Lowering Effects of n-3 Fatty Acid Supplements on Blood Pressure by

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Lowering effects of n-3 fatty acid supplements on blood pressure by reducing plasma angiotensin II in Inner Mongolia hypertensive patients: A double-blind randomized controlled trial# Bo Yang, Lin Shi, Ai M. Wang, Mei Q. Shi, Zi H. Li, Feng Zhao, Xiao J. Guo, and Duo Li J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b05463 • Publication Date (Web): 04 Dec 2018 Downloaded from http://pubs.acs.org on December 10, 2018

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Journal of Agricultural and Food Chemistry

Lowering effects of n-3 fatty acid supplements on blood pressure by reducing plasma angiotensin II in Inner Mongolia hypertensive patients: A double-blind randomized controlled trial Bo Yang†,§, Lin Shi#, Ai-min Wang#, Mei-qi Shi§, Zi-hao Li§, Feng Zhao‡, Xiao-juan Guo†*, Duo Li‡,§* †Institute

of Lipids Medicine, Wenzhou Medical University, Wenzhou, China

‡Institute

of Nutrition and Health, Qingdao University, Qingdao, China

#Ejin

Horo Banner Centre for Disease Prevention and Control, Ordos, Inner Mongolia, China

§Department

of Food Science and Nutrition, Zhejiang University, Hangzhou, China

*Co-corresponding Author: Prof. Xiao-juan Guo Institute of Lipids Medicine, Wenzhou Medical University Chashan University Town, Wenzhou, China, 325035 Phone: +86-577-82991018; Fax: +86-577-86689848 E-mail: [email protected] *Corresponding Author: Prof. Duo Li Institute of Nutrition and Health, Qingdao University 308 Ningxia Road, Qingdao, China, 266003 Phone: +86-532-82991018; Fax: +86-532-82991018 E-mail: [email protected]

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ACS Paragon Plus Environment


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Abstract

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Whether n-3 fatty acid (FA) has hypotensive actions among Chinese adults remains

3

inconclusive. Hypertensive patients from Inner Mongolia, China (n=126) were recruited to a

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double-blind, randomized controlled trial. We investigated the effects of n-3 FA supplements

5

on blood pressure (BP, mm Hg), plasma concentrations of angiotensin II (Ang II, pg/mL) and

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nitric oxygen (NO, µmol/L), using fish oil (n=41, 4 capsules/day, equivalent to 2 grams of

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eicosapentaenoic acid plus docosahexaenoic acid) and flaxseed oil (n=42, 4 capsules/day,

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equivalent to 2.5 grams of α-linolenic acid). Comparing to the control group (corn oil, n=43),

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the mean systolic BP (-4.52±9.28 vs. -1.51±9.23, P=0.040) and the plasma Ang II levels

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(-12.68±10.87 vs. -4.93±9.08, P=0.023) were significantly lowered in fish oil group, whereas

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diastolic BP (P=0.285) and plasma NO levels (P=0.220) were not. Such findings suggest that

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marine-based n-3 FA has a hypotensive efficacy in Chinese hypertensive patients possibly

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through inhibiting Ang II-dependent vasoconstrictions.

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Key Words: n-3 fatty acid; Fish oil; Flaxseed oil; Randomized controlled trial; Hypertension;

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Ang II

17 18 19 20 21 22 23 24 25

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Introduction

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The World Health Organization has identified high blood pressure (BP) as a global public

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crisis because it is the leading risk factor for cardiovascular disease (CVD) mortality and

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morbidity worldwide. Hypertension defined as a systolic BP (SBP) ≥140 mm Hg and/or

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diastolic BP (DBP) ≥ 90 mm Hg has been the biggest contributor to the total disease burden

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and the total mortality in China, with a dramatic up trend from nearly 19.0% in 2002 to 27.8%

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in 2016.1 Hence it is necessary to identify effective and desirable trial-based implementations

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to control the elevated BP in China.

34 35

BP can be modulated through diet and lifestyle intervention as a potential therapeutic strategy.

