Barley ß-glucan increases fecal bile acid excretion and short chain fatty acid levels in mildly hypercholesterolemic individuals.

The cholesterol-lowering effect of barley ß-glucan has been proposed to be the result of a pleiotropic effect, which involves several biological mechanisms such as gut fermentation, inhibition of intestinal cholesterol absorption and increased bile acid excretion and its synthesis. However, one of the recent studies from our laboratory indicated that increased bile acid excretion and subsequent increase in its synthesis, but not the inhibition of cholesterol absorption or synthesis might be responsible for the cholesterol-lowering effect of barley ß-glucan. Accordingly, the primary objective of the present study was to investigate the concentration of bile acids (BA), neutral sterols (NS) and short chain fatty acids (SCFA) excreted through the feces by mildly hypercholesterolemic subjects who consumed diets containing barley ß-glucan with varying molecular weights (MW) and concentrations. In a controlled, four phase, crossover trial, 30 mildly hypercholesterolemic but otherwise healthy subjects were randomly assigned to receive breakfast containing 3 g high MW (HMW), 5 g low MW (LMW), 3 g LMW barley ß-glucan or a control diet for 5 weeks. The concentrations of BA, NS and SCFA in the feces were measured at the end of each treatment phase. Compared to the other treatment groups, 3 g day-1 HMW barley ß-glucan consumption resulted in increased lithocholic acid (LCA) excretion (P < 0.001) but not LMW ß-glucan, even at the high dose of 5 g day-1. Increased fermentability of fibre was also evident from a significant increase in fecal total SCFA concentrations in response to the 3 g HMW ß-glucan diet compared to the 3 g LMW barley ß-glucan and control diet (P = 0.0015). In summary, the current results validate our previous report on the role of fecal bile acid excretion in cholesterol lowering through the consumption of barley ß-glucan. In addition, increased SCFA concentrations indicate that an increase in ß-glucan molecular weight promotes hindgut fermentation, which might also be playing a role in attenuating cholesterol levels.

Barley ß-glucan reduces blood cholesterol levels via interrupting bile acid metabolism.

Underlying mechanisms responsible for the cholesterol-lowering effect of ß-glucan have been proposed, yet have not been fully demonstrated. The primary aim of this study was to determine whether the consumption of barley ß-glucan lowers cholesterol by affecting the cholesterol absorption, cholesterol synthesis or bile acid synthesis. In addition, this study was aimed to assess whether the underlying mechanisms are related to cholesterol 7α hydroxylase (CYP7A1) SNP rs3808607 as proposed by us earlier. In a controlled, randomised, cross-over study, participants with mild hypercholesterolaemia (n 30) were randomly assigned to receive breakfast containing 3 g high-molecular weight (HMW), 5 g low-molecular weight (LMW), 3 g LMW barley ß-glucan or a control diet, each for 5 weeks. Cholesterol absorption was determined by assessing the enrichment of circulating 13C-cholesterol over 96 h following oral administration; fractional rate of synthesis for cholesterol was assessed by measuring the incorporation rate of 2H derived from deuterium oxide within the body water pool into the erythrocyte cholesterol pool over 24 h; bile acid synthesis was determined by measuring serum 7α-hydroxy-4-cholesten-3-one concentrations. Consumption of 3 g HMW ß-glucan decreased total cholesterol (TC) levels (P=0·029), but did not affect cholesterol absorption (P=0·25) or cholesterol synthesis (P=0·14). Increased bile acid synthesis after consumption of 3 g HMW ß-glucan was observed in all participants (P=0·049), and more pronounced in individuals carrying homozygous G of rs3808607 (P=0·033). In addition, a linear relationship between log (viscosity) of ß-glucan and serum 7α-HC concentration was observed in homozygous G allele carriers. Results indicate that increased bile acid synthesis rather than inhibition of cholesterol absorption or synthesis may be responsible for the cholesterol-lowering effect of barley ß-glucan. The pronounced TC reduction in G allele carriers of rs3808607 observed in the previous study may be due to enhanced bile acid synthesis in response to high-viscosity ß-glucan consumption in those individuals.

