Jonathan M. Hodgson

Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes

Objective: Our objective was to assess effects of dietary supplementation with coenzyme Q10 (CoQ) on blood pressure and glycaemic control in subjects with type 2 diabetes, and to consider oxidative stress as a potential mechanism for any effects.Subjects and design: Seventy-four subjects with uncomplicated type 2 diabetes and dyslipidaemia were involved in a randomised double blind placebo-controlled 2×2 factorial intervention.Setting: The study was performed at the University of Western Australia, Department of Medicine at Royal Perth Hospital, Australia.Interventions: Subjects were randomly assigned to receive an oral dose of 100 mg CoQ twice daily (200 mg/day), 200 mg fenofibrate each morning, both or neither for 12 weeks.Main outcome measures: We report an analysis and discussion of the effects of CoQ on blood pressure, on long-term glycaemic control measured by glycated haemoglobin (HbA1c), and on oxidative stress assessed by measurement of plasma F2-isoprostanes.Results: Fenofibrate did not alter blood pressure, HbA1c, or plasma F2-isoprostanes. There was a 3-fold increase in plasma CoQ concentration (3.4±0.3 µmol/l, P<0.001) as a result of CoQ supplementation. The main effect of CoQ was to significantly decrease systolic (−6.1±2.6 mmHg, P=0.021) and diastolic (−2.9±1.4 mmHg, P=0.048) blood pressure and HbA1c (−0.37±0.17%, P=0.032). Plasma F2-isoprostane concentrations were not altered by CoQ (0.14±0.15 nmol/l, P=0.345).Conclusions: These results show that CoQ supplementation may improve blood pressure and long-term glycaemic control in subjects with type 2 diabetes, but these improvements were not associated with reduced oxidative stress, as assessed by F2-isoprostanes.Sponsorship: This study was supported by a grant from the NH&MRC, Australia.

Specific dietary polyphenols attenuate atherosclerosis in apolipoprotein E-knockout mice by alleviating inflammation and endothelial dysfunction.

Objective—Animal and clinical studies have suggested that polyphenols in fruits, red wine, and tea may delay the development of atherosclerosis through their antioxidant and anti-inflammatory properties. We investigated whether individual dietary polyphenols representing different polyphenolic classes, namely quercetin (flavonol), (−)-epicatechin (flavan-3-ol), theaflavin (dimeric catechin), sesamin (lignan), or chlorogenic acid (phenolic acid), reduce atherosclerotic lesion formation in the apolipoprotein E (ApoE)−/− gene–knockout mouse. Methods and Results—Quercetin and theaflavin (64-mg/kg body mass daily) significantly attenuated atherosclerotic lesion size in the aortic sinus and thoracic aorta (P<0.05 versus ApoE−/− control mice). Quercetin significantly reduced aortic F2-isoprostane, vascular superoxide, vascular leukotriene B4, and plasma-sP-selectin concentrations; and augmented vascular endothelial NO synthase activity, heme oxygenase-1 protein, and urinary nitrate excretion (P<0.05 versus control ApoE−/− mice). Theaflavin showed similar, although less extensive, significant effects. Although (−)-epicatechin significantly reduced F2-isoprostane, superoxide, and endothelin-1 production (P<0.05 versus control ApoE−/− mice), it had no significant effect on lesion size. Sesamin and chlorogenic acid treatments exerted no significant effects. Quercetin, but not (−)-epicatechin, significantly increased the expression of heme oxygenase-1 protein in lesions versus ApoE−/− controls. Conclusion—Specific dietary polyphenols, in particular quercetin and theaflavin, may attenuate atherosclerosis in ApoE−/− gene–knockout mice by alleviating inflammation, improving NO bioavailability, and inducing heme oxygenase-1. These data suggest that the cardiovascular protection associated with diets rich in fruits, vegetables, and some beverages may in part be the result of flavonoids, such as quercetin.

Flavonoid-rich apples and nitrate-rich spinach augment nitric oxide status and improve endothelial function in healthy men and women: a randomized controlled trial.

