Advanced glycation end-products (AGEs) and functionality of reverse cholesterol transport in patients with type 2 diabetes and in mouse models.

AIMS/HYPOTHESIS: We investigated the contribution of AGEs to the impairment of reverse cholesterol transport (RCT) variables in diabetic individuals and in two animal models of diabetic obesity and of renal impairment. METHODS: The capacity of plasma and HDL from 26 individuals with moderately controlled type 2 diabetes to support cholesterol efflux was compared with 26 age- and sex-matched individuals without diabetes. We also compared the rates of RCT in vivo in two animal models: db/db mice and mice with chronic renal failure. RESULTS: Diabetic individuals had characteristic dyslipidaemia and higher levels of plasma AGEs. The capacity of whole plasma, ApoB-depleted plasma and isolated HDL to support cholesterol efflux was greater for diabetic patients compared with controls despite their lower HDL-cholesterol levels. The capacity of plasma to support cholesterol efflux correlated with plasma levels of cholesteryl ester transfer protein and levels of ApoB, but not with levels of AGE. RCT was severely impaired in db/db mice despite elevated HDL-cholesterol levels and no change in AGE concentration, whereas RCT in uraemic mice was unaffected despite elevated AGE levels. CONCLUSIONS/INTERPRETATION: AGEs are unlikely to contribute significantly to the impairment of RCT in type 2 diabetes.

The effects of dietary weight loss with or without exercise training on liver enzymes in obese metabolic syndrome subjects.

AIM: Insulin resistance and visceral adiposity are predisposing factors for fatty liver disease. The main objectives of this study were (i) to compare the effects of caloric restriction (CR) alone or together with moderate-intensity aerobic exercise training (CR+EX) on liver enzymes, a surrogate marker of liver injury, in obese metabolic syndrome (MetS) subjects and (ii) to identify anthropometric, metabolic, cardiovascular and dietary predictors of changes in liver enzymes. METHODS: Sedentary men and women (n = 63), aged 55 ± 6 (s.d.) years with body mass index 32.7 ± 4.1 kg/m(2) and confirmed MetS, were randomized to 12-week CR, CR+EX or no treatment (Control). RESULTS: Weight loss averaged 7.6% in the CR and 9.1% in the CR+EX group (time effect, p < 0.001; group effect, p = 0.11); insulin sensitivity improved by 49 and 45%, respectively (both p < 0.001). Fitness (maximal oxygen consumption) increased by 19% in the CR+EX group only (p < 0.001). Alanine aminotransferase (ALT) levels decreased by 20% in the CR and 24% in the CR+EX group (time effect, both p < 0.001; group effect, p = 0.68); corresponding values for γ-glutamyltransferase (GGT) were -28 and -33%, respectively (time effect, both p < 0.001; group effect, p = 0.28). Reduction in abdominal fat mass (measured by DXA from L1 to L4) independently predicted ΔALT (r = 0.42, p = 0.005) and ΔGGT (r = 0.55, p < 0.001), whereas change in dietary saturated fat intake was independently associated with ΔALT (r = 0.35, p = 0.03). CONCLUSIONS: Reductions in central adiposity and saturated fat intake are key drivers of improvement in liver enzymes during lifestyle interventions. Exercise training did not confer significant incremental benefits in this study.

Cholesterol efflux from macrophages is influenced differentially by plasmas from overweight insulin-sensitive and -resistant subjects.

OBJECTIVE: In vitro measurements of cholesterol efflux from macrophages have recently been shown to associate with cardiovascular risk. We investigated whether cholesterol efflux from macrophages incubated with plasmas from overweight/obese subjects with metabolic syndrome was influenced by the presence of insulin resistance. METHODS: Plasmas were obtained from 47 men and women with metabolic syndrome, of whom 25 were found to be insulin resistant (IR) and 22 insulin sensitive (IS) (Matsuda, De Fronzo equation based on oral glucose tolerance test). Activated human macrophage THP-1 cells in which cholesterol had been radiolabelled were incubated with the subjects' plasmas to allow calculation of % cholesterol efflux. RESULTS: Body mass index and waist measurements, as well as plasma lipid levels, did not differ between the two groups. Homeostatic model assessment-insulin resistance value as well as plasma insulin and leptin concentrations were higher in IR subjects. Cholesterol efflux was found to be significantly greater with plasmas from IR subjects (9.1%) than from IS subjects (6.7%) (P=0.005). Further, cholesterol efflux was significantly inversely associated with insulin sensitivity index (P<0.001), directly with arterial insulin concentration (P<0.001) and directly with cholesteryl ester transfer protein (CETP) mass (P=0.044). CONCLUSION: Plasmas from overweight subjects with insulin resistance induced greater in vitro cholesterol efflux compared with IS subjects. Efflux inversely correlated with insulin sensitivity suggesting an increase in reverse cholesterol transport in the IR state that may lead to greater transfer of cholesterol to apoB lipoproteins from high-density lipoproteins via CETP as a factor in the association between IR and atherosclerosis.

