Role of Flaxseed as a Functional Food for the Heart

The Role of Flaxseed as a Functional Food for the Heart

Abstract

The aim of the present literature review was to evaluate the potential use of flaxseed, which is notably rich in omega-3 fatty acids, lignans and fibre, in the management of cardiovascular disease risk factors. The results of three meta-analyses and other studies which had been carried out in the intervening time were analysed to determine the effects of flaxseed on serum lipid profile and blood pressure, as well as the hypothesised mechanisms of action of the three main bioactive compounds found in flaxseed. The main findings were that flaxseed supplementation resulted in significant decreases in total and low-density lipoprotein cholesterol, and systolic and diastolic blood pressure, compared to control; the overall magnitude of these improvements was relatively small, but a much greater benefit was seen in certain patient subgroups, in particular those with high baseline measurements (i.e. hypercholesterolaemia and hypertension). In conclusion, evidence suggests that daily ingestion of 30-50g of ground flaxseed would be a safe, cost-effective and well-tolerated intervention. Although its positive effects alone are limited, there is clear potential for it to be used alongside conventional drug therapies and long-term lifestyle changes, including healthy diet and exercise, to provide maximum benefit to patients in mitigating cardiovascular disease risk.

Introduction

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, representing approximately 30% of all deaths, and is strongly associated with behavioural risk factors such as lack of exercise, smoking and unhealthy diet (World Health Organisation, 2017). Current dietary recommendations focus on modifying eating habits and improving the overall quality of the diet by increasing intake of whole grains, fruits and vegetables, and reducing unhealthy components such as saturated fats and sodium – however, an area of emerging interest in recent years are ‘functional foods’, which may be added into the diet to provide physiological benefits and mitigate the risk of developing disease (Hu, 2011). One such example is flaxseed (Linum usitatissimum), which is being investigated for potential cardioprotective effects associated with its high content of three main biologically active compounds – omega-3 fatty acids, lignans and soluble fibre (Kajla et al., 2014).

Nutritional Composition of Flaxseed

Flaxseed is considered to be a rich source of fat, fibre and protein (Morris, 2007). The protein content of flaxseed is usually between 20-30% and it has an amino acid profile similar to that of soybeans (Goyal et al., 2014).

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Flaxseed contains 35-45% oil, which is made up of around 10% saturated fatty acids (SFAs; mainly palmitic and stearic), around 20% monounsaturated fatty acids (MUFAs; mainly oleic), and 70% polyunsaturated fatty acids (PUFAs) (Martinchik et al., 2012). The PUFA component consists of linoleic acid (LA), an essential omega-6 fatty acid, and alpha-linoleic acid (ALA), an essential omega-3 fatty acid, in a favourable ratio of roughly 0.3:1 (Morris, 2007). Flaxseed is the richest plant source of ALAs, and 5-10% are converted in the body into longer chain omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid (Singh et al., 2011).

Flaxseed is also the richest plant source of lignans, which are thought to function as phytoestrogens and antioxidants (Goyal et al., 2014). The main lignan in flaxseed, secoisolariciresinol diglucoside (SDG), is metabolised by intestinal bacteria first to secoisolariciresinol, then to enterodiol and finally to enterolactone; however, the efficiency of this conversion is less than 75% and varies considerably between individuals (Peterson et al., 2010).

Fibre accounts for around 30% of the weight of the whole seed, and the ratio of soluble to insoluble fibre ranges between 20:80 and 40:60 (Goyal et al., 2012). The insoluble fibre fraction consists mainly of cellulose and lignin, and its main role is to maintain bowel health by improving laxation; it is the water-soluble fibre found in flaxseed (also called mucilage) that is thought to play a direct role in lowering blood cholesterol levels (Goyal et al., 2014). Mucilage consists of polysaccharides and forms a viscous gel when mixed with water or other fluids (Singh et al., 2011).

Blood Lipids

CVD occurs as a result of atherosclerosis, which is characterised by inflammation and the formation of plaques in the blood vessel walls (Morris, 2007). Hypercholesterolaemia, which is defined as high total cholesterol and/or low-density lipoprotein (LDL)-cholesterol in the blood, is one of the main risk factors for atherosclerosis (Santos and Martin, 2018). Several studies with flaxseed have been carried out to investigate its potential beneficial effects on serum lipid profile.

A meta-analysis investigating the effects of flaxseed on lipid levels found that among the studies that reported total cholesterol, including 1548 participants, the flaxseed intervention lowered total cholesterol by 0.10 mmol/L (95% CI: –0.20, 0.00 mmol/L; P=0.06) compared to control (Pan et al., 2009). The same meta-analysis found that among the studies that reported LDL-cholesterol, including 1471 participants, those in the intervention groups had a reduction in LDL-cholesterol by 0.08 mmol/L (95% CI: –0.16, 0.00 mmol/L; P=0.04) compared to control.