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One type of the candidate food components or nutrients was n-3 fatty acid (FA), including

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plant-derived (e.g., flaxseed oil) 18:3n-3 (α-linolenic acid, ALA) and marine-derived (e.g.,

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fish oil) 20:5n-3 (eicosapentaenoic acid, EPA) and 22:6n-3 (docosahexaenoic acid, DHA).

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Experimental studies have demonstrated n-3 FA can protect against BP elevations by multiple

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cardiometabolic improvements in the balance of vasodilator and vasoconstrictor,2-4 the

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systemic arterial compliance mediated by nitric oxygen (NO) release5, 6and the voltage

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dependent L-type Ca2+ channel levels.7 Of note, most investigations using rodent models take

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amounts of dietary n-3 FA that are in considerable excess (on a pro rata basis) to that allowed

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in human; and therefore the results may not be applicable among humans. Strong evidence

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has been provided by numerous meta-analyses based on intervention trials to justify that n-3

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FA treatments can notably reduce BP in treated or untreated hypertensive subjects.8-10

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However, all the intervention studies included in the meta-analyses are conducted in Western

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populations. There were several intervention trials to show that the effects of n-3 FA on BP

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could be modified by different genetic variants and support the existence of gene-diet

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interaction for BP-lowering outcomes.11-13 For example, a fish oil trial among health adults

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showed that pronounced BP reductions were found only in non-carriers of rs1378942 in the

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c-Src tyrosine kinase gene, but no replication in carriers of the risk allele.12

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Several epidemiological studies of food n-3 FA or biomarker in relation to BP have been

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conducted in China, and their results are rather consistent in manifesting that circulating

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marine n-3 FA as a biomarker may be negatively associated with BP levels in middle-aged

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and elderly Chinese.14-16 Till now, there has been only one randomized controlled trial (RCT)

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using a12-wk supplementation with omega-3Q10 formulation to support the BP-lowering

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effect in Chinese hypertensive adults with hypercholesterolemia.17 However, the benefits for

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BP may be attributed to a mixed effect of the omega-3Q10 formulation including fish oil,

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co-enzyme Q10, lycopene and other active ingredients. The BP-lowing effect of fish oil n-3

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FA in Chinese population may still be impaired by lack of sufficient evidence. We therefore

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designed a randomized, placebo-controlled, double-blinded trial in Inner Mongolia of China

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to determine whether n-3 FA supplements, from either marine (fish oil) or plant-based

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(flaxseed oil), could reduce BP. We hypothesized that treatments with n-3 FA have a notably

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lowering effect on BP in Chinese hypertensive patients, and marine-based n-3 FA would be

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more potent.

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Methods

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Study design

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The randomized, double-blind, placebo-controlled trial was designed by the steering

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committee from APCNS Center of Nutrition and Food Safety, and was undertaken at a

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single-site treatment center in Ordos, Inner Mongolia, China. Ordos is a well development

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region with a good medicare system even in remote areas. Most of the local residents are

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native Inner Mongolia people, and their complete medical records were documented in the

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local community hospitals. The study protocol was approved by the Ethics Committee of

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College of Biosystem Engineering and Food Science at Zhejiang University (No. 2015002),

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and written informed consent was obtained from all the participants before enrollment. The

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trial has been registered on ClinicalTrails.gov (ChiCTR-ICR-15006978).

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Study participants

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Totally, 147 hypertensive patients aged between 35-70 years old were recruited based on the

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inclusion and exclusion criteria from April 2015 to July 2015 among those attending the

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outpatient department of the local community hospitals. Of those, 132 participants agreed to

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participate and completed baseline assessments including the collection of blood samples,

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anthropometric measurements and a face-to-face questionnaire interview (served as a

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screening tool). Out of the 132 enrolled participants, 55 men and 71 women were eligible

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patients who met the following inclusion criteria: (1) clinically diagnosed hypertension with

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BP cutoff value (systolic BP (SBP) ≥ 140 mm Hg and (or) diastolic BP (DBP) ≥ 90 mm Hg)

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or receiving antihypertensive treatment for less than 2 years; (2) aged between 35-70 years

