Wong, Rachel H.X.; Howe, Peter R.C.; Coates, Alison M.; Buckley, Jonathan D.; Berry, Narelle M.
A hallmark of the initial pathogenesis of atherosclerosis is poor endothelium-dependent vasodilatation in response to vasodilator stimuli . Flow-mediated dilatation (FMD) of the brachial artery is a common method of assessing systemic vasodilator function, which is well correlated with vasodilator function in the coronary arteries . FMD progressively declines with age even among healthy individuals  and is an independent predictor of future cardiovascular events in older adults without preexisting cardiovascular risk factors  and future cerebrovascular events following a first-ever episode of ischaemic stroke . In fact, it has been shown that both peripheral and cerebral vasodilator functions are diminished in lacunar ischaemic stroke patients compared with healthy age-matched controls , suggesting a global impairment of circulatory function. There is, however, a lack of association between impaired vasodilator function in systemic and in cerebral arteries [7,8]. Nonetheless, there is retrospective evidence that coronary artery disease patients who improve FMD without changes in other risk factors have a lower incidence of cardiovascular events . Although there is no evidence of lower mortality risk from cerebrovascular events with improved cerebral vasodilator function, maintaining good vascular health is vital for primary prevention.
Prospective epidemiologic studies suggest that a high intake of whole-grain foods can help to reduce coronary heart disease risk [10,11]. Oats (Avena sativa L.), in particular, are known to have beneficial heart health effects including lowering of total and low-density lipoprotein cholesterol [12,13], lowering of SBP and DBP  and improvement of vasodilator function . Indeed, oats in various forms and extracts have been used for their physical and psychologically fortifying properties for centuries . The heart protective benefit of oat grains may be attributable to not only the cereal fibre, β-glucan , but also other bioactive constituents like avenanthramides – polyphenols exclusive to oats [18–21]. One study found a marginally significant increase in FMD when overweight, dyslipidemic adults with attenuated FMD responses consumed oatmeal following a high fat meal, compared to the consumption of vitamins E and C, a combination of oats and vitamins or placebo . This preliminary finding suggested that the phytochemicals in oats might have a role in improving vasodilator function, as the antioxidant effects of the vitamins consumed alone or in combination with oats were ineffective . One limitation in using commercially available oats or oat-containing products in dietary interventions is the potential loss of phytochemicals, especially avenanthramides, with various processing techniques (i.e. milling, rolling or exposure to heat) . In addition, different oat cultivars, growing environment and stages of harvest would yield substantial variations in avenanthramide concentrations .
Avenanthramide-A, avenanthramide-B and avenanthramide-C are the three most abundant compounds belonging to a group of alcohol-soluble hydroxycinnamoylanthranilate alkaloids and are bioavailable in humans, particularly avenanthramide-A . However, early in-vitro studies showed that avenanthramide-C, which accounts for 30% of total avenanthramides in oat grain, is a potent antioxidant, which prompted the authors to recommend it as a key focus for future studies . Subsequently, in-vivo experiments tested only avenanthramide-C and found that avenanthramide-C dose-dependently inhibited vascular smooth muscle cell proliferation and upregulated mRNA expression of endothelial nitric oxide synthase leading to increased nitric oxide production in human aortic endothelial and smooth muscle cells . This latter effect may increase vasodilatory responses to stimuli such as shear stress. More recently, both avenanthramide-C  and avenanthramide-A  were effective in suppressing proinflammatory cytokines via inhibition of nuclear factor-κB (NF-κB) in endothelial cells, suggesting that the potential to improve human vascular function with regular oat consumption is not limited to the antioxidant properties of avenanthramide-C.
Oat leaves contain higher concentrations of avenanthramide-A than avenanthramide-B or avenanthramide-C . Wild green oat extract (WGOE; Neuravena EFLA995) is obtained from the top third of the old wild green oat herb, a variety of Avena sativa L., contract-grown to ensure consistent bioavailability. In-vitro studies of effects of WGOE on endothelial cells indicate vasodilatory potential ; however, whether this translates to improvements of circulatory function in humans has yet to be determined. We recently reported that a single 1600 mg oral dose of encapsulated WGOE reduced the number of errors made in the Stroop colour-word test in older adults with below average cognition . It has been hypothesized that the improvement in human cognition may be mediated by enhanced cerebral vasodilator function ; however, this has yet to be demonstrated. Other potentially bioactive constituents in WGOE including saponins, vitexin and isovitexin may also have the potential to improve endothelial function [29,30]. The vasodilator potential of WGOE consumption has not been evaluated in humans. In this study, we aimed to determine whether daily consumption of WGOE would result in sustained improvements of vasodilatation in both systemic and cerebral arteries in older adults.
