Introduction

Hypertension accounts for approximately half of the nearly 17 million cardiovascular deaths worldwide making it the leading risk factor attributed to death globally [1]. Approximately 40 % of adults aged 25+ years have hypertension worldwide [1]. It is not surprising, therefore, that the cost of heart disease globally from 2011–2015 is estimated at $3.76 trillion USD [1].

In view of these alarming statistics, the control of hypertension should be of paramount medical and economic importance. The most common treatment strategy for hypertension includes medications. However, a large proportion of newly diagnosed hypertensive patients do not adhere to their routine of anti-hypertensive medication. Of 18,806 study patients, only 18.8 % of patients were high adherers, with 32.3 and 48.9 % being intermediate and low adherers, respectively [2]. This could explain why up to 73 % of patients in Europe and North America do not have control of their blood pressure (BP) [3]. Nonadherence was associated with a higher risk for developing cardiovascular events [2]. Obstacles to anti-hypertensive drug compliancy, therefore, exist for many patients.

A dietary therapeutic strategy may be preferable and just as effective in managing hypertension. The emphasis on lifestyle modifications that include nutritional strategies has increased recently due to changes in the hypertension management guidelines [4, 5]. According to Canadian and European guidelines, individuals with grade or stage 1 hypertension without macrovascular target organ damage or other risk factors should not be prescribed anti-hypertensive medication [4, 5]. Rather, these patients are encouraged to adopt lifestyle changes. Even patients with grade or stage 2 hypertension with risk factors are encouraged to make lifestyle changes for several weeks before determining the dosage of medication and if medication is still necessary [4, 5]. American guidelines also recommend that lifestyle interventions begin before prescribing medication [6].

Lifestyle changes to manage hypertension include weight loss, aerobic exercise, cessation of smoking, adopting the Dietary Approaches to Stop Hypertension diet and reducing alcohol and sodium intake. However, in the last decade, a greater research emphasis has been placed on functional foods that may influence BP. Functional foods are foods that provide health benefits beyond basic nutritional qualities. One functional food that may help patients manage hypertension is flaxseed.

Flaxseed, Linum usitatissimum, is an oilseed crop grown all over the world (Fig. 1). It produces pale blue flowers and fruit capsules filled with small, brown seeds. Flaxseed is one of the richest plant sources of the omega-3 (n-3) fatty acid, alpha-linolenic acid (ALA; C18:3n-3) [7]. Oils comprise about 41 % of the overall seed weight with 57 % of that oil representing ALA. Flaxseed is also a major source of the lignan secoisolariciresinol diglucoside (SDG), a potent antioxidant [8]. SDG constitutes 34–38 % of the overall lignans in flaxseed [9]. Matairesinol, lariciresinol and pinoresinol are also present in much smaller amounts [10]. Conversion of SDG in the colon by gut microbiota yields the unconjugated derivative secoisolariciresinol (SECO) which is further converted into the primary metabolites enterolactone (ENL) and enterodiol (END). These compounds structurally mimic oestrogen and can competitively bind to the oestrogen receptor [11]. Proteins, another major constituent in flaxseed, comprise 20 % of the overall seed composition. Flaxseed is also a prominent source of both soluble and insoluble fibres. Flax oil is devoid of fibre and very low in lignans [12].

Fig. 1
figure 1

World Atlas of Countries Growing Flaxseed. *Based on data from the Food and Agriculture Organization of United Nations Database (2011) [58]

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The health-related actions of dietary flaxseed may be due to four bioactive ingredients: ALA, lignans, fibre or peptides or it may be due to a synergistic effect of these components together [12]. The bioavailability of ALA is optimal when ingested as flaxseed oil but poor when ingested as a whole seed. Milled flaxseed provides the best option for the bioavailability for each of these bioactive components and is well tolerated [13, 14].

