Search

Background: Reports have suggested that the consumption of dairy foods may reduce risk of type 2 diabetes on the basis of evidence of raised circulating ruminant fatty acids., Objective: We determined whether certain phospholipid species and fatty acids that are associated with full-fat dairy consumption may also be linked to diminished insulin resistance., Design: Four variables of insulin resistance and sensitivity were defined from oral-glucose-tolerance tests in 86 overweight and obese subjects with metabolic syndrome. Plasma phospholipids, sphingolipids, and fatty acids were determined by using a lipidomic analysis and gas chromatography-mass spectrometry to provide objective markers of dairy consumption. Food records provided information on dairy products. Associations were determined by using linear regression analyses adjusted for potential confounders age, sex, systolic blood pressure, waist:hip ratio, or body mass index (BMI) and corrected for multiple comparisons., Results: Lysophosphatidylcholine, lyso-platelet-activating factor, and several phospholipid fatty acids correlated directly with the number of servings of full-fat dairy foods. Lysophosphatidylcholine and lyso-platelet-activating factor were also associated directly with insulin sensitivity when accounting for the waist:hip ratio (Matsuda index unadjusted, P < 0.001 for both; adjusted for multiple comparisons, P < 0.02 for both) and inversely with insulin resistance (fasting insulin unadjusted, P < 0.001 for both; adjusted, P = 0.04 and P < 0.05, respectively; homeostasis model assessment of insulin resistance adjusted, P = 0.04 for both; post-glucose insulin area under the plasma insulin curve during the 120 min of the test adjusted, P < 0.01 for both). The substitution of BMI for the waist:hip ratio attenuated associations modestly. Phospholipid fatty acid 17:0 also tended to be associated directly with insulin sensitivity and inversely with resistance., Conclusion: Variables of insulin resistance were lower at higher concentrations of specific plasma phospholipids that were also indicators of full-fat dairy consumption. This trial was registered at clinicaltrials.gov as NCT00163943.

The association between consumption of full-fat dairy foods and CVD may depend partly on the nature of products and may not apply to low-fat dairy foods. Increased circulating levels of inflammatory biomarkers after consumption of dairy product-rich meals suggest an association with CVD. In the present study, we tested the effects of low-fat and full-fat dairy diets on biomarkers associated with inflammation, oxidative stress or atherogenesis and on plasma lipid classes. Within full-fat dairy diets, we also compared fermented v. non-fermented products. In a randomised cross-over study, twelve overweight/obese subjects consumed during two 3-week periods two full-fat dairy diets containing either yogurt plus cheese (fermented) or butter, cream and ice cream (non-fermented) or a low-fat milk plus yogurt diet, with the latter being consumed between and at the end of the full-fat dairy dietary periods. The concentrations of six inflammatory and two atherogenic biomarkers known to be raised in CVD were measured as well as those of plasma F2-isoprostanes and lipid classes. The concentrations of six of the eight biomarkers tended to be higher on consumption of the low-fat dairy diet than on that of the fermented dairy diet and the concentrations of two plasmalogen lipid classes reported to be associated with increased oxidisability were also higher on consumption of the low-fat dairy diet than on that of the fermented dairy diet (P< 0.001), although plasma F2-isoprostane concentrations did not differ on consumption of any of the diets. On the other hand, the concentrations of plasma sphingomyelin and IL-6 were significantly higher on consumption of the non-fermented dairy diet than on that of the low-fat dairy diet (P< 0.02). In conclusion, short-term diets containing low-fat dairy products did not lead to a more favourable biomarker profile associated with CVD risk compared with the full-fat dairy products, suggesting that full-fat fermented dairy products may be the more favourable.

Objective: Association between lipoprotein(a) (Lp(a)) level and a first-ever coronary (CHD) event is recognized. Less is evident in patients with overt CHD and stable symptoms in whom we investigated associations between Lp(a) and future events., Approach and Results: Relationships between Lp(a) concentration and CHD and cardiovascular disease outcomes during 6 years' median follow-up were evaluated in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study. Lp(a) concentrations were measured in plasma from 7863 patients who had sustained a previous coronary event and been randomized to pravastatin or placebo. Lp(a) levels were categorized by lowest half, third quartile, 75th to 90th percentile, and highest decile. The prognostic value of Lp(a) on outcomes was assessed by fitting a Cox proportional-hazards model after adjustment for other risk factors and baseline cardiovascular disorders. The prognostic value of a change in Lp(a) at year 1 categorized by quartiles was assessed using Cox regression in a landmark model incorporating the above factors and baseline levels. Baseline Lp(a) concentration was associated with total CHD events (P<0.001), total cardiovascular disease events (P=0.002), and coronary events (P=0.03). Greatest risk occurred at >73 mg/dL, upper decile. For events after year 1, an increase in Lp(a) at 1 year was associated with adverse outcomes for total CHD events and total cardiovascular disease events (P=0.002 each)., Conclusions: In the LIPID study, baseline Lp(a) was associated with future cardiovascular disease and CHD events. Increased Lp(a) concentrations after 1 year were also associated with future events, supporting measurement of Lp(a) for risk assessment of patients with known CHD.

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with coronary heart disease (CHD) in healthy individuals and in patients who have had ischemic events., Methods and Results: The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study randomized 9014 patients with cholesterol levels of 4.0 to 7.0 mmol/L to placebo or pravastatin 3 to 36 months after myocardial infarction or unstable angina and showed a reduction in CHD and total mortality. We assessed the value of baseline and change in Lp-PLA2 activity to predict outcomes over a 6-year follow-up, the effect of pravastatin on Lp-PLA2 levels, and whether pravastatin treatment effect was related to Lp-PLA2 activity change. Lp-PLA2 was measured at randomization and 1 year, and levels were grouped as quartiles. The prespecified end point was CHD death or nonfatal myocardial infarction. Baseline Lp-PLA2 activity was positively associated with CHD events (P < 0.001) but not after adjustment for 23 baseline factors (P = 0.66). In 6518 patients who were event free at 1 year, change in Lp-PLA2 was a significant independent predictor of subsequent CHD events after adjustment for these risk factors, including LDL cholesterol and LDL cholesterol changes (P < 0.001). Pravastatin reduced Lp-PLA2 by 16% compared with placebo (P < 0.001). After adjustment for Lp-PLA2 change, the pravastatin treatment effect was reduced from 23% to 10% (P = 0.26), with 59% of the treatment effect accounted for by changes in Lp-PLA2. Similar reductions in treatment effect were seen after adjustment for LDL cholesterol change., Conclusion: Reduction in Lp-PLA2 activity during the first year was a highly significant predictor of CHD events, independent of change in LDL cholesterol, and may account for over half of the benefits of pravastatin in the LIPID study.