Circulating inflammatory and atherogenic biomarkers are not increased following single meals of dairy foods.

BACKGROUND/OBJECTIVES: Inflammation characterizes obesity and is nutritionally modifiable. The hypothesis of this study is that full-fat dairy foods influence circulating inflammatory and atherogenic biomarkers according to fermentation status. SUBJECTS/METHODS: Thirteen overweight subjects participated in five test meals. Single breakfasts containing control low-fat milk or 45 g fat from butter, cream, yoghurt or cheese were tested over 3 weeks. Plasmas obtained 3 and 6 h were later analyzed for inflammatory markers interleukin (IL)-6, IL-1ß, tumor necrosis factor-α and high-sensitive C-reactive protein, and atherogenesis-related markers monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. A 4-week study in 12 subjects compared the effects on these biomarkers of diets containing ≈50 g dairy fat daily as either butter, cream and ice cream (non-fermented) or cheese plus yoghurt (fermented) dairy foods. RESULTS: In single-meal study, one outlier subject showed marked increments in biomarkers, hence the following results apply to 12. Within group analysis includes significant falls at 3 h in four inflammatory markers after cream, butter and low fat, and three atherogenesis-related biomarkers after cream. Changes were few after cheese and yoghurt. By 6 h, most values returned to baseline. However, between group analysis showed no differences between the five meals. The 4-week study showed no significant differences in fasting biomarker concentrations between non-fermented and fermented dairy diets. CONCLUSIONS: Single high-fat meals containing sequentially four different full-fat dairy foods did not increase eight circulating biomarkers related to inflammation or atherogenesis. Among subjects, significant falls occurred at 3 h in inflammatory biomarkers after cream and butter but were not specific for full-fat dairy foods. We could not confirm the reported increments in inflammation after fat meals.

Leptin, but not adiponectin, is a predictor of recurrent cardiovascular events in men: results from the LIPID study.

OBJECTIVE: To investigate the relationships between plasma leptin and adiponectin levels and recurrent cardiovascular events (cardiovascular death, nonfatal myocardial infarction and stroke) in men with earlier acute coronary syndromes. DESIGN, SUBJECTS AND MEASUREMENTS: A nested case-control study examined circulating leptin and adiponectin levels in plasma obtained 4-6 years after entry into the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial. Plasma was assayed from 184 men who suffered recurrent events within 4.4 years after blood collection and 184 matched controls who remained free of further events. The association between cardiovascular events and the explanatory variables was examined by conditional logistic regression analysis. RESULTS: Relative risk (RR) increased across increasing leptin quartiles; the highest quartile compared with the lowest quartile was related to the highest risk (P for trend=0.002); the increased risk remained after adjustment for risk factors (P=0.018) or for obesity (P=0.038), but in the final model (adjusted for randomized treatment, other drugs, LIPID risk score, age and body mass index), the risk was attenuated (RR=1.61, 95% CI: 0.72-3.57, P for trend=0.34). Adiponectin did not predict cardiovascular events. Subjects randomly allocated to pravastatin had 6% lower leptin levels (P=0.04) than those allocated to placebo. CONCLUSION: Plasma leptin was a significant and independent predictor of recurrent cardiovascular events (cardiovascular death, nonfatal myocardial infarction and stroke) in men with earlier acute coronary syndromes.

Dietary supplementation with chickpeas for at least 5 weeks results in small but significant reductions in serum total and low-density lipoprotein cholesterols in adult women and men.

