Dietary Intervention

Potent Antihypertensive Action of Dietary Flaxseed

in Hypertensive Patients
Delfin Rodriguez-Leyva, Wendy Weighell, Andrea L. Edel, Renee LaVallee, Elena Dibrov,
Reinhold Pinneker, Thane G. Maddaford, Bram Ramjiawan, Michel Aliani,
Randolph Guzman, Grant N. Pierce

Abstract—Flaxseed contains ω-3 fatty acids, lignans, and fiber that together may provide benefits to patients with
cardiovascular disease. Animal work identified that patients with peripheral artery disease may particularly benefit from
dietary supplementation with flaxseed. Hypertension is commonly associated with peripheral artery disease. The purpose
of the study was to examine the effects of daily ingestion of flaxseed on systolic (SBP) and diastolic blood pressure (DBP)
in peripheral artery disease patients. In this prospective, double-blinded, placebo-controlled, randomized trial, patients
(110 in total) ingested a variety of foods that contained 30 g of milled flaxseed or placebo each day over 6 months. Plasma
levels of the ω-3 fatty acid α-linolenic acid and enterolignans increased 2- to 50-fold in the flaxseed-fed group but did not
increase significantly in the placebo group. Patient body weights were not significantly different between the 2 groups
at any time. SBP was ≈10 mm Hg lower, and DBP was ≈7 mm Hg lower in the flaxseed group compared with placebo
after 6 months. Patients who entered the trial with a SBP ≥140 mm Hg at baseline obtained a significant reduction of
15 mm Hg in SBP and 7 mm Hg in DBP from flaxseed ingestion. The antihypertensive effect was achieved selectively
in hypertensive patients. Circulating α-linolenic acid levels correlated with SBP and DBP, and lignan levels correlated
with changes in DBP. In summary, flaxseed induced one of the most potent antihypertensive effects achieved by a dietary
•
intervention.  (Hypertension. 2013;62:1081-1089.) Online Data Supplement
Key Words: alpha linolenic acid ◼ flax ◼ hypertension
◼ myocardial infarction ◼ peripheral arterial disease ◼ polyunsaturated fatty acid ◼ stroke
Downloaded from http://ahajournals.org by on November 11, 2024

H ypertension is one of the most important risk factors

associated with both cardiovascular and cerebrovascular
disease.1,2 Hypertension is defined as a systolic blood pressure
including hypertension. The dietary factors that influence BP
have traditionally included Na+, K+, caloric content, caffeine,
and alcohol.8
(SBP) of ≥140 mm Hg or a diastolic blood pressure (DBP) of The purpose of this research was to study another nutri-
≥90 mm Hg.3 A SBP of >115 mm Hg has been suggested to be tional intervention—flaxseed. The seed has a pleasant nutty
the single most important determinant for death in the world flavor that can be eaten as is or incorporated into a num-
today.3 The direct and indirect economic cost of hypertension ber of food products. In animal trials, flaxseed has shown
was >$76 billion 2 years ago.4 Understanding how to reduce an unusually strong capacity to regulate CVD through its
BP has become, therefore, a critical challenge. antiatherogenic effects,9–12 anti-inflammatory properties,11
Improper nutrition has been implicated in hypertensive improvements in vascular contractile function,10 and a potent
cardiovascular disease (CVD). At the same time that BP was antiarrhythmic action during ischemic challenge.13 Flaxseed
increasing in the United States in the 1990s, healthy eating may achieve these cardiovascular actions through its compo-
patterns and the intake of fresh fruits and vegetables were sition. It is high in dietary fiber, one of the richest sources of
decreasing and the incidence of obesity was increasing.5 the short-chain ω-3 fatty acid α-linolenic acid (ALA), and
People who were eating more vegetables (ie, vegetarians) it also contains lignans, which are potent antioxidants.9–13
or who had low sodium intake do not exhibit any change in Although these data provide compelling evidence to justify
BP with advancing age.6 It has been estimated that nutri- the use of flaxseed in CVD, few studies have investigated its
tional factors may be responsible for ≈40% of all CVD,7 efficacy in a patient population.