High-Molecular-Weight ß-Glucan Decreases Serum Cholesterol Differentially Based on the CYP7A1 rs3808607 Polymorphism in Mildly Hypercholesterolemic Adults.

BACKGROUND: ß-Glucan, a soluble fiber with viscous property, has a documented cholesterol-lowering effect. The molecular weight (MW) of ß-glucan, which contributes to viscosity, and an individual's genotype might influence the cholesterol-lowering efficacy of ß-glucan. OBJECTIVES: This study was designed to determine whether the cholesterol-lowering efficacy of barley ß-glucan varied as a function of MW and the daily dose consumed. Our second aim was to determine whether any gene-diet interactions are associated with the cholesterol-lowering efficacy of ß-glucan. METHODS: In a randomized controlled crossover trial, 30 mildly hypercholesterolemic adults [12 men and 18 women, aged 27-78 y; body mass index (in kg/m(2)): 20-40; total cholesterol (TC): 5.0-8.0 mmol/L; LDL cholesterol: 2.7-5.0 mmol/L] were randomly assigned to receive a breakfast that contained either barley ß-glucan at 3 g high MW (HMW)/d, 5 g low MW (LMW)/d, or 3 g LMW/d or a control diet, each for 5 wk. The washout period between the phases was 4 wk. Fasting blood samples were collected at the start and end of each phase for blood lipid analysis and genotyping. RESULTS: Consumption of 3 g HMW ß-glucan/d lowered TC by -0.12 mmol/L (95% CI: -0.24, -0.006 mmol/L) compared with the control diet (P= 0.0046), but the LMW ß-glucan, at either 3 g/d or 5 g/d, did not change serum cholesterol concentrations. This effect of HMW ß-glucan was associated with gene-diet interaction, whereby individuals with the single nucleotide polymorphism (SNP) rs3808607-G allele (GG or GT) of the cytochrome P450 family 7 subfamily A member 1 gene (CYP7A1) had greater responses to 3 g HMW ß-glucan/d in lowering TC than TT carriers (P= 0.0006). CONCLUSIONS: The HMW ß-glucan rather than LMW ß-glucan reduced circulating TC effectively in mildly hypercholesterolemic adults. The cholesterol-lowering effect of ß-glucan may also be determined by the genetic characteristics of an individual. These data show that individuals carrying theCYP7A1SNP rs3808607-G allele are more responsive to the cholesterol-lowering effect of ß-glucan with HMW than TT carriers. This trial was registered atclinicaltrials.govasNCT01408719.

Soy Protein Alleviates Hypertension and Fish Oil Improves Diastolic Heart Function in the Han:SPRD-Cy Rat Model of Cystic Kidney Disease.

Abnormalities in cardiac structure and function are very common among people with chronic kidney disease, in whom cardiovascular disease is the major cause of death. Dietary soy protein and fish oil reduce kidney disease progression in the Han:SPRD-Cy model of cystic renal disease. However, the effects of these dietary interventions in preventing alterations in cardiac structure and function due to kidney disease (reno-cardiac syndrome) in a cystic kidney disease model are not known. Therefore, weanling Han:SPRD-Cy diseased (Cy/+) and normal (+/+) rats were given diets containing either casein or soy protein, and either soy or fish oil in a three-way design for 8 weeks. Diseased rats had larger hearts, augmented left ventricular mass, and higher systolic and mean arterial blood pressure compared to the normal rats. Assessment of cardiac function using two-dimensional guided M-mode and pulse-wave Doppler echocardiography revealed that isovolumic relaxation time was prolonged in the diseased compared to normal rats, reflecting a diastolic heart dysfunction, and fish oil prevented this elevation. Soy protein resulted in a small improvement in systolic and mean arterial pressure but did not improve diastolic heart function, while fish oil prevented diastolic heart dysfunction in this model of cystic kidney disease.

Effect of consuming novel foods consisting high oleic canola oil, barley ß-glucan, and DHA on cardiovascular disease risk in humans: the CONFIDENCE (Canola Oil and Fibre with DHA Enhanced) study - protocol for a randomized controlled trial.