Study design and participants
A 24-week randomized, double-blind, placebo-controlled crossover dietary intervention trial of a 1500 mg/day supplement of WGOE compared with placebo was conducted at the Nutritional Physiology Research Centre, University of South Australia, Adelaide, in accordance with principles of Good Clinical Practice. The study was approved by the University of South Australia Human Research Ethics Committee and registered with the Australia and New Zealand Clinical Trials Registry (ACTRN 12610000012077).
With the crossover design, we calculated that 38 participants would give 80% power to detect a statistically significant (P < 0.05) difference of 2% in FMD with SD equal to 3% (based on our previous study ). Allowing for dropouts, 42 men and women aged over 60 years were recruited between March and June 2010 from a database of existing volunteers who had consented to be contacted for participation in future studies and from the general public via electronic media, radio and TV announcements. All participants provided written, informed consent prior to participation.
During an initial screening visit, volunteers underwent a series of assessments to determine their eligibility to participate in the trial. They were excluded if they met any of the following conditions: taking cognitive enhancers, anticholinergic medication or mood-altering medications; had a history of serious head injury, diagnosed and/or treated mental illness, alcoholism, stroke or neurological condition; had cardiovascular disease, renal disease, diabetes, gastrointestinal disease or dyslexia; smoked or used nicotine replacement therapy; changed antihypertensive medication in the preceding 3 months or were likely to do so during the trial; and consumed more than one serve of oats (including oat products) on average per day.
Additional exclusion criteria determined at screening included suspected dementia  (DEMTECT score <9), supine blood pressure (BP) more than 160/100 mmHg or inability to obtain a satisfactory image of the middle cerebral artery (MCA) by transcranial Doppler (TCD) ultrasound.
The WGOE supplement (Neuravena EFLA955) is an extract of a variety of Avena sativa L., wild green oat herb, selected from approximately 70 strains of seeds collected from different sites and seed banks throughout Europe. Avena sativa L. is a listed food in the European Herbal Infusion Association and is registered for human consumption in foods or medicines in Switzerland. The top third of the mature wild green oat herb is used to prepare the extract via alcohol water extraction of the dried plant. The ratio of herbal bioactive to extract was 3.5 to 1. In-vivo and in-vitro toxicity testing of WGOE indicated that the extract is safe and well tolerated for acute and chronic consumption (Neuravena Frutarom Safety Dossier 2008).
The WGOE and placebo supplements used in this intervention were supplied by ASK Intercity Co. Ltd, Ichikawa-shi, Japan, as authorized by Frutarom Switzerland Ltd, in powder form and pressed into 315 mg capsules. Each capsule of WGOE contained 300 mg of active ingredient and 15 mg of calcium stearate. Placebo capsules contained microcrystalline cellulose (154.5 mg), lactose (154.5 mg), cacao brown (4 mg) and safflower colour (2 mg) that readily passes through the body and has no known effect on vasodilator function. WGOE and placebo capsules were near-identical in appearance and presented in opaque bottles.
Randomization and blinding
A random number generator was used to randomize participants to active or placebo treatments (marked with the letter A or B). An investigator who was not involved in data collection performed the randomization. Supplement capsules were stored in a locked and limited access area. Investigators remained blinded until all data analysis had been performed.
Treatment regime and monitoring
Enrolled participants were instructed to take five capsules per day containing 300 mg of WGOE or placebo, all in one sitting, and to record each intake in the assigned supplement diary. The 1500 mg dose was chosen as it was similar to the safe and efficacious 1600 mg dose used in our previous study of acute effects of WGOE . If a dose was missed, participants were requested to indicate the reason for missing and not to carry over the dose to the next day. Participants were instructed not to deviate from their usual dietary and physical activity habits during the period of intervention. Any changes in medication and/or dietary supplement intake during the intervention were to be self-reported in a supplement diary. At the end of 6 weeks, the bottle, diary and any unused capsules were returned before a new bottle and a supplement diary were issued for the next 6 weeks. A compliance check was conducted at each 6-week visit during which the investigator asked about the participant's welfare, how were they coping with the supplements, reports of any side-effects, changes in diet, physical activity and medications. At the end of the trial, all capsules were manually counted and tallied with the corresponding diary records to monitor compliance.
The intervention took place between March 2010 and November 2010. Outcome measures were obtained in week 12 and repeated in the same order in week 24 of the trial. Participants arrived at the Research Centre after fasting for at least 4 h (no food, medication, fluids except water) and at least 18 h after taking their last dose of supplement. All vascular assessments were performed after lying supine for at least 10 min by one investigator (R.W.) in the order listed below.
