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Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease
Open accessAbstract
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).
Checked 2026-10-06 · 4 references not checked yet
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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.
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14 Not checked yet · 14 Own result · 9 Own method · 6 Own interpretation
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Composition of Matched Flavanol-Containing Test Materials Ingested Twice Daily
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Results
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- Also stated in: § Composition of Matched Flavanol-Containing Test Materials Ingested Twice Daily · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After HiFI, the number of CD34 ϩ /KDR ϩ -CACs, as measured by flow cytometry, increased 2.2-fold as compared with after LoFI.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The CAC functions, as measured by the capacity to survive, differentiate, proliferate, and to migrate were not different between the groups.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Results
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Composition of Matched Flavanol-Containing Test Materials Ingested Twice Daily
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Composition of Matched Flavanol-Containing Test Materials Ingested Twice Daily
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Discussion
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In the paper
“Our data demonstrate that a further increase of endothelial function can be achieved by complementing standard treatments with a flavanol-based dietary intervention.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Discussion
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In the paper
“The average baseline FMD values were 4.4 Ϯ 0.5% and 4.6 Ϯ 0.5% (p ϭ 0.125) before starting the LoFI or HiFI regimen, respectively (Fig. 2).”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Improvement of FMD.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Discussion
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nitrate levels were not significantly affected by either treatment (average at first visit: 23 Ϯ 5 M).”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Improvement of FMD.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Improvement of FMD.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Composition of Matched Flavanol-Containing Test Materials Ingested Twice Daily
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The cocoa drinks were well tolerated, and none of the patients experienced major adverse events, cardiovascular-specific events, or hospitalization during the study period.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Characteristics of study group.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mean heart rate and diastolic BP were not significantly affected by either treatment.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Composition of Matched Flavanol-Containing Test Materials Ingested Twice Daily
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Improvement of FMD. · plain
In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Discussion
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“All individual medications and treatment paradigms, as well as body mass indexes remained unaltered throughout the study.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Characteristics of study group.
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In the paper
“The study protocol was approved by the University of California-San Francisco Committee on Human Research, and subjects gave written informed consent.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Study design.
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None of the sources cited for this claim have been checked yet.
In the paper
“Physiologically, the mobilization of CACs contributes to the repair response after vascular injury (3,4).”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Discussion
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Flavanol-containing test material.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Study design.
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In the paper
“Functional CAC characterization was performed after ex vivo expansion (8).”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Cell assays.
What the sources say
- Not checked yetcites [8] Heiss, 2005, Impaired progenitor cell activity in age-related endothelial dysfunction, J Am Coll Cardiol source
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In the paper
“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).”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Flavanol-containing test material.
What the sources say
- Not checked yetcites [7] Schroeter, 2006, (−)-epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans, Proc Natl Acad Sci U S A source
plain- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Endothelial vasomotor function assessed as flowmediated dilation (FMD), as well as CAC numbers and function were defined as primary and secondary outcomes, respectively.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Study design.
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In the paper
“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).”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Conclusions
What the sources say
- Not checked yetcites [2] Corti, 2009, Cocoa and cardiovascular health, Circulation source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“using a randomized, double-masked, crossover study design (Fig. 1) with 1 week of wash-out between interventions.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Study design.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The 16 CAD patients studied are representative of CAD patients medically managed according to current guidelines.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“From the 20 patients initially included, 16 patients completed the study and were included in data analyses.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Study design.
plainn = 16- Asserted: passes — The authors put it forward as true.
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In the paper
“we observed an increase in plasma nitrite, which represents both a marker of NO bioavailability and a bioactive NO donor (10).”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Discussion
What the sources say
- Not checked yetcites [10] Lundberg, 2009, Nitrate and nitrite in biology, nutrition and therapeutics, Nat Chem Biol source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Cell assays.
What the sources say
- Not checked yetcites [8] Heiss, 2005, Impaired progenitor cell activity in age-related endothelial dysfunction, J Am Coll Cardiol source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Discussion
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The current demonstration of significant reductions in both systolic and diastolic blood pressure levels after regular cocoa flavanol consumption is consistent with previous findings obtained both in normotensives and in hypertensive subjects, as well as medicated individuals.17,18,29,30”
In the citing paper
“The associative relation, increased plasma nitrite levels and an increased mobilization of CD34 ϩ /Flk-1 ϩ cells from the bone marrow, has also been observed in patients with coronary artery disease receiving nutrients that increased NO bioavailability.40”
From Dietary nitrate supplementation improves revascularization in chronic ischemia (2012) · cites this paper as [40]
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.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Results
“The HiFI led to a decrease in systolic blood pressure (mean change over LoFI: Ϫ4.2 Ϯ 2.7 mm Hg)”
§ Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease > Composition of Matched Flavanol-Containing Test Materials Ingested Twice Daily
“corresponding to a 4.2 Ϯ 0.3 mm Hg decrease as compared with LoFI.”