Context: Altered cardiac structure and function have been reported in prediabetic and diabetic populations; however, the contribution of the sympathetic nervous system (SNS) to these changes has yet to be delineated., Objective: Our objective was to examine interrelationships between glucose metabolism, left ventricular mass and function, and SNS activity in obese metabolic syndrome subjects., Participants and Methods: Unmedicated impaired glucose tolerant (IGT) (n = 31) or treatment-naive type 2 diabetic (T2D) (n = 25) subjects, matched for age (mean 58 ± 1 years), gender, body mass index (32.2 ± 0.5 kg/m(2)), and blood pressure, participated. They underwent echocardiography and assessments of whole-body norepinephrine kinetics, muscle sympathetic nerve activity, and insulin sensitivity by euglycemic clamp (M value)., Results: T2D subjects had higher left ventricular mass index (LVMI) (93.6 ± 3.5 vs 77.2 ± 3.4 g/m(2), P = .002) and Doppler-derived isovolumetric relaxation and deceleration times (both P < .05) and lower early/late transmitral inflow velocities (E/A) (P = .02) compared with IGT. Total muscle sympathetic nerve activity and arterial norepinephrine concentration were higher in the T2D group (by 18% and 32%, respectively, both P ≤ .05), whereas plasma norepinephrine clearance was reduced (1.94 ± 0.11 vs 2.26 ± 0.10 L/min, P = .02). M value correlated inversely with left ventricular septal thickness (r = -0.46, P = .007). Whole-body noradrenaline spillover rate correlated with LVMI in the T2D subgroup (r = 0.47, P = .03). In the pooled cohort, LVMI was independently predicted by pulse pressure (r = 0.38, P = .004) and E/A ratio by 2-hour glucose (r = -0.38, P = .005)., Conclusions: Transition from IGT to T2D is associated with cardiac enlargement and diastolic dysfunction, which relate to metabolic, hemodynamic, and SNS alterations.

Purpose of Review: Plant sterols as ingredients to functional foods are recommended for lowering LDL cholesterol. However, there is an ongoing discussion whether the use of plant sterols is safe., Recent Findings: Genetic analyses showed that common variants of the ATP binding cassette transporter G8 (ABCG8) and ABO genes are associated with elevated circulating plant sterols and higher risk for cardiovascular disease. However, these data do not prove a causal role for plant sterols in atherosclerosis because the risk alleles in ABCG8 and ABO are also related to elevated total and LDL cholesterol levels. The ABO locus exhibits still further pleiotropy. Moreover, analyses in the general population indicated that moderately elevated circulating plant sterols are not correlated with present or future vascular disease. In agreement, novel studies using food frequency questionnaires, studies in experimental animals, and dietary intervention studies support that ingestion of plant sterols may be beneficial to cardiovascular health., Summary: Taken together, current evidence supports the recommendations for the use of plant sterols as LDL cholesterol-lowering agents. Nevertheless, a prospective, randomized, controlled, double-blinded, intervention trial conclusively showing that plant sterol supplementation will prevent hard cardiovascular endpoints is not available to date.

Context: Cellular cholesterol efflux is a key step in reverse cholesterol transport and may depend on the metabolism of apolipoprotein (apo) B-100, apoA-I, and apoA-II., Objective: We examined the associations between cholesterol efflux and plasma concentrations and kinetics of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL)-apoB-100, high-density lipoprotein (HDL)-apoA-I, and HDL-apoA-II in men. DESIGN, SUBJECTS, AND METHODS: Thirty men were recruited from the community with a wide range of body mass index. The capacity of plasma and HDL to efflux cholesterol was measured ex vivo. Apolipoprotein kinetics were measured using stable isotope techniques and multicompartmental modeling., Results: Cholesterol efflux to whole plasma was correlated with plasma levels of cholesterol, triglyceride, apoB-100, insulin, cholesteryl ester transfer protein, and lecithin-cholesterol acyltransferase, body mass index and waist circumference (P < 0.05 in all). Cholesterol efflux was inversely correlated with the fractional catabolic rate (FCR) of VLDL (r = -0.728), IDL (r = -0.662), and LDL-apoB-100 (r = -0.479) but positively correlated with the FCR (r = 0.438) and production rate (r = 0.468) of HDL-apoA-II. In multiple regression analysis, the concentration and FCR of VLDL-apoB-100 (β-coefficient = 0.708 and -0.518, respectively) and IDL-apoB-100 (β-coefficient = 0.354 and -0.447, respectively) were independent predictors of cholesterol efflux. The association of cholesterol efflux with apoB-100 metabolism was diminished after removal of apoB-100-containing lipoproteins from plasma prior to efflux. All associations, except for cholesteryl ester transfer protein, were lost when cholesterol efflux to isolated HDL was tested., Conclusions: The plasma concentration and kinetics of apoB-100-containing lipoproteins are significant predictors of the capacity of whole plasma to effect cellular cholesterol efflux.

Objectives: Infusion of reconstituted HDL (rHDL) leads to changes in HDL metabolism as well as to an increased capacity of plasma to support cholesterol efflux providing an opportunity to investigate mechanisms linking cholesterol efflux to changes in plasma HDL., Methods and Results: Patient plasmas after infusion of rHDL were tested ex vivo for their capacity to stimulate cholesterol efflux. Reconstituted HDL enhanced mobilization of cholesterol from tissues in vivo as shown by rising HDL cholesterol concentrations over the infusion period. Infusion of rHDL in vivo led to increased cholesterol efflux ex vivo; surprisingly, removing apoB-containing lipoproteins while preserving all HDL subfractions eliminated this increase. Infusion of rHDL led to the remodelling of plasma HDL; however, the capacity of plasma to support cholesterol efflux did not correlate with changes in the concentrations of any of HDL subfractions. Unmodified rHDL accounted for only a proportion of the increment in cholesterol efflux capacity. Furthermore, studies using HeLa and BHK cells overexpressing ABCA1, ABCG1, and SR-B1 showed that the contribution of these cellular mediators of cholesterol efflux to the enhanced capacity of plasma for the efflux was minimal., Conclusion: Enhanced cholesterol efflux from tissues requires the presence of apoB-containing lipoproteins and may involve enhanced flow of cholesterol through multiple components of the reverse cholesterol transport pathway rather than being determined by a specific HDL subfraction.

Context: The sympathetic nervous system is an important physiological modulator of basal and postprandial energy expenditure., Objective: Our objective was to investigate whether the variability of weight loss attained during hypocaloric dietary intervention is related to individual differences in baseline sympathetic drive and nutritional sympathetic nervous system responsiveness., Participants and Methods: Untreated obese subjects (n = 42; body mass index = 32.1 ± 0.5 kg/m(2)), aged 57 ± 1 yr, who fulfilled Adult Treatment Panel III metabolic syndrome criteria participated in a 12-wk weight loss program using a modified Dietary Approaches to Treat Hypertension (DASH) diet. Muscle sympathetic nerve activity (MSNA) was measured by microneurography at rest and in a subset of subjects during a standard 75-g oral glucose tolerance test., Results: Weight loss (6.7 ± 0.5 kg) was independently predicted by baseline resting MSNA burst incidence (r = 0.38; P = 0.019), which accounted for 14.3% of the variance after adjustment for age and baseline body weight. Weight loss-resistant subjects in the lower tertile of weight loss (4.4 ± 0.3%) had significantly blunted MSNA responses to oral glucose at baseline compared with successful weight losers (9.6 ± 0.8%). Absolute Δ MSNA averaged -7 ± 2, -6 ± 5, and -3 ± 3 bursts per 100 heartbeats at 30, 60, and 90 min after glucose in the weight loss-resistant group. Corresponding values in the successful weight loss group were 9 ± 3, 12 ± 3, and 15 ± 4 bursts per 100 heartbeats (time × group interaction, P = 0.004)., Conclusions: These findings indicate that baseline sympathetic drive and nutritional sympathetic responsiveness may be important prognostic biological markers for weight loss outcome.

