Sustained Benefits in Vascular Function Through Flavanol-Containing Cocoa in Medicated Diabetic Patients. A Double-Masked, Randomized, Controlled Trial

Department for Cardiology, Pulmonology, and Vascular Medicine, University Hospital RWTH Aachen, Aachen, Germany.
Journal of the American College of Cardiology (Impact Factor: 16.5). 07/2008; 51(22):2141-9. DOI: 10.1016/j.jacc.2008.01.059
Source: PubMed


Our goal was to test feasibility and efficacy of a dietary intervention based on daily intake of flavanol-containing cocoa for improving vascular function of medicated diabetic patients.
Even in fully medicated diabetic patients, overall prognosis is unfavorable due to deteriorated cardiovascular function. Based on epidemiological data, diets rich in flavanols are associated with a reduced cardiovascular risk.
In a feasibility study with 10 diabetic patients, we assessed vascular function as flow-mediated dilation (FMD) of the brachial artery, plasma levels of flavanol metabolites, and tolerability after an acute, single-dose ingestion of cocoa, containing increasing concentrations of flavanols (75, 371, and 963 mg). In a subsequent efficacy study, changes in vascular function in 41 medicated diabetic patients were assessed after a 30-day, thrice-daily dietary intervention with either flavanol-rich cocoa (321 mg flavanols per dose) or a nutrient-matched control (25 mg flavanols per dose). Both studies were undertaken in a randomized, double-masked fashion. Primary and secondary outcome measures included changes in FMD and plasma flavanol metabolites, respectively.
A single ingestion of flavanol-containing cocoa was dose-dependently associated with significant acute increases in circulating flavanols and FMD (at 2 h: from 3.7 +/- 0.2% to 5.5 +/- 0.4%, p < 0.001). A 30-day, thrice-daily consumption of flavanol-containing cocoa increased baseline FMD by 30% (p < 0.0001), while acute increases of FMD upon ingestion of flavanol-containing cocoa continued to be manifest throughout the study. Treatment was well tolerated without evidence of tachyphylaxia. Endothelium-independent responses, blood pressure, heart rate, and glycemic control were unaffected.
Diets rich in flavanols reverse vascular dysfunction in diabetes, highlighting therapeutic potentials in cardiovascular disease.