Citations
Cites
Smith, S. C., Allen, J. K., Blair, S. N., Bonow, R. O., Brass, L. M., Fonarow, G. C., Grundy, S. M., Hiratzka, L. F., Jones, D. W., Krumholz, H. M., et al. (2006) · Circulation · doi:10.1161/circulationaha.106.174516 · Cited by 2,101
Circulating endothelial progenitor cells and cardiovascular outcomes
Werner, N., Kosiol, S., Schiegl, T., Ahlers, P., Walenta, K., Link, A., Böhm, M., & Nickenig, G. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa043814 · Cited by 2,048
Polyphenols and disease risk in epidemiologic studies
Arts, I. C., & Hollman, P. C. (2005) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/81.1.317s · Cited by 1,916 · cited 1×
“Heiss), and an unrestricted research grant from 2 f flavanol-containing foods and coronary artery disease CAD) mortality (1).”
Background(–)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans
Schroeter, H., Heiss, C., Balzer, J., Kleinbongard, P., Keen, C. L., Hollenberg, N. K., Sies, H., Kwik-Uribe, C., Schmitz, H. H., & Kelm, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510168103 · Cited by 1,052
Self-citationSmith, S. C., Allen, J. K., Blair, S. N., Bonow, R. O., Brass, L. M., Fonarow, G. C., Grundy, S. M., Hiratzka, L. F., Jones, D. W., Krumholz, H. M., et al. (2006) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2006.04.026 · Cited by 671
Nitrate and nitrite in biology, nutrition and therapeutics
Lundberg, J. O., Gladwin, M. T., Ahluwalia, A., Benjamin, N., Bryan, N. S., Butler, A., Cabrales, P., Fago, A., Feelisch, M., Ford, P. C., et al. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.260 · Cited by 617
Self-citationImpaired progenitor cell activity in age-related endothelial dysfunction
Heiss, C., Keymel, S., Niesler, U., Ziemann, J., Kelm, M., & Kalka, C. (2005) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2004.12.074 · Cited by 573
Cocoa and Cardiovascular Health
Corti, R., Flammer, A. J., Hollenberg, N. K., & Lüscher, T. F. (2009) · Circulation · doi:10.1161/circulationaha.108.827022 · Cited by 424 · cited 2×
“In line ith previous studies (2), we observed a flavanol intakessociated decrease in SBP, and our data extend these ndings by showing that SBP-lowering effects of dietary avanols may complement standard medical BP manageent.”
BackgroundResultEndothelial progenitor cells in cardiovascular disorders
Shantsila, E., Watson, T., & Lip, G. Y. H. (2007) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2006.09.050 · Cited by 413
Balzer, J., Rassaf, T., Heiss, C., Kleinbongard, P., Lauer, T., Merx, M., Heussen, N., Gross, H. B., Keen, C. L., Schroeter, H., et al. (2008) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2008.01.059 · Cited by 345
Self-citation
Cited by
Sorted by citations
Del Rio, D., Rodriguez-Mateos, A., Spencer, J. P. E., Tognolini, M., Borges, G., & Crozier, A. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.4581 · Cited by 2,601
Hooper, L., Kay, C., Abdelhamid, A., Kroon, P. A., Cohn, J. S., Rimm, E. B., & Cassidy, A. (2012) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.111.023457 · Cited by 610
Tzounis, X., Rodriguez‐Mateos, A., Vulevic, J., Gibson, G. R., Kwik-Uribe, C. L., & Spencer, J. P. E. (2010) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.110.000075 · Cited by 582
Williams, R. J., & Spencer, J. P. E. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.09.010 · Cited by 448
Cocoa and Chocolate in Human Health and Disease
Katz, D. L., Doughty, K. N., & Ali, A. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3697 · Cited by 475
“However, another study in CAD patients published in July 2010 had different results (94).”
Rodriguez‐Mateos, A., Rendeiro, C., Bergillos-Meca, T., Tabatabaee, S., George, T. W., Heiß, C., & Spencer, J. P. E. (2013) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.113.066639 · Cited by 361
Desideri, G., Kwik-Uribe, C., Grassi, D., Necozione, S., Ghiadoni, L., Mastroiacovo, D., Raffaele, A., Ferri, L., Bocale, R., Lechiara, M. C., et al. (2012) · Hypertension · doi:10.1161/hypertensionaha.112.193060 · Cited by 311
Effect of cocoa on blood pressure
Ried, K., Fakler, P., & Stocks, N. (2017) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd008893.pub3 · Cited by 278
Ottaviani, J. I., Borges, G., Momma, T. Y., Spencer, J. P. E., Keen, C. L., Crozier, A., & Schroeter, H. (2016) · Scientific Reports · doi:10.1038/srep29034 · Cited by 256
Self-citationChocolate consumption and cardiometabolic disorders: systematic review and meta-analysis
Buitrago-Lopez, A., Sanderson, J., Johnson, L., Warnakula, S., Wood, A., Di Angelantonio, E., & Franco, O. H. (2011) · BMJ · doi:10.1136/bmj.d4488 · Cited by 252
Shrime, M. G., Bauer, S. R., McDonald, A. C., Chowdhury, N. H., Coltart, C. E. M., & Ding, E. L. (2011) · The Journal of Nutrition · doi:10.3945/jn.111.145482 · Cited by 234
“Nine studies (16,22,25,26,28,31, 33,34,37) examined the impact of FRC intake on FMD.”
BackgroundInfluentialZhu, Y., Xia, M., Yang, Y., Liu, F., Li, Z., Hao, Y., Mi, M., Jin, T., & Ling, W. (2011) · Clinical Chemistry · doi:10.1373/clinchem.2011.167361 · Cited by 224
Central Role of eNOS in the Maintenance of Endothelial Homeostasis
Heiß, C., Rodriguez‐Mateos, A., & Kelm, M. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6158 · Cited by 206
“In this study, we observed a significant improvement in endothelial function as measured by FMD, increase in plasma nitrite indicative of increased NO availability, and decrease in systolic blood pressure (35).”
