title: Tetrahydrobiopterin Supplementation Improves Endothelial Function But Does Not Alter Aortic Stiffness in Patients With Rheumatoid Arthritis.
abstract: 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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, University of Cambridge, UK km391@medschl.cam.ac.uk.
authors.forename: Kaisa M
authors.initials: KM
authors.lastname: Mäki-Petäjä
authors.affiliation: Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, University of Cambridge, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Day
authors.affiliation: Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, University of Cambridge, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cheriyan
authors.affiliation: Rheumatology Research Unit, Addenbrooke's Hospital, University of Cambridge, UK.
authors.forename: Frances C
authors.initials: FC
authors.lastname: Hall
authors.affiliation: Rheumatology Research Unit, Addenbrooke's Hospital, University of Cambridge, UK.
authors.forename: Andrew J K
authors.initials: AJ
authors.lastname: Östör
authors.affiliation: Rheumatology Research Unit, Addenbrooke's Hospital, University of Cambridge, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Shenker
authors.affiliation: Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Hospital, University of Cambridge, UK.
authors.forename: Ian B
authors.initials: IB
authors.lastname: Wilkinson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D001708:Biopterins / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018592:Cross-Over Studies; D019587:Dietary Supplements / Q000009:adverse effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004739:England; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010865:Pilot Projects; D063177:Pulse Wave Analysis; D013997:Time Factors; D016896:Treatment Outcome; D014652:Vascular Diseases / Q000175:diagnosis / Q000503:physiopathology / Q000517:prevention & control*; D059289:Vascular Stiffness / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects; D055815:Young Adult
chemical_list: D015415:Biomarkers; D002317:Cardiovascular Agents; D018836:Inflammation Mediators; D001708:Biopterins; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin
keywords: arteriosclerosis; endothelial function; inflammation; rheumatoid arthritis; tetrahydrobiopterin