Received July 22, 2013; first decision August 12, 2013; revision accepted September 6, 2013.
From the Cardiovascular Research Division, V.I. Lenin Universitary Hospital, Holguin, Cuba (D.R.-L.); and Department of Surgery, St Boniface Hospital
and the Asper Clinical Research Institute (W.W., R.G.), Canadian Centre for Agri-food Research in Health and Medicine, St Boniface Hospital Research
Centre, Department of Physiology, Faculties of Medicine and Pharmacy (A.L.E., R.L., E.D., R.P., T.G.M., B.R., G.N.P.), and Department of Human
Nutritional Sciences, Faculty of Human Ecology (M.A.), University of Manitoba, Winnipeg, Manitoba, Canada.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.
113.02094/-/DC1.
Correspondence to Grant N. Pierce, St Boniface Hospital Research Centre, 351 Tache Ave, Winnipeg, Manitoba, Canada R2H 2A6. E-mail
[email protected]
© 2013 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.113.02094

1081
 1082  Hypertension  December 2013

Hypertension is strongly associated with patients who Methods

have peripheral artery disease (PAD). Ninety-two percent The study design has been described previously.18 This clinical trial
of PAD patients in the PARTNER trials had high BP.14 BP was registered (NCT00781950) at ClinicalTrials.gov. Briefly, 110
PAD patients were recruited into this double-blinded, placebo-con-
is a strong predictor of PAD.15 BP is a major risk factor for trolled, randomized trial. Inclusion criteria were patients must be
both symptomatic and noninvasively determined PAD.15 It >40 years and have had PAD for >6 months with an ankle brachial
is not surprising, therefore, that the majority of deaths in index <0.9. Exclusion criteria included inability to walk, bowel dis-
patients with PAD are the result of cardiovascular events.15,16 ease, moderate to severe renal failure, life expectancy <2 years with
high baseline cardiac risk, allergies to any ingredient in the study
Approximately 20% of people >70 years of age have PAD. product, patients who plan to undergo surgery during the course
PAD patients also have a prevalence of heavy smoking hab- of the trial, and no more than 2 fish meals per week. In this trial,
its, diabetes mellitus, hypercholesterolemia, and coronary changes in SBP and DBP were defined as secondary end points.
atherosclerosis.17 Because of the vascular effects of flaxseed During the baseline visit, a questionnaire related to past and pres-
ent medical history as well as medications was administered by the
in animal studies, it was thought that a patient population attending nurses.18 As depicted previously,18 the baseline character-
with PAD may be ideal to respond to dietary flaxseed. This istics of the FLAX-PAD patients are shown in the Table. Briefly,
double-blinded, placebo-controlled, randomized FLAX- these patients had an average age of 67 years, 90% were current or
ex-smokers, 75% were hypertensive, 32% diabetic, and 79% hyper-
PAD (FLAX effects in Peripheral Arterial Disease) trial18
lipidemic. Some of these patients were on blood sugar–lowering,
has focussed on the effects of dietary flaxseed on SBP and lipid-lowering, antihypertensive, or antithrombotic medication. The
DBP over a 6-month ingestion period. patients were fed a variety of foods (bagels, muffins, bars, buns,

Table. Baseline Characteristics of the 110 Patients Enrolled in the FLAX-PAD (FLAX effects in Peripheral Arterial
Disease) Study
Parameter All patients (N=110) Flaxseed (n=58) Placebo (n=52) P Value
Age, mean±SD 67.3±8.5 67.4±8.06 65.3±9.4 0.2
Cardiovascular risk factors
 Ex-smokers, % 66.4 68.4 65.3 0.8
 Current smokers, % 26.3 19.2 34.6 0.1
 Hypertension, %* 75.4 81.0 69.2 0.2
 Diabetes mellitus, %† 31.8 36.2 26.1 0.3
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 Hyperlipidemia, %‡ 79.1 81.0 76.9 0.7