BackgroundMethodInfluentialFlavanols and cardiovascular disease prevention
Heiß, C., Keen, C. L., & Kelm, M. (2010) · European Heart Journal · doi:10.1093/eurheartj/ehq332 · Cited by 195
“In parallel with the FMD and PAT effects, an increase in circulating plasma NO storage forms, RXNO (S- and N-nitros(yl)ated NO species (RX designates that NO is bound to different residues ‘R’ via different bonds ‘X’) and nitrite, has been observed in several of these dietary intervention trials including one applying…”
BackgroundResultInfluentialSelf-citationDo polyphenols enter the brain and does it matter? Some theoretical and practical considerations
Schaffer, S., & Halliwell, B. (2012) · Genes & Nutrition · doi:10.1007/s12263-011-0255-5 · Cited by 178
“Reasonable evidence exists that PPs from cocoa (Francis et al. 2006; Heiss et al. 2007; Heiss et al. 2010) and other dietary sources, such as tea (Grassi et al. 2009) and grapes (Lekakis et al. 2005), increase blood flow in humans, thus possibly helping to provide the brain with greater amounts of…”
Sansone, R., Rodriguez‐Mateos, A., Heuel, J., Falk, D., Schuler, D., Wagstaff, R., Kuhnle, G., Spencer, J. P. E., Schroeter, H., Merx, M. W., et al. (2015) · British Journal Of Nutrition · doi:10.1017/s0007114515002822 · Cited by 178
Self-citationRangel-Huerta, Ó. D., Pastor‐Villaescusa, B., Aguilera, C. M., & Gil, Á. (2015) · Nutrients · doi:10.3390/nu7075177 · Cited by 177
“Additionally, BP decreased significantly in hypertensive subjects using flavanol-rich chocolate during 15 days [47] and in CAD patients [49] with 375 mg twice daily during 30 days.”
BackgroundInfluentialEFSA Panel on Dietetic Products, N. A. A. (. (2012) · EFSA Journal · doi:10.2903/j.efsa.2012.2809 · Cited by 158
Cocoa and Dark Chocolate Polyphenols: From Biology to Clinical Applications
Magrone, T., Russo, M. A., & Jirillo, E. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00677 · Cited by 162
“Conversely, in another research, 16 CAD patients were divided into 2 groups, one receiving high flavanol cocoa (375 mg) and another one consuming low flavanol cocoa (9 mg) 2 times a day for 30 days, randomly (57).”
Ottaviani, J. I., Momma, T. Y., Kuhnle, G., Keen, C. L., & Schroeter, H. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.12.010 · Cited by 149
“This drink was similar in composition to flavanol-rich drinks that have been reported to induce an acute vascular response in humans after consumption [10,13].”
BackgroundSelf-citationHeiß, C., Sansone, R., Karimi, H., Krabbe, M., Schuler, D., Rodriguez‐Mateos, A., Kræmer, T., Cortese-Krott, M. M., Kuhnle, G., Spencer, J. P. E., et al. (2015) · AGE · doi:10.1007/s11357-015-9794-9 · Cited by 145
Self-citationPolyphenols: Planting the seeds of treatment for the metabolic syndrome
Cherniack, E. P. (2011) · Nutrition · doi:10.1016/j.nut.2010.10.013 · Cited by 130
Intake of dietary procyanidins does not contribute to the pool of circulating flavanols in humans
Ottaviani, J. I., Kwik-Uribe, C. L., Keen, C. L., & Schroeter, H. (2012) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.111.028340 · Cited by 127
Self-citationOxidative stress and endothelial dysfunction: Therapeutic implications
Gori, T., & Münzel, T. F. (2011) · Annals of Medicine · doi:10.3109/07853890.2010.543920 · Cited by 126
Heiß, C., Rodriguez‐Mateos, A., Bapir, M., Skene, S. S., Sies, H., & Kelm, M. (2022) · Cardiovascular Research · doi:10.1093/cvr/cvac095 · Cited by 122
Schroeter, H., Heiß, C., Spencer, J. P. E., Keen, C. L., Lupton, J. R., & Schmitz, H. H. (2010) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2010.09.008 · Cited by 120
Self-citationSansone, R., Ottaviani, J. I., Rodriguez‐Mateos, A., Heinen, Y., Noske, D., Spencer, J. P. E., Crozier, A., Merx, M. W., Kelm, M., Schroeter, H., et al. (2016) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.116.140046 · Cited by 119
“These findings are in agreement with previous studies that have reported beneficial vascular effects after the intake of CFs or foods containing flavanols (7, 8).”