BACKGROUND: Metabolic syndrome (MetS) has been identified as a major contributor to the development of cardiovascular disease (CVD). Current recommendations for dietary management of people with MetS involve quantitative and qualitative modifications of food intake, such as high consumption of vegetables, fruits, and whole grain foods. The results from our previous human trials revealed the potential of the dietary components high-oleic acid canola oil (HOCO)-docosahexaenoic acid (DHA) and high molecular weight barley ß-glucan individually in managing CVD risk factors. Foods with a combination of HOCO-DHA and barley ß-glucan have never been tested for their effects on CVD risk. The objective is to determine the effects of consuming novel foods HOCO-DHA, and barley ß-glucan on managing CVD risk factors in people with MetS. METHODS/DESIGN: We are conducting a randomized, single-blind crossover trial with four treatment phases of 28 days each separated by a 4-week washout interval. Participants (n=35) will be provided with weight-maintaining, healthy balanced diet recommendations according to their energy requirements during the intervention periods. Participants will receive muffins and cookies as treatment foods in a random order and will consume at least one meal per day at the research center under supervision. The four treatments include muffins and cookies consisting of (1) all-purpose flour and HOCO-DHA (50 g/day); (2) barley flour (4.36 g/day of ß-glucan) and a blend of sunflower oil, safflower oil, and butter as control oil (50 g/day); (3) barley flour (4.36 g/day of ß-glucan) and HOCO-DHA (50 g/day; dosage of DHA would be 3 g/day); and (4) all-purpose flour and control oil (50 g/day). At the beginning and end of each phase, we will evaluate anthropometrics; systolic and diastolic blood pressure; blood lipid profile; low-density lipoprotein subfractions and particle size; 10-year Framingham CVD risk score; inflammatory status; and plasma and red blood cell fatty acid profiles, fecal microbiome, and body composition by dual-energy X-ray absorptiometry. CONCLUSION: Cholesterol synthesis will also be studied, using a stable isotope approach. The proposed study will lead to innovation of novel food products, which may result in improvement in the overall cardiovascular health of humans. TRIAL REGISTRATION: Clinical trials.gov identifier: NCT02091583 . Date of registration: 12 March 2014.

A double-blind randomised controlled trial testing the effect of a barley product containing varying amounts and types of fibre on the postprandial glucose response of healthy volunteers.

The aim of the present study was to determine if the consumption of barley tortillas varying in fibre and/or starch composition affected postprandial glucose, insulin, glucagon-like peptide-1 (GLP-1) or peptide YY concentrations. A double-blind, randomised, controlled trial was performed with twelve healthy adults. They each consumed one of five barley tortillas or a glucose drink on six individual visits separated by at least 1 week. Tortillas were made from 100% barley flour blends using five different milling fractions to achieve the desired compositions. All treatments provided 50 g of available carbohydrate and were designed to make the following comparisons: (1) low-starch amylose (0%) v. high-starch amylose (42%) with similar ß-glucan and insoluble fibre content; (2) low ß-glucan (4.5 g) v. medium ß-glucan (7.8 g) v. high ß-glucan (11.6 g) with similar starch amylose and insoluble fibre content; and (3) low insoluble fibre (7.4 g) v. high insoluble fibre (19.6 g) with similar starch amylose and ß-glucan content. Blood was collected at fasting and at multiple intervals until 180 min after the first bite/sip of the test product. Amylose and insoluble fibre content did not alter postprandial glucose and insulin, but high-ß-glucan tortillas elicited a lower glucose and insulin response as compared to the low-ß-glucan tortillas. The tortillas with high insoluble fibre had a higher AUC for GLP-1 as compared to the tortillas with low insoluble fibre, whereas amylose and ß-glucan content had no effect. Results show that processing methods can be used to optimise barley foods to reduce postprandial blood glucose responses and factors that may influence satiety.

Vascular and cardiac effects of grape powder in the spontaneously hypertensive rat.