A single investigator measured BP in participants lying supine for at least 10 min. Four consecutive readings were taken at 1-min intervals by automated oscillometry with a Cardiovascular Profiler (HDI Cardiovascular Profiler CR2000) in accordance with the procedures outlined by the Joint National Committee on Prevention, Evaluation and Treatment of High Blood Pressure (VI): US Department of Health and Human Services . After discarding the first reading, an average of the remaining measurements was recorded for analysis.
Cerebral vasodilator responsiveness
Cerebral vasodilator responsiveness (CVR) was assessed using TCD (General Electric Logiq 5 Expert). TCD is a noninvasive technique used to assess blood flow velocity in the MCA with participants lying supine on a bed in a temperature-controlled room. Participants rested for at least 15 min prior to the commencement of the examination. During the TCD examination, participants inhaled 5% CO2 for 2 min. The hypercapnia induced cerebrovascular dilatation, evidenced by an acute increase of blood flow velocity in the MCA
Participants were fitted with a nonrebreathing two-way valve and facemask that encompassed the nose and mouth. They remained in a comfortable supine position during the whole assessment. The transtemporal window (between ear and along zygomatic bone) is the best acoustic window for insonation of the MCA, which was identified by its unique sound and waveform .
The mean depth of insonation from the ultrasound probe to the start of Doppler signal for detecting mean blood flow velocity in the MCA was 50 ± 1 mm. After obtaining a clear signal, a 30-s baseline was recorded before the participant inhaled carbogen gas (5% CO2/95% O2) for 2 min. Mean flow velocity in the MCA was recorded for each cardiac cycle during the whole 150 s. To improve test reliability, this assessment was performed three times with a 2-min rest period between tests to allow flow velocity to return to baseline levels. All measurements were performed on the left transtemporal window. Data were stored on the ultrasound hard drive until subsequent analysis. Baseline data consisted of a 30-s average of the mean flow velocity. Data collected during hypercapnia were smoothed by fitting a spline curve (TableCurve 2D by Systat Software Inc., San Jose, California, USA) and the peak increase in mean flow velocity was determined. CVR was expressed as a percentage change from baseline [(peak mean flow velocity – baseline mean flow velocity) × 100 /baseline mean flow velocity].
Endothelial vasodilator function was assessed in the systemic circulation (brachial artery) by FMD using ultrasound with a two-dimensional B-mode 12 MHz transducer (General Electric Logiq 5 Expert) in accordance with published guidelines . An occlusion cuff was positioned over the forearm and the ultrasound transducer was placed on the upper arm approximately 3–7 cm from the top of the occlusion cuff. After 30 s of baseline video recording of the brachial artery, the cuff was inflated to 200 mmHg for 5 min before being rapidly deflated. Postdeflation images of the brachial artery were recorded continuously at end-diastole for 3 min with a DVD recorder.
FMD video files were analysed using edge-detection software (Brachial Analyser; Medical Imaging Application, Iowa City, Iowa, USA). For both baseline and postdeflation, a region of interest was defined over a clear image of the brachial artery walls. Baseline artery diameter was averaged from the last 30-s predeflation. A spline curve was then fitted through all values of the diameter obtained for 3-min postdeflation and from this curve, the peak diameter was estimated (TableCurve 2D by Systat Software Inc.). FMD (expressed as % change) is calculated as (peak diameter − baseline diameter)/baseline diameter × 100.
All statistical analyses were performed using SPSS Version 17.0 (SPSS, Chicago, Illinois, USA). A two-sample t-test was used to test for any carryover effects by comparing the differences in the sum of responses for supine BP, FMD and CVR for each participant at the end of each intervention period (i.e. WGOE to placebo and placebo to WGOE). The effect of supplementation was determined by within-individual comparison of the values obtained at the end of each supplementation period using a paired t-test. Participants who showed improvement in outcomes with WGOE compared to placebo were considered responders. Two-sample t-tests were used to compare the differences in outcome measurements between responders and nonresponders and whether participants with concomitant medication/supplement showed significant differences in their response to chronic WGOE supplementation. All data are presented as mean ± SEM, unless stated otherwise.