Flavonoids and nitrates in fruits and vegetables may protect against cardiovascular disease. Dietary flavonoids and nitrates can augment nitric oxide status via distinct pathways, which may improve endothelial function and lower blood pressure. Recent studies suggest that the combination of flavonoids and nitrates can enhance nitric oxide production in the stomach. Their combined effect in the circulation is unclear. Here, our objective was to investigate the independent and additive effects of flavonoid-rich apples and nitrate-rich spinach on nitric oxide status, endothelial function, and blood pressure. A randomized, controlled, crossover trial with healthy men and women (n=30) was conducted. The acute effects of four energy-matched treatments (control, apple, spinach, and apple+spinach), administered in random order, were compared. Measurements included plasma nitric oxide status, assessed by measuring S-nitrosothiols+other nitrosylated species (RXNO) and nitrite, blood pressure, and endothelial function, measured as flow-mediated dilatation of the brachial artery. Results are means and 95% CI. Relative to control, all treatments resulted in higher RXNO (control, 33 nmol/L, 26, 42; apple, 51 nmol/L, 40, 65; spinach, 86 nmol/L, 68, 110; apple+spinach, 69 nmol/L, 54, 88; P<0.01) and higher nitrite (control, 35 nmol/L, 27, 46; apple, 69 nmol/L, 53, 90; spinach, 99 nmol/L, 76, 129; apple+spinach, 80 nmol/L, 61, 104; P<0.01). Compared to control, all treatments resulted in higher flow-mediated dilatation (P<0.05) and lower pulse pressure (P<0.05), and apple and spinach resulted in lower systolic blood pressure (P<0.05). No significant effect was observed on diastolic blood pressure. The combination of apple and spinach did not result in additive effects on nitric oxide status, endothelial function, or blood pressure. In conclusion, flavonoid-rich apples and nitrate-rich spinach can independently augment nitric oxide status, enhance endothelial function, and lower blood pressure acutely, outcomes that may benefit cardiovascular health.

Regular ingestion of black tea improves brachial artery vasodilator function.

A higher intake of black tea has been associated with lower cardiovascular disease risk. The antioxidant effects of tea polyphenols may enhance endothelial function and thereby reduce the risk of coronary events. The objective of the present study was to determine whether regular ingestion of black tea can improve brachial artery vasodilator function. The effects of regular ingestion of 5 cups per day of black tea for 4 weeks were compared with control conditions (hot water ingestion) in 21 subjects with mild elevations in serum cholesterol or triacylglycerol (triglyceride) concentrations in a parallel designed study. Endothelial function of the brachial artery was assessed ultrasonographically by measurement of post-ischaemic (endothelium-dependent) dilatation of the brachial artery. Endothelium-independent dilatation of the brachial artery was measured following administration of 400 microg of sublingual glyceryl trinitrate. Regular ingestion of black tea resulted in a significant and consistent increase in endothelium-dependent dilatation (2.3%; P=0.008) and in a significant increase in endothelium-independent dilatation (4.2%; P=0.03), compared with ingestion of hot water. These differences remained after adjustment for age, sex and body mass index. These results suggest that one mechanism by which black tea may reduce cardiovascular risk is via improved vasodilator function of conduit arteries.

Tea flavonoids and cardiovascular health.

The two main types of tea are green and black. Both green and black teas are rich dietary sources of flavonoids. Available evidence suggests that regular tea consumption may reduce the risk of cardiovascular disease. The cardiovascular health benefits of drinking tea are thought to be largely due to flavonoids. Tea intake and intake of flavonoids found in tea have been associated with reduced risk of cardiovascular disease in cross-sectional and prospective population studies. Isolated flavonoids found in tea have also been consistently shown to inhibit the development of atherosclerosis in animal models. A number of possible pathways and mechanisms have been investigated. There is now consistent data indicating that tea and tea flavonoids can enhance nitric oxide status and improve endothelial function, which may be at least partly responsible for benefits on cardiovascular health. There is also evidence, although limited, to suggest benefits of green tea (flavonoids) on body weight and body fatness. Data supporting reduced oxidative damage, inflammation, platelet activation, blood pressure, and risk of type 2 diabetes with tea (flavonoids) remains inadequate to draw any conclusions.