Anti-hypertensive Effects of Dietary Flaxseed in Animals

Whole Flaxseed

Only one study has used whole flaxseed as an anti-hypertensive strategy (Table 1). In spontaneously hypertensive rats (SHR), there was a moderate but insignificant decrease in systolic blood pressure (SBP) compared to control [15]. More studies using ground flaxseed are needed in different hypertensive animal models.

Table 1 Animal models with reported blood pressure changes as a result of consuming dietary flaxseed
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Flax Oil and ALA

The first study to examine flax oil as an anti-hypertensive strategy observed a significant decrease in systolic blood pressure (SBP) within hours of ingestion versus a high oleic sunflower oil control [16] (Table 1). Subsequent works using a variety of dietary interventions that contained oils enriched in ALA have shown a consistent pattern of BP reduction (Table 1). This was also found even in the offspring from mothers fed ALA [16].

Flaxseed Lignans

Dietary supplementation with SDG has induced a significant lowering of SBP, but only when administered in the presence of a high-fat diet [17] (Table 1). However, when SDG was delivered intravenously [18], substantial decreases in SBP (15–40 %), diastolic BP (DBP) (24–48 %) and mean arterial pressure (MAP) (22–43 %) were observed as early as 15 min after injection and were maintained for 4 h. The mechanism of action was suggested to involve guanylate cyclase activation and angiotensin I inhibition [18, 19]. Intravenous SDG may represent a useful pharmacological therapy; however, the anti-hypertensive effects from consuming flaxseed lignans will likely not proceed via SDG itself but rather through its metabolites. SDG is not present in circulation in the conjugated form, but rather is converted by gut microflora to its aglycone, SECO [20]. SECO is bioavailable, but may be further metabolized to the enterolignans, END and ENL, which are the physiological forms of lignans circulating as a result of flaxseed ingestion [20].

Flaxseed Protein and Peptides

Recently, a flax protein hydrolysate and an isolated fraction (KCl-F1) reduced SBP 2–8 h post oral gavage (P < 0.05) [21•]. These outcomes mimicked those of the anti-hypertensive captopril. The maximal reduction in SBP for all three treatments occurred after 4 h (−27 mm Hg), was maintained until 8 h, but was ineffective after 24 h. The beneficial action of these interventions was attributed to low molecular weight peptides which are abundant in arginine [22].

Anti-hypertensive Effects of Dietary Flaxseed in Clinical Trials

Whole Flaxseed

Flaxseed and components of flaxseed have been associated with BP reduction in both observational studies and randomized controlled trials. The most tightly controlled and longest study, the FLAX-PAD Trial, was a randomized, double-blinded, controlled year-long trial investigating the effects of flaxseed consumption on patients with peripheral arterial disease (75 % were hypertensive). Patients consumed either ground flaxseed or control food products every day for 1 year (n = 110). Ground flaxseed was chosen as the dietary supplement because it provides optimal bioavailability of all four potential anti-hypertensive bioactives (ALA, lignans, fibre and peptides). Patients in the flax group exhibited a significant reduction in SBP and DBP of 10 and 7 mm Hg, respectively, over 6 months (Table 2). In those with diagnosed hypertension at baseline, the reduction in SBP was even greater (15 mm Hg) [23••]. It is important to note that the drop in BP was greater than the average decrease observed with the standard dose of anti-hypertensive medications [24].

Table 2 Characteristics of the clinical studies reporting blood pressure results as a result of consuming whole flaxseed, flax oil, flaxseed lignans or flax fibre
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Ultimately, dietary flaxseed changed the distribution of patients within the different categories of hypertension. The percentage of patients in the flax group with uncontrolled high BP decreased from 65 to 48 % by 1 year. By comparison, in the placebo group, the percentage of patients with uncontrolled hypertension increased from 57 to 65 % (Fig. 2). Therefore, after 1 year of standard of care, the control group exhibited a worsening of BP control whereas the flaxseed group improved. The decrease in BP was less striking at 1 year, but this may have been due to a decrease in dietary compliancy.

