Edgar et al presented in this journal the results of a meta-analysis (14 trials, total n = 38,941) indicating that the administration of folic acid (0.5 to 5 mg/day) has no overall effect on cardiovascular disease (CVD), mortality, or stroke despite a significant decrease in homocysteine (ranging from −13.0% to −38.2%). Analysis of within-trial results suggested an increased CVD risk in patients with high homocysteine levels at baseline and a lower CVD risk in those with lower homocysteine levels at baseline.

These findings challenge the pathogenetic role of elevated plasma levels of homocysteine in the onset and progression of CVD and hence the therapeutic usefulness of lowering these levels.

Although the results of Edgar et al are intriguing, they demonstrate discrepancies with a number of other studies that were not considered. The investigators focused on the homocysteine-lowering effects of folic acid, while recent research has demonstrated that ≥1 other major effects of folic acid in the cardiovascular system are independent of homocysteine lowering. Moat et al demonstrated in patients with coronary artery disease that folic acid dose-dependently improves endothelial function through a mechanism independent of homocysteine lowering. Antoniades et al independently demonstrated in human vessels that the beneficial effect of folic acid on endothelial dysfunction is explained by the interaction of folic acid and uncoupled endothelial nitric oxide synthase (eNOS); that is, folic acid increases the vascular availability of the essential eNOS cofactor tetrahydrobiopterin and reduces eNOS-derived superoxide generation. After myocardial infarction, folic acid is beneficial to high-energy phosphate metabolism and ventricular dysfunction. Finally, the administration of folic acid improves endothelial progenitor cell function. In addition, an important distinction must be made between folic acid as a long-term, low-dose fortification or dietary supplement and as a short-term, high-dose treatment.

Therefore, we would highly recommend that future studies and meta-analyses of vitamin B trials focus not only on their relation with homocysteine but also on dosage, duration of administration, study population, and the interaction of folic acid with the nitric oxide pathway and indicators for uncoupled eNOS such as asymmetrical dimethyl arginine.