ResultSelf-citationDietary nitrate supplementation improves revascularization in chronic ischemia
Hendgen-Cotta, U. B., Luedike, P., Totzeck, M., Kropp, M., Schicho, A., Stock, P., Rammos, C., Niessen, M., Heiss, C., Lundberg, J. O., et al. (2012) · Circulation · doi:10.1161/circulationaha.112.112912 · Cited by 110
“The associative relation - increased plasma nitrite levels and an increased mobilization of CD34/Flk-1 cells from the bone marrow – has also been observed in patients with coronary artery disease receiving nutrients that increased NO bioavailability.(40) In line with these findings, the results of the current study fu…”
ResultSelf-citationCocoa, Blood Pressure, and Vascular Function
Ludovici, V., Barthelmes, J., Nägele, M. P., Enseleit, F., Ferri, C., Flammer, A. J., Ruschitzka, F. T., & Sudano, I. (2017) · Frontiers in Nutrition · doi:10.3389/fnut.2017.00036 · Cited by 114
Valls, R. M., Farràs, M., Suárez, M., Fernández‐Castillejo, S., Fitó, M., Konstantinidou, V., Fuentes, F. J., López‐Miranda, J., Giralt, M., Covas, M., et al. (2014) · Food Chemistry · doi:10.1016/j.foodchem.2014.06.107 · Cited by 106
“In human studies, an improvement in endothelial function has been observed after the consumption of dietary flavanols (Balzer et al., 2008; Heiss et al., 2010) or natural virgin OO (VOO) versus a very low-polyphenol content oil (Ruano et al., 2005).”
BackgroundSutulic, S., & Williamson, G. (2013) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071811-150642 · Cited by 112
“Cocoa beverage twice per day for 12 weeks Cocoa-free beverage Randomized; 25 healthy males (38 ± SE 1 years) ↓LDL susceptibility to oxidation and urinary [dityrosine]; ↑ HDL cholesterol (10) Low-, medium-, or high-pp cocoa beverage twice per day for 4 weeks Nutrient-matched beverage (trace amounts of cocoa pp) Double-…”
MethodInfluentialRecommendations on reporting requirements for flavonoids in research
Balentine, D. A., Dwyer, J. T., Erdman, J. W., Ferruzzi, M. G., Gaine, P. C., Harnly, J. M., & Kwik-Uribe, C. L. (2015) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.113.071274 · Cited by 104
“Although ideal controls have, to date, not often been fully realized in the field of flavonoid research, several noteworthy examples have been published for well-matched control products for cocoa/chocolate (31), tea (74, 75), purple grape juice (76), and cranberry (77).”
BackgroundActivities of Tannins – from in Vitro Studies to Clinical Trials
Sieniawska, E. (2015) · Natural Product Communications · doi:10.1177/1934578x1501001118 · Cited by 107
“The systolic blood pressure of those subjects taking the dose of cocoa decreased, which was not seen in another group that consumed only 9 mg twice a day [77].”
BackgroundEllinger, S., Reusch, A., Stehle, P., & Helfrich, H. (2012) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.111.029330 · Cited by 97
“3 Taubert et al, 2003 (21); Taubert et al, 2007 (22); Grassi et al, 2005 (25) (hypertensive group); Grassi et al, 2008 (26); van den Bogaard et al, 2010 (27); Heiss et al, 2010 (28); Monagas et al, 2009 (29); Muniyappa et al, 2008 (30); Mellor et al, 2010 (31); Davison et al, 2010 (33) (3 trial arms).”
MethodInfluentialThe impact of chocolate on cardiovascular health
Fernández-Murga, M. L., Tarín, J. J., García‐Pérez, M. Á., & Cano, A. (2011) · Maturitas · doi:10.1016/j.maturitas.2011.05.011 · Cited by 94
Arranz, S., Valderas-Martínez, P., Chiva‐Blanch, G., Casas, R. M., Urpí-Sardà, M., Lamuela-Raventós, R. M., & Estruch, R. (2013) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201200595 · Cited by 91
“This was observed in two out of three studies in patients under pharmacological treatment for coronary artery disease [92, 93].”
Rodriguez-Mateos, A., Hezel, M., Aydin, H., Kelm, M., Lundberg, J. O., Weitzberg, E., Spencer, J. P. E., & Heiss, C. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.12.009 · Cited by 88
Sieniawska, E., & Baj, T. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802104-0.00010-x · Cited by 92
Mobilization of stem and progenitor cells in cardiovascular diseases
Wojakowski, W., Landmesser, U., Bachowski, R., Jadczyk, T., & Tendera, M. (2011) · Leukemia · doi:10.1038/leu.2011.184 · Cited by 85
van den Bogaard, B., Draijer, R., Westerhof, B., van den Meiracker, A. H., van Montfrans, G. V., & van den Born, B. H. (2010) · HYPERTENSION · doi:10.1161/hypertensionaha.110.158139 · Cited by 72
Monahan, K. D., Feehan, R. P., Kunselman, A. R., Preston, A. G., Miller, D. L., & Lott, M. E. J. (2011) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00865.2011 · Cited by 84
Dietary inorganic nitrate mobilizes circulating angiogenic cells
Heiß, C., Meyer, C. G., Totzeck, M., Hendgen-Cotta, U. B., Heinen, Y., Luedike, P., Keymel, S., Ayoub, N., Lundberg, J. O., Weitzberg, E., et al. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.02.051 · Cited by 81
Self-citationda Luz, P. L., Tanaka, L. Y., Brum, P. C., Dourado, P. M. M., Favarato, D., Krieger, J. E., & Laurindo, F. R. M. (2012) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2012.06.007 · Cited by 77
Flammer, A. J., Martin, E. A., Gössl, M., Widmer, R. J., Lennon, R. J., Sexton, J. A., Loeffler, D. L., Khosla, S., Lerman, L. O., & Lerman, A. (2012) · European Journal of Nutrition · doi:10.1007/s00394-012-0334-4 · Cited by 77
“However, after 4 months of cranberry juice intake, we did not observe significant changes in EPC numbers, similar to other studies with polyphenol-rich food [22], where others showed modest increases in EPC number [23, 24].”