Fig. 2
figure 2

Distribution of hypertension categories (controlled, stage 1 uncontrolled, stage 2 uncontrolled blood pressure) in the placebo and flax group by time point. Data extracted from the FLAX-PAD Trial [23]

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The anti-hypertensive effect of flaxseed in the FLAX-PAD Trial was observed in the presence of standard anti-hypertensive medication. Thus, flaxseed does not inhibit the anti-hypertensive action of conventional therapy. However, it is not clear yet if it can replace anti-hypertensive medication or be effective in patients without peripheral arterial disease. Further work is ongoing to determine if dietary flaxseed can independently lower BP and reduce the need for anti-hypertensive medication in patients with stage 1 hypertension [25].

Flax Oil and ALA

The anti-hypertensive effects of ALA were first observed in a small observational study where adipose ALA concentrations were inversely associated with SBP and DBP in men [26]. Large epidemiological trials have concluded a similar relationship between ALA and cardiovascular disease. In a landmark trial examining a diet rich in ALA, the incidence of secondary myocardial infarctions and mortality was reduced in 605 patients post myocardial infarction compared to a typical diet [27]. In another large epidemiological study of 4680 men and women (The INTERMAP trial), a significant inverse relationship between dietary ALA and SBP and DBP was observed [28].

Randomized controlled trials have concluded similar effects of ALA on BP. In a randomized, double-blinded, controlled study, pre-hypertensive men and women (n = 101), with an average SBP and DBP of 136 and 88 mm Hg, respectively, ingested 2.6 g of ALA/day for 12 weeks. After 12 weeks, the ALA group exhibited a significant reduction in SBP and DBP of ~10 and 3 mm Hg, respectively (Table 2). After a 4-week washout period, SBP and DBP increased by 4 and 3 mm Hg from the 12-week measurements [29]. Therefore, individuals needed to continually consume a source of ALA in order to obtain the anti-hypertensive effect. In a trial of dyslipidemic patients, flaxseed oil containing 8 g of ALA was provided daily for 12 weeks. The flaxseed oil group exhibited a significant reduction in SBP, DBP and MAP of 10, 8 and 8 mm Hg, respectively, versus placebo [30].

Flaxseed Lignans

To ascertain whether lignans or ALA within flaxseed elicits anti-hypertensive action, three strains of flaxseed were compared in postmenopausal women with vascular disease using a randomized, Latin square, double-blind, three-way crossover design [31]. Patients consumed 30 g/day of ground flaxseed either as high ALA, low lignan (Flanders), low ALA, high lignan (Linola 989) and moderate ALA and lignan (AC Linora). When each diet was compared to baseline or pre-treatment values, all three strains attenuated BP when individuals were given a stressful cognitive task. Peripheral resistance during stress was least affected when the low-ALA, high-lignan Linola 989 flaxseed strain was consumed [31].

In a randomized controlled trial involving adults >50 years of age participating in a walking programme, normotensive subjects (14 % had metabolic syndrome) were asked to consume 543 mg/day of SDG from flaxseed lignan for 6 months [32]. When the data was stratified by gender, only males demonstrated a decrease in DBP when consuming a flax lignan diet compared to those in the placebo group. This significant group × sex × time interaction existed only for DBP and was not observed in females. When all individuals (no gender exclusions) with metabolic syndrome were subgrouped, the flax lignan group once again demonstrated a significant 7-mm Hg reduction in DBP over time compared to placebo (Table 2).

Recently, a high SDG lignan supplement was assessed for its hypotensive effects in a healthy population >48 years of age [33]. BeneFlax is a commercially available source of SDG lignan that provides 543 mg of SDG in a single tablet. Individuals consumed one BeneFlax tablet, or a placebo, daily for 6 months in this randomized, double blind, placebo-controlled trial. After study completion, there were no observable differences in either SBP or DBP between treatment groups. A limitation of this paper was that most of the participants were either healthy at baseline or had their BP controlled through medications (average baseline SBP was 127 ± 12 mm Hg and DBP was 81 ± 7 mm Hg).