 Known CAD, % 39.1 44.8 32.7 0.2
Treatment
 Insulin therapy or BSLD, % 25.4§ 29.3 19.2 0.1
 Lipid-lowering drugs, % 73.6 77.5 71.1 0.4
 Antihypertensive drugs, % 79.1 84.4 73.0 0.1
 Antithrombotic drugs, % 90.0║ 89.6 90.3 0.9
Baseline lipids, mean±SD
 Total-C, mmol/L 4.5±1.2 4.4±1.1 4.5±1.3 0.6
 Triglycerides, mmol/L 1.6±0.7 1.6±0.7 1.7±0.8 0.4
 HDL-C, mmol/L 1.2±0.3 1.2±0.3 1.2±0.3 1
 LDL-C, mmol/L 2.5±1.0 2.5±1.0 2.6±1.0 0.6
 Cholesterol/HDL ratio 3.9±1.2 3.9±1.1 3.9±1.2 1
 LDL/HDL ratio 2.2±1.0 2.2±1.1 2.3±0.9 0.6
Other measurements
 Body mass index, kg/m2 27.8±4.5 27.4±4.4 28.1±4.4 0.4
 Baseline systolic BP, mm Hg 142.9±20.1 143.3±22.2 142.4±17.5 0.7
 Baseline diastolic BP, mm Hg 77.5±12.8 77.0±9.5 79.0±15.6 0.4
 Baseline right ABI 0.78±0.2 0.77±0.23 0.78±0.22 0.8
 Baseline left ABI 0.77±0.2 0.78±0.21 0.76±0.22 0.6
ABI indicates ankle brachial index; BP, blood pressure; BSLD, blood sugar–lowering drugs; CAD, coronary artery disease; HDL-C, high-density lipoprotein;
LDL-C, low-density lipoprotein; and total-C, total cholesterol. Part of this table (the All Patients column) is reproduced from Leyva et al18 with permission.
*Hypertension is classified according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure (JNC 7).
†Previous personal history of diabetes mellitus or insulin therapy/oral blood glucose–lowering drugs.
‡Total-C ≥5.2 mmol/L, LDL-C ≥3.4 mmol/L, triglycerides ≥1.7 mmol/L, HDL-C ≤1.0 mmol/L, or on lipid-lowering drugs.
§80% of diabetic patients were under insulin therapy or blood sugar–lowering drugs.
║At least 1 antithrombotic drug.
 Rodriguez-Leyva  Flaxseed and Hypertension  1083

