We investigated whether reducing post-methionine homocysteine concentrations via various treatments other than folic acid affects vascular function, as measured through flow-mediated dilation (FMD) of the brachial artery. High fasting and post-methionine homocysteine concentrations are associated with cardiovascular disease risk, but homocysteine might be a surrogate marker for low folate status.
This was a randomized, placebo-controlled, double-blind, crossover study.
The study took place at Wageningen University in Wageningen in the Netherlands.
Participants were 39 apparently healthy men and women, aged 50–70 y.
Participants ingested 10 mg of folic acid, 3 g of betaine, 5 g of serine, and placebo together with an oral methionine load. Each supplement was tested on two different days.
On each of the eight treatment days, plasma homocysteine concentrations and FMD were measured before (t = 0 h, fasting) and 6 h (t = 6 h) after methionine loading.
The mean (± SD) fasting homocysteine concentrations averaged over the eight test days were 9.6 ± 2.1 μmol/l. Mean fasting FMD was 3.1 ± 2.4 FMD%. A methionine load with placebo increased homocysteine concentrations by 17.2 ± 9.3 μmol/l at 6 h after loading, similar to the increase following methionine loading with folic acid. A methionine load together with betaine and with serine increased homocysteine by 10.4 ± 2.8 μmol/l (p < 0.001 relative to placebo) and by 12.1 ± 8.2 μmol/l (p < 0.001 relative to placebo), respectively. Methionine loading with placebo did not affect FMD, and neither did methionine loading with folic acid, betaine, or serine; differences relative to placebo were +0.7 FMD% (95%CI, −0.6; 1.9), +0.2 FMD% (−1.0; 1.3), and +0.3 FMD% (−0.8; 1.4), respectively.
Experimentally induced acute changes in homocysteine concentrations did not affect FMD in healthy volunteers. This implies that potential adverse effects of high homocysteine concentrations on the cardiovascular system are not mediated through vascular function. However, homocysteine or folate may affect cardiovascular disease risk through other mechanisms.
Background: It is already known from observational studies that people with high concentrations of homocysteine (an amino acid) in the blood are at increased risk of disease involving the heart and blood vessels, known as cardiovascular disease. Some randomized trials have also shown that lowering homocysteine levels decreases the risk of cardiovascular disease, but not all trials show this. The mechanisms linking homocysteine levels and cardiovascular disease are not well understood. Olthof and colleagues wanted to explore further the mechanisms linking homocysteine levels and the risk of cardiovascular disease. The investigators did a trial in healthy volunteers in which homocysteine concentrations were experimentally raised, then lowered, over short periods of time. The volunteers took a methionine supplement (an amino acid that is converted to homocysteine in the body) to raise homocysteine levels and either betaine (a dietary nutrient), serine (an amino acid), or folic acid (a B vitamin) to lower them. During the trial, the researchers then looked at how well the volunteers' arm arteries functioned, as a surrogate for measuring cardiovascular disease risk.
What this trial shows: The investigators found that functioning of the volunteers' arteries, as measured through flow-mediated dilation (FMD), was not affected by the changes in homocysteine levels that were brought about in the experiment.
Strengths and limitations: Although the number of participants analyzed in the trial was small (n = 39), it was large enough to adequately test the researchers' hypothesis. The vast majority of participants received the experimental treatment, with only one participant dropping out of the study. However, the observations were made over a short period of time, within 6 h of the experimental treatments being given. The investigators did not look at clinical outcomes, such as heart disease or stroke. Therefore, this trial does not provide evidence on whether altered homocysteine levels cause, or could be manipulated to prevent, such clinical outcomes.
Contribution to the evidence: This trial adds information on the short-term effects of changes in homocysteine levels.