ResultEffect of cocoa on blood pressure
Ried, K., Sullivan, T. R., Fakler, P., Frank, O. R., & Stocks, N. P. (2012) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd008893.pub2 · Cited by 150
Date Palm Fruit (Phoenix dactylifera): Effects on Vascular Health and Future Research Directions
Al-Dashti, Y. A., Holt, R. R., Keen, C. L., & Hackman, R. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094665 · Cited by 87
Self-citationThe Cardiovascular Effects of Cocoa Polyphenols—An Overview
Aprotosoaie, A. C., Miron, A., Trifan, A., Luca, V., & Costache, I. I. (2016) · Diseases · doi:10.3390/diseases4040039 · Cited by 74
“They improve cardiovascular function but also facilitate endogenous repair mechanisms [18].”
BackgroundKiyimba, T., Yiga, P., Bamuwamye, M., Ogwok, P., der Schueren, B. V., & Matthys, C. (2023) · Advances in Nutrition · doi:10.1016/j.advnut.2023.01.002 · Cited by 82
The Impact of Epicatechin on Human Cognition: The Role of Cerebral Blood Flow
Haskell‐Ramsay, C. F., Schmitt, J. A. J., & Actis‐Goretta, L. (2018) · Nutrients · doi:10.3390/nu10080986 · Cited by 71
van Bussel, B. C. T., Henry, R. M. A., Schalkwijk, C. G., Ferreira, I., Feskens, E. J. M., Streppel, M. T., Smulders, Y. M., Twisk, J. W. R., & Stehouwer, C. D. A. (2011) · Journal of Nutrition · doi:10.3945/jn.111.139733 · Cited by 67
Craenenbroeck, E. M. V., Craenenbroeck, A. H. V., van Ierssel, S. H., Bruyndonckx, L., Hoymans, V. Y., Vrints, C. J., & Conraads, V. M. (2012) · International Journal of Cardiology · doi:10.1016/j.ijcard.2012.10.047 · Cited by 67
“Possible mechanisms for this risk reduction include the release of EPC after chronic ingestion [43].”
BackgroundSansone, R., Stanske, B., Keymel, S., Schuler, D., Horn, P., Saeed, D., Boeken, U., Westenfeld, R., Lichtenberg, A., Kelm, M., et al. (2015) · The Journal of Heart and Lung Transplantation · doi:10.1016/j.healun.2015.03.004 · Cited by 65
“Brachial artery FMD was measured by ultrasound (10 MHz transducer; Vivid i; GE Healthcare) in combination with an automated analysis system (Brachial Analyzer; Medical Imaging Applications, Iowa City, IA) in a 211C temperature-controlled room after 15 minutes of rest in the supine position.(29) A forearm blood pressur…”
MethodHorn, P., Amabile, N., Angeli, F. S., Sansone, R., Stegemann, B., Kelm, M., Springer, M. L., Yeghiazarians, Y., Schroeter, H., & Heiß, C. (2013) · British Journal Of Nutrition · doi:10.1017/s0007114513003693 · Cited by 63
“The CAD patients (n 16) were given a HiFI (375 mg of CF) or a nutrientmatched low-CF drink (LoFl, 9 mg of CF) twice daily over a 30-d period, using a randomised, double-masked, cross-over study design with 1 week of wash-out between the interventions (for a detailed published protocol, see Heiss et al.(21)).”
BackgroundMethodResultInfluentialSelf-citationMeasurement of Endothelium-Dependent Vasodilation in Mice—Brief Report
Schuler, D., Sansone, R., Freudenberger, T., Rodriguez‐Mateos, A., Weber, G., Momma, T. Y., Goy, C., Altschmied, J., Haendeler, J., Fischer, J. W., et al. (2014) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.114.304699 · Cited by 62
Rodriguez‐Mateos, A., Weber, T., Skene, S. S., Ottaviani, J. I., Crozier, A., Kelm, M., Schroeter, H., & Heiß, C. (2018) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqy229 · Cited by 64
“FMD and power analysis of the primary endpoint FMD was measured in the brachial artery of the right arm by the use of 5-min forearm occlusion by ultrasound (Vivid I; GE Healthcare) in combination with a semiautomated analysis system (Brachial Analyzer, MIA) (9).”
MethodSelf-citationSun, Y., Zimmermann, D., Castro, C. A. D., & Actis‐Goretta, L. (2019) · Food & Function · doi:10.1039/c9fo01747j · Cited by 59
Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis
Rassaf, T., Rammos, C., Hendgen-Cotta, U. B., Heiß, C., Kleophas, W., Dellanna, F., Floege, J., Hetzel, G. R., & Kelm, M. (2015) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.05560515 · Cited by 58
“Interventional studies have shown that CFs exert beneficial effects regarding the regulation of BP and recovery of endothelial function (17,18).”
