Background: Rheumatoid arthritis (RA) is a systemic inflammatory condition associated with increased cardiovascular risk. The aetiology is most likely multi-factorial, including endothelial dysfunction, caused by uncoupling of the endothelial nitric oxide synthase (eNOS). We hypothesised that oral tetrahydrobiopterin (BH₄), an essential co-factor for eNOS, would lead to an improvement of endothelial function and subsequently, aortic stiffness.

Methods: This was a randomised, double-blinded crossover study, consisting of two separate regimes, 1: a single dose of BH₄ 400mg vs. placebo and 2: a one-week treatment with BH₄ 400mg OD vs. placebo. In study 1, aortic pulse wave velocity (aPWV), and flow mediated dilatation (FMD) were studied before and 3 hours after BH4 supplementation and placebo. In study 2, FMD and aPWV were assessed four times, separated by a week.

Results: A single dose of BH₄, but not placebo, improved endothelial dysfunction (+3.57±4.14 vs.+0.05±1.17%, P=0.03; n=18). There was no change in aPWV following BH4 or placebo (−0.13±0.58 vs. −0.21±0.43m/s; P=0.6). One-week treatment with BH₄, improved endothelial function, whereas placebo did not (+3.69±4.90 vs. +0.19±2.51%, P=0.02; n=15). There was no change in aPWV following BH₄ or placebo (−0.22±1.3 vs. −0.25±0.51m/s, P=0.4) and no correlation between change in aPWV and FMD in either regime.

Conclusion: Both acute and chronic BH₄ supplementation lead to an improvement of endothelial function, but did not reduce aortic stiffness. This suggests that there is no causality between endothelial function and aortic stiffness and that these conditions may just exist in parallel, both influences by common risk factors, such as inflammation.