Mild to moderate hyperhomocysteinaemia is linked to increased cardiovascular disease risk, but there is little to no evidence of a causal relationship between the two.
Previous studies have shown that mildly or moderately elevated homocysteine (between 12 and 30 lmol/L) is associated with certain aspects of atherogenesis, such as vascular inflammation, endothelial dysfunction, and hypercoagulability.
Still, how far these pathogenic mechanisms underlie the link to heart disease has been unclear.
The Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), conducted among women at high risk of heart disease, demonstrated that treatment combining folic acid and vitamins B6 and B12 for 7.3 years significantly lowered homocysteine levels, but did not reduce cardiovascular events on the whole.
Other studies have hypothesised that the beneficial effects of reduced homocysteine may be "countered by adverse effects of high-dose B vitamins, such as an increase in inflammation or endothelial dysfunction".
Current evidence implies that B vitamin-induced reduction of homocysteine does not affect plasma biomarkers of inflammation and endothelial dysfunction, but the sample sizes in most of these studies have been too small (fewer than 200 subjects) and the treatment duration too short (under two years).
Researchers at Harvard Medical School therefore conducted a study to determine if decreasing plasma homocysteine with long-term supplementation of folic acid and vitamins B6 and B12 changes plasma biomarkers of inflammation and endothelial dysfunction in women who face higher heart disease risk.
They recruited 300 participants from the WAFACS and conducted a blood sub-study on them. They then divided them equally into one active treatment group and one placebo group.
The subjects had their plasma concentration of three inflammation biomarkers (C-reactive protein, fibrinogen and interleukin-6), as well as an endothelial dysfunction biomarker (intercellular adhesion molecule 1), measured at baseline and after treatment and follow-up.
After 7.3 years of combined folic acid and vitamin B6 and B112 treatment, the researchers reported an 18% decrease in homocysteine concentrations in the intervention group, compared with the placebo group.
However, they noted no difference between the two groups for any of the biomarkers in blood concentration, from baseline to follow-up.
They noted that the sub-study might have been limited by inaccurate cellular biomarker status. There may also have been other inflammation or endothelial function biomarkers affected by the treatment that were not taken into account.
At the same time, since the WAFACS participants were at high risk of cardiovascular disease, the results may not be applicable to the general population.
They concluded: "These sub-study findings from a large, randomised trial of women at increased risk of CVD indicate that long-term, combined treatment with folic acid, vitamin B6, and vitamin B12 has no effect on plasma biomarkers of inflammation and endothelial dysfunction, despite significant reductions in plasma homocysteine.
"This may partly explain the absence of clinical benefit for homocysteine-lowering in the WAFACS and other secondary prevention trials of CVD.
"The findings also appear consistent with a growing body of evidence that suggests that mildly or moderately elevated homocysteine may not be an important causal factor in vascular inflammation in patients at high risk for CVD, and that the association of homocysteine with CVD is unlikely to be attributed to chronic vascular inflammation."
Source: Journal of the American Heart Association
"Effect of Combined Treatment With Folic Acid, Vitamin B6, and Vitamin B12 on Plasma Biomarkers of Inflammation and Endothelial Dysfunction in Women"
Authors: William G. Christen, et al.