BackgroundSelf-citationConcord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships
Blumberg, J. B., Vita, J. A., & Chen, C. (2015) · Nutrients · doi:10.3390/nu7125519 · Cited by 57
“Among the 15 studies reviewed for the impact of polyphenol on FMD, eight trials used the principle flavonoid or sum of all quantified flavonoids [62,64,66,68–71,73], six used a Folin value [51,56,59,63,65,67], and one was not”
BackgroundResultTotzeck, M., Hendgen-Cotta, U. B., Rammos, C., Frommke, L.-M., Knackstedt, C., Predel, H.-G., Kelm, M., & Rassaf, T. (2012) · Nitric Oxide · doi:10.1016/j.niox.2012.05.003 · Cited by 56
Self-citationPhilip, P., Sagaspe, P., Taillard, J., Mandon, C., Constans, J., Pourtau, L., Pouchieu, C., Angelino, D., Mena, P. R., Martini, D., et al. (2019) · Antioxidants · doi:10.3390/antiox8120650 · Cited by 54
“In addition, clinical investigations have shown that dietary flavanols intake was associated with improvement in endothelial functions [46,47].”
BackgroundOttaviani, J. I., Balz, M., Kimball, J., Ensunsa, J. L., Fong, R. Y., Momma, T. Y., Kwik-Uribe, C. L., Schroeter, H., & Keen, C. L. (2015) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.115.116178 · Cited by 54
Self-citationStern, M. E., Broja, M., Sansone, R., Gröne, M., Skene, S. S., Liebmann, J., Suschek, C. V., Born, M., Kelm, M., & Heiß, C. (2018) · European Journal of Preventive Cardiology · doi:10.1177/2047487318800072 · Cited by 59
Bo’, C. D., Porrini, M., Fracassetti, D., Campolo, J., Klimis‐Zacas, D. J., & Riso, P. (2014) · Food & Function · doi:10.1039/c4fo00570h · Cited by 52
Ramírez‐Sánchez, I., Maya-Ramos, L., Ceballos, G. M., & Villarreal, F. J. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00406.2010 · Cited by 52
“(16) where the cardiovascular effects of cocoa flavanols in patients with coronary artery disease are mediated by increases in the bioavailability of NO as reflect of endothelial function improvement.”
BackgroundRendeiro, C., Dong, H., Saunders, C., Harkness, L., Blaze, M., Hou, Y., Belanger, R. L., Corona, G., Lovegrove, J. A., & Spencer, J. P. E. (2016) · British Journal Of Nutrition · doi:10.1017/s0007114516004219 · Cited by 52
“Notably, flavanol-rich cocoa has been consistently 61 shown to improve endothelium-dependent vasodilation in healthy individuals (24, 27, 31, 39, , smokers (23, 62 , patients with coronary artery disease (CAD) ((41)), hypertension ((42)), or diabetes ((43)).”
BackgroundCicero, A. F. G., Colletti, A., von Haehling, S., Vinereanu, D., Bielecka-Dabrowa, A. M., Sahebkar, A., Toth, P. P., Reiner, Ž., Wong, N. D., Mikhailidis, D. P., et al. (2020) · Nutrition Research Reviews · doi:10.1017/s0954422420000049 · Cited by 53
“The mechanisms of action through which cocoa polyphenols could act on HF have not been yet fully clarified – the most reliable hypotheses concern the improvement of the endothelium-dependent vasodilator responses, mediated by increase in NO synthesis, suppression of endothelin-1 synthesis and reduction of NT-proBNP(94…”
BackgroundInfluentialEffects of high flavanol dark chocolate on cardiovascular function and platelet aggregation
Rull, G., Zain, Z. N. M., Shiel, J. I., Lundberg, M. H., Collier, D., Johnston, A. E., Warner, T. D., & Corder, R. (2015) · Vascular Pharmacology · doi:10.1016/j.vph.2015.02.010 · Cited by 51
Heinen, Y., Stegemann, E., Sansone, R., Benedens, K., Wagstaff, R., Balzer, J., Rassaf, T., Lauer, T., Kelm, M., & Heiß, C. (2015) · Journal of the American Heart Association · doi:10.1161/jaha.114.001472 · Cited by 49
“Ultrasound Measurements of Arterial Function, IMT, and Local Stiffness FMD was measured, as described previously.(8) Briefly, the diameter and the angle-corrected flow velocity of the BA and the SFA were measured using a 12-MHz transducer (Vivid I;”
MethodSelf-citationChen, Q., Sievers, R. E., Varga, M., Kharait, S., Haddad, D. J., Patton, A. K., Delany, C., Mutka, S. C., Blonder, J. P., Dubé, G. P., et al. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01302.2012 · Cited by 49
“FMD measurement has been applied as a diagnostic tool in a range of physiological studies 412 including vascular effects of intrinsic health factors and of environmental and behavioral 413 influences on cardiovascular health (5, 13, 15, 16).”