Download full-text


Available from: Carl L Keen,
  • Source
    • "Regular consumption of dark chocolate has been linked to a lower incidence of myocardial infarction and stroke, and to an overall reduction in cardiovascular mortality [1] [2] [3] [4]. Such observations are consistent with reports that cocoa products lower blood pressure [5] [6] [7] [8], improve endothelium-dependent vasodilator responses [7] [8] [9] [10] [11] [12] [13], and inhibit platelet aggregation [12] [13] [14] [15] [16] [17] [18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Regular consumption of chocolate and cocoa products has been linked to reduced cardiovascular mortality. This study compared the effects of high flavanol dark chocolate (HFDC; 1064mg flavanols/day for 6 weeks) and low flavanol dark chocolate (LFDC; 88mg flavanols/day for 6 weeks) on blood pressure, heart rate, vascular function and platelet aggregation in men with pre-hypertension or mild hypertension. Vascular function was assessed by pulse wave analysis using radial artery applanation tonometry in combination with inhaled salbutamol (0.4 mg) to assess changes due to endothelium-dependent vasodilatation. HFDC did not significantly reduce blood pressure compared to baseline or LFDC. Heart rate was increased by LFDC compared to baseline, but not by HFDC. Vascular responses to salbutamol tended to be greater after HFDC. Platelet aggregation induced by collagen or the thromboxane analogue U46619 was unchanged after LFDC or HFDC, whereas both chocolates reduced responses to ADP and the thrombin receptor activator peptide, SFLLRNamide (TRAP6), relative to baseline. Pre-incubation of platelets with theobromine also attenuated platelet aggregation induced by ADP or TRAP6. We conclude that consumption of HFDC confers modest improvements in cardiovascular function. Platelet aggregation is modulated by a flavanol-independent mechanism that is likely due to theobromine. Copyright © 2015. Published by Elsevier Inc.
    Vascular Pharmacology 04/2015; 71. DOI:10.1016/j.vph.2015.02.010 · 3.64 Impact Factor
    • "Whereas flavanols are found in cocoa, tea, apples, berries, and wine, inorganic nitrate is mainly found in beetroot and green leafy vegetables. Several well-controlled randomized human intervention studies have shown that cocoa flavanols have beneficial effects on blood pressure [4] [5], endothelial function [6] [7] [8] [9] [10], and other biomarkers of cardiovascular risk [11] [12]. These putative beneficial vascular effects, correlated with changes in plasma flavanol metabolites over time, were repeatable with pure (À )-epicatechin intake and inhibited by a nitric oxide synthase inhibitor, suggesting a cause-andeffect relationship between flavanols and vascular function improvements [10] [13]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dietary intervention studies have shown that flavanols and inorganic nitrate can improve vascular function, suggesting that these two bioactives may be responsible for beneficial health effects of diets rich in fruits and vegetables. To study interactions between cocoa flavanols (CF) and nitrate focusing on absorption, bioavailability, excretion, and efficacy to increase endothelial function. In a double-blind randomized, dose-response cross-over study, flow-mediated dilation (FMD) was measured in 15 healthy subjects before and at 1, 2, 3, and 4h following consumption of CF (1.4-10.9mg/kg body weight [bw]) or nitrate (0.1-10mg/kg bw). In order to study flavanol-nitrate interactions, an additional intervention trial was performed with nitrate and CF taken in sequence at low and high amounts. FMD was measured before (0h) and at 1h after ingestion of nitrate (3 or 8.5mg/kg bw) or water. Then subjects received a CF drink (2.7 or 10.9mg/kg bw) or a micro- and macronutrient matched CF-free drink. FMD was measured at 1, 2, and 4h thereafter. Blood and urine samples were collected and assessed for CF and NO-metabolites with HPLC and gas phase reductive chemiluminescence. Finally, intragastric formation of nitric oxide (NO) after CF and nitrate consumption was investigated. Both CF and nitrate induced a similar intake-dependent increase in FMD. Maximal values were achieved at 1h post ingestion and gradually decreased to reach baseline values at 4h. These effects were additive at low intake levels whereas CF did not further increase FMD after high nitrate intake. Nitrate did not affect flavanol absorption, bioavailability, or excretion but CF enhanced nitrate-related gastric NO formation and attenuated the increase in plasma nitrite after nitrate intake. Both flavanols and inorganic nitrate can improve endothelial function in healthy subjects at intake amounts that are achievable with a normal diet. Even low dietary intake of these bioactives may exert relevant effects on endothelial function when ingested together. Copyright © 2014 Elsevier Inc. All rights reserved.
    Free Radical Biology and Medicine 12/2014; 80. DOI:10.1016/j.freeradbiomed.2014.12.009 · 5.74 Impact Factor
  • Source
    • "Finally, but somewhat contrary to the peptide ligand theory, foods such as teas and chocolate are known to lower blood pressure. These foods also contain high concentrations of bitter compounds such as flavanols; leading to the speculation that the lower vascular tone associated with consumption of these foods is driven by bitter taste receptor engagement [24]–[26]. Overall, our data show the expression of taste receptors is much more extensive than previously appreciated and includes MSC and VSMCs as TAS2R expressing cell types. These observations open a new area for fertile research in discovering the cognate ligands and various biologic in vivo role of this unique receptor class. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The ability of cells to detect changes in the microenvironment is important in cell signaling and responsiveness to environmental fluctuations. Our interest is in understanding how human bone marrow stromal-derived cells (MSC) and their relatives, vascular smooth muscle cells (VSMC), interact with their environment through novel receptors. We found, through a proteomics screen, that MSC express the bitter taste receptor, TAS2R46, a protein more typically localized to the taste bud. Expression was also confirmed in VSMCs. A prototypical bitter compound that binds to the bitter taste receptor class, denatonium, increased intracellular calcium release and decreased cAMP levels as well as increased the extracellular release of ATP in human MSC. Denatonium also bound and activated rodent VSMC with a change in morphology upon compound exposure. Finally, rodents given denatonium in vivo had a significant drop in blood pressure indicating a vasodilator response. This is the first description of chemosensory detection by MSC and VSMCs via a taste receptor. These data open a new avenue of research into discovering novel compounds that operate through taste receptors expressed by cells in the marrow and vascular microenvironments.
    PLoS ONE 03/2013; 8(3):e58945. DOI:10.1371/journal.pone.0058945 · 3.23 Impact Factor
Show more