Flaxseed Fibre

Flaxseed is composed of 28 % total fibre. It is comprised of both soluble and insoluble fibres at a proportion of about 20:80 to 40:60 [34]. The anti-hypertensive action of dietary fibre is well established in several meta-analyses [35, 36]. In data from 24 trials published from 1966–2003, an average fibre dose of 11.5 g/day can decrease SBP by −1.13 mm Hg and DBP by −1.26 mm Hg [36]. Based upon eight clinical trials, 7.2–18.9 g/day provides maximal reductions (−3.4 mm Hg in SBP and −1.97 mm Hg in DBP) [35]. Fibre doses >19 g/day do not provide additional BP lowering. Soluble fibre produces most of the anti-hypertensive benefits, accounting for 85 % of the fibre-associated decreases in SBP and 59 % in DBP [36]. In a randomized controlled trial, hypertensive, type 2 diabetic patients consuming 5 g/day of flaxseed gum (soluble mucilage) for 12 weeks noted substantial, yet insignificant, decreases in SBP, DBP and MAP (−16, −8 and −10 mm Hg) [37]. Higher doses of soluble fibre may be required to elicit significant anti-hypertensive action.

Proposed Anti-hypertensive Mechanism of Flaxseed

The underlying mechanisms for the anti-hypertensive properties of flaxseed are not entirely clear, but the data above would suggest ALA may be responsible for most of the anti-hypertensive action of flaxseed. Circulating levels of ALA were significantly correlated with SBP and DBP [23••]. The mechanism for the anti-hypertensive action of ALA may involve its capacity to reduce the activity of soluble epoxide hydrolase [38••]. This enzyme currently is a target for anti-hypertensive treatment. Soluble epoxide hydrolase produces oxylipins that can cause a loss of vasodilation and promote inflammation. ALA reduced the activity of soluble epoxide hydrolase resulting in a reduction of the soluble epoxide hydrolase products, the dihydroxyoctadecenoic acids (DiHOMES) and dihydroxyeicostrienoic acids (DHETs). The DiHOMEs are associated with inflammation and cytotoxicity and the DHETs are associated with a concomitant loss of vasodilation. As a result, a decrease in soluble epoxide hydrolase-derived oxylipins was associated with a significant reduction in SBP of about 8 mm Hg [38••].

ALA may also exhibit its anti-hypertensive potential through an anti-inflammatory effect. In a randomized, controlled, crossover trial, 23 hypercholesterolemic patients were provided a high-ALA (6.5 % of energy), high linoleic acid (12.5 % of energy), or a typical western diet for 6-week periods each. The high-ALA diet significantly reduced peripheral blood mononuclear cell production of interleukin-6, interleukin-1 and tumour necrosis factor-alpha compared to the high linoleic acid diet [39]. Ground flaxseed consumption also reduced pro-inflammatory oxylipins in the plasma of older adults after 4 weeks [40]. Essential hypertension has been hypothesized to be a result of inflammation and endothelial dysfunction which causes an imbalance between endothelial-derived vasoconstrictive factors and vasodilative factors [41]. If ALA has anti-inflammatory effects, it is possible that it may prevent the inflammation-induced imbalance of molecules that regulate vascular tone. ALA may also affect inflammation and BP through an alteration of the oxylipin profile, as discussed above.

Circulating levels of total enterolignans and the enterolignan species END and ENL, following the ingestion of ground flaxseed, have been correlated with DBP [23••]. Enterodiol levels were inversely correlated with SBP [23••]. Although total enterolignan levels trended towards a significant inverse correlation with SBP, they were not statistically significant (P = 0.06) [23••]. The lignans within flaxseed may be anti-hypertensive through an anti-oxidative action. Reactive oxygen species have been suggested to play a role in hypertension [42]. The antioxidant effects of lignans may not come from SDG itself but from its metabolites END and ENL. These behave as potent antioxidants in both in vitro [8, 43, 44] and in vivo [45] models. Furthermore, ENL can induce phase 2 protein activation which leads to decreased oxidative stress [46].