Red Wine and Beer Elevate Blood Pressure in Normotensive Men

A positive relationship between alcohol consumption and blood pressure (BP) is well-established but the relative effect of specific alcoholic beverages is controversial. This study aimed to determine whether red wine may improve vascular function and have less of an impact on blood pressure because of its high content of antioxidant vasodilator polyphenolic compounds. Healthy normotensive men entered a 4-period crossover study comparing in random order 4 weeks of control–abstinence with similar periods of daily consumption of red wine (375 mL; 39 grams alcohol), de-alcoholized red wine (375 mL), or beer (1125 mL; 41 grams alcohol). Ambulatory systolic BP and diastolic BP and heart rate (HR) were measured together with vascular function as assessed by flow-mediated dilatation (FMD) and glyceryl trinitrate-mediated (GTNMD) dilatation of the brachial artery. The systolic and diastolic BP and HR were not different between control–abstinence and de-alcoholized red wine. However, compared with control–abstinence, both red wine and beer increased awake systolic BP (2.9 and 1.9 mm Hg, respectively; P<0.05) and asleep HR (5.0 and 4.4 bpm; P<0.05). There were no specific effects of red wine, de-alcoholized red wine, or beer on FMD or GTNMD. Daily consumption of ≈40 grams alcohol as either red wine or beer for 4 weeks results in similar increases in systolic BP and HR. De-alcoholized red wine did not lower BP, and neither red wine nor de-alcoholized red wine influenced vascular function, suggesting that red wine polyphenolics do not have a significant role in mitigating the blood pressure-elevating effects of alcohol in men.

Soybean isoflavonoids and their metabolic products inhibit in vitro lipoprotein oxidation in serum

Abstract Isoflavonoids are compounds present in many legumes, but are derived in the human diet mainly from soybeans and various soybean-based food products. The major isoflavonoids occurring in soy are the glycosides of genistein and daidzein. The metabolic products of genistein metabolism in humans have not been clearly shown. The two main products of daidzein metabolism in humans appear to be equol and O-desmethylangolensin. Increasing evidence suggests that oxidative modification to low-density lipoprotein is involved in atherogenesis, and that natural antioxidants that prevent or inhibit oxidative damage to low-density lipoprotein may beneficially influence atherogenesis. In the present experiments, the effects of genistein and daidzein, and the daidzein metabolites equol and O-desmethylangolensin on Cu 2+ -induced oxidation of lipoproteins in serum were examined. Three concentrations of each compound (0.1 μM, 1 μM, 10 μM) were tested for antioxidant activity in six individual serum samples. All compounds tested inhibited lipoprotein oxidation. The minimum concentration for significant inhibition was 1 μM for genistein and daidzein ( P P

Definition of ambulatory blood pressure targets for diagnosis and treatment of hypertension in relation to clinic blood pressure: prospective cohort study.

Background Twenty-four hour ambulatory blood pressure thresholds have been defined for the diagnosis of mild hypertension but not for its treatment or for other blood pressure thresholds used in the diagnosis of moderate to severe hypertension. We aimed to derive age and sex related ambulatory blood pressure equivalents to clinic blood pressure thresholds for diagnosis and treatment of hypertension. Methods We collated 24 hour ambulatory blood pressure data, recorded with validated devices, from 11 centres across six Australian states (n=8575). We used least product regression to assess the relation between these measurements and clinic blood pressure measured by trained staff and in a smaller cohort by doctors (n=1693). Results Mean age of participants was 56 years (SD 15) with mean body mass index 28.9 (5.5) and mean clinic systolic/diastolic blood pressure 142/82 mm Hg (19/12); 4626 (54%) were women. Average clinic measurements by trained staff were 6/3 mm Hg higher than daytime ambulatory blood pressure and 10/5 mm Hg higher than 24 hour blood pressure, but 9/7 mm Hg lower than clinic values measured by doctors. Daytime ambulatory equivalents derived from trained staff clinic measurements were 4/3 mm Hg less than the 140/90 mm Hg clinic threshold (lower limit of grade 1 hypertension), 2/2 mm Hg less than the 130/80 mm Hg threshold (target upper limit for patients with associated conditions), and 1/1 mm Hg less than the 125/75 mm Hg threshold. Equivalents were 1/2 mm Hg lower for women and 3/1 mm Hg lower in older people compared with the combined group. Conclusions Our study provides daytime ambulatory blood pressure thresholds that are slightly lower than equivalent clinic values. Clinic blood pressure measurements taken by doctors were considerably higher than those taken by trained staff and therefore gave inappropriate estimates of ambulatory thresholds. These results provide a framework for the diagnosis and management of hypertension using ambulatory blood pressure values.

