Study on the Effects of Epicatechin and Quercetin Supplementation on Vascular Function and Blood Pressure (FLAVO)

Study Overview
=================
Brief Summary
-----------------
Flavonoid-rich foods such as tea and cocoa have been identified as having a blood pressure-lowering effect. Part of this effect is thought to be due to the flavonoid content of these foods although it is currently unknown which flavonoids play a role. Epicatechin is one the major flavonoids in cocoa while quercetin is largely found in tea. During this study the investigators plan to investigate the effects of pure epicatechin and quercetin supplementation on vascular function and blood pressure in untreated (prehypertensive) subjects by way of a three-armed double-blind crossover intervention. Participants will sequentially consume supplements containing quercetin, epicatechin or placebo for a period of 4 weeks. Before and after this 4 week period, measurements of vascular function and blood pressure will be taken. The investigators hypothesize that the supplementation of epicatechin and quercetin will improve vascular function and blood pressure.

Detailed Description
-----------------
By means of a three-armed double-blind crossover intervention, the effects of pure flavonoid supplementation will be investigated. The products under investigation will be epicatechin and quercetin-3-glucoside. Subjects will be asked to consume either 160mg of quercetin-3-glucoside, 100mg of epicatechin or a placebo capsule for a period of 4 weeks. Measurements of vascular function and blood pressure will be taken before and after each 4-week intervention period. A 4-week washout period will be planned between each intervention. Measurements of vascular function will include flow-mediated dilation, pulse wave analysis, pulse wave velocity and vasomotion as well as biomarkers of inflammation and vascular function.

Official Title
-----------------
Study on the Effects of Epicatechin and Quercetin Supplementation on Vascular Function and Blood Pressure in Untreated (Pre)Hypertensive Subjects

Conditions
-----------------
Hypertension, Endothelial Dysfunction

Intervention / Treatment
-----------------
* Dietary Supplement: Epicatechin
* Dietary Supplement: Quercetin
* Dietary Supplement: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Systolic Blood Pressure between 125 and 160 mmHg Age between 30 and 80 years BMI > 20 and ≤ 40 No reported current or previous metabolic diseases No history of cardiovascular diseases No history of renal, liver or thyroid diseases No history of gastrointestinal diseases No diabetes mellitus Fasting laboratory parameters within normal range: complete blood count (RBC, WBC, PLT, HB, HT), renal function (serum creatinine, urea), liver function (ALAT, ASAT, ɣ-GT), and serum glucose. Exclusion Criteria: Body mass index > 40 and ≤20 Secondary hypertension Weight loss or weight gain of 5 kg or more during the last 2 months Usage of non-steroidal anti-inflammatory drugs (acetylsalicylic acid, ibuprofen, naproxen) and not able or willing to stop taking them from at least 4 weeks prior to the study Usage of cholesterol-lowering medication Daily usage of corticosteroids Medical treatment that may affect blood pressure and not able (or willing) to stop Taking nutritional supplements and unwilling to discontinue Lactating, pregnant or intention to become pregnant during study Reported dietary habits, medically prescribed diet, slimming diet Reported average alcohol consumption > 2 glasses/d (men) or >1 glass/d (women) Problems with consuming the supplements or following the study guidelines Unwilling to undergo home or office blood pressure measurements Recent blood donation i.e. 1 month (male subjects) or 2 months (female subjects) prior to the study and planned donation during the study period Reported intense sporting activities > 10 h/w Not agreeing to be informed about unexpected and medically relevant personal test-results, or not agreeing that their general practitioner will be informed about these results Participation in another biomedical trial less than 2 months before the start of the study or at the same time No signed informed consent form Clinical disorders that could interfere with the intervention Unable to comply with the study procedure (e.g. holidays, urine collection, blood sampling) Smokers Difficulty imaging brachial artery by ultrasonography

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Epicatechin<br>Subjects will be asked to consume supplements containing 100mg of epicatechin daily | Dietary Supplement: Epicatechin<br>* Subjects will be asked to consume supplements containing 100mg of epicatechin daily<br>|
| Active Comparator: Quercetin<br>Subjects will be asked to consume supplements containing 160mg of quercetin-3-glucoside daily | Dietary Supplement: Quercetin<br>* Subjects will be asked to consume 160mg of quercetin-3-glucoside daily<br>|
| Placebo Comparator: Placebo<br>Subjects will be asked to consume capsules containing a placebo (cellulose) daily | Dietary Supplement: Placebo<br>* Subjects will be asked to consume capsules containing placebo (cellulose) daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Endothelium-dependent flow-mediated dilation as a result of epicatechin and quercetin-3-glucoside supplementation | Change in arterial diameter as a result of 5 minute arterial occlusion (200mmHg). Arterial diameter will be measured by means of ultrasonography. | Baseline and every 4 weeks thereafter (weeks 4, 8, 12, 16 and 20) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in blood pressure as a result of epicatechin and quercetin-3-glucoside supplementation | Office BP (Dinamap, 4 consecutive measurements with 2-min intervals)and 24-hour ABPM (Spacelab; 1x24h) | Baseline and every 4 weeks thereafter (weeks 4, 8, 12, 16 and 20) | 
| Change in pulse wave velocity as a result of epicatechin and quercetin supplementation | Measured using a SphygmoCor device at baseline and the end of each intervention | Baseline and every 4 weeks thereafter (weeks 4, 8, 12, 16 and 20) | 
| Change in vasomotion as a result of epicatechin and quercetin supplementation | Measured using a PeriFlux 5001 device at baseline and the end of each intervention. | Baseline and every 4 weeks thereafter (weeks 4, 8, 12, 16 and 20) | 
| Changes in biomarkers of endothelial function as a result of epicatechin and quercetin supplementation | Plasma analysis of endothelin-1, ADMA, MCP-1, sVCAM-1, sICAM-1, sE-selectin, sTM, CRP, SAA, IL-6, IL-8, TNF-α, vWF, nitric oxide | Baseline and every 4 weeks thereafter (weeks 4, 8, 12, 16 and 20) | 
| Changes in peripheral blood mononuclear cell gene expression of markers of inflammation as a result of epicatechin and quercetin supplementation | PBMC gene expression of markers of inflammation | Baseline and every 4 weeks thereafter (weeks 4, 8, 12, 16 and 20) | 
| Change in cardiovascular parameters in plasma as a result of epicatechin and quercetin supplementation | Total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, insulin and glucose | Baseline and every 4 weeks thereafter (weeks 4, 8, 12, 16 and 20) | 
| Changes in pulse wave analysis as a result of epicatechin and quercetin supplementation | Measured using a SphygmoCor device at baseline and the end of each intervention | Baseline and every 4 weeks thereafter (weeks 4, 8, 12, 16 and 20) | 
| Adverse events | During the study subjects will be asked to maintain a diary in which they can report any adverse events they may have a result of the supplements. Diaries will be checked every 2 weeks. Study subjects will also be asked to contact the research team if they experience repeated adverse events. | Baseline and every 2 weeks thereafter (weeks 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Flavonoids, Quercetin, Epicatechin, Vascular function, Blood pressure, Endothelial function