MethodSelf-citationEllinger, S., & Stehle, P. (2016) · Nutrients · doi:10.3390/nu8060321 · Cited by 48
“The regular consumption trials were further subdivided according to the subjects investigated: trials performed with healthy subjects [51–59] (Table 2), pre-/hypertensive subjects [51,60–62] (Table 3), and trials investigating patients suffering from type 2 diabetes, impaired glucose tolerance [61,63–68] (Table 4), an…”
BackgroundInfluentialThe Impact of Cocoa Flavanols on Cardiovascular Health
Vlachojannis, J., Erne, P., Zimmermann, B., & Chrubasik-Hausmann, S. (2016) · Phytotherapy Research · doi:10.1002/ptr.5665 · Cited by 40
Sabbatinelli, J., Orlando, P., Galeazzi, R., Silvestri, S., Cirilli, I., Marcheggiani, F., Dludla, P. V., Giuliani, A., Bonfigli, A. R., Mazzanti, L., et al. (2020) · Nutrients · doi:10.3390/nu12041098 · Cited by 47
Ottaviani, J. I., Britten, A., Lucarelli, D., Luben, R., Mulligan, A. A., Lentjes, M. A. H., Fong, R. Y., Gray, N., Grace, P. B., Mawson, D. H., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-74863-7 · Cited by 44
Self-citationSoleti, R., Andriantsitohaina, R., & Martínez, M. C. (2018) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2018.03.004 · Cited by 42
Chocolate and Coronary Heart Disease: A Systematic Review
Khawaja, O. A., Gaziano, J. M., & Djoussé, L. (2011) · Current Atherosclerosis Reports · doi:10.1007/s11883-011-0203-2 · Cited by 41
Ramírez‐Sánchez, I., Mansour, C. M., Navarrete-Yañez, V., Ayala-Hernandez, M., Guevara, G., Castillo, C., Loredo, M. L., Bustamante, M., Ceballos, G. M., & Villarreal, F. J. (2018) · Food & Function · doi:10.1039/c8fo00483h · Cited by 41
“Studies also demonstrate that cocoa consumption can mobilize angiogenic cells (32) and improve memory following 3 months of supplementation in normal 60-year-old subjects while increasing brain blood volume (33).”
BackgroundCocoa Flavanols Improve Vascular Responses to Acute Mental Stress in Young Healthy Adults
Baynham, R., Zanten, J. V., Johns, P. W., Pham, Q. S., & Rendeiro, C. (2021) · Nutrients · doi:10.3390/nu13041103 · Cited by 43
Flavan-3-ols and Vascular Health: Clinical Evidence and Mechanisms of Action
Godos, J., Romano, G. L., Laudani, S., Gozzo, L., Guerrera, I., Azpíroz, I. D., Diaz, R. M., Quiles, J. L., Battino, M. A., Drago, F., et al. (2024) · Nutrients · doi:10.3390/nu16152471 · Cited by 40
“…dietary high-flavan-3-ol intervention (providing 750 mg flavan-3-ols) and low-flavan-3-ol intervention for 30 days showed an improvement in brachial artery FMD by 4.6% ( p < 0.05) and a reduction in SBP ( − 4.2 ± 2.7 mmHg; p = 0.013) in the treated group compared to the control group [51].”
ResultInfluentialCocoa, Blood Pressure, and Cardiovascular Health
Ferri, C., Desideri, G., Ferri, L., Proietti, I., Agostino, S., Martella, L., Mai, F., Giosia, P. D., & Grassi, D. (2015) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5b01064 · Cited by 42
Dower, J. I., Geleijnse, J. M., Kroon, P. A., Philo, M. R., Mensink, M., Kromhout, D., & Hollman, P. C. H. (2016) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201600045 · Cited by 40
Nutrition epidemiology of flavan-3-ols: The known unknowns
Kuhnle, G. (2017) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2017.10.003 · Cited by 42
“Such studies inevitably rely on the assessment of surrogate endpoints, such as measures of vascular function (Heiss et al., 2010b), which inherently limits efforts aimed at translating study outcomes into high-rigor impact assessments of disease risk reduction and primary disease prevention…”
BackgroundAgeing, Age-Related Cardiovascular Risk and the Beneficial Role of Natural Components Intake
Rysz, J., Franczyk, B., Rysz-Górzyńska, M., & Gluba-Brzózka, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010183 · Cited by 41
Uptake and metabolism of (−)-epicatechin in endothelial cells
Rodriguez‐Mateos, A., Toro-Funes, N., Cifuentes‐Gomez, T., Cortese-Krott, M. M., Heiß, C., & Spencer, J. P. E. (2014) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2014.03.014 · Cited by 39
Sansone, R., Baaken, M., Horn, P., Schuler, D., Westenfeld, R., Amabile, N., Kelm, M., & Heiß, C. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.04.012 · Cited by 39
Self-citationRoss, F. C., Mayer, D. E., Horn, J. V., Cryan, J. F., Rio, D. D., Randolph, E., Gill, C. I. R., Gupta, A., Ross, R. P., Stanton, C., et al. (2024) · Nutritional Neuroscience · doi:10.1080/1028415x.2023.2298098 · Cited by 39
“In clinical studies, the intake of fl avonoids have been associated with a reduction in blood pressure [70,71], arterial sti ff ness [71], and increased vasodilation [70,72].”
Influence of sugar type on the bioavailability of cocoa flavanols
Rodriguez‐Mateos, A., Oruña-Concha, M. J., Kwik-Uribe, C. L., Vidal‐Diez, A., & Spencer, J. P. E. (2012) · British Journal Of Nutrition · doi:10.1017/s0007114512000475 · Cited by 37
“…shown to be capable of promoting clinically significant improvements in cardiovascular health through their potential to lower blood pressure (7,12–15) , improve endothelial function (16–21) , inhibit platelet aggregation (22–24) and curtail the inflammatory response (25–27) following oral intake.”