pasta, tea biscuits) that contained 30 g of milled flaxseed or a pla- compared with a 2-tailed Student t test. When smaller than expected
cebo. Each product contained 30 g of milled flaxseed, and 1 product frequencies were found, a Fisher exact test was used. Pearson cor-
was ingested per day over the 6-month period of the study. Some of relation coefficients were used to explore the bivariate associations
the foods had different flavorings to give the foods sufficient vari- between SBP, DBP, plasma lipids, and enterolignans. Differences
ety to ensure compliancy over the time of the study. The placebo were considered significant when probability values were <0.05.
product contained the same flavorings but did not contain flaxseed.
Milled wheat replaced the flaxseed. In some products, wheat was Results
mixed with a very small amount of bran, and molasses was used so
that the color and texture resembled that of a product that contained A total of 110 patients were enrolled in the FLAX-PAD study.
flaxseed. Details concerning the ingredients have been described After randomization, 58 were allocated to the flaxseed group
previously.18–20 In preliminary tests, subjects could not easily iden- and 52 to the placebo group (Figure 1). Their baseline char-
tify if the food contained the flaxseed or not. Furthermore, at the acteristics are found in the Table.18 There were no significant
end of the study, 44% of subjects failed to correctly identify the
group in which they participated. Food composition is described in differences in any of the characteristics of the patients when
detail elsewhere.18–20 BP measurements were done according to pre- they were examined as a function of the group in which they
viously published recommendations.21 Briefly, resting BP was mea- were enrolled (Table). After 6 months, 13 patients from the
sured in the seated position in a quiet room by well-trained nurses flaxseed group and 11 from placebo group withdrew from
using a mercury sphygmomanometer. The average of a total of 3
the study (Figure 1). Overall, the dropout rate was 22.4%
readings was used as the final measurement. The measurement was
performed under controlled conditions in a quiet room and using and 21.2% for the flaxseed and the placebo groups, respec-
the same protocol at both the baseline and follow-up examinations. tively (P>0.05).
Plasma fatty acids were quantified as described.10–13,18 Enterolignans Body weights of the patients were not significantly dif-
were deconjugated as previously described22 followed by supported ferent between flaxseed versus placebo groups at baseline
liquid extraction to isolate the liberated compounds. Analysis was
by gas chromatography/mass spectrometry in microselected ion
(81.0±14.9 versus 82.4±14.8; P=0.6) or after 6-month inter-
storage mode using a target ion of 180 for quantitation of both vention (83.8±14.8 versus 81.4±14.5; P=0.4). Body mass
enterolignans. The study was conducted in accordance with the index (Table) and waist circumference values (data not
Declaration of Helsinki. Written approval from Health Canada and shown) were not significantly different between the 2 groups
its Natural Health Products Directorate, the University of Manitoba at any time point.
Research Ethics Board, and St Boniface Hospital was obtained.
Each FLAX-PAD participant provided written consent. The pro- Plasma levels of enterolignans and the ω-3 fatty acid ALA
cedures followed were in accordance with institutional guidelines. were used as markers of dietary compliancy. Both ALA and
A Safety Monitoring Committee met during the study to ensure lignans are enriched in flaxseed, and both are not commonly
patient safety was monitored. found in most food products. Therefore, the identification of 1
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or both of these bioactives in the blood of the patients repre-

Statistical Analysis sents a clear indication of dietary compliancy. Levels of ALA,
Continuous variables were expressed as a mean±SD. Categorical vari-
ables were expressed as proportions. A Z test was used to compare the eicosapentaenoic acid, and docosahexaenoic acid at baseline,
proportions of 2 groups found within a single category. Categorical 1 month, and 6 months are shown in Figure 2A–C. Plasma
variables were compared with χ2 test. Continuous variables were levels of all of the ω-3 fatty acids were similar at baseline