A flow chart of participants and data analyses is shown in Figure 1. Of the 42 participants who were enrolled, 37 completed the two assessment time points in the 24-week intervention. Three of the withdrawals were taking WGOE supplement and two were on placebo at the time of withdrawal. Two of the five withdrawals were classified as serious adverse events (hospitalized for angina and breast cancer), which were unrelated to the investigational product, and were reported to the University of South Australia Human Research Ethics Committee. Two participants withdrew due to gastrointestinal discomfort (one being on placebo and the other on the active product at the time). Consequently, 37 participants completed all assessment time points and were included in the data analysis of cognitive and FMD assessments. Table 1 shows the participant characteristics. Participants in this study were healthy, normotensive but slightly overweight (mean BMI >25.0 kg/m2). They also had normal cognition with a range of DEMTECT scores between 14 and 19 out of a maximum score of 19 (mild cognitive impairment 9–12 points, suspected dementia <9 points) . During the intervention, the concomitant medication and dietary supplement use by participants included cholesterol-lowering (19%), antihypertensive (16%) and gout (5%) medications, fish oil (35%), calcium (14%) and multivitamins (17%). Dosage of medication and dietary supplement remained unchanged prior to and during the intervention.
Compliance with the intervention was greater than 99% for both intervention arms (99 ± 0.8% for WGOE and 100 ± 0.6% for placebo). Despite having satisfactory image quality of the MCA using TCD at the time of screening as one of the eligibility criteria, we were only able to obtain complete and analysable TCD files at week 12 and 24 from 18 participants for the crossover comparison. In addition, there were two unanalysable FMD data from two of the 18 participants with complete TCD data.
Two-sample t-tests indicated no carryover effects in any outcome measures with supplementation [SBP: P = 0.428; DBP: P = 0.714; heart rate (HR): P = 0.488; FMD: P = 0.129; CVR: P = 0.083].
Compared with placebo, WGOE supplementation resulted in a significant mean absolute improvement of 1.80 ± 0.50% (41% increase) in FMD (d = 0.62, 95% confidence interval: 0.78–2.82, P = 0.0011) and a mean absolute improvement of 8.3 ± 2.1%, or a 42% mean within-individual increase, in CVR (d = 0.93, 95% confidence interval: 3.80–12.73, P = 0.0011; Fig. 2). No significant correlation between the treatment-induced improvements in CVR and FMD was observed (r = 0.143, r2 = 0.02, P = 0.598, n = 16).
Resting diameter of the brachial artery (WGOE: 5.27 ± 0.15 mm vs. placebo: 5.17 ± 0.17 mm; P = 0.245) did not differ significantly with WGOE supplementation, whereas peak diameter during reactive hyperaemia (WGOE: 5.59 ± 0.15 mm vs. placebo: 5.40 ± 0.18 mm; P = 0.049) was significantly larger with WGOE compared with placebo. WGOE supplementation did not affect both the resting (WGOE: 35.6 ± 1.3 cm/s vs. placebo: 37.2 ± 1.8 cm/s; P = 0.365) and peak mean blood flow velocities in the MCA during hypercapnia (WGOE: 45.3 ± 1.9 cm/s vs. placebo: 37.2 ± 1.8 cm/s; P = 0.578).
Regular daily WGOE supplementation for 12 weeks did not affect supine BP and HR [mean SBP/DBP (HR) for WGOE: 126.4/71.9 mmHg (62.8 bpm); placebo: 125.9/72.1 mmHg (62.8 bpm); P > 0.05]. Weight (WGOE: 77.52 ± 2.11 kg; placebo: 77.57 ± 2.08 kg; P = 0.856) and BMI (WGOE: 26.53 ± 0.56 kg/m2; placebo: 26.54 ± 0.56 kg/m2; P = 0.867) were also unaffected by supplementation.
Participants who showed an improvement in FMD with WGOE supplementation (responders: 66.2 ± 0.8 years old; n = 27) were slightly younger compared with those who showed no or negative change in FMD (nonresponders: 71.3 ± 1.7 years old; n = 6; P = 0.010). However, there was no difference in mean age between responders (64.7 ± 0.9 years old; n = 15) and nonresponders (66.7 ± 3.2 years old; n = 3) for CVR outcomes (P = 0.417). FMD nonresponders (n = 6) tended to have higher SBP (136.0 ± 4.6 vs. 124.6 ± 2.5 mmHg; P = 0.057) and DBP (77.7 ± 3.1 vs. 69.5 ± 2.4 mmHg; P = 0.059) at screening than the responders (n = 27). Nonresponders to WGOE in CVR outcome (n = 3) showed similar trend in screening SBP and DBP; however, these differences were not significant.
Concomitant use of antihypertensive or cholesterol-lowering medication prior to and during the study did not influence the effect of WGOE supplementation on the outcome measures (Table 2). However, we observed that participants who were not taking fish oil supplements prior to and during the study intervention had absolute FMD values 2.86 ± 0.63% higher (n = 17) with WGOE than with placebo, whereas those on fish oil supplements had FMD values 0.67 ± 0.68% higher (n = 16; P = 0.027).
