Lawrence J. Beilin

Advanced glycation end-products: a review.

Abstract Advanced glycation end-products are a complex and heterogeneous group of compounds that have been implicated in diabetes related complications. At present it is not known if they are the cause or the consequence of the complications observed. We discuss the chemistry of advanced glycated end-product formation and their patho-biochemistry particularly in relation to the diabetic microvascular complications of retinopathy, neuropathy and nephropathy as well as their role in the accelerated vasculopathy observed in diabetes. The concept of carbonyl stress as a cause for advanced glycated end-product toxicity is mentioned. We discuss alterations in the concentrations of advanced glycated end-products in the body, particularly in relation to changes occuring with age, diabetes and its complications such as nephropathy. Problems relating to current methods of advanced glycated end-product detection and measurement are highlighted including the lack of a universally established method of detection or unit of measurement. Agents used for the treatment of advanced glycated end-product accumulation are reviewed, with an emphasis on the results of the recent phase III trials using aminoguanidine and diabetes related complications. [Diabetologia (2001) 44: 129–146]

Docosahexaenoic Acid but Not Eicosapentaenoic Acid Lowers Ambulatory Blood Pressure and Heart Rate in Humans

Animal studies suggest that the 2 major omega3 fatty acids found in fish, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have differential effects on blood pressure (BP) and heart rate (HR). The aim of this study was to determine whether there were significant differences in the effects of purified EPA or DHA on ambulatory BP and HR in humans. In a double-blind, placebo-controlled trial of parallel design, 59 overweight, mildly hyperlipidemic men were randomized to 4 g/d of purified EPA, DHA, or olive oil (placebo) capsules and continued their usual diets for 6 weeks. Fifty-six subjects completed the study. Only DHA reduced 24-hour and daytime (awake) ambulatory BP (P<0.05). Relative to the placebo group, 24-hour BP fell 5.8/3.3 (systolic/diastolic) mm Hg and daytime BP fell 3.5/2.0 mm Hg with DHA. DHA also significantly reduced 24-hour, daytime, and nighttime (asleep) ambulatory HRs (P=0. 001). Relative to the placebo group, DHA reduced 24-hour HR by 3. 5+/-0.8 bpm, daytime HR by 3.7+/-1.2 bpm, and nighttime HR by 2. 8+/-1.2. EPA had no significant effect on ambulatory BP or HR. Supplementation with EPA increased plasma phospholipid EPA from 1. 66+/-0.07% to 9.83+/-0.06% (P<0.0001) but did not change DHA levels. Purified DHA capsules increased plasma phospholipid DHA levels from 4.00+/-0.27% to 10.93+/-0.62% (P<0.0001) and led to a small, nonsignificant increase in EPA (1.52+/-0.12% to 2.26+/-0.16%). Purified DHA but not EPA reduced ambulatory BP and HR in mildly hyperlipidemic men. The results of this study suggest that DHA is the principal omega3 fatty acid in fish and fish oils that is responsible for their BP- and HR-lowering effects in humans. These results have important implications for human nutrition and the food industry.

Differential Effects of Eicosapentaenoic Acid and Docosahexaenoic Acid on Vascular Reactivity of the Forearm Microcirculation in Hyperlipidemic, Overweight Men

