title: Intake and time dependence of blueberry flavonoid-induced improvements in vascular function: a randomized, controlled, double-blind, crossover intervention study with mechanistic insights into biological activity.
abstract: BACKGROUND
  There are very limited data regarding the effects of blueberry flavonoid intake on vascular function in healthy humans.
  
  
  OBJECTIVE
  We investigated the impact of blueberry flavonoid intake on endothelial function in healthy men and assessed potential mechanisms of action by the assessment of circulating metabolites and neutrophil NADPH oxidase activity.
  
  
  METHODS
  Two randomized, controlled, double-blind, crossover human-intervention trials were conducted with 21 healthy men. Initially, the impact of blueberry flavonoid intake on flow-mediated dilation (FMD) and polyphenol absorption and metabolism was assessed at baseline and 1, 2, 4, and 6 h after consumption of blueberry containing 766, 1278, and 1791 mg total blueberry polyphenols or a macronutrient- and micronutrient-matched control drink (0 mg total blueberry polyphenols). Second, an intake-dependence study was conducted (from baseline to 1 h) with 319, 637, 766, 1278, and 1791 mg total blueberry polyphenols and a control.
  
  
  RESULTS
  We observed a biphasic time-dependent increase in FMD, with significant increases at 1-2 and 6 h after consumption of blueberry polyphenols. No significant intake-dependence was observed between 766 and 1791 mg. However, at 1 h after consumption, FMD increased dose dependently to ≤766 mg total blueberry polyphenol intake, after which FMD plateaued. Increases in FMD were closely linked to increases in circulating metabolites and by decreases in neutrophil NADPH oxidase activity at 1-2 and 6 h.
  
  
  CONCLUSIONS
  Blueberry intake acutely improves vascular function in healthy men in a time- and intake-dependent manner. These benefits may be mechanistically linked to the actions of circulating phenolic metabolites on neutrophil NADPH oxidase activity. This trial was registered at clinicaltrials.gov as NCT01292954 and NCT01829542.
authors.affiliation: Department of Food and Nutritional Sciences, School of Chemistry, Food and Pharmacy, University of Reading, Reading, United Kingdom (AR-M, CR, TB-M, ST, TWG, and JPES); the Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Düsseldorf, Düsseldorf, Germany (AR-M and CH); and the Department of Applied Sciences, Faculty of Health and Life Sciences, University of Northumbria, Newcastle upon Tyne, United Kingdom (TWG).
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez-Mateos
authors.forename: Catarina
authors.initials: C
authors.lastname: Rendeiro
authors.forename: Triana
authors.initials: T
authors.lastname: Bergillos-Meca
authors.forename: Setareh
authors.initials: S
authors.lastname: Tabatabaee
authors.forename: Trevor W
authors.initials: TW
authors.lastname: George
authors.forename: Christian
authors.initials: C
authors.lastname: Heiss
authors.forename: Jeremy Pe
authors.initials: JP
authors.lastname: Spencer
mesh_terms: D000293:Adolescent; D000328:Adult; D000872:Anthocyanins / Q000008:administration & dosage / Q000097:blood; D029798:Blueberry Plants / Q000737:chemistry*; D001916:Brachial Artery / Q000187:drug effects / Q000378:metabolism; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004311:Double-Blind Method; D023381:Endpoint Determination; D006801:Humans; D062385:Hydroxybenzoates / Q000097:blood; D008297:Male; D013058:Mass Spectrometry; D019255:NADPH Oxidases / Q000378:metabolism; D059808:Polyphenols / Q000008:administration & dosage* / Q000097:blood; D063177:Pulse Wave Analysis; D014664:Vasodilation / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000872:Anthocyanins; D062385:Hydroxybenzoates; D059808:Polyphenols; D019255:NADPH Oxidases; C017616:phenolic acid