Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies

Sansone, Roberto; Ottaviani, Javier I.; Rodriguez-Mateos, Ana; Heinen, Yvonne; Noske, Dorina; Spencer, Jeremy P.E.; Crozier, Alan; Merx, Marc W.; Kelm, Malte; Schroeter, Hagen; Heiß, Christian

doi:10.3945/ajcn.116.140046

Cited by 97 publications

(89 citation statements)

References 30 publications

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“…In the meantime, Caco-2 cells are no longer considered as a good model to study epicatechin absorption as the profile of (−)-epicatechin metabolites from Caco-2 cells and human enterocytes in vivo is different and determines the efflux of (−)-epicatechin metabolites back into the apical side of Caco-2 cells and to the gut lumen, respectively [36]. An RCT with healthy volunteers has recently shown that methylxanthines (1.48 mg theobromine and 0.15 mg caffeine per kg BW) enhance the absorption of (−)-epicatechin [37]. As our subjects ingested similar amounts of methylxanthines from NALC (18.55 mg theobromine, 0.58 mg caffeine) and ALC (18.42 mg theobromine, 0.88 mg caffeine) per kg BW, an impact of methylxanthines on the plasma appearance of (−)-epicatechin in our study is unlikely.…”

Section: Discussionmentioning

confidence: 99%

Low Plasma Appearance of (+)-Catechin and (−)-Catechin Compared with Epicatechin after Consumption of Beverages Prepared from Nonalkalized or Alkalized Cocoa—A Randomized, Double-Blind Trial

et al. 2020

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Flavan-3-ols are claimed to be responsible for the cardioprotective effects of cocoa. Alkalized cocoa powder (ALC), commonly used for many non-confectionary products, including beverages, provides less (+)-catechin, (−)-epicatechin, and procyanidins and more (−)-catechin than nonalkalized cocoa powder (NALC). This may affect the plasma appearance of monomeric flavan-3-ol stereoisomers after consumption of NALC vs. ALC. Within a randomized, crossover trial, 12 healthy nonsmokers ingested a milk-based cocoa beverage providing either NALC or ALC. Blood was collected before and within 6 h postconsumption. (+)-Catechin, (−)-catechin, and epicatechin were analyzed in plasma by HPLC as sum of free and glucuronidated metabolites. Pharmacokinetic parameters were obtained by a one-compartment model with nonlinear regression methods. For epicatechin in plasma, total area under the curve within 6 h postconsumption (AUC0–6h) and incremental AUC0–6h were additionally calculated by using the linear trapezoidal method. After consumption of NALC and ALC, (+)-catechin and (−)-catechin were mostly not detectable in plasma, in contrast to epicatechin. For epicatechin, total AUC0–6h was different between both treatments, but not incremental AUC0–6h. Most kinetic parameters were similar for both treatments, but they varied strongly between individuals. Thus, epicatechin is the main monomeric flavan-3-ol in plasma after cocoa consumption. Whether NALC should be preferred against ALC due to its higher (−)-epicatechin content remains unclear with regard to the results on incremental AUC0–6h. Future studies should investigate epicatechin metabolites in plasma for a period up to 24 h in a larger sample size, taking into account genetic polymorphisms in epicatechin metabolism and should consider all metabolites to understand inter-individual differences after cocoa intake.

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Section: Discussionmentioning

confidence: 99%

Low Plasma Appearance of (+)-Catechin and (−)-Catechin Compared with Epicatechin after Consumption of Beverages Prepared from Nonalkalized or Alkalized Cocoa—A Randomized, Double-Blind Trial

et al. 2020

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“…A recent study with cocoa revealed that the C max of SREMs 2 hr after intake of cocoa was enhanced significantly by co‐ingestion of the purine alkaloid, theobromine 46 , in parallel with an accompanying significant increase in flow‐mediated vasodilation (FMD; Sansone et al., ). The mechanism by which theobromine mediates an increased plasma concentration of SREMs remains to be determined.…”