This is the first study to investigate the effects of chronic WGOE supplementation (1500 mg per day for 12 weeks) on supine BP, FMD and CVR in older adults. Although WGOE supplementation did not affect supine BP, we found independent improvements in FMD and CVR after 12 weeks. These improvements were not transient effects as vascular assessments were obtained following a minimum fast of 4 h and at least 18 h after participants consumed their last supplement dose. This improvement was seen in 82% of our study participants (27 of 33). There is an emerging body of literature demonstrating acute increases in FMD with plant-derived supplements but less evidence that such effects are sustainable following chronic consumption . Davison et al. previously reported that overweight/obese adults consuming a high-flavanol cocoa drink (902 mg flavanols/day) had a 46% net improvement in FMD after 12 weeks compared with those consuming low-flavanol cocoa (36 mg flavanols/day). We now find a similar improvement in FMD (41% increase) following 12 weeks of supplementation with WGOE. One limitation of this study is that we did not exclude participants who were already supplementing their diet with omega-3 fish oil. Interestingly, although concomitant antihypertensive medication had no significant effect on vasodilator responsiveness in this study, reduced responsiveness was seen in those participants who took fish oil supplements. Meta-analysis of omega-3 fatty acid supplementation trials found an average 2.30% improvement in FMD with chronic consumption , suggesting a possible ceiling effect which prevented further enhancement of FMD with additional vasoactive supplementation. Thus, WGOE may be an alternative nutrient supplement to fish oil or cocoa flavanols for improvement of arterial function.
FMD has prognostic value in predicting future cardiovascular disease and cardiac events as it correlates with dysfunction in the coronary circulation [38,39]. With ageing, normal endothelial function is diminished due to the reduction in nitric oxide secretion from endothelial cells, which may increase cardiovascular disease risks . Cardiovascular diseases such as hypertension and obesity are known to further accelerate endothelial dysfunction . Indeed, others have shown that elderly adults (averaging 78 years) with cardiovascular risk factors have lower FMD values 2.80 and 2.92% compared with their healthy counterparts who have values between 3  and 6% . In a cohort of coronary heart disease patients, an absolute improvement of at least 3% in FMD response (82% increase from baseline FMD), through smoking cessation, cholesterol-lowering and angiotensin-converting enzyme inhibitor therapies, over 44 months from baseline resulted in fewer cardiovascular events compared with nonimprovers. The number of cardiovascular events, however, did not differ between groups when split by median FMD , suggesting that the difference in FMD values over time and/or with treatment would be more meaningful than a single FMD value. Given the lack of standardized values for ‘normal’ FMD across the lifespan, a sustained improvement in FMD (i.e. 41% increase with WGOE supplementation) could contribute substantially and would be clinically important in reducing cardiovascular disease risk. We also found that nonresponders of FMD in our study population tended to be older (mean age of 71.3 ± 1.7 vs. 66.2 ± 0.8 years), reflecting structural and functional changes in the endothelium which may not be responsive to 12 weeks of WGOE supplementation.
Twelve weeks of daily supplementation with WGOE also resulted in significant improvement of CVR (42%), suggesting a similar sustained improvement of endothelial function in the cerebral arteries. To our knowledge, this is the first study in humans to show sustained improvement of cerebral vasodilator function following a chronic dietary supplementation. Decreased nitric oxide bioavailability in cerebral endothelial cells contributes to the impairment of cerebral vasodilator function . Impaired cerebral vasodilator function has been reported as an independent predictor of stroke and transient ischaemic attack ; however, its prognostic significance is still debatable . A 10% reduction in CVR to a hypercapnic stimulus was found in asymptomatic carotid artery disease patients who suffered transient ischaemic attack compared to those without incidents during the 2 years of follow-up . In this chronic WGOE supplementation study, we observed a 42% increase in CVR with WGOE compared with placebo in most of our study participants (15 of 18). This CVR enhancement was unaffected by the concomitant use of antihypertensive, cholesterol-lowering medication, fish oil supplementation or baseline characteristics (i.e. age, resting SBP and DBP).
