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Aims\ud To test if 6 months' intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness, respectively, vs. placebo/doxazosin, to control for blood pressure (BP).\ud \ud Methods\ud A subgroup of participants in our double-blind, randomized-controlled, factorial VaSera trial had carotid imaging. Patients with hypertension and with/at risk of type 2 diabetes were randomized to active nitrate-containing beetroot juice or placebo nitrate-depleted juice, and spironolactone or doxazosin. Vascular ultrasound for carotid diameter (CD, mm) and intima–media thickness (CIMT, mm) was performed at baseline, 3- and 6-months. Carotid local stiffness (CS, m/s) was estimated from aortic pulse pressure (Arteriograph) and carotid lumen area. Data were analysed by modified intention to treat and using mixed-model effect, adjusted for confounders.\ud \ud Results\ud In total, 93 subjects had a baseline evaluation and 86% had follow-up data. No statistical interactions occurred between the juice and drug arms and BP was similar between the juices and between the drugs. Nitrate-containing vs. placebo juice significantly lowered CIMT (−0.06 [95% confidence interval −0.12, −0.01], P = .034), an overall difference of ~8% relative to baseline; but had no effect on CD or CS. Doxazosin appeared to reduce CS from baseline (−0.34 [−0.62, −0.06]) however, no difference was detected vs. spironolactone (−0.15 [−0.46, 0.16]). No differences were detected between spironolactone or doxazosin on CIMT and CD.\ud \ud Conclusions\ud Our results show that 6 months' intervention with dietary nitrate influences vascular remodelling, but not carotid stiffness or diameter. Neither spironolactone nor doxazosin had a BP-independent effect on carotid structure and function.

Background: Interesterified (IE) fats are widely used in place of trans fats; however, little is known about their metabolism. \ud Objective: To test the impact of a commonly consumed IE versus a non-IE equivalent fat on in vivo postprandial and in vitro lipid metabolism, compared with a reference oil (rapeseed oil; RO).\ud Design: A double-blinded, 3-phase crossover, randomized controlled trial was performed in healthy adults (n=20) aged 45-75 years. Postprandial plasma triacylglycerol (TG) and lipoprotein responses (including stable isotope tracing) to a test meal (50g fat) were evaluated over 8 hours. The test fats were IE 80:20 palm stearin/palm kernel fat, an identical non-IE fat, and RO (control). In vitro, mechanisms of digestion were explored using a dynamic gastric model (DGM). \ud Results: Plasma TG 8h incremental area under the curves were lower following non-IE versus RO (-1.7 mmol/L.h (95% confidence interval -3.3, -0.0)), but there were no differences between IE and RO nor IE and non-IE. Low density lipoprotein (LDL) particles were smaller following IE and non-IE versus RO (P=0.005). Extra, extra large (XXL)-, extra large (XL)- and large (L)- VLDL particle concentrations were higher following IE and non-IE versus RO at 6-8 h (P

Aims:\ud Dietary nitrate from sources such as beetroot juice lowers blood pressure (BP) via the nitrate-nitrite-nitric oxide (NO) pathway. However, NO and nitrite are inactivated via re- oxidation to nitrate, potentially limiting their activity. Cytochrome P450-3A4 inhibition with troleandomycin prevents nitrite re-oxidation to nitrate in rodent liver. Grapefruit juice contains the CYP3A4 inhibitor furanocoumarin. We therefore hypothesized that grapefruit juice would enhance BP-lowering with beetroot juice by maintaining circulating [nitrite].\ud Methods:\ud We performed a randomized, placebo-controlled, 7-hour crossover study in 11 healthy volunteers, attending on 3 occasions, receiving: a 70ml-shot of active beetroot juice (Beet- It®) and either (i) 250 ml grapefruit juice (“Active Beet+GFJ”), or (ii) 250 ml water (Buxton®, “Active Beet+H2O”); or (iii) Placebo Beet+GFJ.\ud Results:\ud The addition of grapefruit juice to active beetroot juice lowered systolic BP (SBP): Active Beet+GFJ versus Active Beet+H2O (P=0.02), and pulse pressure, PP (P=0.0003). Peak mean differences in SBP and PP were seen at T=5 hours: -3.3mmHg (95% CI -6.43 to -0.15) and at T=2.5 hours: -4.2 mmHg (95% CI -0.3 to -8.2), respectively. Contrary to the hypothesis, plasma [nitrite] was lower with Active Beet+GFJ versus Active Beet+H2O (P=0.006), as was salivary nitrite production (P=0.002) and saliva volume (-0.34 ml/min (95% CI -0.05 to - 0.68)). The taste score of Beet+GFJ was 1.4/10 points higher than Beet+H2O (P=0.03).\ud This article is protected by copyright. All rights reserved.\ud Conclusions:\ud Grapefruit juice enhanced beetroot juice’s effect on lowering SBP and PP despite decreasing plasma [nitrite]. Besides suggesting more complex mechanisms, there is potential for maximising the clinical benefit of dietary nitrate and targeting isolated systolic hypertension.