Figure 1. Screening, randomization, and follow-up

of study participants.
 1084  Hypertension  December 2013

Figure 2. Plasma levels of α-linolenic acid

(ALA; A), eicosapentaenoic acid (EPA; B),
docosahexaenoic acid (DHA; C), enterodiol
(END; D), enterolactone (ENL; E), and total
enterolignans (F) at baseline, 1 month,
and 6 months in the flaxseed (FX) and
placebo (PL) groups. Values represent
the mean±SEM. *P<0.001 compared with
placebo and compared with flaxseed
at baseline; †P<0.001 compared with
placebo and compared with flaxseed at
baseline; ‡P=0.02 compared with placebo;
§P=0.006 compared with flaxseed at
baseline. Baseline: flaxseed n=58,
placebo n=52; 1 month: flaxseed n=51,
placebo n=47; 6 months: flaxseed n=44,
placebo n=41.
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in the placebo and flaxseed-fed groups. A significant 2-fold the study. After 6 months, SBP in the flaxseed group dropped
increase in plasma ALA levels was detected in the flaxseed significantly to 136±22 mm Hg (P=0.04). On the contrary, in
group (P=0.003 versus placebo group) at 1 and 6 months. the placebo group, SBP rose slightly to 146±21 mm Hg. After
A significant increase in plasma eicosapentaenoic acid lev- 6 months of intervention, DBP in the flaxseed group fell to
els was also observed in the flaxseed group versus placebo. 72±11 mm Hg (P=0.004), whereas DBP in the placebo group
Docosahexaenoic acid levels in the flaxseed group did not remained the same (79±10 mm Hg). In summary, the flaxseed
change over the course of the study. No significant changes in intervention maintained SBP at 10 mm Hg lower than placebo
any of the plasma ω-3 fatty acid levels of the placebo group (−6.5% reduction) and DBP at 7 mm Hg lower (−9.8% reduc-
were detected. tion). Although the present article has focussed on a report
Plasma levels of the enterolignans were all similar at base- of data up to 6 months of intervention, this study continued
line in the placebo and flaxseed-fed groups. However, plasma to 1 year in duration. At 1 year, SBP had increased slightly
levels of enterolactone increased about 10-fold in the flax- to 138.2±20.4 mm Hg from 136.2 mm Hg at 6 months in the
seed group, whereas enterodiol levels increased by ≈50-fold flaxseed group. SBP in the placebo group remained virtually
after 1 and 6 months of intervention (P<0.001 versus placebo; unchanged from 145.6 at 6 months to 144.6±16.1 mm Hg at 1
Figure 2D and 2E). Levels of total enterolignans also increased year. DBP was also relatively unchanged in the flaxseed group
significantly (≈10-fold) in the flaxseed group (P<0.001 versus from its 6-month value of 71.8 to 71.3±10.8 mm Hg at 1 year.
placebo) after 1 and 6 months (Figure 2F). No statistically sig- DBP in the placebo group was 78.5 at 6 months and 75.4±9.1
nificant changes were found in any enterolignans in the pla- mm Hg at 1 year.
cebo group at any time point. Changes in SBP and DBP were examined in a subgroup
BP measurements at baseline did not differ significantly of patients that entered the trial with a SBP ≥140 mm Hg
between the 2 experimental groups (Figure 3). SBP and DBP (Figure 4). The patients who received flaxseed obtained a
consistently decreased in the flaxseed group over the course of sustained and larger reduction in SBP (15 mm Hg) and DBP
 Rodriguez-Leyva  Flaxseed and Hypertension  1085

enzyme inhibitors and diuretics were present in 85% and 65%

of the treatment regimes for the flaxseed and placebo groups,
respectively (P>0.05).
Ankle brachial index did not change significantly dur-
ing the intervention period (0.77±0.23 versus 0.78±0.22;
P=0.8) at baseline for flaxseed and placebo groups, respec-
tively (0.80±0.24 versus 0.81±0.22; P=0.8) at the end of the
study.
Markers of renal function were examined. Plasma creati-
nine, uric acid, and blood urea nitrogen (Table S1 in the online-
only Data Supplement) did not show any significant changes
(P>0.05) in either group at any time point. Furthermore, sub-
group analysis of these variables in patients with BP ≥140/90
mm Hg did not demonstrate any variation over time (data not
shown).
The relationship of plasma lipids and enterolignan lev-
els to BP was studied. Circulating levels of ALA were sig-
nificantly correlated with SBP (P<0.04) and DBP (P<0.01;
Figure 5). Circulating levels of total enterolignans (Figure 6),
enterodiol (Figure 7), and enterolactone (Figure 8) also

Figure 3. Mean systolic and diastolic blood pressure at baseline,

1 month, and 6 months for placebo (PL) and flaxseed (FX)
groups. *P=0.04, flaxseed vs placebo for systolic blood pressure
at 6 months;†P=0.004, flaxseed vs placebo for diastolic blood
pressure at 6 months.

