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Oats, Antioxidants and Endothelial Function in Overweight, Dyslipidemic Adults

Yale Prevention Research Center, Derby (D.L.K., M.A.E., W.C., H.N., B.P.C., M.L.H., V.Y.N., P.M.S.), Connecticut
Yale University School of Medicine, New Haven (D.L.K., H.N., P.M.S.), Connecticut

Address reprint requests to: David L. Katz, MD, MPH, FACPM, FACP, Yale Prevention Research Center, 130 Division Street, Derby, CT 06418. E-mail: katzdl{at}pol.net with copy to: shelli.larovera{at}yalegriffinprc.org

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Objective: To determine effects of oat and antioxidant vitamin (C 500 mg, E 400 IU) ingestion on endothelial function in overweight, dyslipidemic adults.

Design: Randomized, blinded, placebo-controlled, crossover trial

Intervention(s): Subjects (16 males age 35; 14 postmenopausal females) were assigned, in random order, to oats (60 g oatmeal), vitamin E (400 IU) plus vitamin C (500 mg), the combination of oats and vitamins, or placebo, and underwent brachial artery reactivity scans (BARS) following a single dose of each treatment, and again following 6 weeks of daily ingestion, with 2-week washout periods. At each test, a provocation high-fat meal (50 g, predominantly saturated) was administered and subjects were scanned pre, and 3 hours post-ingestion.

Results: Mean flow-mediated vasodilation (FMD; measured as percent diameter change before and after treatments) at baseline was 6.35 ± 3.37. Oats increased FMD non-significantly (p > 0.05) with both single acute dose (from 6.07 ± 6.25 to 9.22 ± 8.82) and six weeks of sustained treatment (from 6.01 ± 10.07 to 8.69 ± 8.42). The direction of effect was negative for vitamins and the oat/vitamin combination with both acute and sustained treatment. There were no significant differences in FMD change among the treatments in either phase of the study, however when acute and sustained effects were pooled, oat treatment significantly augmented FMD (p < 0.05).

Conclusions: This trial suggests but does not confirm a beneficial influence of oat ingestion on endothelial function in overweight, dyslipidemic adults. Further study of this potential association is warranted.

Key words: endothelial function, brachial artery, blood flow velocity, dyslipidemia, vascular reactivity, nutrition

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Endothelial function refers to arterial vasomotor responses mediated through release of chemicals including nitric oxide (vasodilating) and endothelin (vasoconstricting) from the vascular endothelium [1]. Impaired release of nitric oxide results in endothelial dysfunction which can be detected non-invasively by use of ultrasound as the propensity of vessels to constrict and impede flow in response to stimuli that should lead to dilatation and flow augmentation [2]. One method of assessing endothelial function non-invasively is by the induction of hyperemic flow and sheer stress to stimulate nitric oxide release [3]. Due to the strong correspondence between peripheral and coronary endothelial responses [4] measurement of flow-mediated dilatation (FMD) of the brachial artery using high-resolution ultrasound is a standard assessment method [5].

Endothelial dysfunction anticipates the development of anatomically overt coronary artery disease [4], correlates strongly with both coronary disease and its risk factors [6], and reverses in response to risk modification efforts [7]. While a definitive association between endothelial function and clinical events awaits the results of an on-going multi-center trial, endothelial dysfunction has increasingly been viewed as an indicator of coronary risk [4], and its amelioration as an indicator of risk reduction [7,8].

Obesity, diabetes, impaired glucose tolerance, and insulin resistance are epidemic in the U.S. [9–13] and are associated with endothelial dysfunction [14–16]. Endothelial function is a potentially important indicator of the risk of both microvascular and macrovascular [17,18] sequelae in these populations. It is estimated that more than 47 million U.S. adults are insulin resistant, including over 40% of individuals above age 60 [9]. Hypertriglyceridemia or a high cholesterol-HDL ratio [19] and abdominal obesity are among the early clinical features of insulin resistance [20,21].

Dietary fibers, especially soluble (viscous) fibers, are associated with reduced risk of coronary heart disease [22]. Oat fiber tends to lower plasma total and LDL cholesterol [23] and has recently been shown to lower blood pressure in hypertensives [24,25]. Cereals confer a range of metabolic benefits in diabetes [26]; a 50% decrease in glycemic response can be seen with 3–5 g of beta-glucan [27]. Oat-based meals evoke a smaller glucose and insulin response than other cereals, and lead to gradual reductions in fasting glucose and insulin levels in diabetics [22].