Endothelial nitric oxide synthase-derived nitric oxide plays a crucial role in increasing blood flow caused by vasodilatation, decreasing platelet aggregation and adhesion and inhibiting smooth muscle cell proliferation . Even in healthy individuals, ageing is a benign risk factor for developing cardiovascular and/or cerebrovascular diseases, which is partly attributable to the downregulation of endothelial nitric oxide synthase expression and nitric oxide bioavailability . Experimental evidence of avenanthramide-treated human aortic endothelial and smooth muscle cells showed a direct upregulation in mRNA expression of endothelial nitric oxide synthase, parallel with an increase in nitric oxide production after 24 h of exposure. This occurred simultaneously in the attenuation of smooth muscle cell proliferation, which persisted 48 h after exposure . It could explain the similarity in the magnitude of sustained vasodilator improvements we observed in systemic and cerebral arteries 18 h after our participants consumed their last WGOE supplement. The direct mechanisms of WGOE on systemic and cerebral arteries are still unknown. Given their bioavailability and alcohol-soluble nature , the avenanthramides in WGOE may have become incorporated into plasma lipoproteins and tissues to exert their biological effects. Human plasma and tissue biopsies should be obtained in future studies with WGOE to determine the level and site of avenanthramide accumulation following chronic supplementation. In addition, the anti-inflammatory properties of the avenanthramides in oats  may have contributed to the improvement of vasodilator function seen in this study and, therefore, should be explored in future research.
Consistent with a previous observation , the lack of correlation in the improvement of FMD and CVR responses with chronic WGOE supplementation could reflect heterogeneity in the responsiveness of endothelial cells in different regions to vasoactive agents or, alternatively, lack of uniformity in the degree of impairment of the endothelium in systemic vs. central arteries within an individual. This may have implications for future dietary interventions with bioactive nutrients that seek to evaluate effects on a specific biomarker and endpoint (i.e. enhancement of cerebral blood flow with bioactive nutrients to attenuate cognitive decline).
Our study had several limitations: the vasodilator benefits observed in healthy older adults may not be reproducible in patients with existing hypertensive or coronary heart disease. Nonetheless, it is important to identify nonpharmacological interventions with the potential to sustain normal arterial function in a healthy population. Having demonstrated for the first time a vasodilator benefit of chronic WGOE supplementation, we can further evaluate this benefit in specific risk groups, that is in those with hypertension, hypercholesterolaemia or other contributors to endothelial dysfunction. Concomitant fish oil consumption prior to and during the intervention is a potential confounding variable, which we discovered in post-hoc analyses. Although participants who were taking fish oil supplements during the study showed a modest vasodilator improvement in FMD and CVR, the true vasodilator potential of the WGOE may be underestimated. Hence, regular consumption of fish oil supplements should be considered as an exclusion factor in future studies. We did not obtain venous blood samples from our participants in this study to determine the changes in metabolic parameters, inflammatory biomarkers, blood lipids and other haematological profiles following regular daily consumption of WGOE. Considering the heart health benefits of oats , it would be of interest to evaluate whether vasodilator effects of WGOE could also improve other clinical outcomes and also the possible mechanistic of action. Finally, inclusion of baseline assessments in future studies would avoid potential underestimation of the differences in treatment effects.
In conclusion, 12 weeks of daily supplementation with WGOE resulted in sustained improvements in arterial vasodilator function in both systemic and cerebral circulations of healthy older adults. We suggest that a dose–response evaluation that includes assessment of outcome measures at multiple time points is warranted to determine the most effective dose and optimal supplementation period for this population group. Given that impaired FMD is a well established marker for future cardiovascular disease and cardiac events , our observations in healthy human participants clearly indicate that the WGOE has significant potential to counteract arterial disease and, therefore, should be further investigated in population groups with cardiovascular and cerebrovascular disorders.
All authors contributed to the research design. R.H.X.W. recruited, collected and analysed the data and prepared the article. N.B. provided assistance during transcranial Doppler assessments. J.B. and P.R.C.H. provided statistical advice. All authors proofread, edited and approved the final article.
Conflicts of interest
The authors declared no conflicts of interest.
Frutarom Switzerland Ltd provided financial support and investigational product for this trial.
Reviewers’ summary evaluations Reviewer 1
The study provides the interesting evidence that wild green oat extract supplementation can improve vasodilator function in both systemic and cerebral arteries, suggesting a potential role in the maintenance of cardiovascular health.
However, this vasodilator benefit was observed in healthy older adults and may not be reproducible in patients with existing hypertensive or coronary heart disease. On the other hand, concomitant fish oil consumption prior to and during the intervention by study participants could have determined an underestimation of the true vasodilator potential of the wild green oat extract supplementation.
The strength of the study is the finding of a nutrient capable of favourably influencing arterial vasodilator function. Moreover, this nutrient property has been demonstrated in two different vascular beds with appropriate methodology.