(7 mm Hg) after 6 months of intervention, whereas the BP did

not change significantly in the placebo group.
Forty-nine patients from the flaxseed group (84.4%) and 38
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from the placebo group (73.0%) were under treatment with

23 different combinations of antihypertensive drugs based on
5 pharmacological groups (diuretics, β-blockers, angiotensin-
converting enzyme inhibitors, angiotensin receptor block-
ers, and calcium channel blockers). Angiotensin-converting

Figure 5. Correlation of mean systolic blood pressure with mean

plasma α-linolenic acid (ALA) levels (top) or diastolic blood
Figure 4. Mean systolic and diastolic blood pressure among pressure (bottom) in patients fed flaxseed at baseline (a), for 1
hypertensive patients (BP ≥140/90 mm Hg) on flaxseed (FX) at month (b) and 6 months (c) and in the placebo group at baseline
baseline, 1 month, and 6 months. *P=0.04 baseline vs 1 month; (d), for 1 month (e) and 6 months (f). The Pearson correlative r
†P=0.002 baseline vs 6 months; ‡P=0.01 baseline vs 1 month; values were statistically significant for ALA and both systolic
§P=0.003 baseline vs 6 months. PL indicates placebo. (P=0.037) and diastolic (P=0.007) blood pressures.
 1086  Hypertension  December 2013
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Figure 6. Correlation of mean systolic blood pressure (top) or Figure 7. Correlation of mean systolic blood pressure (SBP; top)
mean diastolic blood pressure (bottom) with the mean plasma or mean diastolic blood pressure (DBP; bottom) with the mean
levels of total enterolignans in patients fed flaxseed at baseline plasma levels of enterodiol in patients fed flaxseed at baseline
(a), for 1 month (b) and 6 months (c), and in the placebo group (a), for 1 month (b), and 6 months (c), and in the placebo group
at baseline (d), for 1 month (e) and 6 months (f). The Pearson at baseline (d), for 1 month (e), and 6 months (f). The Pearson
correlative r values were statistically significant for total correlative r values were statistically significant for enterodiol and
enterolignans and diastolic (P=0.025) blood pressure. SBP (P=0.036) and DBP (P=0.013). END indicates enterodiol.

correlated with DBP (P<0.05). Circulating levels of entero- the FLAX-PAD study was the potent antihypertensive effect
diol (Figure 7) correlated with SBP (P<0.05). Total entero- shown by patients who ingested flaxseed. This represents a
lignans levels also trended toward a significant correlation major advance in the treatment of hypertension from a num-
with SBP (Figure 6) but did not reach statistical significance ber of perspectives. First, it is the first demonstration of the
(P=0.056). No other significant correlations of different lip- effects of dietary flaxseed on a hypertensive population. It
ids with BP were detected (Table S2). is noteworthy that the present study was done in a placebo
The use of flaxseed in PAD patients was relatively safe. controlled, double-blinded, randomized manner. In contrast
Two patients in the placebo group and 1 in the flaxseed group to the flaxseed-fed group, patients who fed the placebo food
suffered strokes during the trial. Four patients in the placebo had BP values that were stable or slightly elevated over the
group and 2 patients in the flaxseed group suffered a myocar- course of the study. Compliance was carefully monitored
dial infarction. One additional patient in the flaxseed group through plasma ALA and enterolignan levels. The absence of
died from a myocardial infarction, but this occurred <3 weeks a rise in these parameters for a patient in flaxseed group would
of enrolling in the study. There were no statistically significant strongly argue that the patient was noncompliant with the diet.
differences between the groups in any of these parameters. Conversely, unexpected increases in both of these parameters
in the blood from a patient in placebo group would strongly
Discussion suggest dietary noncompliance as well. We did not detect
SBP was elevated in many of the patients entering this study either of these scenarios in patients enrolled in this study.
despite the presence of a variety of antihypertensive medica- Furthermore, the lack of a rise in plasma docosahexaenoic
tions. This is not unusual in a PAD patient population where acid in both groups suggests all patients were compliant with
the physician is commonly trying to control a myriad of car- restrictions in the intake of fish during this trial, and, therefore,
diovascular risk factors.23 The most important finding from marine ω-3 fats were not a confounding factor. It has been
 Rodriguez-Leyva  Flaxseed and Hypertension  1087