Section: Bioavailabilitymentioning

confidence: 99%

“…The cumulative benefit of affecting such a diverse array of vascular biomarkers was observed in a recent human RCT reporting a significant lowering of 10‐yr risk for CVD and CHD as established by the Framingham risk score (Sansone et al., ). Significant evidence exists for the contribution of (−)‐epicatechin 38 to the benefits of cocoa consumption (Schroeter et al., ), yet interestingly a recent human RCT revealed that beneficial changes to FMD, pulse wave velocity (PWV), DBP, and circulating angiogenic cells were more pronounced when cocoa flavan‐3‐ols were ingested with methylxanthines, principally in the form of theobromine 46, implicating the impact of multiple bioactives present within cocoa (Sansone et al., ). For extensive reviews summarizing cocoa intervention studies refer to Ellam and Williamson (), Heiss et al.…”

Section: Bioactivitymentioning

confidence: 99%

The Bioavailability, Transport, and Bioactivity of Dietary Flavonoids: A Review from a Historical Perspective

Williamson

Kay

Crozier

2018

Comp Rev Food Sci Food Safe

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438

288

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Flavonoids are plant-derived dietary components with a substantial impact on human health. Research has expanded massively since it began in the 1930s, and the complex pathways involved in bioavailability of flavonoids in the human body are now well understood. In recent years, it has been appreciated that the gut microbiome plays a major role in flavonoid action, but much progress still needs to be made in this area. Since the first publications on the health effects of flavonoids, their action is understood to protect against various stresses, but the mechanism of action has evolved from the now debunked simple direct antioxidant hypothesis into an understanding of the complex effects on molecular targets and enzymes in specific cell types. This review traces the development of the field over the past 8 decades, and indicates the current state of the art, and how it was reached. Future recommendations based on this historical analysis are (a) to focus on key areas of flavonoid action, (b) to perform human intervention studies focusing on bioavailability and protective effects, and (c) to carry out cellular in vitro experiments using appropriate cells together with the chemical form of the flavonoid found at the site of action; this could be the native form of compounds found in the food for studies on digestion and the intestine, the conjugated metabolites found in the blood after absorption in the small intestine for studies on cells, or the chemical forms found in the blood and tissues after catabolism by the gut microbiota.

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“…Although more studies are needed to confirm these contrasting findings, it may be that investigations using a purified dietary constituent do not fully mimic the effects or effect sizes observed when the same constituent is consumed in its native food/food matrix. In a very recent study, Sansone et al [81] reported that cocoa methylxanthines (theobromine and caffeine) enhanced the vascular effects exerted by cocoa flavanols and also improve their bioavailability. This shows that synergistic effects between polyphenols and other dietary compounds exist, which may explain the different effects observed when pure compounds and polyphenol rich foods or extracts were tested.…”

Section: Flavanolsmentioning

confidence: 99%

Pure Polyphenols Applications for Cardiac Health and Disease

Santos

Gomes

Oudot

et al. 2018

CPD

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Polyphenols are natural compounds present in fruits and vegetables that can exert beneficial effects on human health and notably, on the cardiovascular system. Some of these compounds showed significant protective activities toward atherosclerosis, hypertension, myocardial infarction, anthracyclin-induced cardiomyopathy, angiogenesis as well as heart failure. Polyphenols can act through systemic effects as well as through modulation of signaling pathways such as redox signaling, inflammation, autophagy and cell death in the heart and vessels. These effects can be mediated by changes in expression level and by post-translational modifications of proteins (e.g. Stat1, CaMKII, Sirtuins, BCL-2 family members, PDEs, TRF2, eNOS and SOD). This non-comprehensive short review aims to summarize recent knowledge on the main pharmacological effects and mechanisms of cardioprotection of pure polyphenols, using different approaches such as cell culture, animal models and human studies.

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Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies

Cited by 97 publications

References 30 publications

Low Plasma Appearance of (+)-Catechin and (−)-Catechin Compared with Epicatechin after Consumption of Beverages Prepared from Nonalkalized or Alkalized Cocoa—A Randomized, Double-Blind Trial

Low Plasma Appearance of (+)-Catechin and (−)-Catechin Compared with Epicatechin after Consumption of Beverages Prepared from Nonalkalized or Alkalized Cocoa—A Randomized, Double-Blind Trial

The Bioavailability, Transport, and Bioactivity of Dietary Flavonoids: A Review from a Historical Perspective

Pure Polyphenols Applications for Cardiac Health and Disease

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