AIM: To compare the effects of a chickpea-supplemented diet and those of a wheat-supplemented diet on human serum lipids and lipoproteins. METHODS: Forty-seven free-living adults participated in a randomized crossover weight maintenance dietary intervention involving two dietary periods, chickpea-supplemented and wheat-supplemented diets, each of at least 5 weeks duration. RESULTS: The serum total cholesterol and low-density lipoprotein cholesterol levels were significantly lower (both p < 0.01) by 3.9 and 4.6%, respectively, after the chickpea-supplemented diet as compared with the wheat-supplemented diet. Protein (0.9% of energy, p = 0.01) and monounsaturated fat (3.3% of total fat, p < 0.001) intakes were slightly but significantly lower and the carbohydrate intake significantly higher (1.7% of energy, p < 0.001) on the chickpea-supplemented diet as compared with the wheat-supplemented diet. Multivariate analyses suggested that the differences in serum lipids were mainly due to small differences in polyunsaturated fatty acid and dietary fibre contents between the two intervention diets. CONCLUSIONS: Inclusion of chickpeas in an intervention diet results in lower serum total and low-density lipoprotein cholesterol levels as compared with a wheat-supplemented diet.

Fish oils, phytosterols and weight loss in the regulation of lipoprotein transport in the metabolic syndrome: lessons from stable isotope tracer studies.

1. Dyslipoproteinaemia is a cardinal feature of the metabolic syndrome that accelerates atherosclerosis. It is characterized by high plasma concentrations of triglyceride-rich and apolipoprotein (apo) B-containing lipoproteins, with depressed concentrations of high-density lipoprotein (HDL). Dysregulation of lipoprotein metabolism in these subjects may be due to a combination of overproduction of very-low density lipoprotein (VLDL) apoB-100, decreased catabolism of apoB-containing particles and increased catabolism of HDL apoA-I particles. 2. Nutritional interventions may favourably alter lipoprotein transport in the metabolic syndrome. We review our collaborative studies, using stable isotopes and compartmental modelling, of the kinetic effects of fish oils, plant sterols (phytosterols) and weight reduction on the dyslipoproteinaemia in this disorder. 3. Fish oil supplementation diminished hepatic secretion of VLDL-apoB and enhanced conversion of VLDL to low-density lipoprotein (LDL)-apoB, without altering catabolism. 4. Plant sterols (phytosterols) did not have a significant effect on plasma concentrations of lipids and lipoprotein or the kinetics of apoB and apoA-I. 5. Modest weight reduction optimally decreased plasma triglyceride and LDL-cholesterol via reduction in hepatic apoB secretion and reciprocal upregulation of LDL catabolism. 6. The scope and potential of future studies using stable isotope tracers is discussed.

Dairy fat in cheese raises LDL cholesterol less than that in butter in mildly hypercholesterolaemic subjects.

OBJECTIVE: To determine whether dairy fat in cheese raises low-density lipoprotein (LDL) cholesterol as much as in butter, since epidemiology suggests a different impact on cardiovascular disease. DESIGN: A randomised crossover trial testing the daily consumption of 40 g dairy fat as butter or as matured cheddar cheese, each of 4 weeks duration, was preceded by and separated by 2-week periods when dietary fat was less saturated. SETTING: Free-living volunteers. SUBJECTS: A total of 14 men and five women of mean age 56+/-8 y, with mean total cholesterol of 5.6+/-0.8 mmol/l. MAIN OUTCOME MEASURES: Plasma cholesterol, LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triacylglycerol and glucose. RESULTS: Saturated fat intake was significantly lower during the run-in than during the cheese and butter periods. Mean lipid values did not differ significantly between the cheese and run-in periods, but total cholesterol and LDL-C were significantly higher with butter: total cholesterol (mmol/l): butter 6.1+/-0.7; run-in 5.6+/-0.8 (P < 0.05; ANOVA with Bonferroni adjustment); vs cheese 5.8+/-0.6 (P > 0.05); median LDL-C (mmol/l): butter 3.9 (3.5-4.1) vs run-in 3.4 (3.0-4.1) (P < 0.05; Tukey test); vs cheese 3.7 (3.3-3.9) (P > 0.05). Among 13 subjects whose initial LDL-C was >4 mmol/l, the difference between butter (4.4+/-0.3 mmol/l) and cheese (3.9+/-0.3 mmol/l) was significant (P = 0.014). HDL-C was highest with butter and triacylglycerol with cheese (neither was significant). CONCLUSION: A total of 40 g dairy fat eaten daily for 4 weeks as butter, but not as cheese, raised total and LDL cholesterol significantly compared with a diet containing significantly less saturated fat. Dietary advice regarding cheese consumption may require modification.