Further subgroup analysis in the meta-analysis by Pan et al. (2009) revealed that the beneficial effects of flaxseed were significant only in interventions that used whole flaxseed, which showed a decrease in total cholesterol of –0.19 mmol/L (95% CI: –0.29, –0.09 mmol/L; P=0.0003), and studies using lignan extract (–0.28 mmol/L; 95% CI: –0.55, –0.01 mmol/L; P=0.04). A similar pattern was observed in the reduction of LDL-cholesterol also. The differences observed may be attributed to the distinct mechanisms of action of the different bioactive compounds found in whole flaxseed.

The effects of ALAs on cholesterol metabolism are not yet fully understood, but some of the cardioprotective effects may be due to their ability to inhibit local inflammatory reactions in the endothelium associated with atherosclerosis – human studies have shown that consumption of flaxseed oil results in a fall in production of pro-inflammatory eicosanoids from arachidonic acid, such as thromboxane A₂ (which promotes platelet aggregation, a key factor in the pathogenesis of atherosclerosis, as well as heart attacks and stroke) and leukotriene B₄ (which increases the production of reactive oxygen species and cytokines, including TNF-, IL-1, IL-6 and IL-8) (Morris, 2007). Evidence also suggests that ALAs directly suppress the production of these pro-inflammatory cytokines by immune cells in the endothelium (Zhao et al., 2007), as well as the production of oxygen free radicals (Prasad, 1997). In addition to this, a study found that consumption of a diet rich in ALAs (from walnuts, walnut oil and flaxseed oil) resulted in a significant decrease in expression of cell adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and E-selectin, which are thought to mediate the attachment of immune cells to the endothelium and drive the formation of atherosclerotic plaques (Zhao et al., 2004). It is interesting to note that the meta-analysis by Pan et al. (2009) reported that interventions using flaxseed oil did not result in a significant change in total cholesterol; however, they hypothesise that this may be because the effects of flaxseed oil were masked by the use of oils rich in MUFAs or PUFAs as the control regimen, which may have similar physiological effects to the ALAs found in flax.

The precise role that lignans play in lowering cholesterol has not yet been fully determined, but animal studies indicate that SDG may decrease mRNA expression of sterol regulatory element binding protein-1c (SREBP-1c) in the liver, which is a transcription factor involved in regulating the activity of synthetase enzymes that are needed for the metabolism of cholesterol and fatty acids (Fukumitsu et al., 2008). In addition to this, SDG may exert a protective effect by scavenging oxygen free radicals, which are thought to contribute to endothelial cell injury and atherosclerosis (Prasad, 1997).

The exact mechanism of water-soluble fibre action is also uncertain, but evidence suggests that it most likely reduces cholesterol by increasing viscosity in the intestine, thereby limiting absorption of cholesterol from the diet, as well as decreasing reuptake of bile acids, which triggers increased synthesis of bile acid by the liver, causing serum cholesterol levels to fall (Theuwissen and Mensink, 2008). A double-blind, randomised, crossover study of 17 healthy volunteers conducted by Kristensen et al. (2012) showed that daily ingestion of a flaxseed fibre drink over 7 days lowered fasting total cholesterol by 12% and LDL-cholesterol by 15% compared to control (P<0.01) and increased faecal fat excretion by 55% compared to control (P<0.01). The study also found that ingestion of flaxseed fibre-enriched bread resulted in changes in blood lipid levels that while significant, were less pronounced compared to the flax drink intervention (lowering total cholesterol and LDL-cholesterol by 7% and 9% respectively (P<0.05)), suggesting that the physiological effects of flaxseed mucilage is strongly linked to its ability to form a viscous gel when hydrated. Both the drink and the bread used in the study contained a 5g dose of flaxseed fibre, corresponding to roughly 50g of whole flaxseeds.

Another finding of the meta-analysis by Pan et al. (2009) was that there was a strong correlation between the observed efficacy of flaxseed interventions and the baseline cholesterol concentrations. The meta-analysis reported that total cholesterol levels decreased significantly in the group with initial concentration  5.7 mmol/L (–0.17 mmol/L; 95% CI: –0.32, –0.03 mmol/L; P=0.02), but no significant change was detected in the < 5.7 mmol/L group; similarly, LDL-cholesterol levels saw a significant decrease in the group with initial concentration  3.4 mmol/L (–0.13 mmol/L; 95% CI: –0.23, –0.02 mmol/L; P=0.02) but not in the < 3.4 mmol/L group. These findings are consistent with a more recent trial of 25 hyperlipidaemic patients (with average baseline total and LDL-cholesterol of 6.9 mmol/L and 3.5 mmol/L respectively), which reported that daily consumption of 30g of ground flaxseed for 3 months resulted in a significant average decrease in total cholesterol of 1.12 mmol/L and LDL-cholesterol of 0.70 mmol/L (P<0.01 for each) (Saxena and Katare, 2014).

