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.
This was a randomized, placebo-controlled, double-blind, crossover study.
The study was performed at Wageningen University in Wageningen, the Netherlands.
Participants were 39 apparently healthy men and women, aged 50–70 y.
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.
At the end of each supplementation period, plasma homocysteine concentrations and flow-mediated dilation (FMD) of the brachial artery were measured in duplicate.
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.
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.
Background: Evidence from observational studies indicates a link between high concentrations of homocysteine (an amino acid) in the blood and increased risk of cardiovascular disease. However, the basis for the link between homocysteine concentrations and cardiovascular disease risk is not clear. Supplementing the diet with B-vitamins lowers homocysteine levels, and large-scale trials are underway that will determine whether B-vitamin supplementation has an effect on cardiovascular outcomes, such as heart attacks and strokes. These trials also involve administration of folic acid as well as other B-vitamins. It is not obvious, however, whether the effects of B-vitamin supplementation arise as a result of homocysteine lowering or via some other biochemical pathway.
What this trial shows: Olthof and colleagues aimed to further understand the effects of homocysteine lowering by randomizing 40 healthy volunteer participants to receive either folic acid supplementation; placebo; or betaine, a nutrient that lowers homocysteine levels via a different biochemical pathway than folic acid. Each participant in the trial received each supplement for 6 wk, with a 6-wk washout period before the next supplement was given. The researchers then used a technique called flow-mediated dilation (FMD) to measure functioning of the main artery of the upper arm, as a surrogate for cardiovascular disease risk. In this trial, both folic acid and betaine supplementation significantly lowered homocysteine levels over the 6-wk supplementation period. However, both forms of supplementation failed to result in any significant change in functioning of the artery, as measured using FMD.
Strengths and limitations: In this trial 40 participants were recruited, and 39 were followed up to trial completion. A crossover design was used, with each participant receiving each supplement and a placebo in sequence. This method enabled a smaller number of participants to be used to answer the question of interest, as compared to parallel-group designs. The majority of participants in the trial were followed up. However, the trial's outcomes are surrogates for cardiovascular disease risk, measured over fairly short time periods, and no clinical outcomes were examined.
Contribution to the evidence: This trial adds to the evidence on the effects of nutrient supplementation on surrogate outcomes for cardiovascular disease risk. The results show that over a 6-wk study period, these surrogate outcomes are not affected by either folic acid or betaine supplementation.