Diet but not aerobic exercise training reduces skeletal muscle TNF-alpha in overweight humans.

AIMS/HYPOTHESIS: Our aim was to test the hypothesis that TNF-alpha protein levels in skeletal muscle are important in mediating the improvements in glucose homeostasis that are associated with diet and exercise regimens intended to reduce cardiovascular risk. METHODS: We recruited 20 people with a body mass index of 32.1 +/- 1.2 kg/m2 (mean +/- SEM) and one other component of the metabolic syndrome. The average age was 51.2 +/- 8.1 years (mean +/- SD). Of the 20 subjects, 6 were men and 14 were women. All subjects completed an 8-week control period, followed by randomisation to 8 weeks of moderate cycling exercise (30 min, three times per week) or to a diet with the following characteristics: low in saturated fat, high in fibre, low glycaemic index, rich in complex carbohydrates. RESULTS: Diet induced a small reduction in body mass index (3.0 +/- 0.7%, p<0.05), although weight loss was not intended. Exercise training increased maximum oxygen consumption by 12 +/- 6% (p<0.05). Both interventions reduced fasting plasma insulin levels by about 20%. Diet reduced skeletal muscle TNF-alpha protein by 54 +/- 10% (p<0.05), an effect that was independent (p=0.94 in covariate analysis) of the small concurrent weight loss (-2.8 +/- 0.7 kg). Levels of GLUT4 protein were unchanged in the diet group. In contrast, exercise training did not significantly change TNF-alpha protein expression, but GLUT4 protein expression increased by 105 +/- 37% (p<0.05). CONCLUSIONS/INTERPRETATION: These data indicate that the metabolic benefits of a diet aimed at cardiovascular risk reduction are associated with a decrease in skeletal muscle TNF-alpha protein.

The isoflavone metabolite dehydroequol produces vasodilatation in human resistance arteries via a nitric oxide-dependent mechanism.

BACKGROUND: Isoflavones (phytoestrogens) offer potential cardioprotective benefits. We recently reported on the vasodilatory activity of the isoflavone metabolite, dehydroequol, in rat isolated aortic ring preparations. In the current study, we examine the effect of this metabolite on the vascular haemodynamic profile in human forearm resistance arteries. METHODS AND RESULTS: Responses to brachial artery infusion of dehydroequol (0.1, 0.3, 1 and 3 micromol/min) in forearm resistance arteries were obtained in six healthy males. These were done, on two separate occasions, in the absence and presence of endogenous nitric oxide synthase inhibition using NG-monomethyl-L-arginine, with sufficient sodium nitroprusside to maintain vascular tone. Dehydroequol produced a dose-dependent increase in forearm blood flow from 2.44 +/- 0.37 (basal) to 5.25 +/- 1.07 mL/100 mL/min (P < 0.05) at dehydroequol 3 micromol/min. Responses to dehydroequol were significantly dampened with inhibition of endogenous nitric oxide synthase (at 3 micromol/min: % increase in forearm blood flow fell from 114.3 +/- 22.81 to 19.45 +/- 9.19; P < 0.01). CONCLUSION: This is the first report of dehydroequol, a metabolite derived from the isoflavone diadzein, demonstrating potent vasodilatory properties in human resistance arteries via a nitric oxide-dependent mechanism.

The use of iron-fortified wheat flour to reduce anemia among the estate population in Sri Lanka.

The use of flour fortified with 66 mg/kg of electrolytic or reduced iron to reduce the prevalence of anemia was determined in a two-year, double-blind, controlled trial. The trial was conducted in Sri Lanka among preschoolers between 9 and 71 months old, primary schoolers 6 to 11 years old, and nonpregnant women. At baseline, 18.4% of the preschoolers had low hemoglobin (Hb) concentrations. Neither electrolytic nor reduced iron had an effect on Hb concentration among preschoolers. Only 7% of the primary schoolers were anemic at the start of the trial and, again, fortification had no effect on Hb concentration. Twenty-nine percent of women had a low Hb at outset and there was no evidence that fortification had an effect on Hb in this group. The findings from this study suggest that fortification of flour with electrolytic iron or reduced iron was not beneficial in reducing anemia in this population. This was probably due to the low prevalence of anemia and low bioavailability of the fortificant iron. Fortification with either iron fortificant was acceptable.