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old; and (3) complying with protocol requirements and providing informed consent. Patients

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were excluded from the trial if they had the following: (1) secondary hypertension; (2)

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gestational hypertension; (3) stage 2 hypertension (BP ≥ 160/100 mm Hg); (4) history of

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chronic hepatitis, renal failure, lung disease, malignant tumor, severe diabetics and

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cardiovascular diseases (e.g., myocardial infarction, arrhythmia, heart failure and stroke),

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schizophrenia or bipolar disorder, and/or major neurological disorder; (5) daily consumption

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of fish oil capsules or with a hypersensitivity to n-3 FA; (6) clinical conditions with poor

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short-term prognosis, and other conditions that would affect the ability to provide informed

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consent or comply with the protocol.

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Study procedures

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With the assumption of a detectable difference in blood pressure of 3.5 mmHg between the 2

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groups at 3 mo, 112 participants were required to achieve 80% power of detecting a treatment

104

effect at a 2-sided significance level of 5%. With allowance for a 10% drop-out rate over the 3

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mo, a sample size of 124 was needed to enable adequate power to assess our primary outcome

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as shown in a previous study.18

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Totally, 126 eligible patients were randomized allocated to one of the 3 treatments by a

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computer-generated block randomization stratified by ethnicity (Han vs. Mongol), age (< 45

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vs. ≥ 45 yr) and gender: fish oil group (FO, n=41), flaxseed oil group (FLO, n=42) or corn oil

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group (CO served as a placebo, n=43). Allocation sequence was generated by Dr. BY only

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and was concealed in sealed study folders that were held in a secured location. Patients,

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community general practitioners, coordination and outcome assessors were blinded to the

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study assignments until the final analyses were completed. Each of FO, FLO, and CO

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capsules was standardized to 1 g with identical appearance, and n-3 FA profiles in the 3 types

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of capsules were presented as previously described.19 Briefly, each FO capsule provided

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500mg of EPA + DHA (EPA: DHA=3:2), and other major fatty acids in each FO capsule

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were 16:0 (71.4 mg), 18:1n-9 (58.4 mg), 16:1n-7 (56 mg), 20:0 (39.4 mg) and 14:0 (34.6 mg).

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Each FLO capsule contained 630 mg of ALA, 155 mg of 18:2n-6 and 137 mg of 18:1n-9.

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Major FAs in each CO capsule were 18:2n-6 (534 mg), 18:1n-9 (299 mg) and 16:0 (121 mg).

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The patients in each of the trial arms were required to take four capsules per day over a

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treatment period of 90 days, which would totally provide a daily dose of 2g EPA+DHA

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(EPA:DHA=2:1) for those assigned to the FO group, 2.5g ALA for those assigned to the FLO

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group, or 2.14g 18:2n-6 for those assigned to the CO group, respectively. None of the

125

participants or the staff member in the local hospital knew the oil types during the

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intervention.

127 128

Participants were instructed to continue the usual diet, physical activity, living habits, use of

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prescribed medications and avoid use of n-3 FA supplements throughout the trial. After two

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bottles of capsules per capita were distributed at baseline, we followed up them to assess any

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potential side effect and adherence by telephone at third-weekly interval. If adherence was

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80% or lower, community practitioners would conduct a door-to-door follow-up interview at

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two-weekly interval when additional supplements had been distributed in the mid-point of

134

follow-up. At the clinical visit of 90 days of supplement period, participants attended

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appointments for end-of-study procedures and the final on-site physical examination.

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Compliance was assessed by capsule count and erythrocyte FA analysis.

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Questionnaire interview

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At baseline, a face-to-face questionnaire interview was completed by trained investigators14 to

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collect the pre-specified information on the socio-demographic characteristics, lifestyle habits,

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family history of hypertension, current clinical conditions, and medical treatments. Average

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intake of dietary nutrients was monitored by the general practitioner of the patients

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throughout the study, with the 3-day 24-hour dietary-recall record (2 weekdays and 1

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weekend day). Each patient’s 24-hour dietary intakes were calculated using Nutrition System

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of Traditional Chinese Medicine Combining with Western Medicine, version 11.0 (Qingdao

146

University, Shandong, China). The nutritional system has a food-composition table,

147

permitting calculation of nutrient intake from reported food intake.20

148 149

Outcome measurements

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Anthropometrical measurements using the same standard protocols at both the baseline and

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final follow-up visit were performed by the trained physicians, including height (m), body

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weight (kg), heart rate (HR, beat/min), waistline (WC, m), hipline (HC, m) and BP (mm Hg).