Background: High-density lipoprotein (HDL) encompasses a heterogeneous population of lipoproteins with differences in functionality. The impact of HDL heterogeneity on its ability to support HDL-mediated cholesterol efflux has not been previously studied in patients with type 2 diabetes mellitus (T2DM)., Objectives: To examine the relationships between various HDL subtypes and cholesterol efflux from macrophages in patients with T2DM., Methods: Lipoprotein molecular profiles of 44 patients were studied by NMR spectroscopy. Cholesterol efflux was expressed as percentage efflux of radioactivity from lipid-laden THP-1 macrophages preincubated with (3)H-cholesterol and then incubated with serum depleted of apolipoprotein B to provide an HDL-enriched acceptor medium., Results: There was a predominance of small HDL particles (59%) and small putatively atherogenic low-density lipoprotein particles (56%). Neither HDL-C nor ApoA-I concentrations showed statistically significant correlations with percentage cholesterol efflux, but a significant positive relationship was found with the total HDL particle concentration (r = 0.41, P = .005) contributed to largely by medium HDL particles (r = 0.41, P = .006). The correlation between medium-sized HDL particle concentration remained significantly associated with cholesterol efflux when assessed with the use of a linear regression model that included all the HDL lipoprotein subclass concentrations as well as apolipoprotein A-I. Importantly, no statistically significant association was observed between the number of small HDL particles and cholesterol efflux. Hemoglobin A1c showed a significant inverse correlation with cholesterol efflux (r = -0.31, P = .04)., Conclusion: In patients with moderately controlled type 2 diabetes mellitus, cholesterol efflux from macrophages incubated with apolipoprotein B-depleted plasmas correlated significantly and positively with the concentration of total and medium-sized HDL and not with that of the smallest particles., (Copyright © 2011 National Lipid Association. All rights reserved.)

Current dietary recommendations advise reducing the intake of saturated fatty acids (SFAs) to reduce coronary heart disease (CHD) risk, but recent findings question the role of SFAs. This expert panel reviewed the evidence and reached the following conclusions: the evidence from epidemiologic, clinical, and mechanistic studies is consistent in finding that the risk of CHD is reduced when SFAs are replaced with polyunsaturated fatty acids (PUFAs). In populations who consume a Western diet, the replacement of 1% of energy from SFAs with PUFAs lowers LDL cholesterol and is likely to produce a reduction in CHD incidence of ≥2-3%. No clear benefit of substituting carbohydrates for SFAs has been shown, although there might be a benefit if the carbohydrate is unrefined and has a low glycemic index. Insufficient evidence exists to judge the effect on CHD risk of replacing SFAs with MUFAs. No clear association between SFA intake relative to refined carbohydrates and the risk of insulin resistance and diabetes has been shown. The effect of diet on a single biomarker is insufficient evidence to assess CHD risk. The combination of multiple biomarkers and the use of clinical endpoints could help substantiate the effects on CHD. Furthermore, the effect of particular foods on CHD cannot be predicted solely by their content of total SFAs because individual SFAs may have different cardiovascular effects and major SFA food sources contain other constituents that could influence CHD risk. Research is needed to clarify the role of SFAs compared with specific forms of carbohydrates in CHD risk and to compare specific foods with appropriate alternatives.

Objective: Metabolic syndrome (MetS) obesity is an independent risk factor for chronic kidney disease. This study was conducted to examine the effects of lifestyle interventions on renal parameters and putative metabolic, neuroadrenergic and hemodynamic mediators of renal injury., Methods: Untreated men and women (mean age 55 ± 1 years; BMI 32.7 ± 0.6 kg/m) without pre-existing renal dysfunction, who fulfilled MetS criteria were randomized to dietary weight loss (WL, n = 13), weight loss combined with aerobic exercise (WL + EX, n = 13), or no treatment (control, n = 12). Estimated glomerular filtration rate (eGFR), 24 h urinary albumin excretion, plasma renin activity (PRA), muscle sympathetic nerve activity (MSNA), baroreflex sensitivity (BRS), anthropometric, metabolic and fitness variables were measured at baseline and week 12., Results: Body weight decreased by -8.2 ± 0.8% in the WL and -10.7 ± 0.9% in the WL + EX groups (both P < 0.001). Fitness (maximal oxygen consumption) increased by 15 ± 5% and BRS by 5.5 ± 2.4 ms/mmHg in the WL + EX group only (P < 0.05). Serum creatinine decreased by -8.1 ± 4.8%, (WL, P = 0.016) and -14.9 ± 3.0% (WL + EX, P < 0.001). Estimated GFR increased commensurately but the increment was greater in the WL + EX group (P = 0.04). Albuminuria (P < 0.05) and MSNA (P < 0.001) decreased similarly in both groups, whereas PRA, high sensitivity C-reactive protein, uric acid and DBP decreased only in the WL + EX group (all P < 0.05)., Conclusion: Moderate weight loss in obese MetS patients is associated with a reduction in albuminuria and an improvement in eGFR which is augmented by exercise co-intervention.

Background: Glucose ingestion stimulates sympathetic nervous system (SNS) activity in lean subjects, whereas blunted responses have been reported in the obese., Objective: The objective was to investigate the impact of insulin resistance on the SNS response to oral glucose., Design: Nineteen insulin-resistant (IR) and 12 insulin-sensitive (IS) obese subjects with the metabolic syndrome and matched for age, sex, and blood pressure participated. Simultaneous measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine spillover rate, cardiac baroreflex sensitivity (BRS), calf blood flow, and arterial blood pressure were made at baseline and 30, 60, 90, and 120 min after a 75-g glucose load., Results: IR subjects had a higher insulin area under the curve from 0 to 120 min (AUC(0-120): 13,468 +/- 677 compared with 6399 +/- 612 mU/L . min; P < 0.001), glucose AUC(0-120) (P < 0.05), and resting MSNA (41 +/- 3 compared with 31 +/- 3 bursts/min; P = 0.03) than did IS subjects. MSNA and the norepinephrine spillover rate increased from baseline (by 29 +/- 7% and 40 +/- 13%, respectively; P < or = 0.001 for both) in IS subjects after the glucose load. In contrast, there was a blunted and delayed sympathetic response in IR subjects. Cardiac BRS and diastolic blood pressure decreased, whereas calf blood flow increased after the glucose load and by a similar magnitude in both groups (P < 0.01). Body mass index, abdominal fat, and insulin AUC(0-120) were independent (inverse) predictors of the SNS response., Conclusions: IR subjects with the metabolic syndrome have a blunted SNS response to oral glucose compared with IS subjects with the metabolic syndrome, which is related to central adiposity and the insulin response but not to differences in skeletal muscle vasodilation or BRS.

This review considers within the epidemiology of dairy fats and cardiovascular risk including the effects of 1. Fats within different dairy foods, 2. Specific dairy fatty acids including ruminant trans fats (TFA), conjugated linoleic acid (CLA), myristic acid and 3. The influence of metabolic syndrome.

Background: Dyslipidaemia is a common condition managed in general practice., Objective: This article reviews the evidence and gives practical advice for the management of dyslipidaemia in general practice., Discussion: It is essential to identify people at risk of cardiovascular disease (CVD) and to instigate appropriate treatment strategies. An assessment of absolute risk is the most appropriate method of identifying those at a higher risk of CVD where CVD is not overt. People with an absolute risk of >15% of a cardiovascular event in the next 5 years should be actively treated. Drug therapy should also be considered in those estimated to be at 10-15% risk of a cardiovascular event in the next 5 years if they have additional risk factors. It is important to select an appropriate lipid lowering therapy (or combination of drugs) in order to reach lipid targets, which need to consider not just LDL-c but also HDL-c and triglycerides. Lifestyle management should underpin all lipid management strategies.