BackgroundRecent evidence supports differential effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the 2 major &ohgr;3 fatty acids of marine origin, on blood pressure in humans and vascular reactivity in adult spontaneously hypertensive rats. We investigated possible differences in the effects of purified EPA or DHA on forearm vascular reactivity in overweight hyperlipidemic men that might contribute to the blood pressure–lowering effects of fish oils. Methods and ResultsWith a double-blind, placebo-controlled trial of parallel design, 59 overweight, mildly hyperlipidemic men were randomized to receive 4 g/d purified EPA, DHA, or olive oil (placebo) capsules while continuing their usual diets for 6 weeks. Forearm blood flow (FBF) was measured with venous occlusion, strain-gauge plethysmography during the sequential intra-arterial administration of acetylcholine (7.5, 15, and 30 &mgr;g/min), sodium nitroprusside (1.5, 3, and 10 &mgr;g/min), norepinephrine (10, 20, and 40 ng/min), a single-dose infusion of NG-monomethyl-l-arginine (L-NMMA) (1 mg/min), and coinfusion of acetylcholine (7.5, 15, and 30 &mgr;g/min) and L-NMMA. Forty of the 56 subjects who completed the study underwent FBF measurements. Plasma phospholipid EPA levels increased significantly (P <0.0001) after supplementation with EPA, and DHA composition increased with DHA supplementation (P <0.0001). Relative to placebo, DHA, but not EPA, supplementation significantly improved FBF in response to acetylcholine infusion (P =0.040) and coinfusion of acetylcholine with L-NMMA (P =0.040). Infusion of L-NMMA alone showed no group differences. DHA significantly enhanced dilatory responses to sodium nitroprusside (P <0.0001) and attenuated constrictor responses to norepinephrine (P =0.017). ConclusionsRelative to placebo, DHA, but not EPA, enhances vasodilator mechanisms and attenuates constrictor responses in the forearm microcirculation. Improvements in endothelium-independent mechanisms appear to be predominant and may contribute to the selective blood pressure–lowering effect observed with DHA compared with EPA in humans.

EFFECT OF EICOSAPENTAENOIC ACID AND DOCOSAHEXAENOIC ACID ON OXIDATIVE STRESS AND INFLAMMATORY MARKERS IN TREATED- HYPERTENSIVE TYPE 2 DIABETIC SUBJECTS

n-3 fatty acids reduce the risk of cardiovascular disease via a number of possible mechanisms. Despite this, there has been concern that these fatty acids may increase lipid peroxidation. The data in vivo are inconclusive, due in part to limitations in the methodologies. In this regard, the measurement of F2-isoprostanes provides a reliable assessment of in vivo lipid peroxidation and oxidant stress. This study aimed to assess the effects of supplementation with purified eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), the two major n-3 fatty acids, on urinary F2-isoprostanes and markers of inflammation, in type 2 diabetic patients. In a double-blind, placebo controlled trial of parallel design, 59 nonsmoking, treated-hypertensive, type 2 diabetic subjects, were randomized to 4 g daily of purified EPA, DHA, or olive oil for 6 weeks, while maintaining their usual diet. F2-isoprostanes, measured using gas chromatography-mass spectrometry in 24 h urines and C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), were measured before and after intervention. Thirty-nine men and 12 women aged 61.2 +/- 1.2 years, with body mass index (BMI), 29.5 +/- 0.5 kg/m2; 24 h blood pressure, 138/73 mmHg; HbA1c, 7.3 +/- 0.1% and fasting glucose, 7.9 +/- 0.2 mmol/l completed the intervention. Baseline urinary F2-isoprostanes were positively associated with HbA1c (p=.011) and fasting glucose (p=.032). Relative to the olive oil group, postintervention urinary F2-isoprostanes were decreased 19% by EPA (p=.017) and 20% by DHA (p=.014). There were no significant changes in CRP, IL-6, and TNF-alpha following EPA or DHA supplementation. In regression analysis, Delta F2-isoprostanes were positively associated with Delta HbA1c (p=.007) independent of treatment group; and with Delta TNF-alpha (p=.034) independent of age, gender, BMI, and treatment group. There were no associations with Delta CRP or Delta IL-6. This study is the first report demonstrating that either EPA or DHA reduce in vivo oxidant stress without changing markers of inflammation, in treated hypertensive, type 2 diabetic subjects.

Evidence for a direct effect of alcohol consumption on blood pressure in normotensive men. A randomized controlled trial.