The meta-analysis by Pan et al. (2009) also reported that a greater effect was observed in women compared to men – a significant net change of –0.24 mmol/L (P<0.0001) and –0.17 mmol/L (P=0.003) in total and LDL-cholesterol respectively. The reason for this is unclear; however, the meta-analysis did note that most of the comparisons in women used whole flaxseed or lignan extract interventions and all comparisons had high initial concentrations, whereas most of the comparisons in men used flaxseed oil and had low initial concentrations.

The individuals who experienced the greatest benefit in the meta-analysis by Pan et al. (2009) – i.e. those using whole flaxseed, those with high baseline cholesterol levels and women – showed a reduction in total cholesterol of around 0.2 mmol/L, which although small, is estimated to correspond to a 3.5% risk reduction in all-cause mortality, a 4.9% risk reduction in coronary heart disease-related mortality and a 5.9% risk reduction in all coronary heart disease events (Gould et al., 2007).

Blood Pressure

High blood pressure, or hypertension, is defined as systolic blood pressure (SBP)  140mmHg and/or diastolic blood pressure (DBP)  90mmHg (World Health Organisation, 2017). Several animal and human studies have been carried out investigating the potential beneficial effects of flaxseed or its components on blood pressure.

A meta-analysis including 15 trials with a total of 1302 participants found significant reductions in both SBP (–2.85mmHg; 95% CI: –5.37, –0.33; P=0.027) and DBP (–2.39mmHg; 95% CI: –3.78, –0.99; P=0.001) following flaxseed supplementation (Ursoniu et al., 2016). These findings were consistent with an earlier meta-analysis, which included 14 trials with a total of 1004 participants and reported significant reductions in both SBP (–1.77mmHg; 95% CI: –3.45, –0.09; P=0.04) and DBP (–1.58mmHg; 95% CI: –2.64, –0.52; P=0.003) following flaxseed supplementation (Khalesi et al., 2015). Even though the magnitude of the reduction in blood pressure reported by these meta-analyses is small, this may still have significant clinical implications at the population level – according to a meta-analysis investigating the relationship between blood pressure and vascular disease mortality, lowering SBP by 2mmHg may reduce stroke mortality by 10% and mortality from ischaemic heart disease by 7% (Lewington et al., 2002).

Both meta-analyses displayed similar trends on comparison of the subgroup analyses. A greater reduction in DBP was observed in trials lasting 12 weeks or more, of more than 2mmHg (see table 1; significant results have been highlighted).

Another consistent finding between the meta-analyses was that a significant reduction in blood pressure was observed only in interventions using whole or ground flaxseed, compared to consumption of oil or lignan extract alone, with one exception (see table 2; significant results have been highlighted).

This explains why among the trials included in the meta-analyses, the trial carried out by Rodriguez-Leyva et al. (2013) showed the most potent antihypertensive effect, as it had the longest study period (6 months) and the participants in the intervention arm ingested foods containing 30g ground flaxseed every day. The study reported that the flaxseed intervention maintained SBP at 9.4mmHg lower than placebo (P=0.04), and DBP at 6.7mmHg lower than placebo (P=0.004). It is important to note that these results were achieved from a trial that was carried out in a placebo-controlled, double-blinded, randomised manner, and participant compliance was monitored via plasma ALA and enterolignan levels. Another finding of the study was that the magnitude of reduction in blood pressure was closely correlated to the baseline blood pressure, as the subgroup of patients with an initial SBP  140mmHg responded to dietary flaxseed with a greater average decrease of 15.2mmHg over the 6 month period (P=0.002).

The exact physiological mechanisms by which blood pressure is reduced are not fully understood, but the greater reductions found in whole flaxseed (compared to extracts alone) suggest that ALAs, lignans and fibre may all contribute to the overall antihypertensive effects of flax. It is hypothesised that hypertension occurs a result of inflammation and endothelial dysfunction, leading to an imbalance in the production of vasodilatory and vasoconstrictive factors (Puddu et al., 2000). One proposed mechanism, based on the results of a double-blind randomised controlled trial including 110 participants, is that ALAs inhibit the activity of soluble epoxide hydrolase, resulting in decreased production of oxylipins (including eicosanoids) that are responsible for loss of vasodilation and promote endothelial inflammation, as discussed previously (Caligiuri et al., 2014). A different study showed that consumption of 3.7-6.0g of ALAs from walnuts per day significantly improved vasodilation by 64% (P=0.043) compared to the control olive oil diet, which may be attributed to incorporation of ALAs into the membrane of endothelial cells, resulting in increased membrane fluidity and synthesis or release of the endogenous vasodilator nitrous oxide (Ros et al., 2004). Experimental evidence suggests that SDG may independently lower blood pressure by inhibiting angiotensin-converting enzyme (ACE) via the stimulation of guanylate cyclase (Prasad, 2013). Soluble fibre may also favourably affect blood pressure by reducing postprandial glucose absorption, thereby improving insulin sensitivity, which is relevant as it thought that insulin may play a role in the pathogenesis of hypertension (Streppel et al., 2005).