Aims: We sought to determine the association between two major biomarkers, the inactive N-terminal fragment of brain natriuretic peptide (NT-proBNP) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and long-term cardiovascular outcomes in a cohort of subjects who had a myocardial infarction or unstable angina 3-36 months previously., Methods and Results: Plasma NT-proBNP and TIMP-1 were measured in a nested case control study of 250 randomly matched subject pairs enrolled in the long-term intervention with pravastatin in ischaemic disease (LIPID) and LIPID extended follow-up studies. Cases (n = 250) were defined as those who had a cardiovascular death, non-fatal myocardial infarction or stroke during the studies. Controls (n = 250) remained event-free for the same follow-up duration (average 2.5 years) as the matched cases. The relationships between cases and plasma NT-proBNP and TIMP-1 were adjusted for the LIPID risk score, treatment allocation and other biomarkers (CRP, IL-6 and white cell count), and examined using a multivariable conditional logistic regression model. NT-proBNP levels were significantly higher in the cases than in the controls [389 (152-864) vs. 198 (93-416) pg/mL, median (25%-75% percentiles), P < 0.001]. The odds ratio (OR) of recurrent cardiovascular events in individuals in the highest quartile was three times higher than those in the lowest quartile (95% confidence interval (CI) 1.8-5.1; P < 0.001). Similarly, TIMP-1 levels were significantly higher among cases compared with controls (806 vs. 736 pg/mL, median: highest vs. lowest quartile: OR 2.8, 95% CI 1.6-4.7; P < 0.001). After adjustment for the LIPID risk score, treatment with pravastatin and other biomarkers, both NT-proBNP and TIMP-1 predicted cardiovascular events significantly and independently of each other., Conclusion: The study suggests that in subjects with stable ischaemic disease, NT-proBNP and TIMP-1 are independent predictive markers of coronary heart disease outcome.

Plasma concentration of high density lipoprotein (HDL) is one of the most reliable negative risk factors for CVD. There is however convincing experimental and clinical evidence that plasma concentration of HDL does not convey the full picture of atheroprotective properties of HDL. HDL functionality, i.e. the ability of HDL to perform its many atheroprotective functions, is partly independent of HDL concentration and may be as important, if not more important, in determining the atheroprotective capacity of HDL. The capacity of HDL to support cholesterol efflux, its anti-inflammatory, anti-oxidant, anti-thrombotic and other atheroprotective functions are affected dramatically in conditions like coronary artery disease, chronic and acute inflammation, diabetes as well as through various interventions. The mechanisms connecting changes in HDL functionality to HDL structure are only beginning to emerge. Modifications of HDL proteins and lipids, such as advanced glycation and oxidation, changes in HDL composition and size of HDL particles, changes in abundance of various proteins and lipids carried by HDL are among factors affecting HDL functionality. A single common denominator reflecting the multiple HDL functions is yet to be found and may not exist leaving direct measurements of each HDL function as the way to assess atheroprotective capacity of HDL.

Background: Low plasma concentration of high-density lipoprotein (HDL) cholesterol is a risk factor for cardiovascular disease and a feature of the metabolic syndrome. Rosuvastatin has been shown to increase HDL cholesterol concentration, but the mechanisms remain unclear., Methods and Results: Twelve men with the metabolic syndrome were studied in a randomized, double-blind, crossover trial of 5-wk therapeutic periods with placebo, 10 mg/d rosuvastatin, or 40 mg/d rosuvastatin, with 2-wk placebo washout between each period. Compared with placebo, there was a significant dose-dependent increase in HDL cholesterol, HDL particle size, and concentration of HDL particles that contain apolipoprotein A-I (LpA-I). The increase in LpA-I concentration was associated with significant dose-dependent reductions in triglyceride concentration and LpA-I fractional catabolic rate, with no changes in LpA-I production rate. There was a significant dose-dependent reduction in the fractional catabolic rate of HDL particles containing both apolipoprotein A-I and A-II (LpA-I:A-II), with concomitant reduction in LpA-I:A-II production rate, and hence no change in LpA-I:A-II concentration., Conclusions: Rosuvastatin dose-dependently increased plasma HDL cholesterol and LpA-I concentrations in the metabolic syndrome. This could relate to reduction in plasma triglycerides with remodeling of HDL particles and reduction in LpA-I fractional catabolism. The findings contribute to understanding mechanisms for the HDL-raising effect of rosuvastatin in the metabolic syndrome with implications for reduction in cardiovascular disease.

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis. Statins are widely and successfully used for lowering plasma cholesterol levels causing up to 45% reduction of plasma cholesterol and considerable reduction in risk of cardiovascular diseases. The main atheroprotective action of statins is reduction of plasma low density lipoprotein levels due to improved clearance of this lipoprotein by the liver. In addition, statins cause mild elevation of high density lipoprotein (HDL) concentration, but the mechanism responsible for this effect of statins on HDL metabolism is not well understood. It has been hypothesized that statins affect the HDL level through inhibition of cholesteryl ester transfer protein activity or by stimulating apolipoprotein A-I synthesis. Increased cholesterol efflux from liver due to raised expression of the ABCA1 transporter may also elevate HDL levels. Whereas raising the plasma HDL-C concentration may contribute to the atheroprotective effect of statins, its magnitude is uncertain and additional mechanisms that improve the functionality of HDL may be equally or more important. In this review we analyze what is currently known about effect of statins on HDL metabolism and on reverse cholesterol transport in particular.

Objectives: Isoflavones reduce arterial stiffness, a predictor of cardiovascular events. Whether metabolites of isoflavones have similar bioactivity is unknown. The effect of supplemental trans-tetrahydrodaidzein (THD) a metabolite of daidzein on pulse wave velocity (PWV), a measure of arterial stiffness was tested in overweight men and postmenopausal women., Methods: 25 subjects, 11 postmenopausal women, 14 men (age, 57 [7] years; body mass index, 30.3 [4.7]kg/m(2); mean [S.D.]) participated in a double-blind, randomized, cross-over trial of THD versus placebo., Design: 2 weeks run-in followed by either THD 1g daily or placebo, each intervention 5 weeks. Aorta-femoral artery PWV, blood pressure and plasma lipids were measured after run-in, THD and placebo., Results: PWV was significantly reduced (signifying diminished central arterial stiffness): medians (25th and 75th%), placebo 9.9 m/s (8.7, 11.1), THD 8.8m/s (7.9, 10.9); RM ANOVA P=0.023, with Tukey procedure P<0.05. Systolic blood pressure was significantly reduced: means (S.D.), placebo 125.6 (14.7), THD 121.3 (12.2)mmHg; Tukey P<0.05. Plasma cholesterol, triglyceride and LDL cholesterol did not differ significantly. Absorption of THD >80% substantially exceeded that of parent isoflavones., Conclusion: A metabolite normally formed after consumption of isoflavones (formononetin, daidezein), taken orally, reduced blood pressure and central arterial stiffness indicating reduced cardiovascular risk.