Acute fat ingestion, long associated with an acute rise in coronary event rates in susceptible individuals [28] has been shown to induce endothelial dysfunction in healthy subjects [29], although this effect varies by type of fat [30] and has been challenged [31,32]. Endothelial dysfunction in response to foods may be an important mechanism of acute coronary vulnerability [7].

In a previous trial, we demonstrated beneficial effects of oat ingestion on endothelial function following a high-fat test meal in healthy adults [33,34]. The effects of antioxidants on endothelial function in insulin resistance have been investigated [35,36], but to date postprandial effects have not been reported. We therefore conducted a randomized, blinded, 2 x 2 factorial crossover trial of oats and the combination of vitamins E and C on endothelial function pre- and post-high-fat test meal in 30 overweight, dyslipidemic adults.

	MATERIALS AND METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Subjects
A total of 30 adult subjects (16 men and 14 women) residing in Southwestern Connecticut were recruited through mass media print advertisements. Recruitment took place over a 5-month period, beginning May 2000. The study was conducted at the Yale-Griffin Prevention Research Center, Derby, CT. Sample size was predicated on 80% power to detect a minimal difference of 3% in FMD change between the oats and placebo treatments at 6 weeks, with adjustment for multiple comparisons, a 2-tailed alpha level of 0.05, and an attrition rate of 15%. Inclusion criteria were: (1) age 35 to 75 years for males; (2) post-menopausal and not currently using hormone replacement therapy for females (upper age limit of 75); (3) non-smoker; (4) no known coronary artery or other vascular disease; (5) no vasoactive medication use (subjects who were taking regular antihypertensives other than ACE inhibitors were asked to hold their morning dose on the day of testing) (6) no regular use of high dose vitamin E, C or fiber supplements, or willingness to discontinue before the study (7) total cholesterol > 200 mg/dL, fasting triglycerides 150 mg/dL, and BMI 25.

Subjects from all ethnic and minority groups were equally eligible. Individuals failing to meet inclusion criteria, physically unable to comply with the study protocol, or maintained on ACE inhibitor therapy were excluded.

Subject participation and progress through the study is shown in Fig. 1. Those subjects (n = 139) who responded to recruitment efforts were pre-screened using a semi-structured telephone interview. Subjects who met initial screening criteria (n = 49) underwent a screening examination (height, weight, body mass index (BMI), waist, hip, and blood pressure measurements) performed by a clinical research specialist, and laboratory testing (fasting total cholesterol, triglycerides, high density lipoprotein (HDL), fasting blood glucose, and Hemoglobin A1c). The 30 eligible subjects enrolled were randomly assigned to a treatment sequence. Subjects were blinded to the vitamin treatment, however could not be blinded to oat assignment. The ultrasonographer was strictly blinded to treatment assignment. All subjects provided informed consent prior to randomization. Participants were compensated monetarily for their time. The study was approved by the Institutional Review Board (IRB) of Griffin Hospital (Derby, CT).

View larger version (42K): [in this window] [in a new window]   Fig 1. Trial Profile.

Following completion of the acute phase, subjects were randomly assigned to each of the 4 treatment assignments daily for a period of 6-weeks, followed by BARS, a 2-week washout period, then crossover to the next treatment. The daily oat treatment during the sustained phase consisted of 60g oatmeal consumed in the morning and an oat bran ready-to-eat cereal snack in the afternoon providing an additional 2g of ß-glucan. On scan days, the fatty test meal and treatment were administered concurrently immediately following the preprandial scan, as in the acute phase.

Each vascular reactivity test consisted of pre- and postprandial BARS. Endothelial function was measured non-invasively in the right brachial artery by means of high frequency ultrasound (Phillips Medical Systems; Sonos 4500) in accordance with published guidelines [5]. Subjects were required to lie at rest in the quiet, temperature-controlled, softly lit room for at least 15 minutes before scanning was initiated. The baseline diameter of the brachial artery was measured from 2-dimensional ultrasound images using a high frequency, 10–15 MHz, vascular ultrasound transducer (Phillips Medical Systems L7540 linear array transducer). Arterial flow-velocity was measured by means of a pulsed Doppler signal at a 70° angle to the vessel, with the range gate in the center of the artery. The timing of each image frame with respect to the cardiac cycle is determined with simultaneous ECG gating during image acquisition via the mainframe ultrasound system. The brachial artery was imaged at a location 3–7 cm above the antecubital fossa in the longitudinal plane. A segment with clear anterior and posterior intimal interfaces between the lumen and vessel wall was selected for continuous 2D gray scale imaging. The transmit (focus) zone was set to the depth of the near wall because of difficulty in differentiating the near from the far wall "m" line (the interface between media and adventitia).