BACKGROUND: We previously reported that resveratrol, a polyphenol found in red grapes, attenuated changes in small artery geometry and stiffness, as well as cardiac hypertrophy and cardiac function in the spontaneously hypertensive rat (SHR). However, in addition to resveratrol, grapes contain a variety of bioactive polyphenols such as catechins, anthocyanins, and flavonoids. Therefore, we investigated the effects of grape consumption in SHR. METHODS: Wistar-Kyoto (WKY) rats and SHR were treated with freeze-dried grape powder for 10 weeks. Dilatory, geometry, and stiffness properties of mesenteric small arteries were assessed by pressurized myography. Left ventricular mass index and cardiac function were assessed by two-dimensional guided M-mode and pulse-wave Doppler echocardiography. RESULTS: Elevated blood pressure in SHR was associated with remodeling and impaired endothelium-dependent relaxation of small arteries. Augmented left ventricular mass index (reflecting hypertrophy) and diminished cardiac function were also evident in SHR. Although grape treatment failed to affect cardiac dysfunction, it elicited a significant reduction in blood pressure, improved arterial relaxation, increased vascular compliance, and attenuated cardiac hypertrophy. CONCLUSIONS: Treatment with whole grape powder conferred mild vascular and cardiac benefits in SHR. Therefore, dietary grape consumption may be a feasible and salutary adjunct to pharmacological treatment of human hypertension.

Treatment with low-dose resveratrol reverses cardiac impairment in obese prone but not in obese resistant rats.

We hypothesized that a low-dose resveratrol will reverse cardiovascular abnormalities in rats fed a high-fat (HF) diet. Obese prone (OP) and obese resistant (OR) rats were fed an HF diet for 17 weeks; Sprague-Dawley rats fed laboratory chow served as control animals. During the last 5 weeks of study, treatment group received resveratrol daily by oral gavage at a dosage of 2.5 mg/kg body weight. Assessments included echocardiography, blood pressure, adiposity, glycemia, insulinemia, lipidemia, and inflammatory and oxidative stress markers. Body weight and adiposity were significantly higher in OP rats when compared to OR rats. Echocardiographic measurements showed prolonged isovolumic relaxation time in HF-fed OP and OR rats. Treatment with resveratrol significantly improved diastolic function in OP but not in OR rats without affecting adiposity. OP and OR rats had increased blood pressure which remained unchanged with treatment. OP rats had elevated fasting serum glucose and insulin, whereas OR rats had increased serum glucose and normal insulin concentrations. Resveratrol treatment significantly reduced serum glucose while increasing serum insulin in both OP and OR rats. Inflammatory and oxidative stress markers, serum triglycerides and low-density lipoprotein were higher in OP rats, which were significantly reduced with treatment. In conclusion, HF induced cardiac dysfunction in both OP and OR rats. Treatment reversed abnormalities in diastolic heart function associated with HF feeding in OP rats, but not in OR rats. The beneficial effects of resveratrol may be mediated through regression of hyperglycemia, oxidative stress and inflammation.

Resveratrol prevents norepinephrine induced hypertrophy in adult rat cardiomyocytes, by activating NO-AMPK pathway.

Increased adrenergic drive is a major factor influencing the development of pathological cardiac hypertrophy, a stage which precedes overt heart failure. We examined the effect of resveratrol, a polyphenol (found predominantly in grapes), in preventing norepinephrine induced hypertrophy of adult cardiomyocyte, and the role of nitric oxide (NO) and adenosine monophosphate kinase (AMPK) in the effects of resveratrol. Cardiomyocytes isolated from adult rats were pretreated, or not, with resveratrol and then exposed to norepinephrine for 24h. In other experiments cardiomyocytes were also treated with different pharmacological inhibitors of NO synthase, AMPK and sirtuin for elucidating the signaling pathways underlying the effect of resveratrol. In order to validate the role of these signaling molecules in the in vivo settings, we also examined hearts from resveratrol treated spontaneously hypertensive rats (SHR), a genetic model of essential hypertension. Cardiomyocyte hypertrophy was determined by morphometry and (3)H-phenylalanine incorporation assay. NO levels and AMPK activity were measured using a specific assay kit and western blot analysis respectively. In vitro, resveratrol prevented the norepinephrine-induced increase in cardiomyocytes size and protein synthesis. Pharmacological inhibition of NO-AMPK signaling abolished the anti-hypertrophic action of resveratrol. Consistent with the in vitro findings, the anti-hypertrophic effect of resveratrol in the SHR model was associated with increases in NO and AMPK activity. This study demonstrates that NO-AMPK signaling is linked to the anti-hypertrophic effect of resveratrol in adult cardiomyocytes in vitro, and in the SHR model in vivo.

