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Cited by 202Nitric Oxide and Endothelin EffectsPhytochemicals and Antioxidant ActivitiesCardiovascular Health and Disease Prevention

Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease

Open access
Heiss, Christian, Jahn, Sarah, Taylor, Melanie, Real, Wendy May, Angeli, Franca S., Wong, Maelene L., Amabile, Nicolas, Prasad, Megha +10 more·2010·Journal of the American College of Cardiology
DOI 10.1016/j.jacc.2010.03.039
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Abstract

Objectives In patients with coronary artery disease (CAD) medically managed according to currently accepted guidelines, we tested whether a 1-month dietary intervention with flavanol-containing cocoa leads to an improvement of endothelial dysfunction and whether this is associated with an enhanced number and function of circulating angiogenic cells (CACs).Background Dietary flavanols can improve endothelial dysfunction. The CACs, also termed endothelial progenitor cells, are critical for vascular repair and maintenance of endothelial function.Methods In a randomized, controlled, double-masked, cross-over trial, 16 CAD patients (64+/-3 years of age) received a dietary high-flavanol intervention (HiFI [375 mg]) and a macronutrient- and micronutrient-matched low-flavanol intervention (LoFI [9 mg]) twice daily in random order over 30 days.Results Endothelium-dependent vasomotor function, as measured by flow-mediated vasodilation of the brachial artery, improved by 47% in the HiFI period compared with the LoFI period. After HiFI, the number of CD34+/KDR+-CACs, as measured by flow cytometry, increased 2.2-fold as compared with after LoFI. The CAC functions, as measured by the capacity to survive, differentiate, proliferate, and to migrate were not different between the groups. The HiFI led to a decrease in systolic blood pressure (mean change over LoFI: -4.2+/-2.7 mm Hg), and increase in plasma nitrite level (mean change over LoFI: 74+/-32 nM). Applying a mixed-effects linear regression model, the results demonstrated a significant increase in flow-mediated vasodilation and a decrease in systolic blood pressure with increasing levels of CD34+/KDR+-CACs.Conclusions Sustained improvements in endothelial dysfunction by regular dietary intake of flavanols are associated with mobilization of functional CACs. (Effect of Cocoa Flavanols on Vascular Function in Optimally Treated Coronary Artery Disease Patients: Interaction Between Endothelial Progenitor Cells, Reactivity of Micro- and Macrocirculation; NCT00553774).

Verified 2026-10-06 · 4 references not checked yet

AI snapshot

Written from the paper’s full text.

TL;DR

In a 30-day randomized crossover trial in 16 medically managed coronary artery disease patients, high-flavanol cocoa improved endothelial function and increased circulating angiogenic cells compared with low-flavanol cocoa. The improvement in flow-mediated dilation and systolic blood pressure tracked with CD34+/KDR+ circulating angiogenic cell mobilization.

Key findings

  • Flow-mediated dilation improved by 47% during the high-flavanol period compared with the low-flavanol period; baseline values were 4.4 ± 0.5% and 4.6 ± 0.5% before the low- and high-flavanol regimens, respectively.
  • CD34+/KDR+ circulating angiogenic cells increased 2.2-fold after high-flavanol intake versus low-flavanol intake, while assays of survival, differentiation, proliferation, and migration did not differ between groups.
  • Systolic blood pressure decreased with high-flavanol intake, reported as a mean change over low-flavanol of −4.2 ± 2.7 mm Hg in the abstract and as a 4.2 ± 0.3 mm Hg decrease in the results; plasma nitrite increased by a mean change over low-flavanol of 74 ± 32 nM.
  • In mixed-effects linear regression, each 1% increase in CD34+/KDR+ circulating angiogenic cells was associated with a 4.6% increase in flow-mediated dilation, a 0.52 decrease in brachial artery diameter, and a 4.44 mm Hg decrease in systolic blood pressure.

Methods

  • Randomized, controlled, double-masked crossover design: 16 CAD patients (64 ± 3 years; 13 male/3 female) completed the study, receiving high-flavanol cocoa (375 mg) or matched low-flavanol cocoa (9 mg) twice daily for 30 days, with a 1-week washout between interventions.
  • Primary and secondary outcomes were brachial artery flow-mediated dilation and circulating angiogenic cell number/function; cells were measured by flow cytometry for CD34/KDR and CD133/KDR and functionally assessed after ex vivo expansion. Tertiary outcomes included plasma nitrite/nitrate, blood pressure, heart rate, and cytokines involved in cell mobilization (VEGF, SDF-1α, SCF).
  • Analysis used two-way repeated-measures ANOVA with Holm-Sidak post hoc tests, plus random-effects linear regression to test associations between CD34+/KDR+ circulating angiogenic cells and outcomes.