As also remarked by the authors, a limitation of the study is that this nutrient has so far been studied in relatively healthy subjects with normal blood pressure. Therefore, it needs to be assessed in individuals with hypertension and other cardiovascular risk factors to confirm the hypothesis that this nutrient may be useful to treat or prevent arterial disease.
1. Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects related to coronary risk-factors and their interaction. J Am Coll Cardiol 1994; 24:1468–1474.
2. Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 1995; 26:1235–1241.
3. Yavuz BB, Yavuz B, Sener DD, Cankurtaran M, Halil M, Ulger Z, et al. Advanced age is associated with endothelial dysfunction in healthy elderly subjects. Gerontology 2008; 54:153–156.
4. Yeboah J, Crouse JR, Hsu F-C, Burke GL, Herrington DM. Brachial flow-mediated dilation predicts incident cardiovascular events in older adults. Circulation 2007; 115:2390–2397.
5. Santos-Garcia D, Blanco M, Serena J, Rodriguez-Yanez M, Leira R, Castillo J. Impaired brachial flow-mediated dilation is a predictor of a new-onset vascular event after stroke. Cerebrovasc Dis 2011; 32:155–162.
6. Stevenson SF, Doubal FN, Shuler K, Wardlaw JM. A systematic review of dynamic cerebral and peripheral endothelial function in lacunar stroke versus controls. Stroke 2010; 41:e434–e442.
7. Pretnar-Oblak J, Sabovic M, Zaletel M. Associations between systemic and cerebral endothelial impairment determined by cerebrovascular reactivity to L-arginine. Endothelium 2007; 14:73–80.
8. Perko D, Pretnar-Oblak J, Sabovic M, Zaletel M, Zvan B. Associations between cerebral and systemic endothelial function in migraine patients: a posthoc study. BMC Neurol 2011; 11:146.
9. Suessenbacher A, Frick M, Alber HF, Barbieri V, Pachinger O, Weidinger F. Association of improvement of brachial artery flow-mediated vasodilation with cardiovascular events. Vasc Med 2006; 11:239–244.
10. Liu S, Stampfer MJ, Hu FB, Giovannucci E, Rimm E, Manson JE, et al. Whole-grain consumption and risk of coronary heart disease: results from the Nurses’ Health Study. Am J Clin Nutr 1999; 70:412–419.
11. Jacobs DR, Meyer KA, Kushi LH, Folsom AR. Whole-grain intake may reduce the risk of ischemic heart disease death in postmenopausal women: the Iowa Women's Health Study. Am J Clin Nutr 1998; 68:248–257.
12. Ruxton CHS, Derbyshire E. A systematic review of the association between cardiovascular risk factors and regular consumption of oats. Br Food J 2008; 110:1119–1132.
14. Keenan JM, Pins JJ, Frazel C, Moran A, Turnquist L. Oat ingestion reduces systolic and diastolic blood pressure in patients with mild or borderline hypertension: a pilot trial. J Fam Pract 2002; 51:369.
15. Katz DL, Evans MA, Chan W, Nawaz H, Comerford BP, Hoxley ML, et al. Oats, antioxidants and endothelial function in overweight, dyslipidemic adults. J Am Coll Nutr 2004; 23:397–403.
16. Abascal K, Yarnell E. Nervine herbs for treating anxiety. Altern Complement Therap 2004; 10:309–315.
17. Jacobs D, Gallaher D. Whole grain intake and cardiovascular disease: a review. Curr Atheroscler Rep 2004; 6:415–423.
18. Ryan D, Kendall M, Robards K. Bioactivity of oats as it relates to cardiovascular disease. Nutr Res Rev 2007; 20:147–162.
19. Guo W, Wise ML, Collins FW, Meydani M. Avenanthramides, polyphenols from oats, inhibit IL-1β-induced NF-κB activation in endothelial cells. Free Radical Biol Med 2008; 44:415–429.
20. Sur R, Nigam A, Grote D, Liebel F, Southall M. Avenanthramides, polyphenols from oats, exhibit anti-inflammatory and antiitch activity. Arch Dermatol Res 2008; 300:569–574.
21. Nie L, Wise ML, Peterson DM, Meydani M. Avenanthramide, a polyphenol from oats, inhibits vascular smooth muscle cell proliferation and enhances nitric oxide production. Atherosclerosis 2006; 186:260–266.
22. Mattila P, Pihlava JM, Hellstrom J. Contents of phenolic acids, alkyl- and alkenylresorcinols, and avenanthramides in commercial grain products. J Agric Food Chem 2005; 53:8290–8295.
