In the absence of a causal relationship between homocysteine and cardiovascular disease, what remains most promising for folate are studies illustrating its protective © 2007 Elsevier Australia effects, mediated through other mechanisms. This has led some researchers to suggest that folate deficiency may be the primary cause of an increased vascular risk and that elevated homocysteine levels should principally be considered a marker for low folate status rather than a pathogenetic marker (Verhaar et al 2002).
Demonstrations of in vitro antioxidant activity, effects on cofactor availability and direct and indirect interactions with the endothelial NO synthase enzyme have been proposed as plausible mechanisms, through which folate may prevent endothelial dysfunction (Das 2003, Verhaar et al 2002).
Several studies show the cardiovascular protective effects of folic acid, including the predictive value of low folate status on stroke risk (Verhaar et al 2002, Bazzano et al 2002). Few interventional studies have been conducted and on the whole results have been disappointing, which may be because the trials are commonly looking at folate in secondary prevention rather than primary. One such study was an open label trial of 500 ^g/day folate over 2 years in 593 patients, which failed to reduce cardiovascular events (Liem et al 2003).
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