Elevated blood pressure (BP) or hypertension causes endothelial dysfunction and increases the risk of coronary heart disease. In experimental models, epicatechin (a flavan-3-ol flavonoid) has been shown to have cardioprotective effects by activating endothelial nitric oxide synthase (eNOS) and improving endothelial function. The purpose of this single-center, repeated-dose, double-blind, placebo-controlled, crossover study was to test the hypothesis that an apple (Malus pumila, Rosaceae) fruit polyphenol extract rich in epicatechin and flavan-3-ol oligomers may improve endothelial function in subjects with borderline hypertension. Secondary aims of the study were to determine whether the intervention would improve endothelium-independent nitrate-mediated vasodilation (NDM) and biomarkers of vascular function.
Subjects (n = 60, 40-65 years old, 34 women, 26 men) with borderline hypertension or unmedicated mild hypertension were recruited between July 2012 and May 2013 (study location was not reported; however, several of the authors are associated with the University of Turku, Turku, Finland). Inclusionary criteria were the presence of borderline hypertension (BP 130-139/85-89 mmHg) or unmedicated mild hypertension (BP 140-165/90-95 mmHg), good health other than hypertension, and study-compliance. Exclusionary criteria included body mass index (BMI) > 32 kg/m2, total serum cholesterol ≥ 8 mmol/L, an abnormal electrocardiogram, coronary artery disease, pregnancy, lactation, alcohol abuse, regular smoking, diabetes mellitus, allergy to apples, use of medications that lower lipids or modify endothelial function or blood vessel tone, high consumption of flavonoids, excess vitamin intake, regular herbal remedy use, clinical trial participation in the previous 2 months, and any other condition the investigators thought would interfere with analyzing results.
Subjects were randomly assigned to first take either 330 mg/day apple extract or placebo for four weeks, followed by a 4- to 5-week washout period, then four weeks of the alternate treatment. The apple extract (Coressence Ltd; Somerset, United Kingdom) consisted of ~ 90% total polyphenols as catechin equivalents with a minimum 30% (−)-epicatechin and at least 20% flavan-3-ol oligomers. Each 330 mg hard gelatin capsule of apple extract contained 100 mg of epicatechin and 50 mg microcrystalline cellulose (MCC). The identical placebo capsules contained MCC.
Brachial artery flow-mediated vasodilation (FMD) was evaluated with ultrasonography at the beginning and end of each 4-week treatment period. At each of the four study visits, FMD was assessed before and 1.5 hours after ingestion of the study capsule to determine acute changes in FMD. To assess long-term changes in endothelial function, FMD values from the beginning of each treatment period were compared to FMD values at the end of each period. To assess NMD, FMD was measured before and four minutes after 1.25 mg of isosorbide dinitrate was given under the tongue. Blood samples were drawn at each visit and analyzed for coagulation markers, adhesion molecules, markers of inflammation, and epicatechin content. To monitor safety, hematology, clinical chemistry, and serology tests were also conducted. Subjects completed 4-day food diaries after the screening visit and during each treatment period. Before each study visit, subjects had to fast for 10 hours, not exercise for 24 hours, and not use any nicotine products for 10 hours. Nicotine products were also prohibited during the visit. Otherwise, subjects were to carry on their normal lifestyle and diet and keep a food diary.
Fifty-seven subjects completed the study. Three discontinued the study because of the following adverse effects (AE): a migraine, dyspepsia, and increased plasma gamma-glutamyltransferase. Other reported AE included nasopharyngitis, indigestion, headache, dizziness, and ligament sprain. According to the authors, none of the AE had an “obvious association to either treatment,” and there was no statistically significant difference between groups in the incidence of AE.
With the apple extract treatment, there was a significant improvement in acute maximum FMD at the first (P = 0.043) and last (P = 0.02) visits of the treatment period, and for both visits combined (P = 0.005). However, this improvement was not statistically significant when compared with the placebo treatment. The apple extract did not have a significant long-term effect on FMD compared to the placebo treatment. No significant changes in NMD or biomarker concentrations were observed.
In conclusion, there was a “significant acute improvement in FMD of the brachial artery, an indicator of endothelial function, in subjects with borderline or mild hypertension after intake of the epicatechin-containing study product.” However, neither acute ingestion nor long-term consumption of the apple extract had a significant effect on FMD or the secondary endpoints compared to the placebo treatment. The authors suggest the lack of a significant effect may be due to a number of factors, including (1) individual differences in epicatechin pharmacokinetics, (2) inclusion of subjects with normal FMD responses, (3) sub-therapeutic dose of the apple extract, and (4) the study may have been underpowered. The authors recommend that future trials employ a parallel design, use ambulatory blood pressure measurements, and take the significant range in FMD responses into consideration when calculating statistical power.
Funding for this project was provided by DuPont Nutrition and Health (formerly Danisco). Four of the authors (OH, KT, MJL, and AT) are or have been, DuPont employees. The authors declare “no other competing interest regarding this study.”
Saarenhovi M, Salo P, Scheinin M, et al. The effect of an apple polyphenol extract rich in epicatechin and flavan-3-ol oligomers on brachial artery flow-mediated vasodilatory function in volunteers with elevated blood pressure. Nutr J. October 2017;16(1):73. doi: 10.1186/s12937-017-0291-0.