action of flaxseed. Third, the magnitude of the effect on BP

would be expected to result in a significant decrease in the
incidence of cardiovascular events over time. A reduction of
7 mm Hg in DBP would be expected to result in a 46% and
29% decrease in the incidence of stroke and coronary heart
disease, respectively.25,26 A 10 mm Hg decrease in SBP would
result in a 36% and 27% decrease in the incidence of stroke
and myocardial infarctions, respectively.25,26 Our results show
a trend for a beneficial effect of flaxseed in decreasing the
incidence of these events (2 patients and 1 patient suffered
strokes in the placebo and flaxseed groups, respectively; and 4
patients and 2 patients suffered a myocardial infarction in the
placebo and flaxseed groups, respectively), but a larger, com-
prehensive, multicentered trial is likely necessary to unequiv-
ocally show this. Fourth, severely hypertensive patients will
benefit the most from dietary flaxseed. Hypertensive patients
with an initial SBP >140 mm Hg responded to dietary flaxseed
with an average decrease of 15 mm Hg. The magnitude of this
decrease in BP demonstrated by dietary flaxseed, therefore, is
as good or better than other nutritional intervention and com-
parable to many drugs.27 DBP did not react as strongly to the
flaxseed intervention in the present trial (Figure 1), although
this may be because it is not as highly elevated at the start of
the study as was SBP. Finally, the use of flaxseed as an antihy-
pertensive therapy appears to be relatively safe. There were no
significant differences between the groups in any of the major
cardiovascular complications. Furthermore, higher doses (up
to 50 g/day) have been delivered without evidence of compli-
cations.28 In addition, patients with BP values in the normal
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range did not appear to respond to flaxseed with a decrease in

BP, which may be dangerous. This is consistent with previous
Figure 8. Correlation of mean systolic blood pressure (top) or reports of modest (if any) effects of dietary flaxseed on BP in
mean diastolic blood pressure (bottom) with the mean plasma
levels of enterolactone in patients fed flaxseed at baseline (a),
healthy populations.28–30 This lack of effect on BP in previ-
for 1 month (b), and 6 months (c), and in the placebo group ous studies may have been because of the use of normotensive
at baseline (d), for 1 month (e) and 6 months (f). The Pearson populations to examine the effects of flaxseed, or because of
correlative r values were statistically significant for enterolactones the relatively short study period (ie, 3 weeks).30
and diastolic (P=0.034) blood pressure. ENL indicates
enterolactone. Four components within flaxseed may be responsible for
the changes in BP: ALA, lignans, fiber, peptides, or a syner-
gistic action of all 4 components together. The correlation of
shown previously that ALA can be converted in a limited man- plasma ALA with both DBP and SBP (Figure 5) is consis-
ner to the longer-chain polyunsaturated fatty acid, eicosapen- tent with epidemiological associations of dietary ALA with
taenoic acid.24 In addition, the BP effects were gradual. After 1 a lower prevalence of hypertension and lower SBP.31–33 The
month of dietary intervention (when the dose of flaxseed was anti-inflammatory action of ALA11 may explain its antihyper-
still being phased in and gradually increased each week), SBP tensive action. Inflammation has been implicated in the gen-
and DBP were reduced modestly but significantly. Second, the esis of high BP.34 Alternatively, the rich lignan content within
effects were demonstrated even in the presence of the adminis- flaxseed may provide an antihypertensive effect through its
tration of antihypertensive medication to these patients. Thus, antioxidant action.9–13 Free radicals have been suggested to
flaxseed represents an effective combination of nonpharmaco- play a role in hypertension.34 In a randomized controlled trial
logical and pharmacological therapies.3 Approximately 80% of older adults ingesting a lignan complex isolated from flax-
of patients from both groups maintained the same dose of anti- seed, a modest but significant decrease in DBP (but not SBP)
hypertensive medication throughout the trial. Approximately was observed at 6 months.35 The present data extend this to
8% of those patients who ingested flaxseed decreased their now show that both enterolactone and enterodiol are likely
dose of antihypertensive medications versus 3.5% in the pla- responsible for this effect on DBP, and the latter is associated
cebo group. The presence of antihypertensive medication with SBP. The high fiber content within flaxseed may also be
during the trial makes it impossible to conclusively deter- important in regulating BP,36 but this could not be evaluated
mine if the effects of dietary flaxseed on BP were an inde- directly in our trial. Finally, peptides isolated from flaxseed
pendent antihypertensive action of flaxseed or because of a have an inhibitory action on angiotensin-converting enzyme,37
boosting of the effects of the medication. Further trials will and this may provide an antihypertensive action. However,
be needed to clearly identify the independent BP-lowering no changes in renal biomarkers were identified. Ultimately,
 1088  Hypertension  December 2013