BackgroundThe role of inorganic nitrate and nitrite in CVD
Jackson, J. K., Patterson, A. J., MacDonald‐Wicks, L. K., & McEvoy, M. (2017) · Nutrition Research Reviews · doi:10.1017/s0954422417000105 · Cited by 37
“In addition to fl ow-mediated dilatation, CAC have been identi fi ed as an important indicator of vascular endothelial function, as they have a critical role in vascular repair (184) .”
Kirch, N., Berk, L., Liegl, Y., Adelsbach, M., Zimmermann, B. F., Stehle, P., Stoffel‐Wagner, B., Ludwig, N., Schieber, A., Helfrich, H., et al. (2018) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqy066 · Cited by 37
Cocoa Flavanol Cardiovascular Effects Beyond Blood Pressure Reduction
Jumar, A., & Schmieder, R. E. (2015) · Journal of Clinical Hypertension · doi:10.1111/jch.12715 · Cited by 37
Zhang, M., Jagdmann, G. E., Zandt, M. V., Sheeler, R., Beckett, P., & Schroeter, H. (2013) · Journal of Natural Products · doi:10.1021/np300568m · Cited by 36
Self-citationReversing effect of Lupeol on vasculogenic mimicry in murine melanoma progression
Bhattacharyya, S., Mitra, D., Ray, S., Biswas, N., Banerjee, S., Majumder, B., Mustafi, S. M., & Murmu, N. (2018) · Microvascular Research · doi:10.1016/j.mvr.2018.10.008 · Cited by 36
Zhang, M., Jagdmann, G. E., Zandt, M. V., Beckett, P., & Schroeter, H. (2013) · Tetrahedron Asymmetry · doi:10.1016/j.tetasy.2013.02.012 · Cited by 35
Self-citationBioactive compounds in fermented foods: a systematic narrative review
Künili, İ. E., Akdeniz, V., Akpınar, A., Ozturkoglu‐Budak, S., Curiel, J. A., Güzel, M., Karagözlü, C., Kaşıkçı, M. B., Caruana, M., Starowicz, M., et al. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1625816 · Cited by 41
The Potential of Flavanol and Procyanidin Intake to Influence Age-Related Vascular Disease
Holt, R. R., Heiß, C., Kelm, M., & Keen, C. L. (2012) · Journal of Nutrition in Gerontology and Geriatrics · doi:10.1080/21551197.2012.702541 · Cited by 35
“Whether the increase in CAC after flavanol and procyanidin intake is due to changes in angiogenic signaling or possibly an increase in NO availability or NOS activity is untested as the a potential in vivo flavanol effect on CAC activity may likely be lost after seven days cell culture (104).”
BackgroundResultInfluentialSelf-citationEffects of a dietary strawberry powder on parameters of vascular health in adolescent males
Djurica, D., Holt, R. R., Ren, J., Shindel, A. W., Hackman, R. M., & Keen, C. L. (2016) · British Journal Of Nutrition · doi:10.1017/s0007114516002348 · Cited by 36
“The treatment and washout periods, as well as the 1-h acute sampling point, were chosen on the basis of previous reports of improved vascular function after the intake of flavonoid-rich foods((18,19)), with peak plasma levels of strawberry metabolites obtained approximately 1 h after intake((20)).”
BackgroundSelf-citationMonahan, K. D. (2012) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2012.02.021 · Cited by 31
Al-Dashti, Y. A., Holt, R. R., Stebbins, C. L., Keen, C. L., & Hackman, R. M. (2018) · Journal of the American College of Nutrition · doi:10.1080/07315724.2018.1451788 · Cited by 33
“The existence of such a relationship between flavanols and CACs could expand our understanding of vascular effects of flavanols because CACs are thought to play a role in the maintenance, repair, and regeneration of vascular endothelial cells, contributing to normal endothelial function (13,95).”
BackgroundSelf-citationBenefits of flavanol-rich cocoa-derived products for mental well-being: A review
Smith, D. F. (2012) · Journal of Functional Foods · doi:10.1016/j.jff.2012.09.002 · Cited by 32
Stimulatory Effects of the Flavanol (-)-Epicatechin on Cardiac Angiogenesis
Ramírez‐Sánchez, I., Nogueira, L., Moreno‐Ulloa, A., Murphy, A. N., Taub, P. R., Perkins, G. A., Ceballos, G. M., Hogan, M. C., Malek, M. H., & Villarreal, F. J. (2012) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e318269ae0d · Cited by 31
“Studies attribute the low incidence of hypertension to the consumption of cacao and not other factors.(5,6) The flavanol (-)-epicatechin (Epi) (and not other flavanols) seems to underlie the vasodilatory effects of cocoa as recently reported.”
Dietary Flavonoids and Adult Neurogenesis: Potential Implications for Brain Aging
Davinelli, S., Medoro, A., Alì, S., Passarella, D., Intrieri, M., & Scapagnini, G. (2022) · Current Neuropharmacology · doi:10.2174/1570159x21666221031103909 · Cited by 30
“Indeed, there is evidence that flavonoids, in particular flavan-3-ols, are capable of promoting improvements in vascular health through their potential to lower blood pressure, improve endothelial function, inhibit platelet aggregation, and reduce the inflammatory response [53-57].”
Background
Metadata
- 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)
- 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
- bronze
- doi.org
- 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 (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Biochemistry (medical) › 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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