Purpose of Review: HDL is a recognized negative risk factor for the cardiovascular diseases. Establishing the genetic determinants of HDL concentration and functions would add to the prediction of cardiovascular risk and point to the biochemical mechanisms underlying this risk. The present review focuses on various approaches to establish genetic determinants of the HDL concentration, structure and function., Recent Findings: While many genes contribute to the HDL concentration and collectively account for half of the variability, polymorphism of individual candidate genes contributes little. There are strong interactions between environmental and genetic influences. Recent findings have confirmed that APOA1 and ABCA1 exert the strongest influence on HDL concentrations and risk of atherosclerosis. CETP and lipases also affect the HDL concentration and functionality, but their connection to the atherosclerosis risk is conditional on the interaction between environmental and genetic factors., Summary: Analysis of genetic determinants of HDL-cholesterol in patients with specific disease states or in response to the environmental condition may be a more accurate way to assess variations in HDL concentration. This may result in defining the rules of interaction between genetic and environmental factors and lead to understanding the mechanisms responsible for the variations in HDL concentration and functionality.

Objective: To examine the frequency of dyslipidaemia and treatment with lipid-lowering drugs in patients with type 2 diabetes managed in Australian primary care., Design, Setting and Participants: The NEFRON study (National Evaluation of the Frequency of Renal Impairment cO-existing with NIDDM [Non-Insulin Dependent Diabetes Mellitus]) was an incident-driven, cluster-stratified survey of 3893 patients with type 2 diabetes from across Australian primary care between April and September 2005., Main Outcome Measures: The most recent fasting lipid levels were compared with therapeutic targets for lipid control and current prescribing guidelines., Results: 64% of patients with type 2 diabetes presenting in primary care received lipid-lowering medication. Despite the widespread use of statins (61%), 75% of patients had a total cholesterol level >or= 4.0 mmol/L, and 47% had a low-density lipoprotein (LDL) cholesterol level >or= 2.5 mmol/L. Few untreated patients met the Australian Pharmaceutical Benefits Scheme (PBS) criteria current at the time for subsidised primary prevention with lipid-lowering agents (4%). However, new PBS subsidy criteria will potentially include 93% of all diabetic patients seeing their general practitioner in primary care., Conclusion: Changes in the provision of subsidised therapy for high-risk diabetic patients are long overdue. However, more needs to be done to optimise management strategies, which still fail to achieve treatment targets in many treated patients.

Background: The prevalence of the metabolic syndrome among a number of Asian populations as defined by several current criteria has been increasing rapidly and appears to resemble that among Western populations., Methods: We review 25 surveys of the metabolic syndrome in Asian populations (PR China, Hong Kong, Taiwan, Japan, Philippines, Singapore) that report adequate information published during the last 5 years., Results: Using Asian-adapted definitions of obesity (BMI > or = 25 kg/m(2)) and increased waist circumference (for male > or = 90 cm; for female > or =80 cm) prevalence appears to be between 10 to 30%. Those with the syndrome are more likely to have a history of diabetes and cardiovascular disease. The risk of developing Type 2 diabetes is 10 times higher among middle-aged Japanese men with the metabolic syndrome compared to healthy subjects. In Chinese and Japanese populations, people who have the metabolic syndrome are 3 to 10 times more likely to develop cardiovascular disease. Variance in prevalence estimates of the metabolic syndrome even within the same country result from differences in sampling and possibly from definitions., Conclusions: The outstanding conclusion from recent surveys across the Asian-Pacific region is that of a consistent increase in the prevalence of the metabolic derangements associated with abdominal adiposity that lead to high risk of morbidity and mortality.

Objective: Reduction in atherosclerosis has been reported in experimental animals fed mixtures of conjugated linoleic acid (CLA). In this study, the major naturally occurring CLA isomer (cis-9,trans-11) was tested in an atherosclerosis-prone mouse model., Methods: In a model of insulin deficient apoE deficient mice, 16 animals were fed for 20 weeks with supplemental CLA (09.%, w/w) and compared with a similar number of mice of this phenotype. A control comparison was made of metabolic changes in non-diabetic apoE deficient mice that develop little atherosclerosis over 20 weeks. At 20 weeks, plasma lipids were measured and aortic atherosclerosis quantified by Sudan staining in the arch, thoracic and abdominal segments., Results: The diabetic apoE deficient mice developed marked dyslipidemia, primarily as cholesterol-enriched chylomicron and VLDL-sized lipoproteins and atherosclerosis in the aortic arch. However, there were no significant differences between CLA fed and non-CLA fed mice in either phenotype in plasma cholesterol concentration (in diabetic: 29.4+/-7.7 and 29.5+/-5.9 mmol/L, respectively) or in the area of aortic arch atherosclerosis (in diabetic: 24.8+/-10.3 and 27.6+/-7.7%, respectively). However, among diabetic mice the triglyceride concentration in triglyceride-rich lipoproteins was significantly lower in those fed CLA (for plasma 2.2+/-0.8 to 1.1+/-0.3 mmol/L; P<0.001), a significant difference that was seen also in the non-diabetic mice in which HDL cholesterol increased significantly with CLA (0.35+/-0.12-0.56+/-0.15 mmol/L)., Conclusion: In this atherosclerosis-prone model, the diabetic apoE deficient mouse, supplemental 0.9% CLA (cis-9,trans-11) failed to reduce the severity of aortic atherosclerosis, although plasma triglyceride concentration was substantially lowered and HDL cholesterol raised.

1. Cardiovascular risk factors associated with the metabolic syndrome affect vascular functions adversely. The aim of the present study was to assess the relationship between parameters of glucose homeostasis and arterial stiffness in women with characteristics of the metabolic syndrome. 2. Twenty post-menopausal women participated in a cross-sectional study in which systemic arterial compliance (SAC) and plasma glucose, lipids and glycosylated haemoglobin (HbA1c) were measured while subjects were maintained on a diet high in fibre, raised in protein and reduced in saturated fat. 3. Regression analysis suggested that mean ( +/-SD) fasting glucose of 5.9 +/- 1.7 mmol/L, glucose levels 2 h after a 75 g glucose load of 6.8 +/- 3.6 mmol/L, systolic blood pressure of 131 +/- 12 mmHg and HbA1c of 5.3 +/- 1.7% predicted SAC negatively. The following correlations were obtained between SAC and: (i) fasting glucose: R = -0.49, P = 0.028; (ii) 2 h glucose level post-glucose load: R = -0.42, P = 0.064; (iii) HbA1c: R = -0.42, P = 0.056; and (iv) systolic blood pressure: R = -0.55, P = 0.012. 4. Relationships between SAC and fasting glucose and systolic blood pressure were significantly independent of each other. There was no evidence of relationships between SAC and any plasma lipid parameter (other than a trend in relation to plasma triglyceride), bodyweight or waist circumference. 5. In conclusion, in post-menopausal women with metabolic syndrome, fasting plasma glucose and systolic blood pressure, and possibly HbA1c and the 2 h glucose post-glucose load, predicted increased arterial stiffness.

Statins decrease LDL cholesterol and the risk of atherosclerotic cardiovascular disease (CVD). They also decrease coenzyme Q10 (CoQ10), an effect that may negate some of the statin benefit on CVD. We examined the relationship between plasma CoQ10 concentration and CVD in a prospective case-control study of the effect of pravastatin. Plasma samples from 250 LIPID trial patients who over 6 years suffered a recurrent CVD event (CVD death, nonfatal MI or stroke) and 250 matched controls who remained event-free for the same duration of follow-up were assayed for CoQ10 and lipids (cholesterol and cholesterylesters). Mean plasma CoQ10 concentrations were significantly lower in pravastatin-treated patients than in those assigned placebo (0.51 versus 0.60 micromol/L, P = 0.006), and there was a moderate correlation between CoQ10 and common cholesterylesters (Pearson correlation coefficients in patients randomised to placebo, range r = 0.42-0.63). Univariate conditional logistic regression did not suggest any relationship between plasma CoQ10 and the risk of future CVD events (odds ratio 1.18; 95% CI 0.74-1.87; P = 0.49). Instead, we observed a reduction in the rate of recurrent CVD events with increasing ratio of plasma cholesterylarachidonate to cholesteryllinoleate. This study confirms that pravastatin lowers plasma CoQ10 concentrations, but this does not appear to predict the risk of recurrent CVD events.

