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The Effect of Flax Seed Cultivars with Differing Content of -Linolenic Acid and Lignans on Responses to Mental Stress

Robarts Research Institute, London (J.D.S.), CANADA
University of Toronto, Toronto (T.T.), CANADA
Agriculture Canada Research Centre, Saskatoon (A.D.M., N.D.W.), CANADA

Address reprint requests to: Dr. David Spence, Stroke Prevention & Atherosclerosis Research Centre, Siebens-Drake/Robarts Research Institute, 1400 Western Rd., London, ON, N6G 2V2, CANADA. E-mail: dspence{at}robarts.ca

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Background: Phytoestrogens offer a possible alternative to hormone replacement therapy. Flax seed contains large quantities of a phytoestrogen precursor, secoisolariciresinol diglucoside (SDG), as well as large quantities of -linolenic acid; these factors may be protective against vascular disease. We have previously shown that the rise in blood pressure during mental stress is a strong predictor of atherosclerosis progression.

Methods: 35 postmenopausal women with vascular disease, 62 ± 8 years of age, were treated in a random-sequence double-blind Latin square crossover study comparing three strains of flax seed: Flanders (low in lignan and high in -linolenic acid), Linola 989 (high in lignan and low in -linolenic acid) and AC Linora (intermediate in both lignan and -linolenic acid).

Results: Compared to the pre-treatment baseline diet, all three strains of flax significantly reduced blood pressure during mental stress induced by a frustrating cognitive task (Stroop color-word interference task) (p = 0.004). Linola 989, the strain highest in lignan and lowest in -linolenic acid, was associated with the least increase in peripheral resistance during stress, the greatest reduction in plasma cortisol during stress and the smallest increase in plasma fibrinogen during mental stress.

Conclusion: Flax phytoestrogens ameliorate certain responses to stress and thus may afford protection against atherosclerosis; this hypothesis should be tested in clinical trials.

Key words: flax, phytoestrogen, stress, cardiovascular, blood pressure

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Compared to men, women appear to be relatively protected from vascular disease until menopause. Approximately two thirds of people who survive to age 90 are women. Protection by estrogen until menopause may explain much of this survival advantage, and there is considerable epidemiologic evidence that postmenopausal estrogen replacement (HRT) may confer extensive protection on women, with a reduction of vascular risk by approximately 40% [1,2]. However, clinical trials have not substantiated potential benefits of HRT [3,4], and the use of HRT is controversial [5], in part because of increased risk of breast cancer [6] or venous thrombosis [7]. The Womens’ Health Initiative study recently showed an increased risk of breast cancer, thrombosis and vascular events with combined estrogen and progesterone [8]; this result increases the need to find alternatives to HRT such as phytoestrogens. It is likely that the increase in thrombosis with combined HRT is related to aggravation of thrombosis in the 10% of women with the Factor V Leiden mutation [9]; if phytoestrogens can confer some of the benefits of estrogen without increasing thrombosis, they may prove to be a useful alternative to HRT.

Although HRT as currently used is now regarded as unlikely to be useful for vascular prevention, it is important to understand that estrogen per se has many effects that are potentially beneficial to the arteries (see Discussion); it is therefore worth searching for alternatives to HRT.

Estrogen-like compounds in plants, called phytoestrogens, appear to confer some of the vascular benefits of estrogen while providing an anticancer effect in mammalian models of breast cancer. Williams et al. found [10] found that soy isoflavones reduce vascular reactivity to stress in monkeys.

Flaxseed has recently undergone extensive study at Agriculture Canada and elsewhere [11–15] because it contains high amounts of -linolenic acid [11,15–17] and a potent phytoestrogen precursor, secoisolariciresinol diglucoside (SDG), which leads to production of mammalian lignans in humans (facultative organisms in the GI tract produce enterodiol and enterolactone, which are absorbed and achieve high plasma concentrations). The chief phytoestrogen, SDG, has been extracted by Agriculture Canada [18]. Mammalian lignans formed upon the ingestion of flaxseed (i.e. enterodiol and enterolactone) are excreted in the urine in a dose-dependent manner [19]; the balance of metabolites suggests an anti-cancer effect [20]. Furthermore, both -linolenic acid and SDG have anticancer effects in mammalian models of mammary cancer [11,12].

Flax oil is thought to have benefits in addition to those of SDG because the -linolenic acid in the oil increases the plasma concentrations not only of -linolenic acid, but also eicosopentanoic acid and dicosohexanoic acid. These compounds have beneficial effects including reduction of LDL, and antiplatelet effects [14,17]. Partially defatted flax seed reduced total and LDL cholesterol, ApoB and apo A-I [21]. Thus, flax seed may be highly anti-atherosclerotic.

