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.

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Available from: Carl L Keen, Oct 06, 2015
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    • "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]. "
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    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
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    • "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. "
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    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
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    • "In patients with type 2 diabetes, no long-term trials have been conducted to examine the effects of either isoflavones or flavan-3-ols on CVD risk biomarkers, although the available data from short-term studies (maximum duration 12 weeks in both flavonoid subclasses) are suggestive of favorable effects (15–17). To our knowledge, no studies have examined the long-term effects of a combined intervention of these bioactive flavonoids on CVD risk in medicated patients with type 2 diabetes, and given our knowledge of their specific mechanisms of action, there is the potential of synergistic effects. "
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    ABSTRACT: To assess the effect of dietary flavonoids on cardiovascular disease (CVD) risk in postmenopausal women with type 2 diabetes on established statin and hypoglycemic therapy. Despite being medicated, patients with type 2 diabetes have elevated CVD risk, particularly postmenopausal women. Although dietary flavonoids have been shown to reduce CVD risk factors in healthy participants, no long-term trials have examined the additional benefits of flavonoids to CVD risk in medicated postmenopausal women with type 2 diabetes. We conducted a parallel-design, placebo-controlled trial with type 2 diabetic patients randomized to consume 27 g/day (split dose) flavonoid-enriched chocolate (containing 850 mg flavan-3-ols [90 mg epicatechin] and 100 mg isoflavones [aglycone equivalents)]/day) or matched placebo for 1 year. Ninety-three patients completed the trial, and adherence was high (flavonoid 91.3%; placebo 91.6%). Compared with the placebo group, the combined flavonoid intervention resulted in a significant reduction in estimated peripheral insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] -0.3 ± 0.2; P = 0.004) and improvement in insulin sensitivity (quantitative insulin sensitivity index [QUICKI] 0.003 ± 0.00; P = 0.04) as a result of a significant decrease in insulin levels (-0.8 ± 0.5 mU/L; P = 0.02). Significant reductions in total cholesterol:HDL-cholesterol (HDL-C) ratio (-0.2 ± 0.1; P = 0.01) and LDL-cholesterol (LDL-C) (-0.1 ± 0.1 mmol/L; P = 0.04) were also observed. Estimated 10-year total coronary heart disease risk (derived from UK Prospective Diabetes Study algorithm) was attenuated after flavonoid intervention (flavonoid +0.1 ± 0.3 vs. placebo 1.1 ± 0.3; P = 0.02). No effect on blood pressure, HbA(1c), or glucose was observed. One-year intervention with flavan-3-ols and isoflavones improved biomarkers of CVD risk, highlighting the additional benefit of flavonoids to standard drug therapy in managing CVD risk in postmenopausal type 2 diabetic patients.
    Diabetes care 02/2012; 35(2):226-32. DOI:10.2337/dc11-1443 · 8.42 Impact Factor
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