Conclusion

At present, it is difficult to draw conclusions from epidemiological studies regarding the direct role of ALAs and lignans in the prevention of CVD, as the majority of studies evauluate omega-3 fatty acids from marine sources, and lignans are typically only found in very small quantities in the average diet. Further research is also needed to investigate the long-term effects of flaxseed interventions (i.e. over several years), to better understand the impact on cardiovascular mortality and life expectancy. However, current evidence suggests that daily supplementation with 30-50g flaxseed would be a safe, feasible and well-tolerated intervention, that is cost-effective in comparison with modern drug therapies, and may have the potential to improve lipid profile and lower blood pressure in certain patient subgroups, which are two key clinical risk factors for CVD. All three meta-analyses discussed previously reported that ground flaxseed was most effective; this is most likely because it provides optimal bioavailability of all the active compounds found in flaxseed.

According to the study by Rodriguez-Leyva et al. (2013), flaxseed consumption had maximum benefit in those who were severely hypertensive, while those with blood pressure values in the normal range showed a more modest reduction. This is a clear advantage of dietary interventions over conventional drug therapy, as there is no danger of inadvertently lowering blood pressure to a potentially harmful degree. Similarly, the meta-analysis by Pan et al. (2009) reported that the beneficial effects of flaxseed on blood lipid levels were only observed in those with high cholesterol concentrations at baseline, which is again important as the body requires a moderate level of cholesterol for normal physiological functioning. Overall, this makes flaxseed an ideal dietary intervention at the population level, as there is a very low risk of complications or negative side effects if only those with lipid or blood pressure values beyond the normal range experience much of its effects.

Furthermore, a double-blind, randomised, placebo-controlled trial, in which participants consumed 30g of ground flaxseed or placebo a day, showed that flaxseed supplementation may delay the need for cholesterol lowering medications (CLMs) (Edel et al., 2015). In the subgroup of patients who were not taking any CLMs at the start of the trial, those who were consuming flaxseed did not need any CLMs over the course of the study period, which lasted 12 months; on the other hand, one third of the participants in the placebo arm of the trial were prescribed CLMs by the end. This is a clear advantage for patients, as it reduces the time that they are on long-term medications and the potential for negative side effects. In addition, the study by Edel et al. (2015) showed that flaxseed supplementation resulted in significant decreases in LDL-cholesterol both independently and in the presence of CLMs, suggesting that they may also be used as an adjunct for patients who are already taking conventional treatments. Overall, the results from this study indicate that flaxseed supplementation may be beneficial for patients in both the early and late stage of disease.

However, it is important to keep in mind that benefits shown by any functional food (not only flaxseed) will be modest for the vast majority of people. The reported cholesterol- and blood pressure-lowering effects exerted by flaxseed are small and therefore unlikely to correspond to any significant long-term benefit. Such interventions do little to tackle the root cause of the problem, and a much greater and more sustainable effect will be seen by focusing on bigger lifestyle modifications. For example, a study of 97 non-diabetic, sedentary older men showed that a combined aerobic exercise and weight loss intervention over 9 months decreased SBP and DBP by 9.7 mmHg and 7.2 mmHg respectively (P<0.05 for each), whilst also significantly improving fasting glucose levels (Dengel et al., 1998), highlighting the way in which lifestyle interventions can provide additional benefits and promote overall health by combating other serious chronic conditions such as diabetes. Similarly, the Lyon Diet Heart Study found that 302 individuals who followed a Mediterranean-style diet had a 70% reduction in heart attack risk compared to the 303 participants in the control arm of the trial (Kris-Etherton et al., 2001), suggesting that altering multiple components of a diet will have a much more profound effect on CVD risk (Hu, 2011). Achieving this in clinical practice may be difficult, as doctors are more accustomed to prescribing drugs (not diets or exercise regimes), but the rising prevalence of CVD means that a greater emphasis must be placed on helping patients to bring about healthy lifestyle changes, with regard to both prevention and long-term management.

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