A biochanin-enriched isoflavone from red clover lowers LDL cholesterol in men.

OBJECTIVE: To determine whether the two major isoflavones in red clover differ in their effect on low-density lipoprotein cholesterol (LDL-C). DESIGN: A randomised, placebo-controlled, double-blind trial; two parallel groups taking one of the two isoflavones within which treatment and placebo were administered in a crossover design. SETTING: Free-living volunteers. SUBJECTS: A total of 46 middle-aged men and 34 postmenopausal women. INTERVENTION: Two mixtures of red clover isoflavones enriched in either biochanin (n=40) or formononetin (n=40) were compared. Placebo and active treatment (40 mg/day) were administered for 6 weeks each in a crossover design within the two parallel groups. MAIN OUTCOME MEASURES: Plasma lipids were measured twice at the end of each period. RESULTS: Baseline LDL-C concentrations did not differ significantly between men (n=46) and women (n=34), nor between those randomised to biochanin or formononetin. Interaction between time and treatments, biochanin, formononetin and corresponding placebos (two-way ANOVA) on LDL-C showed a significant effect of biochanin treatment alone. The biochanin effect was confined to men; median LDL-C was 3.61 (3.05-4.14) mmol/l with biochanin and 3.99 (3.16-4.29) mmol/l with the corresponding placebo (RM ANOVA with Dunnett's adjustment P<0.05). The difference between placebo and biochanin effects on LDL-C was 9.5%. No other lipid was affected and women failed to respond significantly to treatment. CONCLUSION: Isolated isoflavones from red clover enriched in biochanin (genistein precursor) but not in formononetin (daidzein precursor), lowered LDL-C in men. This may partly explain the previous failure to demonstrate cholesterol-lowering effects with mixed isoflavones studied predominantly in women. SPONSORSHIP: Novogen Ltd, North Ryde NSW, Australia, provided partial support including provision of tablets and outside monitoring.

Cholesterol-lowering effects of plant sterol esters differ in milk, yoghurt, bread and cereal.

OBJECTIVE: To measure the relative effects of each of four phytosterol ester-enriched low-fat foods (bread, breakfast cereal, milk and yoghurt) on serum lipids, plasma phytosterols and carotenoids. DESIGN: : Three research centres undertook a randomised, incomplete crossover, single-blind study consisting of four treatment periods of 3 weeks each, one of which was a control period. Each sterol-enriched test food provided 1.6 g/day of phytosterols as sterol esters. SETTING: General Community. SUBJECTS: In all 58, free-living men and women with mean age (s.d.) 54 (8) y, moderately elevated plasma total cholesterol 6.2 (0.7) mmol/l and body mass index 26.2 (3.0) kg/m(2). MAIN OUTCOME MEASURES: Serum lipids, plasma phytosterols and carotenoids. RESULTS: Serum total and LDL cholesterol levels were significantly lowered by consumption of phytosterol-enriched foods: milk (8.7 and 15.9%) and yoghurt (5.6 and 8.6%). Serum LDL cholesterol levels fell significantly by 6.5% with bread and 5.4% with cereal. They were both significantly less efficacious than sterol-enriched milk (P<0.001). Plasma sitosterol increased by 17-23% and campesterol by 48-52% with phytosterol-enriched milk and bread. Lipid-adjusted beta-carotene was lowered by 5-10% by sterols in bread and milk, respectively. CONCLUSIONS: This is the first study to demonstrate that cholesterol-lowering effects of plant sterol esters may differ according to the food matrix. Plant sterols in low-fat milk was almost three times more effective than in bread and cereal. Despite phytosterol-enriched cereal products resulting in lower serum cholesterol reductions compared to sterol-enriched milk, the detection of similar changes in plasma phytosterols demonstrated that such products still delivered and released phytosterols to the gut.