Limitations

  • The paper states that the mechanisms underlying the blood pressure effect cannot be determined from this study and that long-term intervention trials are needed; it also notes that small increases after the low-flavanol regimen may reflect non-flavanol bioactives such as methylxanthines or regression to the mean.
  • Evident from the text: the sample was small (16 completers, mostly male), the intervention periods were short (30 days), and no clinical event outcomes were assessed, limiting generalizability and inference about long-term cardiovascular benefit.
  • Evident from the text: the study received an unrestricted research grant from Mars, Inc., a coauthor was employed by Mars, Inc., and the company supplied the cocoa beverage powders, indicating a potential conflict of interest.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.jacc.2010.03.039

Cites

8 of 12 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 16 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    For each 1% increase in CD34+/KDR+ circulating angiogenic cell numbers, systolic blood pressure decreased by 4.44 mm Hg.

    “For each 1% increase in CD34 ϩ /KDR ϩ -CAC numbers, there was a significant increase in FMD of 4.6%, and significant decrease in BA diameter and SBP by 0.52 and 4.44 mm Hg, respectively.”
    Quote in the paperSubstantial claim
  • Findingown data

    High-flavanol intervention lowered systolic blood pressure relative to low-flavanol intervention by approximately 4.2 mm Hg.

    “The HiFI led to a decrease in systolic blood pressure (mean change over LoFI: Ϫ4.2 Ϯ 2.7 mm Hg)”
    • Also stated in: § Composition of Matched Flavanol-Containing Test Materials Ingested Twice Daily · plain
      “corresponding to a 4.2 Ϯ 0.3 mm Hg decrease as compared with LoFI.”
    Quote in the paperNot a substantial claim
  • Findingown data

    After the high-flavanol intervention, the number of CD34+/KDR+ circulating angiogenic cells was 2.2 times higher than after the low-flavanol intervention.

    “After HiFI, the number of CD34 ϩ /KDR ϩ -CACs, as measured by flow cytometry, increased 2.2-fold as compared with after LoFI.”
    Quote in the paperSubstantial claim
  • Findingown data

    The ability of circulating angiogenic cells to survive, differentiate, proliferate, and migrate did not differ between the high-flavanol and low-flavanol interventions.

    “The CAC functions, as measured by the capacity to survive, differentiate, proliferate, and to migrate were not different between the groups.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In patients with coronary artery disease, flow-mediated dilation of the brachial artery was 47% higher after 30 days of high-flavanol cocoa than after low-flavanol cocoa.

    “Endothelium-dependent vasomotor function, as measured by flow-mediated vasodilation of the brachial artery, improved by 47% in the HiFI period compared with the LoFI period.”
    Quote in the paperSubstantial claim
  • May combine two claims. 18
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    During the study, patients showed no signs of increased inflammation or increases in the analyzed cytokines VEGF, SDF-1α, and SCF.

    “Notably, during the course of the present study, our patients did not show any signs of augmented inflammation, or increases in the cytokines analyzed (VEGF, SDF-1␣, and SCF).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Nitrate levels were not significantly changed by either the high-flavanol or low-flavanol intervention.

    “Nitrate levels were not significantly affected by either treatment (average at first visit: 23 Ϯ 5 M).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No significant changes occurred in plasma VEGF, SDF-1α, or SCF, or in clinical laboratory parameters including C-reactive protein, erythrocyte sedimentation rate, total cholesterol, LDL, HDL, glucose, triglycerides, and blood cell counts.

    “We observed no significant changes in plasma VEGF, SDF-1␣, or SCF and clinical laboratory parameters, including C-reactive protein, erythrocyte sedimentation rate, total cholesterol, LDL, high-density lipoprotein, glucose, triglycerides, and blood cell counts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Low-flavanol intervention did not significantly change systolic blood pressure, whereas high-flavanol intervention significantly reduced systolic blood pressure to 125 ± 1 mm Hg (p = 0.013 vs day 0).

    “Whereas 30-day LoFI did not significantly change systolic blood pressure (SBP [129 Ϯ 1 mm Hg, p ϭ 0.471 vs. day 0]), HiFI significantly decreased SBP to 125 Ϯ 1 mm Hg (p ϭ 0.013 vs. day 0), corresponding to a 4.2 Ϯ 0.3 mm Hg decrease as compared with LoFI.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The cocoa drinks were well tolerated, and no patient had a major adverse event, cardiovascular-specific event, or hospitalization during the study.

