteine lowering. This is in agreement with other studies in healthy participants, the majority of which also fail to find improved vascular function upon folic acid treatment. However, homocysteine or folate might of course affect cardiovascular disease risk through other mechanisms.

The Basis of Differential Responses to Folic Acid Supplementation

“…Power calculations show that for the sample size and MZ/DZ ratio used here we should have had sufficient power to detect heritability as low as 45% and ample power to detect mean tHcy changes in line with those published in the literature (e.g. Olthof et al [27]). Nevertheless, our results need to be replicated using an independent cohort of North Europeans.…”

“…Hyperhomocysteinemia – elevated tHcy levels – is recognised as a major risk factor for many common conditions, including cardiovascular disease, atherosclerotic and thromboembolic disease as well as for cognitive impairment [22,23,24]. Supplementation with folic acid has been shown to significantly reduce the levels of Hcy and hence in principle reduce the risk and incidence of theses conditions in the general population, as reported by Mayer et al [25], Wald et al [26], Olthof et al [27] and references therein. Several small-scale studies have previously investigated the role of the C677T functional variant at MTHFR in affecting response to folate supplementation [28,29,30].…”

Betaine supplementation decreases plasma homocysteine in healthy adult participants: a meta-analysis

“…[9][10][11][12][13] Although 17 potentially relevant studies were identified and screened, 12 trials did not meet the eligibility criteria for the meta-analysis. Major reasons for exclusion of studies were as follows: not being randomized placebo-controlled trials (5 trials), utilization of patient populations with serious diseases such as chronic renal failure and steatohepatitis (4 trials), absence of data to calculate the net mean change in plasma homocysteine (2 trials), and involvement of methionine loading (1 trial).…”

“…8 Studies in healthy volunteers show that 6 g/d of betaine lowers plasma homocysteine concentrations by 5% to 20%. [9][10][11][12][13][14][15][16][17][18][19][20] The purpose of this study was to perform a meta-analysis of randomized placebo-controlled trials that used daily betaine supplementation to identify the range in betaine's effects on lowering homocysteine.…”

Folate Metabolism and Preeclampsia

“…Young women with hyperhomocysteinemia may be prone not only to systemic endothelial dysfunction but also placental endovasculature dysfunction 102 . Folic acid supplementation can substantially lower blood homocysteine levels in healthy subjects and patients with kidney disease [136][137][138][139] .…”