Flaxseed peptides may also induce an anti-hypertensive effect through their rich arginine content [22]. Arginine is converted in the vascular endothelium to nitric oxide and citrulline. Nitric oxide produces vasodilation when released in the endothelium and thus represents a strategy for reducing hypertension [47]. Another possible mechanism through which the cationic peptides may proceed is through the inhibition of angiotensin-converting enzyme and renin [22]. The mechanism of action of dietary protein hydrolysates may be through the inhibition of the renin-angiotensin system as has been suggested in studies using Lactobacillus helveticus fermented milk [48]. The mechanism may involve angiotensin-converting enzyme inhibition or angiotensin receptor blockage, thus preventing the production of the vasoconstrictor angiotensin II and inactivating the vasodilator bradykinin.

Each of the components of interest within flaxseed, ALA, lignans, fibre and peptides, all contribute towards BP reduction. The cumulative effects on BP may be a reflection of the contributions of each of these components. However, further work in tightly controlled trials over at least 6 months is necessary using appropriate concentrations of the bioactive isolates in hypertensive patients before firm conclusions can be reached. It is also relevant to note from animal work that dietary flaxseed can induce anti-arrhythmic [49], anti-atherosclerotic [50, 51], anti-inflammatory [51], and anti-diabetic effects [52] and plaque regression [53] and has cholesterol [54, 55] and trans fat lowering capacity [50]. Ultimately, any one of these actions may also contribute to the BP lowering effects of dietary flaxseed.

Implications for Hypertension Management

Dietary interventions have been recommended to be used in concert with current pharmacological treatments to reduce the burden of high BP [4–6]. Dietary flaxseed may provide a suitable treatment option for patients. The strengths of flaxseed as an anti-hypertensive therapy include its ability to complement medication, accessibility, desirability, high nutritional content, capacity to simultaneously address other disease biomarkers and symptoms (i.e. hypercholesterolemia), its relative lack of side effects and its low cost.

Flaxseed as a treatment for hypertension may reduce the increasing financial burden that prescription medications put on governments and individuals. Nearly 80 million prescriptions for anti-hypertensive medications were given to patients in Canada alone [56]. This costs over $3 billion in 2006 in Canada [56]. This is more than double the expenditures on hypertension medications 10 years earlier [56]. A greater emphasis needs to be placed on cost-effective strategies [56]. The price of ground flaxseed for 1 month at 30 g/day would be ~$15 maximum based on current consumer prices in North America and Europe. By contrast, the cost of one prescription for anti-hypertensive medication averages $42–45 in Canada and the USA [56, 57]. Most patients must take more than one drug to control their BP which increases the expense further. For patients with resistant hypertension, flaxseed offers a potential solution when all other strategies have been inadequate [23••].

Not only is flaxseed affordable but it is also highly accessible worldwide. It is grown in North America, Asia, Europe, Africa, Australia, Central America and South America (Fig. 1). Many of the countries that grow flaxseed are low to middle income [58]. This is a critical point. In the Global Brief on Hypertension [2013, page 13], the World Health Organization stated, “Nearly 80 % of deaths due to cardiovascular disease occur in low and middle income countries. They are the countries that can least afford the social and economic consequences of ill health.” Many populations or communities in developing countries have limited financial resources or physical access to anti-hypertensive medications. These developing countries have the greatest need for hypertension management [1]. As of 2011, flaxseed is grown in 54 countries [58] and according to the World Bank income classification [59], 50 % of the flax-growing countries listed in Fig. 1 are low- or middle-income regions. Flaxseed, therefore, may prove to be a highly accessible and affordable hypertension treatment for many people worldwide.

The use of a dietary strategy like flaxseed to treat hypertension provides patients the ability to take their health into their own hands. This is desirable by the public. Most Americans (72 %) believe that nutrition plays a very important role in overall health and 85 % are interested in learning about foods with added health benefits [60]. Public interest in functional foods such as flaxseed may motivate self management of chronic disease. Self management of chronic disease results in decreased hospitalizations, fewer nights in the hospital and improved indications of health including self-rated health, indicators of disability, energy, health distress, and social role/activity limitation [61].