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Body weight and height were recorded with patients wearing light clothing and no shoes, and

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body mass index (BMI) was calculated as the participant’s weight (kg) divided by the square

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of standing height (m). Waist-to-hip ratio (WHR) was calculated as the body circumference

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midway between the inferior border of the rib cage and the superior border of the iliac crest,

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divided by the maximal body circumference at the buttocks. Participants were advised to

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avoid consuming alcohol or tobacco, ingesting tea or coffee, and engaging in exercise for at

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least 30 min while HR and BP were measured. A standardized mercury sphygmomanometer

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was used to measure resting BP in a quiet room by well-trained physicians, and one of three

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cuff sizes (regular adult or larger) was chosen based on the circumference of the participant’s

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arm. The final BP and HR measurement for each subject were defined as the mean of three

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readings performed in the subject in sitting position with 2-min intervals at the visit. The

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mean arterial pressure (MAP) was calculated as the DBP plus one third of the SBP.

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The fasting blood samples were collected at the baseline and the end of the 90-day

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intervention period. Assays of blood lipid profiles, fasting glucose [Glu], and the markers of

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liver (alanine transaminase [ALT] and aspartate transaminase [AST]) and kidney function

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(blood urea nitrogen [BUN], creatinine [Cr] and uric acid [UA]) were performed in the

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chemical laboratory of the local hospital. Phospholipids (PL) FA compositions in erythrocytes

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were determined by gas chromatography at the baseline and the end of the trial to evaluate the

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compliance of the patients to the supplements. Briefly, we extracted the lipids from the

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erythrocytes with chloroform/methanol (1:1), and separated phospholipid fraction using

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thin-layer chromatography. The phospholipid fatty acids are converted to methylester, 8


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extracted into n-hexane, and dried on anhydrous Na2SO4. Finally, the fatty acid methylesters

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are filtered by Sep-Pak Silica column before gas chromatography separation and analysis.19

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Plasma concentrations of nitric oxygen (NO) and angiotensin (Ang) II levels were determined

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using commercial ELISA kits following the manufacture protocols.

179 180

The primary efficacy measurements for the treatment comparison were clinical BPs (SBP,

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DBP, PP and MAP), plasma concentrations of NO, and Ang II change from baseline to the

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90-day visit. The second end points were changes in the following anthropometrical

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parameters from baseline to the end of 90-day trial: resting HR, WC, HC, and WHR. All

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adverse events were recorded during the follow-up, including those that were not directly

185

related to the study capsules.

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Statistical analyses

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Data analyses followed the intention-to-treat approach. The missing data from the patients

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lost in the follow-up were imputed according to their last available records. The data for the

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analysis includes all randomized participants. All the outcome variables were firstly checked

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if they fit the normal distribution, and then log-transformed if they were not normal

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distributed (glucose and TG were natural log transformed). Baseline characteristics and

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nutrient intakes in hypertensive patients who underwent randomization were compared by

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means of the chi-square test for categorical variables and One-way ANOVA for continuous

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variables. Change in erythrocyte compositions of n-3 FA in FO or FLO compared with CO

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was examined by a general linear model (GLM), adjusting for age, gender, ethnicity, BMI

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baseline unbalanced values and baseline corresponding FA compositions in erythrocyte.

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Correlational analyses controlling for baseline values and change in BMI, WHR and blood

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lipids were conducted to investigate relationship between changes in erythrocyte PL 9



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compositions of n-3 FA and BP. Changes from baseline to the end of 90-day supplements in

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primary and secondary outcomes within each group were analyzed by Student’s paired t-test.

