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Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies.
Am J Clin Nutr 2017; 105(2):352-360AJ

Abstract

BACKGROUND

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.

OBJECTIVE

We sought to determine whether an interaction between cocoa flavanols and methylxanthines exists that influences cocoa flavanol-dependent vascular effects.

DESIGN

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.

RESULTS

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.

CONCLUSION

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+Show Affiliations

Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.Mars Inc., McLean, VA.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.Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.Molecular Nutrition Group, School of Chemistry, Food and Pharmacy, University of Reading, Reading, United Kingdom; and.Department of Nutrition, University of California Davis, Davis, CA.Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.Mars Inc., McLean, VA.Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany; christian.heiss@med.uni-duesseldorf.de.

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28003203

Citation

Sansone, Roberto, et al. "Methylxanthines Enhance the Effects of Cocoa Flavanols On Cardiovascular Function: Randomized, Double-masked Controlled Studies." The American Journal of Clinical Nutrition, vol. 105, no. 2, 2017, pp. 352-360.
Sansone R, Ottaviani JI, Rodriguez-Mateos A, et al. Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies. Am J Clin Nutr. 2017;105(2):352-360.
Sansone, R., Ottaviani, J. I., Rodriguez-Mateos, A., Heinen, Y., Noske, D., Spencer, J. P., ... Heiss, C. (2017). Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies. The American Journal of Clinical Nutrition, 105(2), pp. 352-360. doi:10.3945/ajcn.116.140046.
Sansone R, et al. Methylxanthines Enhance the Effects of Cocoa Flavanols On Cardiovascular Function: Randomized, Double-masked Controlled Studies. Am J Clin Nutr. 2017;105(2):352-360. PubMed PMID: 28003203.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies. AU - Sansone,Roberto, AU - Ottaviani,Javier I, AU - Rodriguez-Mateos,Ana, AU - Heinen,Yvonne, AU - Noske,Dorina, AU - Spencer,Jeremy P, AU - Crozier,Alan, AU - Merx,Marc W, AU - Kelm,Malte, AU - Schroeter,Hagen, AU - Heiss,Christian, Y1 - 2016/12/21/ PY - 2016/06/14/received PY - 2016/11/22/accepted PY - 2016/12/23/pubmed PY - 2017/6/28/medline PY - 2016/12/23/entrez KW - absorption KW - cardiovascular function KW - cocoa flavanols KW - interaction KW - methylxanthines SP - 352 EP - 360 JF - The American journal of clinical nutrition JO - Am. J. Clin. Nutr. VL - 105 IS - 2 N2 - BACKGROUND: 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. OBJECTIVE: We sought to determine whether an interaction between cocoa flavanols and methylxanthines exists that influences cocoa flavanol-dependent vascular effects. DESIGN: 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. RESULTS: 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. CONCLUSION: 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. SN - 1938-3207 UR - https://www.unboundmedicine.com/medline/citation/28003203/Methylxanthines_enhance_the_effects_of_cocoa_flavanols_on_cardiovascular_function:_randomized_double_masked_controlled_studies_ L2 - https://academic.oup.com/ajcn/article-lookup/doi/10.3945/ajcn.116.140046 DB - PRIME DP - Unbound Medicine ER -