Thus it appears likely that flaxseed should confer the protection from vascular disease of estrogen, without the increased risk of cancer. This is of great interest since, although women with vascular disease are at much higher risk of vascular events than they are from cancer, they are often reluctant to take estrogen.

We therefore conducted this study to assess the effect of different flax cultivars with different concentrations of phytoestrogen vs. linolenic acid on responses to mental stress, evaluating changes in blood pressure, cardiac output and peripheral resistance, as well as changes in fibrinogen and plasma cortisol. We compared three strains of flax seed: one containing more linolenic acid, another containing more lignan (SDG) and a third containing intermediate amounts of both factors.

	MATERIALS AND METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Thirty-five high-risk postmenopausal women (62 ± 8 years of age [mean ± SD]) with vascular disease (a history of coronary artery disease, transient ischemic attacks, stroke or peripheral vascular disease and/or moderate carotid atherosclerosis) were studied at baseline (untreated condition) and then randomized to one of six sequences of treatment in a complete Latin-square, double-blind, double-dummy 3-way crossover study. Table 1 gives the baseline characteristics of the patients. We had no negative control as there was not a strain of flax available that was low in both active components and no credible alternative was available (for example, cellulose is clearly distinguishable from flax seed, and other seeds would have a different appearance and taste and would contain various oils and arachidonic acid). The active treatments were three strains of flax seed: Flanders (low in lignan and high in -linolenic acid), Linola 989^TM (high in lignan and low in -linolenic) and AC Linora (intermediate in both lignan and -linolenic acid). The duration of each treatment period was three months, with a one-month washout between treatments in order to achieve steady-state conditions (based on data from Agriculture Canada which is unpublished pending patent review). Table 2 shows the fatty acid and SDG content of the three strains used [22].

The women were eligible if they were post-menopausal with asymptomatic mild to moderate carotid artery atherosclerosis, were not receiving HRT and did not have contraindications to HRT. Patients were excluded if they were already taking HRT, had contraindications to HRT (unexplained vaginal bleeding, acute or chronic liver disease, history of breast carcinoma, active vascular thrombosis, history of thromboembolism, or history of uterine cancer without hysterectomy), had a family history of breast cancer in a first degree relative, had uncontrolled hypertension, had a recent myocardial infarction or unstable angina, were taking vasoactive drugs in whom it was unwise to stop the drugs for a 12 hour period, were taking concomitant therapy with an investigational drug, had major hematological, renal, gastrointestinal or autoimmune disease, had a history of alcohol or drug abuse, psychological or other emotional problems that were likely to invalidate informed consent, or limit the ability of the patient to comply with protocol requirements.

Following eligibility screening and consent to a protocol approved by the University of Western Ontario standing review board on ethics of human research, the patients were interviewed regarding their age, medical history, family history and history of any adverse effects experienced on previous estrogen supplementation. Blood was drawn for measurement of plasma lipids. A one-month medication adjustment period, during which the subjects taking vasoactive drugs including beta-blockers, angiotensin converting enzyme inhibitors, calcium channel blockers and long acting nitrates with a half-life greater than 12 hours, had the drugs changed to agents of the same pharmacological family, with a half-life of less than 12 hours, and which were taken once daily in the morning.

During the following visits, subjects withheld their cardiovascular drugs on the morning of each study day on which reactivity to mental stress was performed. (They had therefore not taken any of their cardiovascular medication for 24 hours.) In addition, subjects were asked to refrain from eating, drinking, smoking, alcohol, and caffeinated beverages from suppertime the night before.

Following randomization into one of the six sequences of treatments, subjects had their baseline untreated measurements performed, and were provided with a three-month supply of their first treatment. Before beginning treatment, and at the end of the one-month treatment period, a measurement of hemodynamic responses to a computerized Stroop Color-Word Interference Test was carried out. Plasma cortisol and fibrinogen were measured before the Stroop task, and again after a stressful disclosure task which followed immediately after the Stroop task. (The patient was asked to describe the event in her life which made her most angry. In another study we have carried out, this task generally elicits approximately double the rise in blood pressure elicited by the Stroop task, but the response is less reproducible than is the blood pressure response to the Stroop task, with a significant attenuation of the hemodynamic effects on repeat testing. For that reason we did not use the hemodynamic responses during the disclosure task in this study.)

The Stroop Colour-Word Interference Task is a psychomotor task that has been widely used in studies of cardiovascular reactivity. The methodology used in this study was the same as described in our previous study of stress responses and atherosclerosis [23]. Baseline hemodynamic measurements (blood pressure, heart rate, cardiac output and peripheral resistance) were taken after two minutes and seven minutes of rest; then, baseline blood samples were drawn. The Stroop task was then initiated, and blood pressures were taken at 0, 3, 6, 9, 12, 15 and 18 minutes of stress. The mean of the two pre-stress values, and the mean of the seven readings taken during stress was used for analysis. Blood pressures were recorded using a Critikon Dinamapp Vital Signs Monitor 8100 (Johnson & Johnson, Arlington TX), while stroke volume, heart rate and pre-ejection period were measured by a Minnesota impedance cardiograph Model 304B (Surcom Inc., Minneapolis MN). Following the Stroop task, the subjects performed the disclosure task, which took 12 minutes, and then blood samples were repeated.