To create a flow stimulus in the brachial artery, a sphygmomanometer (blood pressure cuff) was placed on the upper arm proximal to the transducer. The cuff was inflated for 5 minutes to at least 40mm Hg above systolic pressure. Repeat scans were obtained at 15, 60, and 120 seconds post-deflation. At each scanning interval (pre and postprandial), both cross-sectional vessel diameter and flow-velocity were recorded. Measures of vessel diameter and flow velocity were obtained by a single dedicated vascular clinical research specialist (ME) blinded to subject treatment status. Images were acquired on videotape and magnetic optical disk for evaluation and analysis. Vessel diameters were obtained manually from the anterior to the posterior "m" line on the "R" of the QRS with electronic calipers using 5 equidistant lines, over a consistent parallel segment of vessel at least 10–15 mm in length. Velocity measures were generated automatically using a time-averaged pulsed Doppler velocity signal obtained from an appropriately measured midartery sample volume, at the pre- and post-cuff (within 15 s) release for a hyperemic velocity. A random sample of 30 BARS were provided to the clinical research specialist for a blinded second reading. The resultant coefficient of intra-observer reliability was 0.95.

Data Analysis
All data were entered and stored by a dedicated data manager using Microsoft Excel 2000. Data were manually checked for entry accuracy. The primary outcome, flow-mediated dilatation (FMD), was measured as the percent diameter change in post-occlusion brachial artery diameter at 60 seconds relative to the measurement pre-cuff inflation. FMD was measured during the preprandial state and postprandial state and a variable created to capture the FMD change from baseline with each treatment.

Data analysis was conducted using SAS software (Version 8 of the SAS System for Windows; SAS Institute Inc., Cary, NC). A 2-tailed p value of 0.05 was considered significant. Two-way repeated measures ANOVA with treatment and time as the main effects was performed to compare treatment-specific FMD responses accounting for time differences. Within-treatment effects were calculated as the difference between post- and pre-treatment FMD using paired t-tests. To account for potential variability in the strength of the stimulus that triggered endothelial reactivity (i.e. the hyperemic flow induced to stimulate endothelial response), FMD was divided by flow at 15 seconds post-cuff deflation to create a stimulus-adjusted response measure (SARM). ANCOVA models were created to assess the association between post-treatment FMD and treatment while adjusting for potential confounders such as pre-treatment FMD, BMI, age, baseline systolic blood pressure, and room temperature on the day of the scan.

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Subjects ranged in age from 37–74, with a mean of 56.3 years. Demographic and baseline data are provided in Table 1. A total of 26 subjects completed both phases of the study. Two women dropped out during the acute phase due to reasons unrelated to the study; 1 woman dropped out after completing the acute phase, and 1 man dropped out during the sustained phase due to out of state relocation.

The direction of treatment effects in the sustained phase was consistent with those seen in the acute phase. Following 6 weeks of treatment with oats, FMD increased non-significantly compared to baseline (from 6.01 ± 10.07 to 8.69 ± 8.42); FMD again decreased with vitamin assignment alone (from 6.50 ± 8.10 to 5.37 ± 6.30) and with the combination (from 8.78 ± 7.07 to 7.19 ± 7.49) (Table 3). Change in FMD did not differ significantly between treatments in either the acute or sustained study phases.

	DISCUSSION

 
This study was designed to test the effects of oat and antioxidant vitamin ingestion on endothelial function in overweight, dyslipidemic adults in whom endothelial dysfunction was provoked by a standardized test meal high in saturated fat. While the subjects demonstrated impaired endothelial function at baseline, the acute induction of endothelial dysfunction by the test meal was not observed, attenuating study power. Nonetheless, a favorable influence of oat ingestion was suggested, with no such effect seen for the antioxidant vitamins. While not specifically powered for sub-group analysis, it is of interest that oats appeared to exert a more potent beneficial effect on FMD in women, while antioxidant effects in women were more distinctly adverse.