A direct pressor effect of alcohol is proposed as the basis for the association between regular alcohol consumption and an increase in blood pressure found in population studies. To examine this further, a randomized controlled crossover trial of the effects of varying alcohol intake on blood pressure in 46 healthy male drinkers was conducted. From an average of 336 ml of ethanol per week, alcohol consumption was reduced by 80% for 6 weeks by drinking a low alcohol content beer alone. This reduction was associated with a significant reduction in systolic and diastolic blood pressure (p less than 0.001 and p less than 0.05 respectively). The mean difference in supine systolic blood pressure during the last 2 weeks of normal or low alcohol intake was 3.8 mm Hg, which correlated significantly with change in alcohol consumption (r = 0.53, p less than 0.001). Reduction of alcohol intake also caused a significant decrease in weight (p less than 0.001). After adjustment for weight change, an independent effect of alcohol on systolic but not diastolic blood pressure was still evident, with a 3.1 mm Hg fall predicted for a decrease in consumption from 350 ml of ethanol equivalent per week to 70 ml per week (p less than 0.01). Systolic blood pressure rose again when normal drinking habits were resumed. These results provide clear evidence for a direct and reversible pressor effect of regular moderate alcohol consumption in normotensive men and suggest that alcohol may play a major role in the genesis of early stages of blood pressure elevation.

Effects of Dietary Fish and Weight Reduction on Ambulatory Blood Pressure in Overweight Hypertensives

Obesity is a major factor contributing to hypertension and increased risk of cardiovascular disease. Regular consumption of dietary fish and omega3 fatty acids of marine origin can lower blood pressure (BP) levels and reduce cardiovascular risk. This study examined the potential effects of combining dietary fish rich in omega3 fatty acids with a weight loss regimen in overweight hypertensive subjects, with ambulatory BP levels as the primary end point. Using a factorial design, 69 overweight medication-treated hypertensives were randomized to a daily fish meal (3.65 g omega3 fatty acids), weight reduction, the 2 regimens combined, or a control regimen for 16 weeks. Sixty-three subjects with a mean+/-SEM body mass index of 31.6+/-0.5 kg/m2 completed the study. Weight fell by 5.6+/-0.8 kg with energy restriction. Dietary fish and weight loss had significant independent and additive effects on 24-hour ambulatory BP. Effects were greatest on awake systolic and diastolic BP (P<0.01); relative to control, awake pressures fell 6.0/3.0 mm Hg with dietary fish alone, 5.5/2.2 mm Hg with weight reduction alone, and 13.0/9.3 mm Hg with fish and weight loss combined. These results also remained significant after further adjustment for changes in urinary sodium, potassium, or the sodium/potassium ratio, as well as dietary macronutrients. Dietary fish also significantly reduced 24-hour (-3.1+/-1.4 bpm, P=0.036) and awake (-4.2+/-1.6 bpm, P=0. 013) ambulatory heart rates. Weight reduction had a significant effect on sleeping heart rate only (-3.2+/-1.7 bpm, P=0.037). Combining a daily fish meal with a weight-reducing regimen led to additive effects on ambulatory BP and decreased heart rate. The effects were large, suggesting that cardiovascular risk and antihypertensive drug requirements are likely to be reduced substantially by combining dietary fish meals rich in omega3 fatty acids with weight-loss regimens in overweight medication-treated hypertensives. The reduction in heart rate seen with dietary fish suggests a cardiac/autonomic component, as well as vascular effects, of increased consumption of omega3 fatty acid from fish.

Interactions Between Dietary Fat, Fish, and Fish Oils and Their Effects on Platelet Function in Men at Risk of Cardiovascular Disease

Recent studies have suggested that omega 3-fats of marine origin may have a protective role in heart disease. This study aimed to compare the effects of fish or fish oil, in the setting of a high- or low-fat diet, on platelet aggregation and platelet thromboxane in men with increased risk of cardiovascular disease. One hundred twenty men who were nonsmokers, 30 to 60 years old, with mildly elevated blood pressure and cholesterol were randomly allocated to one of five high-fat (40% of daily energy) or two low-fat (30%) groups for 12 weeks. The five high-fat groups took either 6 or 12 fish oil capsules daily; fish; a combination of fish and fish oil; or placebo capsules. The two low-fat groups took either fish or placebo capsules. Fish meals provided 1.3 g of eicosapentaenoic acid daily, equivalent to 6 fish oil capsules, and contained an average of 3.65 g/d of omega 3-fatty acids. Multiple regression analysis of the combined groups showed that all groups taking omega 3-fatty acids reduced platelet aggregation to both collagen (P < .0001) and platelet-activating factor (PAF) (P < .05) and platelet thromboxane B2 responses (P < .05) to collagen-induced aggregation. The low-fat diet alone had no effect on PAF-induced platelet aggregation and only a small effect on platelet responses to collagen (P < .05). Platelet aggregation responses to PAF were reduced more by fish oil than fish in a high-fat diet, whereas fish had a greater effect when part of a low-fat rather than a high-fat diet. There was no significant difference in collagen-induced platelet aggregation or platelet thromboxane between fish and fish oils on a high or low fat intake. In conjunction with our previous findings of improvements in lipoproteins, blood pressure, and heart rate in this population, these results on platelet function suggest that dietary omega 3-fatty acids incorporated into a low- rather than a high-fat diet have a wider spectrum of more favorable effects on cardiovascular risk factors.