Effects of subclinical infection on plasma retinol concentrations and assessment of prevalence of vitamin A deficiency: meta-analysis.

BACKGROUND: Vitamin A deficiency adversely affects child morbidity and survival. This deficiency is estimated by measurement of plasma retinol concentrations, but because plasma retinol is reduced by clinical and subclinical infection, this proxy measure can lead to overestimation. Infection and trauma are accompanied by rises in concentrations of acute-phase proteins in plasma. We aimed to estimate vitamin A deficiency more accurately by measuring changes in plasma retinol and acute-phase proteins associated with subclinical infection or convalescence. METHODS: We analysed data for concentrations of plasma retinol and one or more acute-phase proteins (alpha1-acid-glycoprotein, alpha1-antichymotrypsin, C-reactive protein, or serum amyloid A) from 15 studies of apparently healthy individuals. We generated summary estimates of differences in retinol concentrations for incubation, early, and late convalescent phases of infection between people with none and those with one or more raised acute-phase proteins. We compared these groups in two, three, and four group analyses. We also compared a subgroup of apparently healthy preschool (1-5 years) children with results from all other studies. FINDINGS: For all four proteins, retinol values were much higher in people with normal concentrations of protein, than in individuals with raised concentrations (16% higher for alpha1-antichymotrypsin, 18% for alpha1-acid-glycoprotein, 25% for C-reactive protein, and 32% for serum amyloid A). Estimates of the reduction in plasma retinol for individuals with infection compared with healthy individuals, were 13% (incubation), 24% (early convalescent), and 11% (late convalescent). Estimates of vitamin A deficiency in individuals with no raised acute-phase proteins (healthy group) were much the same as those obtained by adjustment of plasma retinol concentrations in the whole group using acute-phase proteins. INTERPRETATION: We recommend that surveys to estimate vitamin A deficiency should include measurements of serum C-reactive protein and alpha1-acid-glycoprotein concentrations. Information about acute-phase proteins will enable plasma retinol concentrations to be corrected where sub-clinical infection exists, and the healthy sub-group to be identified.

Complementary food supplements to achieve micronutrient adequacy for infants and young children.

Many children in developing countries survive on a nutritionally inadequate diet. Dietary inadequacies during the complementary feeding period can be prevented by using complementary food supplements (CFSs) such as water dispersible or crushable micronutrient tablets, micronutrient sprinkles added to food just before feeding, or fortified spreads added to food just before feeding or fed as a snacks. A meeting was convened to discuss technical and operational issues related to the development of these new approaches and to identify knowledge gaps. The technical issues covered: what micronutrients to include, tolerable upper intake limits, bioavailability, micronutrient and macronutrient stability, package systems and amounts, encapsulation technologies, methods to limit or eliminate allergens, bacterial and chemical contamination, interactions between CFSs and complementary foods, and flavoring agents. Operational issues included: identifying the market positioning of CFSs, cost positioning of CFSs, regulatory requirements, CFS production and technology transfer, quality assurance, and public-private sector partnership and coordination. Intervention trials are needed to determine the efficacy of CFSs in preventing micronutrient deficiencies. Other important knowledge gaps relate to technical and operational issues. Sprinkles and tablets are produced using well-known technologies, but further research is needed to modify them for use as CFSs. Spread development is not as advanced as sprinkle and tablet development, and further research is needed to improve the technology. Although none of the products is ready for widespread use, enough information is available to set research priorities and accelerate product development and implementation.

Post-prandial remnant lipids impair arterial compliance.

OBJECTIVES: We sought to examine the effects of plasma lipids, especially in remnants after a fat meal, on systemic arterial compliance (SAC), a newly recognized cardiovascular risk factor. BACKGROUND: Post-prandial remnants correlate with coronary heart disease events through mechanisms that may include vascular dysfunction, although the effect on SAC has not been studied. METHODS: Systemic arterial compliance was measured non-invasively over 6 h after a fat meal in 16 subjects with varying plasma triglyceride levels. Changes were related to rises in plasma lipids and remnant lipids. Systemic arterial compliance was measured in 20 subjects after a control low-fat meal. RESULTS: The fat meal induced increments in plasma triglyceride and remnant cholesterol and triglyceride (respectively +54%, 50% and 290% at 3 h, analysis of variance <0.001). Systemic arterial compliance fell at 3 h and 6 h by 25% and 27% (analysis of variance <0.001). Baseline SAC correlated significantly with all lipid concentrations at 0, 3 h and 6 h, but only with triglyceride on stepwise regression analysis. The SAC response to the low-fat meal was very small and not significant. CONCLUSIONS: This is the first demonstration of SAC becoming impaired after a fat meal. Remnant lipids and plasma total triglyceride appeared to contribute to the fall in SAC.

