title: Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies.
abstract: Cocoa flavanol intake, especially that of (-)-epicatechin, has been linked to beneficial effects on human cardiovascular function. However, cocoa also contains the methylxanthines theobromine and caffeine, which may also affect vascular function.
  
  
  
  We sought to determine whether an interaction between cocoa flavanols and methylxanthines exists that influences cocoa flavanol-dependent vascular effects.
  
  
  
  Test drinks that contained various amounts of cocoa flavanols (0-820 mg) and methylxanthines (0-220 mg), either together or individually, were consumed by healthy volunteers (n = 47) in 4 different clinical studies-3 with a randomized, double-masked crossover design and 1 with 4 parallel crossover studies. Vascular status was assessed by measuring flow-mediated vasodilation (FMD), brachial pulse wave velocity (bPWV), circulating angiogenic cells (CACs), and blood pressure before and 2 h after the ingestion of test drinks.
  
  
  
  Although cocoa flavanol intake increased FMD 2 h after intake, the consumption of cocoa flavanols with methylxanthines resulted in a greater enhancement of FMD. Methylxanthine intake alone did not result in statistically significant changes in FMD. Cocoa flavanol ingestion alone decreased bPWV and diastolic blood pressure and increased CACs. Each of these changes was more pronounced when cocoa flavanols and methylxanthines were ingested together. It is important to note that the area under the curve of the plasma concentration of (-)-epicatechin metabolites over time was higher after the co-ingestion of cocoa flavanols and methylxanthines than after the intake of cocoa flavanols alone. Similar results were obtained when pure (-)-epicatechin and the methylxanthines theobromine and caffeine were consumed together.
  
  
  
  A substantial interaction between cocoa flavanols and methylxanthines exists at the level of absorption, in which the methylxanthines mediate an increased plasma concentration of (-)-epicatechin metabolites that coincides with enhanced vascular effects commonly ascribed to cocoa flavanol intake. This trial was registered at clinicaltrials.gov as NCT02149238.
authors.affiliation: Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sansone
authors.affiliation: Mars Inc., McLean, VA.
authors.forename: Javier I
authors.initials: JI
authors.lastname: Ottaviani
authors.affiliation: Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.|Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez-Mateos
authors.affiliation: Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Heinen
authors.affiliation: Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Dorina
authors.initials: D
authors.lastname: Noske
authors.affiliation: Molecular Nutrition Group, School of Chemistry, Food and Pharmacy, University of Reading, Reading, United Kingdom; and.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Spencer
authors.affiliation: Department of Nutrition, University of California Davis, Davis, CA.
authors.forename: Alan
authors.initials: A
authors.lastname: Crozier
authors.affiliation: Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Merx
authors.affiliation: Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Kelm
authors.affiliation: Mars Inc., McLean, VA.
authors.forename: Hagen
authors.initials: H
authors.lastname: Schroeter
authors.affiliation: Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany; christian.heiss@med.uni-duesseldorf.de.
authors.forename: Christian
authors.identifier: 0000-0002-3212-8995
authors.initials: C
authors.lastname: Heiss
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002097:C-Reactive Protein / Q000378:metabolism; D002099:Cacao / Q000737:chemistry*; D002110:Caffeine / Q000008:administration & dosage; D002319:Cardiovascular System / Q000187:drug effects*; D002392:Catechin / Q000097:blood / Q000652:urine; D018592:Cross-Over Studies; D004311:Double-Blind Method; D023381:Endpoint Determination; D044948:Flavonols / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D059808:Polyphenols / Q000008:administration & dosage*; D063177:Pulse Wave Analysis; D013805:Theobromine / Q000008:administration & dosage; D059289:Vascular Stiffness / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014970:Xanthines / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D044948:Flavonols; D059808:Polyphenols; D014970:Xanthines; C008514:methylxanthine; D002110:Caffeine; D002392:Catechin; D002097:C-Reactive Protein; D013805:Theobromine
keywords: absorption; cardiovascular function; cocoa flavanols; interaction; methylxanthines