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CLINICAL RESEARCH: ENDOTHELIAL FUNCTION

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

Christian Heiss, MD, DrMed^_*,,||,_*, Sarah Jahn, MB^_*, Melanie Taylor, BS^_*, Wendy May Real, BS^_*, Franca S. Angeli, MD^_*, Maelene L. Wong, BS^_*, Nicolas Amabile, MD^_*, Megha Prasad, BA^_*, Tienush Rassaf, MD, DrMed^||, Javier I. Ottaviani, PhD, Shirley Mihardja, PhD^_*, Carl L. Keen, PhD, Matthew L. Springer, PhD^_*,,, Andrew Boyle, MBBS, PhD^_*, William Grossman, MD^_*, Stanton A. Glantz, PhD^_*, Hagen Schroeter, PhD^¶ and Yerem Yeghiazarians, MD^_*,

^_* Division of Cardiology, University of California–San Francisco, San Francisco, California
Cardiovascular Research Institute, University of California–San Francisco, San Francisco, California
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California–San Francisco, San Francisco, California
Department of Nutrition, University of California–Davis, Davis, California
^|| Division of Cardiology, Vascular Medicine, and Pulmonology, Heinrich Heine University, Düsseldorf, Germany
^¶ Mars, Inc., McLean, Virginia

Manuscript received November 9, 2009; revised manuscript received March 18, 2010, accepted March 23, 2010.

^_* Reprint requests and correspondence: Dr. Med. Christian Heiss, Heinrich Heine University, Division of Cardiology, Vascular Medicine, and Pulmonology, Moorenstrasse 5, D-40235 Düsseldorf, Germany (Email: christian.heiss{at}med.uni-duesseldorf.de).

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).

Key Words: nutrition • angiogenic cells • flow-mediated vasodilation • coronary artery disease • flavanols

Abbreviations and Acronyms   BA = brachial artery   CAC = circulating angiogenic cell   CAD = coronary artery disease   FMD = flow-mediated dilation   HiFI = high-flavanol intervention   LDL = low-density lipoprotein   LoFI = low-flavanol intervention   NO = nitric oxide   SCF = stem cell factor   SDF = stromal cell-derived factor   VEGF = vascular endothelial growth factor

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