Flaxseed is recognized as safe to ingest and has additional health-related benefits beyond its anti-hypertensive actions. Flaxseed has been granted GRAS (generally recognized as safe) status by the Food and Drug Administration [62] and in Canada given a health claim for its cholesterol lowering capabilities [63]. In addition, flaxseed has many nutrients including fibre, ALA, and antioxidants which most people do not consume in adequate quantities. For example, the daily mean intake of dietary fibre was estimated at 15.9 g/day in 2008 in the USA [64]. This is well below the recommendation of the Institute of Medicine which is 25 g/day for women and 38 g/day for men [65]. Thirty grams of flaxseed can provide up to 8 g of dietary fibre and can assist individuals in obtaining a healthy diet. In addition, the generation of oxygen-derived free radicals and inflammation are becoming increasingly recognized as important factors in a variety of chronic diseases [66]. The capacity of lignans to act as powerful antioxidants [43] and ALA to reduce inflammation [39, 67] may be useful therapeutic mechanisms in other diseases or conditions besides hypertension.

Some patients may have difficulty with the side effects of medications. Flaxseed also has side effects that can deter its ingestion for some people. Clinical trials of 30–45 g of flaxseed per day can result in mild gastrointestinal discomfort, flatulence and bloating that disappears over time as the individual became accustomed to the high fibre load [23••, 68]. Patients can be gradually introduced to flaxseed in order to lessen the likelihood of these side effects [23••]. Approximately 20 % of patients dropped out of the FLAX-PAD Trial when asked to ingest flaxseed daily for 1 year. The majority of those dropped out of the study within 6 months. However, the placebo group had a similar dropout rate indicating compliance was an issue primarily due to taste, limited food choice variety and maintaining dietary habits. This is an important obstacle to consider when flaxseed is being introduced into the diet. Incorporation of flaxseed into a variety of foods available to the public will provide more dietary choices and improve adherence.

Flaxseed has many advantages as an anti-hypertensive treatment option for patients. It provides an alternative or complementary strategy for patients who cannot control their BP with medication, for patients who cannot afford or do not have access to medication, or for patients who prefer a dietary approach. The ability of flaxseed to independently replace medication will be explored in a trial currently underway [25]. Even if some individuals do not exhibit a decrease in BP with flaxseed, the addition to the diet is positive as it contains many nutrients that most individuals do not consume in adequate quantities. In patients already taking anti-hypertensive medication, flaxseed provided additional BP-lowering capabilities and decreased the percentage of patients with uncontrolled hypertension by 17 % [23••]. Flaxseed may help individuals gain control of their BP and, therefore, may decrease the risk of hypertension-associated morbidity and mortality. Further research on specific parameters of this intriguing new approach is clearly required, but current evidence is strongly in support of its role in controlling hypertension.

Conclusion

Due to the alarming situation of hypertension globally and the need for more desirable and effective strategies, research on new and inventive therapies is of the utmost importance. Current research has supported the contention that dietary flaxseed may lower the risk of hypertension which may in turn decrease hypertension-associated morbidity and mortality. If flaxseed continues to be shown to be effective, it has many advantages as an anti-hypertensive treatment option for patients. It provides an alternative or complementary strategy for patients who cannot control their BP with medication, for patients who cannot afford or do not have access to medication, or for patients who prefer a dietary approach. In patients already taking anti-hypertensive medication, flaxseed has provided additional BP-lowering capabilities and decreased the percentage of patients with uncontrolled hypertension by 17 % [23••]. The ability of flaxseed to independently replace medication will be explored in a trial currently underway [25]. Even if some individuals do not exhibit a decrease in BP with flaxseed, the addition to the diet is positive as it contains many nutrients that most individuals do not consume in adequate quantities. Further research on specific parameters of this promising dietary approach is clearly required to gain further support for its role in controlling hypertension.