The suggested effects of oats in this study are concordant with a body of literature attesting to benefit of whole grain cereals, and soluble fiber in particular, in diabetes [37] cardiovascular disease [22,23], and their antecedent states [38]. Oats have been shown to lower serum lipids, attenuate postprandial spikes in triglycerides, glucose and insulin, and to lower blood pressure [24,26,39]. The potential beneficial influence of oat ingestion on postprandial endothelial function in this and a previous trial [33,34] suggest one more means by which whole grain cereals and soluble fiber may be protective of vascular health.

The combination of vitamin E 400 IU and vitamin C 500 mg did not confer benefit, with the direction of effect on FMD consistently negative. The effects of antioxidants on endothelial function in prior studies have varied considerably. Beneficial effects of vitamins E and C on postprandial endothelial responses in healthy subjects have been reported by Plotnick et al. [29]. In subjects with hyperhomocysteinemia, however, folic acid alone was better than folic acid plus vitamin C and E in enhancing endothelial function [40]. In chronic smokers, vitamin E (600 IU) failed to reverse endothelial dysfunction after 4 weeks [41]. Endothelial dysfunction induced by glucose loading was prevented by administration of vitamin E 800 IU in otherwise healthy adults [15]. However, in both type 1 and 2 diabetics, vitamin E has been reported to lack influence on endothelial function [42,43] although here, too, findings have been inconsistent [44,45]. In response to these uncertainties, the NIH has issued a program announcement to support studies of antioxidants and vascular disease risk in diabetes (PA-01-112, The Role of Antioxidants in the Prevention of Diabetic Complications). The effects of vitamin E on clinical endpoints in cardiovascular disease have also varied considerably [46–48] with the largest trials [48,49] demonstrating no benefit.

The current findings add to the list of unresolved questions about antioxidants and vascular health. Antioxidant effects on endothelial function were in a negative direction, both when administered alone and in combination with oats. The magnitude of these effects was greater in women than men, as was the favorable influence of oats. An explanation for a sex differential in the effects of antioxidants on endothelial function, if indeed real, is lacking at present, and represents an area where further investigation may be warranted. The effects of oats on endothelial function may not be solely attributable to the ß-glucan content. Oats contain phytoestrogens [50], which could enhance endothelial function [51]. Vascular estrogen receptors are considerably more abundant in women than men [52]. Of note, the trial was not powered for analysis of sub-group effects, so all such findings should be regarded as preliminary.

This study has several noteworthy limitations. The sample was small, and derived from the population of one community. The study was intended to evaluate subjects with impaired insulin sensitivity, but was developed prior to the release of current NCEP ATP-III or WHO criteria for insulin resistance [53]. Lack of insulin sensitivity measurements and lack of fully established insulin resistance among subjects in the trial would tend to bias findings toward the null. Also of note is that the intended provocation of endothelial dysfunction, a test meal high in saturated fat, did not demonstrate this effect, again biasing results toward the null. Some recent literature has contested the view that saturated fat consistently induces endothelial dysfunction [32,54], perhaps due to variation in the specific fatty acids represented. In subjects with or at risk for diabetes, a glucose load may be a more reliable provocation [55], based on findings reported after the current study was under way. Dietary intake data were tracked by food diaries, and suggested no significant unintended changes in overall dietary pattern during the study. Nonetheless, changes in diet or behavior that were not captured might have contributed to the findings observed. Other dietary modifications associated with daily intake of oats might serve to exaggerate the effects of oats on FMD, although any such changes in diet might simply be considered a natural consequence of adding oats. If so, the generalizability of the findings should be preserved.

In the context of prior work, the findings reported here suggest the possibility of salutary effects of oat consumption on endothelial function in overweight, dyslipidemic adults. Given the range of established benefits of whole grains to vascular health, this finding is consistent with a recommendation for habitual intake of oats and other soluble-fiber rich foods by individuals with, or at risk for, insulin resistance. In contrast, the findings further compound prevailing uncertainties about the effects of antioxidant supplements on cardiovascular risk. Further investigation of the associations observed in this study is warranted.

	ACKNOWLEDGMENTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
This study was supported by an unrestricted research grant from the Quaker Oats Company, and by Grant #U48-CCU115802 from the Centers for Disease Control & Prevention.

Received May 27, 2003. Accepted February 12, 2004.

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TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 

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