Resveratrol and small artery compliance and remodeling in the spontaneously hypertensive rat.

BACKGROUND: Small arteries from the spontaneously hypertensive rat (SHR) exhibit abnormal stiffness and geometry. This study investigated the effects of resveratrol, a polyphenol found in foods such as red grapes, on small arteries in SHR. METHODS: Wistar-Kyoto (WKY) rats and SHR were treated with resveratrol (2.5 mg/kg/day) for 10 weeks. Mesenteric small artery segments (third-order branches) were mounted in a pressure myograph, and vascular geometry and mechanical properties were calculated from lumen and media dimensions measured at incremental intraluminal pressures. Systolic blood pressure was measured by tail-cuff plethysmography. RESULTS: Increased compliance and reduced wall component stiffness were observed in SHR arteries vs. WKY arteries. Though resveratrol did not prevent lowering of wall component stiffness, it did attenuate, at least in part, the increased compliance of SHR arteries. In contrast, resveratrol increased compliance and reduced wall component stiffness in WKY arteries. SHR arteries exhibited remodeling that consisted of narrowed lumens, thickened media widths, and augmented media-to-lumen ratios. Resveratrol partially attenuated the remodeling process and also abolished exaggerated ERK signaling and expression of proliferating cell nuclear antigen (a marker of proliferation) in SHR arteries. The latter effects might be related to the ability of resveratrol to alleviate oxidative stress in SHR and enhance protein kinase G (PKG) activity. Elevated blood pressure in 20-week-old SHR was unaffected by resveratrol. CONCLUSIONS: The ability of resveratrol to limit the increase in compliance of SHR arteries is likely related to inhibitory effects on remodeling and pro-growth ERK signaling rather than blood pressure or arterial wall component stiffness.

Resveratrol prevents the development of pathological cardiac hypertrophy and contractile dysfunction in the SHR without lowering blood pressure.

BACKGROUND: Cardiac hypertrophy is a compensatory enlargement of the heart in response to stress such as hypertension. It is beneficial in reducing stress placed on the heart. However, when the stress is of a chronic nature, it becomes pathological and leads to cardiac dysfunction and heart failure. Current treatments for hypertension and heart failure have proven beneficial but are not highly specific and associated with side effects. Accordingly, there is an important need for alternative strategies to provide safe and effective treatment. METHODS: Ten-week-old male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were treated with resveratrol (2.5 mg/kg/day) for a period of 10 weeks. Systolic blood pressure, and cardiac structure and function were measured in all groups at different time points of resveratrol treatment. Oxidative stress was also determined in all groups after 10 weeks of resveratrol treatment. RESULTS: SHRs were characterized with high blood pressure and concentric hypertrophy from 15 weeks of age. Cardiac functional abnormalities were also evident in SHR from 15 weeks onwards. Resveratrol treatment significantly prevented the development of concentric hypertrophy, and systolic and diastolic dysfunction in SHR without lowering blood pressure. Resveratrol also significantly reduced the oxidative stress levels of cardiac tissue in SHR. CONCLUSIONS: Resveratrol treatment was beneficial in preventing the development of concentric hypertrophy and cardiac dysfunction in SHR. The cardioprotective effect of resveratrol in SHR may be partially mediated by a reduction in oxidative stress. Thus, resveratrol may have potential in preventing cardiac impairment in patients with essential hypertension.