Blood was drawn for plasma cortisol, fibrinogen and hematocrit after the resting pre-stress period (prior to initiation of the Stroop task) and again after the second (disclosure) task. Blood samples were drawn from a saline lock inserted before the test. This resulted in the same venipuncture being used for blood drawing before and after the mental stress test. Plasma cortisol and fibrinogen were measured in the hospital laboratory. Plasma cortisol was measured using Bayer Cortisol Lite reagent, run on an ADVIA Centaur analyzer. This is a competitive immunoassay using direct chemiluminescent technology. Fibrinogen was measured by the Clauss method using Sigma Diagnostics reagent kit, procedure #886, run on an AMAX analyzer. These measurements were corrected for hematocrit because of the problem of hemoconcentration during stress tasks [24].

Sample size calculated by a standard formula [24] was 30 patients required to give a power of 90% to show a 20% effect on the increase in systolic blood pressure during the stress task, significant at the 5% level. Thirty-five subjects were recruited to guard against dropouts and other unanticipated sources of loss of power. Data were collected on case report forms and entered into Access (Microsoft, Seattle). It was then analyzed in SPSS 10.0 for Windows (SPSS, Chicago). Differences between treatment groups and the pre-treatment baseline untreated diet were tested using Repeated Measures Anova in the General Linear Model. A p-value of 0.05 or less was considered statistically significant according to the Huynh-Feldt test of within-subjects effects; Tukeys’ B test was used for post-hoc comparisons if the main effect was significant. Comparisons were made between the untreated diet before initiation of flax seed and each flax strain, for parameters measured before and after stress and for change from pre-stress to post-stress results.

Baseline Characteristics of the Subjects
As shown in Table 1, the patients were high-risk postmenopausal women. The mean FSH level was 81 mIU/ml ±27 (range, 28.4–130) indicating that all patients were post-menopausal. A third (37%) had hypertension, while only 3% had been diagnosed with diabetes. Only 3% of the subjects were current smokers, but 34% were ex-smokers, with a smoking history averaging 24.5 ± 20 pack-years. Twenty-three percent of the subjects had a significant family history of premature cardiovascular disease. All had elevated total serum cholesterol (>5.2 mmol/L) and LDL cholesterol (mean = 3.3 mmol/L ± 1.2) at the screening visit.

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Hemodynamic Responses
Table 3 shows the hemodynamic variables before stress and during mental stress (the mean of all results over the 20 minutes of the task). Fig. 1 shows the systolic pressure during mental stress, which was significantly lower on all three strains of flax seed than during the baseline untreated condition (for treatment effect p = 0.003, for treatment-time interaction p = 0.46), and the change in blood pressure from pre-stress to during stress. Fig. 2 shows the change in peripheral resistance during mental stress, which tended to be least with Linola 989 (for treatment effect p = 0.28, for treatment-time interaction p = 0.77).

View larger version (16K): [in this window] [in a new window]   Fig. 1. Systolic blood pressure during stress, and change in systolic blood pressure from pre-stress to during stress (mean ± S.E.). Systolic pressure was significantly lower during mental stress on flax seed (p = 0.003 for within-subject main effects; p-value for treatment-time interaction was 0.46). For the change in systolic pressure during stress p = 0.33 for treatment effect, p = 0.80 for treatment-time interaction.

View larger version (18K): [in this window] [in a new window]   Fig. 2. Change in peripheral resistance (mmHg/CI) from pre-stress to during stress (mean ± S.E.) p = 0.28 for within-subject treatment effects, p = 0.78 for treatment-time interaction.

View larger version (17K): [in this window] [in a new window]   Fig. 3. Change in plasma cortisol from pre stress to post stress (nmol/L, Mean ± S.E.) p = 0.12 for within-subject treatment effects, p = 0.13 for treatment-time interaction.

View larger version (16K): [in this window] [in a new window]   Fig. 4. Change in plasma fibrinogen (g/L) from pre-stress to post-stress (for within subject treatment effect p = 0.04, for treatment-time interaction p = 0.77).

	DISCUSSION

Until recently, the mechanism for vascular benefit of estrogen replacement has been thought to be related to improvement in traditional risk factors such as lipoproteins; a 1993 paper reported a 42% improvement in coronary risk based on such predictors [25]. Bush et al. [26] and Clarkson et al. [27], argued that the protective effect of estrogen could only partially be accounted for by changes in lipoproteins and discussed the "residual" protective effect of estrogen, emphasizing that estrogen treatment reduces proliferation of arterial smooth muscle cells [28], reduces production of collagen and elastin [29] and increases degradation of collagen and elastin [30,31] within arterial tissue.