    “The cocoa drinks were well tolerated, and none of the patients experienced major adverse events, cardiovascular-specific events, or hospitalization during the study period.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean heart rate and diastolic blood pressure were not significantly affected by either the high-flavanol or low-flavanol intervention.

    “Mean heart rate and diastolic BP were not significantly affected by either treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    High-flavanol intervention increased plasma nitrite relative to low-flavanol intervention, while low-flavanol intervention did not change plasma nitrite.

    “and increase in plasma nitrite level (mean change over LoFI: 74 Ϯ 32 nM).”
    • Also stated in: § Improvement of FMD. · plain
      “Levels of plasma nitrite significantly increased after HiFI, but remained unaltered after LoFI (Fig. 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Small but significant increases in flow-mediated dilation and CD34+/KDR+ circulating angiogenic cells were observed after the low-flavanol regimen, differing in part from Balzer et al.

    “Differing in part from Balzer et al. (11), we observed small but significant increases in FMD and CD34 ϩ / KDR ϩ -CAC after the LoFI regimen.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Balzer, 2008, Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients a double-masked, randomized, controlled trial, J Am Coll Cardiol source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    All individual medications, treatment paradigms, and body mass indexes remained unchanged throughout the study.

    “All individual medications and treatment paradigms, as well as body mass indexes remained unaltered throughout the study.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study protocol received approval from the University of California-San Francisco Committee on Human Research, and participants provided written informed consent.

    “The study protocol was approved by the University of California-San Francisco Committee on Human Research, and subjects gave written informed consent.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mobilization of circulating angiogenic cells contributes to the repair response after vascular injury.

    “Physiologically, the mobilization of CACs contributes to the repair response after vascular injury (3,4).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Werner, 2005, Circulating endothelial progenitor cells and cardiovascular outcomes, N Engl J Med source

      Not checked in the free run.

    • cites [4] Dimmeler, 2004, Vascular repair by circulating endothelial progenitor cells: the missing link in atherosclerosis?, J Mol Med source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    The high-flavanol and low-flavanol cocoa drinks were standardized for flavanol content and closely matched for macronutrients, micronutrients, calories, theobromine, and caffeine.

    “Cocoa drinks (Mars, Inc., McLean, Virginia) were standardized for flavanol content and profile, and closely matched for macronutrient content, micronutrient content, caloric load, and theobromine and caffeine levels.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Randomization and dispensing of cocoa drinks were done by the Department of Pharmacology, and both patients and investigators were masked to the flavanol content of the test drinks.

    “Randomization and cocoa drink dispensations were performed by the Department of Pharmacology, University of California-San Francisco.Patients and investigators were masked throughout the study with regard to flavanol content of the test drinks.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Functional characterization of circulating angiogenic cells was performed after ex vivo expansion.

    “Functional CAC characterization was performed after ex vivo expansion (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Heiss, 2005, Impaired progenitor cell activity in age-related endothelial dysfunction, J Am Coll Cardiol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Flow-mediated dilation was measured by ultrasonography with an automated analysis system after overnight fasting and 30 minutes of supine rest.

    “Brachial artery (BA) FMD was measured by ultrasonography (13-MHz transducer, Sonosite Micromax, Bothell, Washington) in combination with an automated analysis system (Medical Imaging Applications, Iowa City, Iowa) in a 21°C temperature-controlled room after 30 min of supine rest (7).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Schroeter, 2006, (−)-epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Flow-mediated dilation was the primary outcome, and circulating angiogenic cell number and function were secondary outcomes.

    “Endothelial vasomotor function assessed as flowmediated dilation (FMD), as well as CAC numbers and function were defined as primary and secondary outcomes, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Controlled human dietary trials with flavanol-containing foods and matched low-flavanol controls have shown flavanol-dependent improvements in endothelial function, blood pressure, and platelet aggregation.

    “Several controlled human dietary intervention studies that have utilized flavanol-containing foods and beverages in concert with nutrient-matched, low-flavanol controls have demonstrated flavanol-dependent effects, including the recovery of endothelial function, decreased blood pressure, and reductions in platelet aggregation (2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Corti, 2009, Cocoa and cardiovascular health, Circulation source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The trial used a randomized, controlled, double-masked, crossover design with a one-week washout between the two interventions.

    “using a randomized, double-masked, crossover study design (Fig. 1) with 1 week of wash-out between interventions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    In patients with coronary artery disease, a randomized controlled dietary flavanol intervention improves endothelial dysfunction and blood pressure.