Background: Cardiac transplant recipients frequently have high plasma HDL levels but it is unclear whether these promote a cardioprotective profile., Methods: Parameters of reverse cholesterol transport and endothelial function were compared in 25 cardiac transplant recipients with low (<1.4 mmol/L; n=11) or high (>1.4 mmol/L; n=14) plasma levels of HDL and in a reference healthy group., Results: Patients with high HDL had lower levels of triglyceride and prebeta1-HDL and a higher proportion of large HDL particles. When normalized to apoA-I content, non-ABCA1-dependent cholesterol efflux from RAW 264.7 macrophage cells to plasma from high HDL patients was 33% lower when compared to plasma from patients with low HDL, whereas ABCA1-dependent cholesterol efflux was not impaired. Forearm vascular responses to acetylcholine and sodium nitroprusside were not influenced by HDL levels in these patients. Compared to a reference healthy group (n=26), cardiac transplant recipients had higher levels of triglyceride, lower levels of prebeta1-HDL and LCAT, and lower activities of cholesteryl ester transfer protein and phospholipid transfer protein., Conclusions: Hyperalphalipoproteinaemia in cardiac transplant recipients is associated with the formation of partially dysfunctional HDL. We conclude that high levels of HDL may not confer cardioprotection in this group of patients.

Context: Weight reduction, the first line treatment for the metabolic syndrome, improves insulin sensitivity and associated metabolic and cardiovascular abnormalities, but there is a paucity of data regarding its effect on sympathetic nervous system (SNS) activity in this clinical setting., Objectives: The objectives of this study were to test the hypothesis that dietary weight loss attenuates both insulin resistance and SNS activity and to examine the relationships between SNS activity and metabolic syndrome (MetS) components., Design: This was a single-sample, repeated measures design study., Setting: This study was performed at a tertiary referral center., Participants: Twenty-three MetS subjects (age, 58 +/- 2 yr; body mass index, 33.3 +/- 0.8 kg/m2; mean +/- sem) were studied., Intervention: A hypocaloric modified Dietary Approaches to Stop Hypertension diet (26% fat, 22% protein, and 51% carbohydrate; 100 mmol/d sodium) was consumed for 3 months., Main Outcome Measures: The main outcome measures were postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve), whole-body plasma norepinephrine spillover rate, spontaneous cardiac baroreflex function, and insulin sensitivity., Results: The hypocaloric diet significantly reduced body weight by 7% and improved all MetS components. Norepinephrine spillover decreased from 877 +/- 180 to 503 +/- 39 ng/min (P = 0.005), and muscle sympathetic nerve activity decreased from 40.6 +/- 2.1 to 34.6 +/- 2.4 bursts/min (P = 0.01), whereas cardiac baroreflex sensitivity increased by 23.0 +/- 8.0% (P = 0.02). The change in the norepinephrine spillover rate correlated positively and independently with the change in plasma leptin concentration (r = 0.49; P = 0.03)., Conclusion: Weight loss by a hypocaloric diet with moderate sodium restriction diminishes SNS activity in MetS subjects. This may be due to the consequences of decreased leptin concentration, enhanced insulin sensitivity, or improvements in cardiac baroreflex function.

Background: Comparisons of the relation of diet with coronary heart disease (CHD) between countries with similar socioeconomic environments have been few. Patients in Australia and New Zealand (n = 9014) who participated in a large secondary prevention trial had significantly different CHD mortality rates., Objective: The objective of this study was to ascertain the effects of nutrient consumption on cardiovascular disease risk in patients from the 2 countries., Design: Nutrient consumption patterns were surveyed in a subgroup of 1077 patients on 3 occasions over 4 y during an intervention trial with a statin., Results: Within the entire cohort of 9014 patients, the New Zealanders had significantly (40%) more cardiovascular deaths than did the Australians. In the subgroup of 1077 patients, the New Zealanders were found at entry to have eaten significantly more total (69.34 +/- 12.35 compared with 66.45 +/- 12.9 g/d) and saturated (26.23 +/- 8.41 compared with 24.37 +/- 7.36 g/d) fat (P < 0.001 for each) and to have significantly (4%) higher concentrations of LDL cholesterol (3.96 +/- 0.74 compared with 3.8 +/- 0.76 mmol/L; P < 0.001) than did the Australians. At baseline, patients with previous coronary artery bypass grafting had diets that were significantly different from those of patients without previous coronary artery bypass grafting. Relations between nutrients and plasma lipids confirmed the direct effects of saturated fatty acids on LDL cholesterol and of alcohol on plasma triacylglycerol and HDL cholesterol. Dietary counseling throughout the trial led to significant improvements in compliance with guidelines. However, neither the baseline nor the improved 1-y nutrient intakes predicted future changes in cardiovascular events., Conclusion: Differences in CHD mortality and in LDL-cholesterol concentrations between 2 populations with similar socioeconomic and cultural backgrounds were consistent with the amounts and types of fats eaten.

Background: Elevated serum inflammatory marker levels are associated with a greater long-term risk of cardiovascular events. Because 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) may have an antiinflammatory action, it has been suggested that patients with elevated inflammatory marker levels may have a greater reduction in cardiovascular risk with statin treatment., Methods and Results: We evaluated the association between the white blood cell count (WBC) and coronary heart disease mortality during a mean follow-up of 6.0 years in the Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID) Study, a clinical trial comparing pravastatin (40 mg/d) with a placebo in 9014 stable patients with previous myocardial infarction or unstable angina. An increase in baseline WBC was associated with greater coronary heart disease mortality in patients randomized to placebo (hazard ratio for 1x10(9)/L increase in WBC, 1.18; 95% CI, 1.12 to 1.25; P<0.001) but not pravastatin (hazard ratio, 1.02; 95% CI, 0.96 to 1.09; P=0.56; P for interaction=0.004). The numbers of coronary heart disease deaths prevented per 1000 patients treated with pravastatin were 0, 9, 30, and 38 for baseline WBC quartiles of <5.9, 6.0 to 6.9, 7.0 to 8.1, and >8.2x10(9)/L, respectively. WBC was a stronger predictor of this treatment benefit than the ratio of total to high-density lipoprotein cholesterol and a global measure of cardiac risk. There was also a greater reduction (P=0.052) in the combined incidence of cardiovascular mortality, nonfatal myocardial infarction, and stroke with pravastatin as baseline WBC increased (by quartile: 3, 41, 61, and 60 events prevented per 1000 patients treated, respectively)., Conclusions: These data support the hypothesis that individuals with evidence of inflammation may obtain a greater benefit from statin therapy.

This article emphasizes the importance of weight reduction in obese individuals as the main nutritional focus relevant to the metabolic syndrome. Although other nutrients influence insulin sensitivity, these effects are modest in comparison with the benefit achievable with weight reduction. This article therefore initially discusses the dramatic rise in the prevalence of the metabolic syndrome,especially in the Asian-Pacific region where insulin resistance and the high conversion rate to type 2 diabetes are almost certainly related to weight gain.