the antihypertensive action of dietary flaxseed may repre- 6. Intersalt Cooperative Research Group. Intersalt: an international study
of electrolyte excretion and blood pressure. Results for 24 hour urinary
sent a culmination of the synergistic effects of all of these
sodium and potassium excretion. BMJ. 1988;297:319–328.
components. 7. Willet, WC. Potential benefits of preventative nutrition. In: Bendich A,
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Acknowledgments 2004;134:3250–3256.
We gratefully acknowledge the continued encouragement of Kelley 14. Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager
Fitzpatrick and the Flax Council of Canada. We thank Canada Bread, MA, Olin JW, Krook SH, Hunninghake DB, Comerota AJ, Walsh ME,
the Canadian International Grain Institute (Winnipeg, Canada), and the McDermott MM, Hiatt WR. Peripheral arterial disease detection, aware-
Food Development Centre (Portage La Prairie, Canada) in preparing ness, and treatment in primary care. JAMA. 2001;286:1317–1324.
the foods for this trial. The flaxseed or wheat was provided by Glanbia 15. Bainton D, Sweetnam P, Baker I, Elwood P. Peripheral vascular dis-
Nutritionals Inc. We also thank J. Alejandro Austria for distributing ease: consequence for survival and association with risk factors in the
food to patients during this trial, and the Office for Clinical Research at Speedwell prospective heart disease study. Br Heart J. 1994;72:128–132.
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St Boniface Hospital for their help in the conduct of this trial. 16. Murabito JM, D’Agostino RB, Silbershatz H, Wilson WF. Intermittent
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Sources of Funding 17. Diehm C, Schuster A, Allenberg JR, Darius H, Haberl R, Lange S, Pittrow
The work was supported through grants from Flax2015, the Canola D, von Stritzky B, Tepohl G, Trampisch HJ. High prevalence of peripheral
Council of Canada, the Agri-food Research and Development arterial disease and co-morbidity in 6880 primary care patients: cross-
Initiative, and the Canadian Institutes for Health Research. Indirect sectional study. Atherosclerosis. 2004;172:95–105.
research support was obtained from St Boniface Hospital Foundation. 18. Leyva DR, Zahradka P, Ramjiawan B, Guzman R, Aliani M, Pierce GN.
The effect of dietary flaxseed on improving symptoms of cardiovascu-
lar disease in patients with peripheral artery disease: rationale and design
Disclosures of the FLAX-PAD randomized controlled trial. Contemp Clin Trials.
None. 2011;32:724–730.
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Novelty and Significance

What Is New? d­ ecreases in BP are among the most potent dietary interventions ob-
• This is the first demonstration of the cardiovascular effects of dietary served and comparable to current medications.
flaxseed in a hypertensive population.
Summary
What Is Relevant? In a double-blinded, placebo-controlled, randomized trial conduct-
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• Hypertensive patients with an initial systolic blood pressure of ed >6 months, supplementation of the diet with foods that con-
>140 mm Hg responded to dietary flaxseed with an average decrease tained 30 g of milled flaxseed resulted in a potent antihypertensive
of 15 mm Hg in systolic and 7 mm Hg in diastolic blood pressure. These effect, selectively in patients who were hypertensive.