2.1. Participants

Men and women were recruited in Quebec City primarily through mailing lists and announcements published on our website. Participants had to be aged between 18 and 75 years and have maintained a stable body weight (±2.5 kg) for at least 3 months prior to the study. All participants underwent an array of measurements and answered a medical history questionnaire at screening. The a priori defined eligibility criterion was to have a mean daytime ambulatory SBP ≥125 mmHg and <135 mmHg and a mean daytime ambulatory DBP <85 mmHg. However, this criterion was modified 2 months into recruitment due to difficulties in achieving the intended sample size (only 13% of individuals had met these criteria). Eligibility based on mean daytime ambulatory SBP values was changed to ≥120 mmHg and <140 mmHg and mean daytime ambulatory DBP to <90 mmHg. Exclusion criteria were a history of CVD, type 2 diabetes or monogenic dyslipidemia; uncontrolled endocrine disorder; kidney stones; any clinical signs or laboratory evidence for inflammatory, gastrointestinal, endocrine, renal, pulmonary, neurological, cardiovascular, metabolic or hematological problems or cancer; the use of anticoagulants or thrombocyte aggregation inhibitors, chemotherapeutic agents, anti-inflammatory drugs, medication for blood lipids, diabetes, hypertension, erectile dysfunction or auto-immune diseases; alcohol consumption >14 consumption/week (i.e., >188 g ethanol/week); drug consumption; hypersensitivity or allergy to one of the ingredients in polyphenols/L-citrulline supplement or placebo; use of additional cranberry or grape seed extract or citrulline products; women who were breastfeeding, pregnant or planning a pregnancy; and women in perimenopause. Women with child-bearing potential had to use one of the following contraceptive methods during the study: hormonal birth control methods, intrauterine devices, confirmed successful vasectomy of partner or total abstinence. Pregnancy test was also performed by measuring plasma level of beta human chorionic gonadotropin at screening. Postmenopausal women who did not have regular menses ≥1 year were eligible. However, hormone supplementation status had to be constant for at least 6 months prior to the study and for the duration of the study. When a perimenopausal status was suspected, follicle-stimulating hormone measurements were performed. The use of an anti-inflammatory drug was prohibited during the intervention. Other medications, vitamin and mineral supplements and natural health products were allowed under the approval of the study physician as long as the use and dosage were stable before and throughout the study period. The period of stability before the intervention depended on the type of drug or supplement: anti-inflammatory drugs and antibiotics had to be stopped 10 days before the first day of intervention (D0); vitamins and minerals had to be stable for more than 2 weeks; omega 3 for 1 month; mental health drugs and hormonal contraception should have been stable for more than 3 months and for replacement hormones, 6 months.

The study protocol was approved by local Research Ethics Committees (2017-207) and was fully explained to all participants, who gave their written informed consent before participation. The study protocol is registered at ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT03679195","term_id":"NCT03679195"}}NCT03679195.