The vascular activity of some isoflavone metabolites: implications for a cardioprotective role.

Legume-derived isoflavones such as genistein, diadzein and equol have been associated with a reduction in risk of cardiovascular disease. In the current study, we explore the vascular activity of several isoflavone metabolites namely dihydrodaidzein, cis and trans-tetrahydrodaidzein and dehydroequol for potential cardioprotective properties. Rat isolated aortic rings were used. 17beta-oestradiol, equol, and all four of the metabolites studied significantly antagonized contractile responses to noradrenaline. The direct vasodilatory action of these compounds were examined and in contrast to 17beta-oestradiol, the vasodilatory effect of which was demonstrated to be endothelium independent, the dilatory action of all four compounds could be inhibited by endothelium denudation. Further, the dilatory action of both dihydrodaidzein and cis-tetrahydrodaidzein were inhibited by the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine (NOLA), by the soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and by 40 mM KCl. Dilatory responses to dehydroequol and trans-tetrahydrodaidzein, on the other hand, were inhibited by 40 mM KCL but not by NOLA nor ODQ. Finally, we examined the protective potential of these compounds in inhibiting endothelium damage by oxidized low density lipoprotein (ox-LDL). Trans-tetrahydrodaidzein was at least 10 fold more potent than 17beta-oestradiol in protecting against ox-LDL induced damage. We conclude that the isoflavone metabolites, dihydrodaidzein, cis- and trans-tetrahydrodaidzein and dehydroequol, may potentially represent a novel series of cardioprotective therapeutics.

Simvastatin improves arterial compliance in the lower limb but not in the aorta.

UNLABELLED: Several cardiovascular risk factors adversely affect arterial compliance or the distensibility of large arteries. The role of raised low-density lipoproteins (LDL) cholesterol is uncertain, most studies having shown little effect. We, therefore, investigated whether lowering LDL would improve arterial compliance. Twenty hypercholesterolemic subjects (LDL cholesterol 4.95+/-1.11 mmol/l) were randomized to simvastatin (20 or 40 mg daily) or placebo, each for 4 weeks. Arterial function was assessed at the end of the placebo and simvastatin periods, systemic arterial compliance (SAC) and pulse wave velocities (PWV) centrally (aorto-femoral) and peripherally (femoral-posterior tibial). RESULTS: Lipoproteins (LDL) cholesterol was reduced similarly with 20 and 40 mg simvastatin (ten subjects each dose) and data were pooled. Lipoproteins (LDL) cholesterol fell 39%, plasma triglyceride fell 18% and high-density lipoprotein (HDL) cholesterol rose 12%, all significant. Systemic arterial compliance (SAC) and central PWV did not change significantly but peripheral PWV showed evidence of greater compliance after simvastatin (10.1+/-1.3 vs. 9.4+/-1.3 m/s with placebo and simvastatin, P<0.03), distensibility being inversely related to PWV. Improvement in PWV was greatest in those with poorest baseline values, r=0.50; P<0.02. CONCLUSION: Peripheral PWV was alone improved with LDL lowering probably because of the muscularity of that arterial bed; central PWV and SAC (in the elastic aorta) were not influenced.

Effects of fish oils and fish on cardiovascular disease.

The effects of fish oils, fish, and omega-3 (n-3) fatty acids on cardiovascular functions and outcomes in recently published studies are reviewed. The original hypothesis that eating fish is protective has been largely sustained but refined to indicate benefit mainly in those who are at increased risk. Biologic plausibility has been extended from the established benefit of lipid-lowering to improvements in vascular and arterial functions. A major intervention trial in patients with cardiovascular disease has confirmed the benefits of moderate amounts of long-chain n-3 fatty acids. Thus, the triad of evidence comprising epidemiology, biologic plausibility, and interventional success through a randomized, controlled trial has been established.