Tetrahydrobiopterin supplementation improves endothelial function but does not alter aortic stiffness in patients with rheumatoid arthritis

Background-Rheumatoid arthritis is a systemic inflammatory condition associated with increased cardiovascular risk that may be due to underlying endothelial dysfunction and subsequent aortic stiffening. We hypothesized that supplementation with tetrahydrobiopterin (BH₄) would recouple endothelial nitric oxide synthase and thus improve endothelial function and consequently reduce aortic stiffness. Methods and Results-We conducted 2 randomized, double-blinded, placebo-controlled crossover studies examining 2 separate regimens: an acute regimen, with a single dose of BH₄ 400 mg versus placebo (n=18), and a short-term regimen, composed of a 1-week treatment with BH₄ 400 mg once daily versus placebo (n=15). Flow-mediated dilatation and aortic pulse wave velocity were studied 4 times, before and after each treatment phase. Acute BH₄ supplementation led to an improvement of flow-mediated dilatation, whereas placebo had no effect (mean±SD of effect difference 2.56±4.79%; P=0.03). Similarly, 1-week treatment with BH₄ improved endothelial function, but there was no change with placebo (mean SD of effect difference 3.50±5.05%; P=0.02). There was no change in aortic pulse wave velocity following acute or short-term BH₄ supplementation or placebo (mean±SD of effect difference: acute 0.09±0.67 m/s, P=0.6; short-term 0.03±1.46 m/s, P=0.9). Conclusion-Both acute and short-term supplementation with oral BH₄ improved endothelial function but not aortic stiffness. This result suggests that BH₄ supplementation may be beneficial for patients with rheumatoid arthritis by improving endothelial dysfunction and potentially reducing risk of cardiovascular disease. There appears to be no causal relationship between endothelial function and aortic stiffness, suggesting that they occur in parallel, although they may share common risk factors such as inflammation.