Estrogen given acutely improves exercise-induced myocardial ischemia [32], likely because it appears to affect endothelial function both by increasing production of nitric oxide [27,33,34], and by reduction of endothelin [35].

Owens et al. found [36] that menopausal women had higher reactivity to mental stress than either men or premenopausal women, and that men and menopausal women had higher ambulatory blood pressures. Hemodynamic responses to mental stress are a stronger predictor of carotid atherosclerosis than any of the Framingham risk factors [23]. Lindheim et al. showed increased reactivity to math and speech tasks in menopausal women compared with premenopausal women; these responses were blunted by HRT [37]. Saab et al. [38] also found increased blood pressure and endocrine reactivity to laboratory stressors among postmenopausal women.

This study evaluated the effects of three strains of flaxseed that differed in content of phytoestrogen and linolenic acid on hemodynamic and endocrine responses to laboratory-induced mental stress in postmenopausal women with vascular disease. On the basis of previous studies and the anti-atherogenic properties of flaxseed [36–40], we expected that postmenopausal women on phytoestrogen therapy would exhibit lower hemodynamic and endocrine responses to mental stress. We found that flax seed significantly reduced blood pressure during mental stress. This suggests that flax seed may be anti-atherosclerotic in postmenopausal women, since systolic pressure during mental stress was a stronger predictor of progression of carotid atherosclerosis than any of the Framingham risk factors [23].

However, we did not anticipate that Linola 989, the strain of flax seed that was highest in the phytoestrogen precursor SDG and lowest in -linolenic acid, would have the biggest effect on peripheral resistance during stress and on plasma cortisol during stress. This was particularly interesting since the peripheral resistance before stress was highest on Linola 989, which we suggest was due to the low concentration of -linolenic acid (2% for Linola 989 vs. 59.2% for AC Linora and 56.5% for Flanders). Flanders, the strain with little SDG, was associated with a slightly greater increase in peripheral resistance during stress compared with the untreated condition.

Previous studies have suggested that both lignan and -linolenic acid have independent anti-atherogenic roles [14,39]. Mechanisms include suppression of interleukin-1, tumor necrosis factor and leukotriene B4, and of oxygen free radical production by polymorphonuclear leukocytes and monocytes [39]. In human subjects, flax seed reduced serum lipid oxidation products while lowering total and low-density lipoprotein cholesterol [41].

Prasad et al. showed a 46% reduction of atherosclerosis in aortic atherosclerosis in cholesterol-fed rabbits with flax seed containing large amounts of both -linolenic acid and lignans [39]. Much of the benefit was attributed to -linolenic acid, but, recently, they showed a 70% reduction of atherosclerosis in the same model using a strain of flax that was high in lignans and low in -linolenic acid [40].

An important limitation of the study design that requires discussion is the possible effect of sequence. It may appear likely that the higher blood pressure response to mental stress at baseline, with lower pressures during treatment with the three strains of flax seed, may have been due to attenuation of the effect of the stressor. However, this has been shown by Kamarck et al. not to be the case [42]. Indeed we chose this stressor, the Stroop task, precisely because it has less attenuation on repeat testing than do other stressors such as mental arithmetic. Furthermore, the analysis shows no attenuation of the blood pressure effect from the second to the fourth testing period.

We have previously shown that the blood pressure during mental stress is a stronger predictor of progression of carotid atherosclerosis than any of the Framingham risk factors [23]. Our findings therefore raise the possibility that flax seed high in lignan, or a purified extract of SDG, may be an alternative to HRT for reduction of vascular risk. Further study of the effects of SDG on a surrogate outcome, progression of carotid atherosclerosis, are planned, with a view to larger studies of clinical outcomes in the longer term.

	CONCLUSION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Flax phytoestrogens ameliorate certain responses to stress and thus may afford protection against atherosclerosis; this hypothesis should be tested in clinical trials.

	ACKNOWLEDGMENTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
This study was supported by a grant from the Ontario Heart and Stroke Foundation (Grant #T3737). Dr. Thornton was supported by a Hargreaves Scholarship for her summer job in the Stroke Prevention & Atherosclerosis Research Centre. We wish to thank Janine Boere for her meticulous work in the conduct of the study, data entry and cleanup, and the flax farmers who provided the seed for the study: Jim Trimble of Gainsborough Saskatchewan for the Flanders, David Pizzey of Binscarth, Manitoba for the AC Linora. Mr. John Dean of United Grain Growers of Winnipeg, Manitoba, provided the Linola 989^TM.

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Drs. Muir and Westcott share in patents held by Agriculture Canada on SDG.

Received June 14, 2002. Accepted December 11, 2002.

	REFERENCES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 

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