Curr Hypertens Rep (2014) 16:499 DOI 10.1007/s11906-014-0499-8
PATHOGENESIS OF HYPERTENSION (W ELLIOTT, SECTION EDITOR)
Flaxseed for Hypertension: Implications for Blood Pressure Regulation Stephanie P. B. Caligiuri & Andrea L. Edel & Michel Aliani & Grant N. Pierce
Published online: 24 October 2014 # Springer Science+Business Media New York 2014
Abstract Hypertension is the single largest risk factor attributed to mortality in the world. Medications are the primary treatment for hypertension; however, adherence to drug regimens is low (~50 %). Low adherence may be a contributing factor leading to uncontrolled blood pressure in patients. An effective alternative or complement to medications in managing hypertension is through lifestyle modifications. Adopting a healthy diet is a valuable strategy. A recent, randomized controlled year-long trial observed impressive reductions in blood pressure in patients with hypertension consuming flaxseed daily. Therefore, attention has been garnered for flaxseed as a potentially valuable strategy for the management of hypertension. This review will highlight the recent data for flaxseed and its extracts in blood pressure regulation in both animal models and clinical trials. Insight into the proposed anti-hypertensive mechanism of flaxseed and the implications
of flaxseed as a potential global anti-hypertensive therapy will be discussed. Keywords Dietary flaxseed . Anti-hypertensive therapy . Blood pressure regulation . Alpha-linolenic acid . Lignans . Enterolignans . Enterolactone . Enterodiol Abbreviations ALA Alpha-linolenic acid BP Blood pressure DBP Diastolic blood pressure END Enterodiol ENL Enterolactone MAP Mean arterial pressure SBP Systolic blood pressure SDG Secoisolariciresinol diglucoside SECO Secoisolariciresinol SHR Spontaneously hypertensive rats
Stephanie P. B. Caligiuri and Andrea L. Edel contributed equally to this paper. This article is part of the Topical Collection on Pathogenesis of Hypertension S. P. B. Caligiuri : A. L. Edel : M. Aliani : G. N. Pierce (*) Canadian Centre for Agri-food Research in Health and Medicine (CCARM), St Boniface Hospital Research Centre, 351 Taché Avenue, Winnipeg, MB, Canada R2H 2A6 e-mail: [email protected]
S. P. B. Caligiuri : A. L. Edel : G. N. Pierce The Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Winnipeg, MB, Canada S. P. B. Caligiuri : A. L. Edel : G. N. Pierce The Department of Physiology, University of Manitoba, Winnipeg, Canada M. Aliani Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, Canada
Introduction Hypertension accounts for approximately half of the nearly 17 million cardiovascular deaths worldwide making it the leading risk factor attributed to death globally . Approximately 40 % of adults aged 25+ years have hypertension worldwide . It is not surprising, therefore, that the cost of heart disease globally from 2011–2015 is estimated at $3.76 trillion USD . 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,
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only 18.8 % of patients were high adherers, with 32.3 and 48.9 % being intermediate and low adherers, respectively . This could explain why up to 73 % of patients in Europe and North America do not have control of their blood pressure (BP) . Nonadherence was associated with a higher risk for developing cardiovascular events . 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 . 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, alphalinolenic acid (ALA; C18:3n-3) . 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 . SDG constitutes 34–38 % of the overall lignans in flaxseed . Matairesinol, lariciresinol and pinoresinol are also present in much smaller amounts . 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 . 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 . The health-related actions of dietary flaxseed may be due to four bioactive ingredients: ALA, lignans, fibre or peptides or it
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may be due to a synergistic effect of these components together . 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 antihypertensive strategy (Table 1). In spontaneously hypertensive rats (SHR), there was a moderate but insignificant decrease in systolic blood pressure (SBP) compared to control . More studies using ground flaxseed are needed in different hypertensive animal models.
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  (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 .
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  (Table 1). However, when SDG was delivered intravenously , 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 antihypertensive 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 . 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 .
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Fig. 1 World Atlas of Countries Growing Flaxseed. *Based on data from the Food and Agriculture Organization of United Nations Database (2011) 
Flaxseed Protein and Peptides Recently, a flax protein hydrolysate and an isolated fraction (KCl-F1) reduced SBP 2–8 h post oral gavage (P