Reactive oxygen species (ROS) may contribute to the development of stenosis in balloon catheter injured arteries. As isoflavones exhibit effects on ROS and cell proliferation In vitro that appear useful in preventing such stenosis, we examined the effects of the isoflavone trans-tetrahydrodaidzein (trans-THD) on development of neointimal lesions in relation to elevations in ROS in balloon catheter injured arteries. Carotid arteries of rabbits treated with either vehicle or trans-THD were injured with an inflated balloon catheter and cell proliferation, collagen content, ROS and vessel structure determined over the ensuing 28 days. Seven days after injury neointimal smooth muscle cell proliferation was reduced by 50% (p < 0.05) whilst medial cell proliferation was largely unaffected (p > 0.10). At this time ROS levels in vehicle-treated rabbits were elevated 3-fold compared to uninjured arteries (p < 0.05). Treatment with trans-THD reduced ROS levels to those seen in uninjured arteries (p > 0.05). The antiproliferative effects of trans-THD on intimal cell proliferation persisted 14 days after the injury, and twenty eight days after injury the size of the lumen in trans-THD-treated animals was 27% greater (p < 0.05) and the intima area: vessel area reduced by 40% (p < 0.05). The small effects of trans-THD on collagen accumulation was not statistically significant, indicating that effects on neointimal cell proliferation was the major mechanism by which this isoflavone attenuated development of the neointima. Intimal smooth muscle cells and ROS represent potentially important targets for the antiproliferative actions of trans-THD in injured arteries. Strategies using such isoflavones may be useful for preventing restenosis after vascular manipulations in humans.

The objective of this study was to measure the effects on serum lipids and plasma phytosterols of 6.6 g/day phytosterols from three foods (bread, breakfast cereal, and spread) consumed for 12 weeks compared with a diet that was not enriched with phytosterols. Thirty-five subjects undertook a nonrandomized, single-blind study consisting of a 2 week baseline period, 6 weeks on high-phytosterol intake, 6 weeks on high-phytosterol intake plus increased fruit and vegetable intake, and a final 2 week washout period. Serum total cholesterol decreased by 8.3% from 6.59 to 6.04 mmol/l, and LDL cholesterol decreased by 12.6% from 4.44 to 3.88 mmol/l. Plasma phytosterol levels increased by 45% (sitosterol) and 105% (campesterol). Cholesterol-adjusted plasma alpha- and beta-carotene levels decreased by 19-23%, lutein by 14%, and lycopene by 11%. Levels of alpha-carotene and lutein increased with extra fruit and vegetables. Only lycopene failed to increase during the washout phase. There were no significant changes in biochemical parameters. Serum LDL cholesterol lowering with 6.6 g/day ingested phytosterols was in the range seen with 1.6-3.2 g/day phytosterols. Lowering of plasma carotenoids was greater than that seen with lower phytosterol intake and was partially reversed by increased fruit and vegetable intake., (Copyright 2004 American Society for Biochemistry and Molecular Biology, Inc.)

Background: Physical exercise is associated with a decreased risk of cardiovascular disease, which may be partly caused by the effect of exercise on the lipoprotein profile. The most consistent effect of exercise on lipoprotein metabolism is an increase in high-density lipoprotein (HDL)., Methods and Results: Parameters of reverse cholesterol transport (RCT) in 25 endurance-trained male athletes were compared with 33 age-matched males enjoying an active lifestyle. VO2max was higher in athletes than in controls (53.4+/-1.2 versus 38.8+/-1.0 mL/min per kg; P<0.01). The following differences in parameters of RCT were found: (1) plasma HDL cholesterol and apoA-I levels were higher in athletes compared with controls (1.7+/-0.1 versus 1.4+/-0.1 mmol/L; P<0.001; and 145+/-2 versus 128+/-3 mg/dL; P<0.001, respectively). Both correlated with VO2max up to the value of 51 mL/min per kg; (2) prebeta1-HDL was higher in athletes than in controls (54+/-4 versus 37+/-3 microg/mL; P<0.001) and correlated positively with VO2max; (3) lecithin cholesterol: acyltransferase activity was higher in athletes (29.8+/-1.2 versus 24.2+/-1.4 nmol/microL per hour; P<0.005); and (4) the capacity of plasma to promote cholesterol efflux from macrophages was higher in athletes (18.8%+/-0.8% versus 16.2%+/-0.3%; P<0.03)., Conclusions: The likely reason for higher HDL concentration in physically fit people is increased formation of HDL from apoA-I and cellular lipids.

Phytoestrogens have recently been proposed as alternatives to estrogens for cardiovascular protection; however, the effect of their metabolites on vascular biology is unclear. We studied the effect of a red clover-derived isoflavone metabolite cis-tetrahydrodaidzein (cis-THD) on human vascular smooth muscle cell (VSMC) proliferation. Cis-THD significantly inhibited platelet-derived growth factor (PDGF) BB-induced DNA synthesis (10% at 1 nmol/L, 17% at 10, 100 nmol/L; 17beta-estradiol: 27% inhibition at 1, 10 nmol/L, 33% at 100 nmol/L). Cis-THD reduced PDGF BB-induced increase in cell numbers. Cis-THD showed high binding affinity to estrogen receptors (ER) by ER competitor assays; its inhibitory effect on DNA synthesis was abolished by the ER antagonist ICI 182780 (100 nmol/L), indicating ER-mediation. Immunoprecipitation assays revealed that cis-THD inhibited PDGF BB-stimulated activation of mitogen-activated protein (MAP) kinase ERK-1 by 34% at 1 nmol/L, 58% at 10 nmol/L, and 81% at 100 nmol/L, while MAP kinase JNK and p38 activities were unaltered. Thus, the isoflavone metabolite cis-THD inhibits PDGF-induced ERK-1 activation and cell proliferation in human VSMC, suggesting a potential beneficial effect in cardiovascular protection.

Background: Legumes are recommended for better glucose control in persons with diabetes. Whether subjects with normal insulin sensitivity would also benefit from legume consumption is not clear., Objective: Our goal was to compare the effects on insulin sensitivity of chickpea-based and wheat-based foods when eaten as single meals or over 6 wk., Design: Acute and long-term studies were conducted in healthy middle-aged men and women. In the acute study (n = 19), plasma glucose, insulin, and calculated homeostasis model assessment (HOMA; an index of insulin sensitivity) were measured on 3 separated days over 3 h after the subjects consumed 50-g available carbohydrate loads from either chickpeas, wheat-based foods, or white bread. The long-term comparison (n = 20) was a randomized, crossover study in which chickpea-based and wheat-based foods were eaten for 6 wk each. Plasma glucose, insulin, and HOMA were measured in the fasting state and 2 h after a 75-g glucose load., Results: After single meals, plasma glucose was substantially lower 30 and 60 min after the chickpea meal than after the other 2 meals (P < 0.05), and plasma insulin and HOMA were lower at 120 min (P < 0.05 for both). Despite this, the long-term study failed to show significant differences in plasma glucose, insulin, or HOMA either in the fasting state or after a glucose load., Conclusion: Compared with a wheat-based meal, a single chickpea-based meal led to a lesser response in plasma glucose and insulin concentrations, but this was not translated into long-term improvement in insulin sensitivity over 6 wk, at least in healthy subjects.

