Effects of Pycnogenol on Endothelial Function in Patients With Stable Coronary Artery Disease

A Double-Blind, Randomized, Placebo-Controlled, Cross-Over Study

Frank Enseleit; Isabella Sudano; Daniel Périat; Stephan Winnik; Mathias Wolfrum; Andreas J. Flammer; Georg M. Fröhlich; Priska Kaiser; Astrid Hirt; Sarah R. Haile; Nazmi Krasniqi; Christian M. Matter; Klaus Uhlenhut; Petra Högger; Michel Neidhart; Thomas F. Lüscher; Frank Ruschitzka; Georg Noll

Disclosures

Eur Heart J. 2012;33(13):1589-1597. 

In This Article

Abstract and Introduction

Abstract

Aims Extracts from pine tree bark containing a variety of flavonoids have been used in traditional medicine. Pycnogenol is a proprietary bark extract of the French maritime pine tree (Pinus pinaster ssp. atlantica) that exerts antioxidative, anti-inflammatory, and anti-platelet effects. However, the effects of Pycnogenol on endothelial dysfunction, a precursor of atherosclerosis and cardiovascular events, remain still elusive.
Methods and results Twenty-three patients with coronary artery disease (CAD) completed this randomized, double-blind, placebo-controlled cross-over study. Patients received Pycnogenol (200 mg/day) for 8 weeks followed by placebo or vice versa on top of standard cardiovascular therapy. Between the two treatment periods, a 2-week washout period was scheduled. At baseline and after each treatment period, endothelial function, non-invasively assessed by flow-mediated dilatation (FMD) of the brachial artery using high-resolution ultrasound, biomarkers of oxidative stress and inflammation, platelet adhesion, and 24 h blood pressure monitoring were evaluated. In CAD patients, Pycnogenol treatment was associated with an improvement of FMD from 5.3 ± 2.6 to 7.0 ± 3.1 (P < 0.0001), while no change was observed with placebo (5.4 ± 2.4 to 4.7 ± 2.0; P = 0.051). This difference between study groups was significant [estimated treatment effect 2.75; 95% confidence interval (CI): 1.75, 3.75, P < 0.0001]. 15-F2t-Isoprostane, an index of oxidative stress, significantly decreased from 0.71 ± 0.09 to 0.66 ± 0.13 after Pycnogenol treatment, while no change was observed in the placebo group (mean difference 0.06 pg/mL with an associated 95% CI (0.01, 0.11), P = 0.012]. Inflammation markers, platelet adhesion, and blood pressure did not change after treatment with Pycnogenol or placebo.
Conclusion This study provides the first evidence that the antioxidant Pycnogenol improves endothelial function in patients with CAD by reducing oxidative stress.
Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00641758

Introduction

Extracts from pine tree bark have been used in traditional medicine. Pycnogenol is a bark extract of the French maritime pine tree (Pinus pinaster ssp. atlantica). The extract is prepared using a standardized procedure that includes an extraction of fresh pine bark with ethanol and water according to the requirements published by the United States Pharmacopoeia (USP).[1] The resulting product is a mixture of flavonoids as monomers, i.e. catechin and taxifolin, and condensed polymers (85%), as well as dodeoameric flavonols, designated as procyanidins, differing in structure and chain length. Procyanidins are biopolymers composed of catechin and epicatechin, widely distributed in the plant kingdom. Many edible fruits contain procyanidins, e.g. apples, berries, peanuts, and grapes. Additionally, the extract contains phenolic acids as gallic, caffeic, and ferulic acid as minor constituents. Pycnogenol also contains glycosylation products, i.e. sugar derivatives of phenolcarbonic acids and taxifolin.[2] These molecules have antioxidant properties and may act as modulators of metabolic enzymes and other cellular functions.[2]

In a pharmacokinetic study, healthy volunteers ingested a single dose of 300 mg and repeated doses of 200 mg Pycnogenol.[3] In blood samples, catechin, taxifolin, ferulic acid, caffeic acid, and the metabolite 5-(3′,4′-dihydroxyphenyl)-g-valerolactone (M1) were detected in concentrations up to 100 ng/mL. While the first four compounds are genuinely present in the maritime pine bark extract, the metabolite M1 is formed in vivo from catechin polymers by gut microbiota.[4,5] This metabolite had been previously also found in urine samples after Pycnogenol intake.[6] Additionally to these known constituents and metabolites, 10 yet unknown compounds were detected in human plasma samples.[7]

The effects of the identified compounds have been investigated in vitro with the metabolite M1 revealing the highest activity. On a microgram per millilitre basis, M1 was more potent than the original maritime pine bark extract in inhibiting the activity of matrix metalloproteinase (MMP)-1, -2 and -9.[3] M1 was also about twice as potent as hydrocortisone in inhibiting the release of MMP-9 from freshly isolated human monocytes after stimulation with bacterial lipopolysaccharide. Thus, it appears very likely that M1 plays a major role in mediating the biological effects of Pycnogenol.

However, it cannot be excluded that other yet unknown components or metabolites of Pycnogenol also contribute to its biological activity. Plasma samples of volunteers who ingested Pycnogenol-contained bioactive compounds which in addition to the inhibition of MMP-9 release statistically significantly inhibited nuclear factor kappa B (NF-κB) activation[8] as well as cyclooxygenase 1 and 2 activity.[9]

Pycnogenol has been shown to exert anti-inflammatory effects and to inhibit platelet aggregation, both risk factors for cardiovascular disease.[2] In vitro, Pycnogenol prolonged the ascorbate radical lifetime to the greatest extent by regenerating ascorbic acid.[10] Similarly, Pycnogenol inhibits LDL peroxidation, lipid peroxidation in phospholipid liposomes,[2] and lipid peroxidation caused by t-butylhydroperoxide. Furthermore, Pycnogenol has antioxidant activity.[10] Finally, in isolated blood vessels, Pycnogenol inhibits vasoconstriction caused by adrenalin via the production of nitric oxide.[11] The present study was designed to evaluate the effect of Pycnogenol on endothelial function in patients with coronary artery disease (CAD).

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