23. Peterson DM, Dimberg LH. Avenanthramide concentrations and hydroxycinnamoyl-CoA:hydroxyanthranilate N-hydroxycinnamoyltransferase activities in developing oats. J Cereal Sci 2008; 47:101–108.
24. Chen C-YO, Milbury PE, Collins FW, Blumberg JB. Avenanthramides are bioavailable and have antioxidant activity in humans after acute consumption of an enriched mixture from oats. J Nutr 2007; 137:1375–1382.
25. Peterson DM, Hahn MJ, Emmons CL. Oat avenanthramides exhibit antioxidant activities in vitro. Food Chem 2002; 79:473–478.
26. Moccetti TWC, Schmidt A, Aydogan C, Kreuter MH. Bioactivity-based development of a wild green oat (Avena sativa L.) extract in support of mental health disorders. Z Phytother 2006; 27:24.
27. Berry NM, Robinson MJ, Bryan J, Buckley JD, Murphy JK, Howe PRC. Acute effects of an Avena sativa-herba extract on responses to the Stroop colour-word test. J Altern Complement Med 2011; 17:635–637.
28. Sinn N, Howe PRC. Mental health benefits of omega-3 fatty acids may be mediated by improvements in cerebral vascular function. Biosci Hypoth 2008; 1:103–108. doi: 10.1016/j.bihy.2008.02.003.
29. Peng X, Zheng Z, Cheng K-W, Shan F, Ren G-X, Chen F, Wang M. Inhibitory effect of mung bean extract and its constituents vitexin and isovitexin on the formation of advanced glycation endproducts. Food Chem 2008; 106:475–481.
30. Lacaille-Dubois MA, Wagner H. A review of the biological and pharmacological activities of saponins. Phytomedicine 1996; 2:363–386.
31. Davison K, Coates AM, Buckley JD, Howe PR. Effect of cocoa flavanols and exercise on cardiometabolic risk factors in overweight and obese subjects. Int J Obes (Lond) 2008; 32:1289–1296.
32. Kalbe E, Kessler J, Calabrese P, Smith R, Passmore AP, Brand M, Bullock R. DemTect: a new, sensitive cognitive screening test to support the diagnosis of mild cognitive impairment and early dementia. Int J Geriatr Psychiatry 2004; 19:136–143.
33. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42:1206–1252.
34. Nicoletto HA, Burkman MH. Transcranial Doppler series part II: performing a transcranial Doppler. Am J Electroneurodiagnostic Technol 2009; 49:14–27.
35. Harris RA, Nishiyama SK, Wray DW, Richardson RS. Ultrasound assessment of flow-mediated dilation. Hypertension 2010; 55:1075–1085.
36. Hooper L, Kroon PA, Rimm EB, Cohn JS, Harvey I, Le Cornu KA, et al. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2008; 88:38–50.
37. Wang Q, Liang X, Wang L, Lu X, Huang J, Cao J, et al. Effect of omega-3 fatty acids supplementation on endothelial function: a meta-analysis of randomized controlled trials. Atherosclerosis 2012; 221:536–543.
38. Caramori PR, Zago AJ. Endothelial dysfunction and coronary artery disease. Arq Bras Cardiol 2000; 75:163–182.
39. Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 2001; 104:191–196.
40. Naseem KM. The role of nitric oxide in cardiovascular diseases. Mol Aspects Med 2005; 26:33–65.
41. Yeboah J, Sutton-Tyrrell K, McBurnie MA, Burke GL, Herrington DM, Crouse JR. Association between brachial artery reactivity and cardiovascular disease status in an elderly cohort: the cardiovascular health study. Atherosclerosis 2008; 197:768–776.
42. Davison K, Bircher S, Hill A, Coates AM, Howe PR, Buckley JD. Relationships between obesity, cardiorespiratory fitness, and cardiovascular function. J Obes 2010; 2010:191253.
43. Zimmermann C, Haberl RL. L-arginine improves diminished cerebral CO2 reactivity in patients. Stroke 2003; 34:643–647.
44. Markus H, Cullinane M. Severely impaired cerebrovascular reactivity predicts stroke and TIA risk in patients with carotid artery stenosis and occlusion. Brain 2001; 124:457–467.
45. King A, Serena J, Bornstein NM, Markus HS. Does impaired cerebrovascular reactivity predict stroke risk in asymptomatic carotid stenosis? A prospective substudy of the asymptomatic carotid emboli study. Stroke 2011; 42:1550–1555.
46. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43:109–142.
47. Toda N. Age-related changes in endothelial function and blood flow regulation. Pharmacol Ther 2012; 133:159–176.