    “These outcomes demonstrate that a randomized, controlled dietary flavanol intervention results in improvements in endothelial dysfunction and BP, and that this is associated with the mobilization of functional CACs in patients with CAD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 16 CAD patients studied are representative of CAD patients medically managed according to current guidelines.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Sixteen of the 20 initially enrolled patients completed the study and were included in the analyses.

    “From the 20 patients initially included, 16 patients completed the study and were included in data analyses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Plasma nitrite is both a marker of nitric oxide bioavailability and a bioactive nitric oxide donor.

    “we observed an increase in plasma nitrite, which represents both a marker of NO bioavailability and a bioactive NO donor (10).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Lundberg, 2009, Nitrate and nitrite in biology, nutrition and therapeutics, Nat Chem Biol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Circulating angiogenic cell number was measured by flow cytometry as CD34/KDR and CD133/KDR double-positive cells.

    “The CAC number in whole blood was measured by flow cytometry as CD34/KDR and CD133/KDR doublepositive cells in the lymphomononuclear cell gate (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Heiss, 2005, Impaired progenitor cell activity in age-related endothelial dysfunction, J Am Coll Cardiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    It is unlikely that the small flavanol amounts in the low-flavanol drink explain the observed increases, but other bioactive compounds in both drinks and regression to the mean may need consideration.

    “Based on previous data, it seems unlikely that the small flavanol amounts present in LoFI would explain our findings, but the presence in both test drinks of bioactive compounds other than flavanols, for example, methylxanthines, as well as a general regression to the mean may need to be considered in this context.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Dietary flavanols can facilitate endogenous repair mechanisms that act synergistically with current medical therapy, in addition to improving cardiovascular function.

    “Our data support the concept that dietary flavanols, in addition to improving cardiovascular functions, can facilitate endogenous repair mechanisms that act synergistically with current medical therapy.”
    Quote in the paperSubstantial claim
24 of 24

  • The paper relies on this without support.

    The 30-day intervention period is sufficient to produce sustained improvements in endothelial function and circulating angiogenic cell mobilization.

    “Sustained improvements in endothelial dysfunction by regular dietary intake of flavanols are associated with mobilization of functional CACs.”

  • The paper relies on this without support.

    The 16 CAD patients studied are representative of CAD patients medically managed according to current guidelines.

    “The study group consisted of 16 CAD patients having achieved treatment goals in accordance with current AHA/ACC guidelines”
2 of 2

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Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting uncertainty for the blood-pressure reduction

    Major

    The abstract and results report the same 4.2 mm Hg reduction relative to LoFI, but give different uncertainties: 2.7 and 0.3 mm Hg. This difference affects how strongly the reported blood-pressure effect is supported.

1 of 1

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Authors
Heiss, C., Jahn, S., Taylor, M., Real, W. M., Angeli, F. S., Wong, M. L., Amabile, N., Prasad, M., Rassaf, T., Ottaviani, J. I., Mihardja, S., Keen, C. L., Springer, M. L., Boyle, A., Grossman, W., Glantz, S. A., Schroeter, H., & Yeghiazarians, Y.
Affiliations
  • University of California, San Francisco (US)
  • Heinrich Heine University Düsseldorf (DE)
  • University of California, Davis (US)
  • Mars (United States) (US)
Corresponding author
Heiss, Christian
ORCID
Venue
Journal of the American College of Cardiology
Publisher
Elsevier BV
Published
2010-07
Volume
56
Issue
3
Pages
218-224
ISSN
0735-1097 (ISSN-L)
DOI
10.1016/j.jacc.2010.03.039
OpenAlex
W2046356569
Cited by
202
References
12
Citations by year
2026: 4 · 2025: 8 · 2024: 8 · 2023: 13 · 2022: 4 · 2021: 7 · 2020: 6 · 2019: 9 · 2018: 13 · 2017: 9 · 2016: 15 · 2015: 19 · 2014: 10 · 2013: 17 · 2012: 32
FWCI
16.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American College of Cardiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • Mars, Inc.
  • Mars Inc.
  • N30 Pharmaceuticals
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Keywords
flavan-3-ols, Theobroma cacao, endothelial dysfunction, circulating angiogenic cells, endothelial progenitor cells, coronary artery disease, flow-mediated dilation, CD34+/KDR+ cells, systolic blood pressure, plasma nitrite, dietary intervention, vascular function
MeSH terms
Blood Pressure, Cacao, Coronary Disease, Diet, Double-Blind Method, Endothelium, Vascular, Female, Flavonoids, Humans, Male, Middle Aged, Vasodilation, Neovascularization, Physiologic, Endothelial Cells

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