Acute effects of 5-methyltetrahydrofolate on endothelial function and asymmetric dimethylarginine in patients with chronic heart failure

Background and aims: Folic acid enhances endothelial function in vascular disease states but its effects in chronic heart failure (CHF) are largely unknown. We studied the acute effects of i.v. methyltetrahydrofolate (5MTHF), the active metabolite of folic acid, on endothelial function and asymmetric dimethylarginine (ADMA) in CHF patients. Methods and results: Twenty two CHF patients and 22 controls received one of the following three-step infusions (1h per each step) in a randomized, parallel group, placebo-control study: (1) active treatment (saline, 5MTHF, and 5MTHF+the endothelial nitric oxide inhibitor N ^G -monomethyl l-arginine, LNMMA); or (2) placebo (saline×3). Endothelium-dependent vasodilatation was assessed by pulse-wave analysis (salbutamol-mediated changes in augmentation index, AIx). 5MTHF did not exert any significant effects on endothelium-dependent vasodilatation both in controls [ΔAIx post-salbutamol baseline -7.6% (-24.8/-4.1) vs. 5MTHF -5.5% (-16.7/-3.6), medians and interquartile range, and CHF patients [-1.8% (-17.3/+1.3) vs. -2.4% (-3.8/-1.2)]. However, a significant reduction in ADMA concentrations was observed in both groups [controls baseline 0.68μmol/L (0.64/0.77) vs. 5MTHF 0.65 (0.57/0.74); CHF baseline 0.76 (0.63/0.82) vs. 5MTHF 0.69 (0.66/0.71), P=0.05 for both vs. baseline and placebo. These effects persisted during co-infusion with LNMMA. Conclusion: 5MTHF did not affect endothelial function but significantly reduced serum ADMA concentrations both in CHF patients and controls. This suggests a direct effect of 5MTHF on ADMA metabolism.