Short-term high-dose folic acid does not alter markers of endothelial cell damage in patients with coronary heart disease

Background and objective: Endothelial dysfunction is an early, pre-clinical manifestation of coronary heart disease and is associated with increased plasma levels of von Willebrand factor (vWF), soluble E-selectin, and thrombomodulin, markers of endothelial cell damage/activation and reduced nitric oxide bioavailability. Homocysteine is associated with an increased risk of cardiovascular disease and mortality. High-dose folic acid treatment lowers plasma homocysteine by 25% and improves nitric oxide bioavailability; however, the effects on other indices of endothelial cell activation/damage has not been examined in patients with coronary heart disease and normal renal function. Design and methods: In a randomised, double-blind, cross-over study in 50 patients with coronary heart disease and normal serum creatinine, folic acid (5 mg/daily) was administered for 6 weeks and blood was analysed for von Willebrand factor, soluble E-selectin, and thrombomodulin. Endothelial nitric oxide bioavailability was assessed by flow-mediated dilatation. Results: Plasma folate levels increased (9.1±3.4 vs. 310±235 μg/l; p<0.001) and nitric oxide bioavailability improved (47±35 vs. 110±43 μm; p<0.001) following active treatment. However, markers of endothelial cell injury were not significantly influenced (von Willebrand factor 118±33 vs. 119±34%; E-selectin 52±17 vs. 51±16 μg/l; thrombomodulin 3.94±1.81 vs. 3.94±1.51 μg/l; p=NS comparing post-placebo with post-folate). No correlation was observed between improvement in flow-mediated dilatation and change in endothelial marker proteins. Interepretation and conclusion: These data suggest that endothelial markers are not useful surrogates of endothelial nitric oxide bioavailability in coronary heart disease and may be a less sensitive marker of endothelial function than nitric oxide.