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The difference in treatment effects over time on the primary and secondary outcomes between

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groups were assessed by a full GLM, with adjustment for age, gender, ethnicity, BMI, WHR,

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dietary nutrient intake, erythrocyte n-3 FA, current anti-hypertension treatments and baseline

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values that were unbalanced between groups. For exploratory purpose, the pre-specified

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subgroups of subjects with baseline elevated BP (≥ 120/80 mm Hg) and those with

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erythrocyte compositions of total n-3 FA < median as well as overweight/obese subgroups

208

(BMI>25)21 were assessed in ancillary analyses, respectively. Finally, based on the

209

per-protocol principle, sensitivity analyses removing data from participants who dropped out

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during the trial were conducted to assess the robustness of treatment efficacy on the primary

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outcomes. P value with two-tailed < 0.05 was considered statistically significant.

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Results

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Baseline characteristics

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Totally 126 patients were included in the intention-to-treat analyses. During 90 days

216

follow-up, 6 patients in the FO group, 6 in the FLO group and 5 in the CO group dropped out.

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The remaining 109 subjects completed the trial (Figure 1). All dropouts occurred after the

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mid-term follow-up due to unavailability for complying with the capsules and the schedule of

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the follow-up visits.

220 221

Baseline characteristics concerning the demographic parameters, lifestyle factors,

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anthropometry parameters, prevalent CVD and current anti-hypertensive treatment are shown

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in Table 1. Baseline clinical indicators of BP (mean±SD) across all 3 groups combined were

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134.92±13.98 mmHg for SBP, 88.09±9.64 mmHg for DBP, 103.69±9.99 mmHg for MAP

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and 44.82±10.07 mmHg for PP. Anti-hypertensive medication was taken by 96 of the 126

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patients, and did not change throughout the study. At baseline, 32% and 30% of patients

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taking angiotensin-converting enzyme (ACE) inhibitors were correspondingly allocated to FO

228

and FLO group, compared to 38% of those allocated to the CO group. No significant

229

difference was found for dietary total energy and nutrient intake from baseline analyses of

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3-day diet records among the three trial groups (Supplementary Table 1).

231 232

Erythrocyte phospholipids compositions of individual and total n-3 fatty acid

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Changes in erythrocyte PL compositions of n-3 FA from baseline to end of the 90-day

234

supplements were examined to assess compliance to the treatment assignments (Figure 2).

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Erythrocyte 20:5n-3 and 22:6n-3 were significantly increased in FO compared with CO group

236

(p < 0.01 for both), and 20:5n-3 was significantly increased in FO compared with FLO group

237

(p=0.04). FLO supplements had markedly increased compositions of 18:3n-3, compared with

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FO (p=0.02) and CO supplements (p 6 g/day

9 (21.95)

15 (35.71)

13 (230.23)

0.316

Height, m

164.82±7.17

162.93±9.05

166.53±7.04

0.101

Weight, kg

71.40±9.28

71.22± 9.77

71.95±9.49

0.933

BMI, kg/m2

26.26±2.86

26.82± 2.92

25.93±3.06

0.368

WC, cm

92.73±8.08

94.78±8.45

94.81±9.82

0.905

HC, cm

100.36±10.40

103.68±8.64

102.04±10.32 0.301

WHR

0.94±0.04

0.91±0.13

0.92±0.05

0.240

Family history of hypertension

26 (63.41)a

21(50.00)ab

16 (37.20)b

0.046

Coronary heart disease

7 (17.07)

3 (7.14)

6 (13.95)

0.486

Stroke

4 (9.75)

3 (7.14)

3 (6.97)

0.855

Hypercholesterolemia

9 (21.95)

7 (16.67)

12 (27.90)

0.465

Peripheral artery disease

2 (4.87)

3 (7.14)

3 (6.97)

0.873

SBP, mm Hg

135.28±14.15

133.76±13.68 136.54±14.13 0.967

DBP, mm Hg

88.93±9.94

86.17±8.37

89.01±10.36

0.891

Heart rate, beats/min

77.04±9.32

76.29±9.65

78.39±11.80

0.627

Lifestyle factors—n (%)