Homocysteine appears to be causally related to cardiovascular disease and shown to induce endothelial dysfunction. An adverse effect on large elastic arteries has not been reported. In 18 healthy middle-aged subjects, systemic arterial compliance (SAC) was measured over 5h after a standard methionine load. Arterial pressure waves from the carotid artery and aortic flow were measured non-invasively and SAC calculated. Differences in mean SAC values when plasma homocysteine concentrations were raised with a methionine containing meal and on another day when a control meal was eaten were highly significant. SAC fell (arterial stiffness increased) by 22% at 2.5h and by 19% at 5h (treatment x time interaction: P=0.003 and 0.004, respectively). Adjustment for confounders (age, arterial pressure, BMI, LDL cholesterol) did not affect conclusions. Thus, arterial stiffness in the central elastic arterial system increased rapidly at high plasma homocysteine concentrations.

Objective: This study was undertaken to address the vascular effects of isolated isoflavones as potential contributors to their cardioprotective properties, focusing on biochanin and formononetin., Methods and Results: In a randomized, double-blind trial, 80 healthy subjects, 46 men and 34 women, 45 to 75 years of age, received isoflavones enriched in either biochanin or formononetin (precursors of genistein and daidzein; 80 mg/d) crossed over randomly with placebo in two 6-week periods. The end points were measured at baseline and after each intervention and included large artery stiffness (systemic arterial compliance and pulse wave velocity), endothelial function in conduit arteries (flow-mediated vasodilation), 24-hour ambulatory blood pressure, and total peripheral resistance. Isoflavone intervention significantly reduced arterial stiffness with improved systemic arterial compliance (P=0.04; repeated-measures ANOVA, Bonferroni correction) attributable to a reduction in total peripheral resistance (P=0.03) and a corresponding reduction in central pulse wave velocity (P=0.02) compared with placebo. Isoflavones did not affect blood pressure (P=0.5) or flow-mediated vasodilation (P=0.44). Improvements seemed limited to formononetin-enriched isoflavones (adjusted P=0.06). Formononetin treatment also reduced circulating vascular adhesion cell molecule-1 (P<0.01)., Conclusions: In normotensive men and postmenopausal women, red clover isoflavones enriched in formononetin reduced arterial stiffness and total vascular resistance but had no effect on blood pressure. These effects may partly explain the lower cardiovascular risk in populations eating isoflavone-rich diets.

Key elements of the metabolic syndrome include the development of insulin resistance, glucose intolerance, dyslipidaemia and hypertension, which lead to multiple effects on lipoprotein metabolism and vascular functions and, ultimately an increased risk of cardiovascular disease. There are probably multiple presentations of the metabolic syndrome, and these depend on the interplay of genetic variation and environmental factors. In particular, polymorphisms in genes that are expressed in adipose tissue may play a crucial role in the development of the metabolic syndrome. Elucidation of the aetiology of metabolic syndrome(s) will therefore play an important role in developing strategies to reduce adverse outcome. It is probable that pharmacological therapy will be needed for many patients with the metabolic syndrome to help reduce the risk of future cardiovascular events.

Objective: The role of pre-beta1-high density lipoprotein (pre-beta1-HDL) in cholesterol efflux was investigated by separating human plasma into purified pre-beta1-HDL and pre-beta1-HDL-deficient plasma by using a monoclonal antibody specifically reacting with pre-beta1-HDL., Methods and Results: When compared with whole plasma, pre-beta1-HDL-deficient plasma was equally efficient in promoting cholesterol efflux from human skin fibroblasts and THP-1 human macrophage cells. When added at the same apolipoprotein A-I concentration, pre-beta1-HDL was less effective than whole plasma in promoting cholesterol efflux from fibroblasts but equally effective in promoting cholesterol efflux from THP-1 cells. However, pre-beta1-HDL-deficient plasma reconstituted with 16% pre-beta1-HDL was more active than whole plasma, demonstrating that pre-beta1-HDL does promote cholesterol efflux actively. The amount of cellular cholesterol present in reisolated pre-beta1-HDL was 1.5- to 2-fold greater after incubation of the cells with whole plasma than after incubation of the cells with pre-beta1-HDL-deficient plasma or plasma treated with the anti-pre-beta1-HDL antibody. However, the anti-pre-beta1-HDL antibody did not inhibit cholesterol efflux., Conclusions: We conclude that whereas pre-beta1-HDL is capable of taking up cellular cholesterol, its presence in plasma is not essential for cholesterol efflux, at least in vitro. Instead, pre-beta1-HDL may be the first product of apolipoprotein A-I lipidation during the formation of HDL but may not play a major role in transferring cellular cholesterol to HDL.

Background: n-3 Fatty acids influence vascular function, but the effect of individual fatty acids on systemic arterial compliance (SAC) has not been reported. SAC, which reflects arterial elasticity, is emerging as a new cardiovascular risk factor and appears to predict future cardiovascular events., Objective: We tested whether the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) improve SAC in dyslipidemic subjects., Design: Thirty-eight dyslipidemic subjects were randomly assigned to receive 3 g EPA/d (n = 12), 3 g DHA/d (n = 12), or a placebo (n = 14) in a 7-wk parallel, double-blind trial. Arterial functions were measured at the beginning and end of the interventions. Plasma lipids and plasma fatty acids were also measured., Results: Consumption of the n-3 fatty acids significantly increased SAC, whereas consumption of the placebo did not (P = 0.043; repeated-measures analysis of variance across the 3 groups); the increase was 36% with EPA and 27% with DHA. The major components contributing to the increase in SAC (systolic and pulse pressures and total vascular resistance) tended to decrease but not significantly. Plasma total and VLDL triacylglycerol were significantly lower in the n-3 fatty acid groups (P = 0.026 and 0.006, respectively; repeated-measures analysis of variance) than in the placebo group., Conclusion: EPA and DHA increase SAC and tend to reduce pulse pressure and total vascular resistance, effects that may reduce the risk of adverse cardiovascular events.

Coronary heart disease (CHD) risk is positively linked with dietary saturates and negatively linked with polyunsaturated fatty acids (PUFAs). Consumption of omega-3 fatty acids, such as in fish, appears highly protective against CHD. PUFAs (linoleic acid or omega-6) lower low-density lipoprotein (LDL) cholesterol levels most, and saturates, especially butter fat, raise LDL levels most. Fish oil fatty acids (omega-3) lower triglyceride and raise high-density lipoprotein (HDL) cholesterol levels. A higher ratio of dietary omega-3 to omega-6 fatty acids than is currently consumed in our population may be desirable, and can be achieved by increasing consumption of fish and alpha-linolenic acid in canola, soy and flaxseed oils. Large prospective trials show that people who experience least CHD have a pattern of eating that is rich in fish, PUFAs, whole-grain cereals, fruits and vegetables and low-fat dairy foods, and low in saturates from dairy fat, meat fat and fried foods.

Margarines enriched with plant sterols are effective at lowering low-density lipoprotein (LDL) cholesterol levels when eaten as recommended. LDL-cholesterol level reductions of more than 10% are achieved in most people. Phytosterol-containing foods are valuable additions to other cholesterol-lowering treatments, including statins. They should be considered for all patients with increased cardiovascular risk factors in whom LDL reduction is desirable. The only recognised possible adverse effect is reduction in some carotenoids in plasma, but this can be overcome by eating an additional serving of a carotenoid-rich (yellow or orange) fruit or vegetable.

This review considers the antiatherogenic function of high density lipoprotein (HDL) from the point of view of its dynamics within the sequential steps of reverse cholesterol transport (RCT). It is postulated that the efficiency of cholesterol flux through the RCT pathways is clinically more relevant than the HDL cholesterol concentration. The particular role of pre-beta(1)-HDL is reviewed drawing attention to the relationship between its concentration and the flux of cholesterol through the RCT system.