Obesity-related hypertension: Pathogenesis, cardiovascular risk, and treatment-a position paper of the the obesity society and the American society of hypertension

In light of the worldwide epidemic of obesity, and in recognition of hypertension as a major factor in the cardiovascular morbidity and mortality associated with obesity, The Obesity Society and The American Society of Hypertension agreed to jointly sponsor a position paper on obesity‐related hypertension to be published jointly in the journals of each society. The purpose is to inform the members of both societies, as well as practicing clinicians, with a timely review of the association between obesity and high blood pressure, the risk that this association entails, and the options for rational, evidenced‐based treatment. The position paper is divided into six sections plus a summary as follows: pathophysiology, epidemiology and cardiovascular risk, the metabolic syndrome, lifestyle management in prevention and treatment, pharmacologic treatment of hypertension in the obese, and the medical and surgical treatment of obesity in obese hypertensive patients. Obesity (2012)

Maternal cigarette smoking during pregnancy, low birth weight and subsequent blood pressure in early childhood

Given the widely acknowledged inverse relationship between birth weight and blood pressure, a raised blood pressure in the offspring of smoking mothers as compared to those whose mothers did not smoke, would be anticipated by virtue of the reduction in birth weight associated with smoking during pregnancy. The objective of the present study was to test the hypothesis that maternal cigarette smoking during pregnancy has an effect on blood pressure in childhood independent of its effect on birth weight. Data was obtained from a prospective cohort study of 1708 pregnant women and their singleton offspring, delivered live at term, in Perth, Western Australia, commenced at 16 weeks gestation with serial blood pressure measurements through early childhood. Statistically significant associations were found between maternal smoking during pregnancy and systolic blood pressure at age six, between birth weight and systolic blood pressure at ages three and six, and between maternal smoking during pregnancy and birth weight. The relationship between birth weight and blood pressure in early childhood differed significantly on the basis of maternal cigarette smoking or not during pregnancy. This differential relationship persisted after adjustment for the childs current weight and socio-economic status. We concluded that intra-uterine exposure to maternal cigarette smoking increased childrens blood pressure at age one through to age six. This was not wholly attributable to an effect on birth weight or confounding of the association between birth weight and subsequent blood pressure by the childs current weight or socio-economic factors. Furthermore, maternal smoking during pregnancy does not account for the acknowledged elevation in blood pressure associated with low birth weight. The present study is an exploration of a possible causal pathway underlying the birth weight/blood pressure association rather than simply a confirmation of such an association which has been detailed in many other papers.

Vegetarian diet in mild hypertension: a randomised controlled trial.

In a randomised crossover trial 58 subjects aged 30-64 with mild untreated hypertension were allocated either to a control group eating a typical omnivorous diet or to one of two groups eating an ovolactovegetarian diet for one of two six week periods. A fall in systolic blood pressure of the order of 5 mm Hg occurred during the vegetarian diet periods, with a corresponding rise on resuming a meat diet. The main nutrient changes with the vegetarian diet included an increase in the ratio of polyunsaturated to saturated fats and intake of fibre, calcium, and magnesium and a decrease in the intake of protein and vitamin B12. There were no consistent changes in urinary sodium or potassium excretion or body weight. In untreated subjects with mild hypertension, changing to a vegetarian diet may bring about a worthwhile fall in systolic blood pressure.