Anthropometry parameters

Prevalent CVD—n (%)

Clinical measurements

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fasting glucose, mmol/L

5.09±1.18

5.13±0.86

5.11±1.08

0.985

Log-transformed Insulin, mU/L

2.17±0.61

2.30±0.62

2.26±0.56

0.562

TG, mmol/L

1.78±0.85

2.18±1.04

2.00±0.98

0.170

TC, mmol/L

5.48±1.27

5.57±1.12

5.31±1.05

0.552

ALT, U/L

19.90±7.77

21.07±10.60

20.48±10.53

0.780

AST, U/L

14.08±9.22

19.07±11.90

18.13±8.74

0.076

AST/ALT

0.76±0.42

0.81±0.35

0.94±0.46

0.115

Creatinine, μmol/L

72.21±14.85

73.02±19.51

72.64±16.77

0.910

BUN, μmol/L

5.62±1.72

5.44±1.37

5.74±1.28

0.636

UA, μmol/L

322.73±100.98

329.36±95.37 363.97±84.67 0.089

Oral anti-hypertension drugs

33 (80.47)

31 (73.80)

33 (76.74)

0.767

Oral anti-thrombotic drugs

4 (9.75)

6 (14.28)

8 (18.06)

0.535

Oral lipid-lowering agents

6 (14.63)

5 (11.90)

5 (11.62)

0.726

Current medical treatment—n (%)

Continuous values are presented as mean ± SD, and categorical variables are presented as number (%). WC, waist circumference; HC, hip circumference; WHR, waist to hip ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; UA, blood uric acid. 1P value was calculated by chi-square test (for categorical variables) or One-way ANOVA (for continuous variables) to test the difference between the three trial arms at baseline.

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Table 2. Comparisons with placebo for the primary outcomes in the intention-to-treat patients receiving n-3 fatty acid supplements Between-group 　　 FO (n=41) 　　　 FLO (n=42) 　　　 CO (n=43) 　　 comparisons P-time1

　

Time

Mean (SD)

SBP

Day 0

135.28 (14.15) 0.002

Day 90

130.75 (13.44)

DBP

Day 0

88.93 (9.94)

Day 90

85.18 (9.06)

Day 0

46.59 (10.46)

Day 90

45.56 (9.52)

0.001

Day 90

133.76 (13.68) 0.045

　Day 0

129.92 (11.97)

Day 0

86.17 (8.37)

Day 90

82.28 (10.00)

0.467

Mean (SD)

P-time1 　

136.54 (14.13) 0.287

0.970

0.775

0.082

0.040

0.897

0.793

0.640

0.687

0.182

0.285

0.897

0.793

0.640

0.687

Change -0.02 (6.88)

0.153

0.496

Day 0

104.85 (10.63) 0.255

0.385

0.676

Day 90

103.35 (11.67)

0.063

0.284

135.02 (14.52)

Day 0

89.01 (10.36)

Day 90

87.51 (11.03)

0.171

Change -1.49 (8.19)

Day 0

46.34 (11.39)

Day 90

46.64 (9.17)

0.965

Change 0.05 (7.22)

105.60 (10.42) 0.001

Day 0

102.78 (9.00)

100.10 (10.04)

Day 90

97.77 (10.78)

0.005

P3 0.687

Change -1.51 (9.23)b 0.003

P2

　0.951

Day 90

Change -3.89 (7.34)

Change -0.78 (7.05) MAP Day 0

　 Day 0

Change -3.84 (10.52)ab

Change -3.72 (6.09) PP

Mean (SD)

Day 90

Change -4.52 (9.28)a

P-time1 　Time

　 Time

Day 0

47.52 (10.61)

Day 90

47.50 (10.37)

0.982

Change -5.50 (7.10)a Change -4.89 (8.38)ab Change -1.32 (8.67)b 0.051 0.034 Values are presented as mean ± SD. Groups sharing the different superscript (a or b) have significant difference from each other in the post hoc analysis (p

Lowering Effects of n-3 Fatty Acid Supplements on Blood Pressure by

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