A Single Nucleotide Polymorphism in the CYP4F2 but not CYP4A11 Gene Is Associated With Increased 20-HETE Excretion and Blood Pressure

Arachidonic acid is a major fatty acid that can be metabolized by the cytochrome P450 enzyme to a number of bioactive eicosanoids. A major metabolite of this oxidation is 20-hydroxyeicosatetraenoic acid, which acts as a potent vasoconstrictor. However, in the kidney, its vasoconstrictor actions can be offset by its natriuretic properties. A guanine-to-adenine polymorphism in the CYP4F2 gene was associated with a reduction in 20-hydroxyeicosatetraenoic acid production in vitro. A thymidine-to-cytosine polymorphism in the CYP4A11 gene reduced catalytic activity by >50% in vitro and was associated with hypertension. The aim was to determine whether these 2 mutations are associated with urinary 20-hydroxyeicosatetraenoic acid excretion and blood pressure in humans. For the CYP4F2, 51% were homozygous for the G allele, 40% were carriers, and 9% were homozygous for the A allele. For CYP4A11, 72% were homozygous for the T allele, 25% were carriers, and 3% were homozygous for the C allele. The CYP4F2 GA/AA genotype was significantly associated with an increase in both 20-hydroxyeicosatetraenoic acid excretion and systolic blood pressure. The CYP4A11 CC/TC genotype was significantly associated with a reduction in 20-hydroxyeicosatetraenoic acid excretion but was not associated with blood pressure. We have demonstrated for the first time in humans that polymorphisms of the CYP4F2 and CYP4A11 genes have opposite effects on 20-hydroxyeicosatetraenoic acid excretion. The positive association between the CYP4F2 GA/AA genotype and both systolic blood pressure and 20-hydroxyeicosatetraenoic acid excretion strengthens a role for 20-hydroxyeicosatetraenoic acid in the modulation of blood pressure.

Urinary 20-Hydroxyeicosatetraenoic Acid Is Associated With Endothelial Dysfunction in Humans

Background—20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P450 (&ohgr;-hydroxylase) metabolite of arachidonic acid with vasoconstrictor activity that may be involved in the pathogenesis of hypertension. In humans, there are few data relating 20-HETE to vascular pathophysiology. This study aimed to determine whether urinary 20-HETE excretion is related to blood pressure or vascular endothelial function in humans. Methods and Results—Sixty-six subjects (37 males, 29 females), including 29 with untreated hypertension, had urinary 20-HETE excretion measured by gas chromatography/mass spectrometry. There was no significant difference for 20-HETE excretion between hypertensive and normotensive subjects. 20-HETE excretion was positively related to body mass index and sodium excretion. There was a significant inverse association between urinary 20-HETE and endothelium-dependent vasodilation measured by flow-mediated dilation of the brachial artery (P=0.006). There was no association with vasodilator responses to nitroglycerin. In multiple regression analysis, 20-HETE remained an independent predictor of endothelium-dependent vasodilation after adjustment for age, body mass index, and blood pressure. When gender was included in the model, the relationship between 20-HETE and flow-mediated dilation was attenuated. Separate analysis by gender revealed that in women, hypertensive subjects had significantly higher 20-HETE excretion than normotensive subjects, but this was not seen in men. In women, 20-HETE was positively related to diastolic and systolic blood pressure. In men, 20-HETE was positively related to body mass index. Conclusions—This is the first demonstration of an association between 20-HETE excretion and in vivo vascular function in humans. Given the negative modulatory role of nitric oxide on &ohgr;-hydroxylase, the present results suggest a potentially important role for 20-HETE in human vascular physiology.