Aim\ud To test if spironolactone or dietary nitrate from beetroot juice could reduce arterial stiffness as aortic pulse wave velocity (PWVart), a potential treatment target, independently of blood pressure. \ud Methods\ud Daily spironolactone (≤50mg) versus doxazosin (control ≤16mg) and 70mL beetroot juice (‘Beet-It’ ≤11mmol nitrate) versus nitrate-depleted juice (placebo; 0mmol nitrate) were tested in people at risk or with type-2 diabetes using a double-blind, 6-month factorial trial. Vascular indices (baseline, 12, 24 weeks) were cardiac-ankle vascular index (‘CAVI’), a nominally pressure-independent stiffness measure (primary outcome), pulse wave velocity (PWVart) secondary, central systolic pressure and augmentation. Analysis was intention-to-treat, adjusted for systolic pressure differences between trial arms.\ud Results \ud Spironolactone did not reduce stiffness, with evidence for reduced CAVI on doxazosin rather than spironolactone (mean difference [95% confidence intervals]; 0.25[-0.3, 0.5] units, p=0.080), firmer for PWVart (0.37[0.01, 0.7] ms-1, p=0.045). There was no difference in systolic pressure reduction between spironolactone and doxazosin (0.7[-4.8, 3.3]mmHg, p=0.7). Circulating nitrate and nitrite increased on active versus placebo juice, with central systolic pressure lowered -2.6[-4.5, - 0.8]mmHg, p=0.007 more on the active juice, but did not reduce CAVI, PWVart, nor peripheral pressure. \ud Change in nitrate and nitrite concentrations were 1.5-fold [1.1-2.2] and 2.2-fold [1.3, 3.6] higher on spironolactone than on doxazosin respectively; both p

BACKGROUND & AIMS Polyphenol intake has been linked to improvements in human vascular function, although data on hydroxycinnamates, such as chlorogenic acid (CGA) have not yet been studied. We aimed to investigate the impact of coffee intake rich in chlorogenic acid on human vascular function and whether CGAs are involved in potential effects. METHODS Two acute randomized, controlled, cross-over human intervention trials were conducted. The impact of coffee intake, matched for caffeine but differing in CGA content (89, and 310 mg) on flow-mediated dilatation (FMD) was assessed in 15 healthy male subjects. In a second intervention trial conducted with 24 healthy male subjects, the impact of pure 5-caffeoylquinic acid (5-CQA), the main CGA in coffee (5-CQA; 450 mg and 900 mg) on FMD was also investigated. RESULTS We observed a bi-phasic FMD response after low and high polyphenol, (89 mg and 310 mg CGA) intake, with increases at 1 (1.10 ± 0.43% and 1.34 ± 0.62%, respectively) and 5 (0.79% ± 0.32 and 1.52% ± 0.40, respectively) hours post coffee consumption. FMD responses to coffee intake was closely paralleled by the appearance of CGA metabolites in plasma, notably 3-, 4- and 5-feruloylquinic acid and ferulic-4'-O-sulfate at 1 h and isoferulic-3'-O-glucuronide and ferulic-4'-O-sulfate at 5 h. Intervention with purified 5-CQA (450 mg) also led to an improvement in FMD response relative to control (0.75 ± 1.31% at 1 h post intervention, p = 0.06) and concomitant appearance of plasma metabolites. CONCLUSIONS Coffee intake acutely improves human vascular function, an effect, in part, mediated by 5-CQA and its physiological metabolites. STUDY REGISTRATION The National Institutes of Health (NIH) on ClinicalTrials.govNCT01813981 and NCT01772784.

Dietary nitrate (found in green leafy vegetables such as rocket and in beetroot) is now recognised to be an important source of nitric oxide, via the nitrate-nitrite-NO pathway. Dietary nitrate confers several cardiovascular beneficial effects on blood pressure, platelets, endothelial function, mitochondrial efficiency and exercise. Whilst this pathway may now seem obvious, its realisation followed a rather tortuous course over two decades. Early steps included the discovery that nitrite was a source of NO in the ischaemic heart, but this appeared to have deleterious effects. In addition, nitrate-derived nitrite provided a gastric source of NO. However, residual nitrite was not thought to be absorbed systemically. Nitrite was also considered to be physiologically inert, but potentially carcinogenic, through N-nitrosamine formation. In Part I we describe key twists and turns in the elucidation of the pathway and the underlying mechanisms. This provides the critical foundation for the more recent developments in the nitrate-nitrite-NO pathway which are covered in Part II. This article is protected by copyright. All rights reserved.

Dietary nitrate (found in green leafy vegetables such as rocket and in beetroot) is now recognized to be an important source of nitric oxide, via the nitrate-nitrite-NO pathway. Dietary nitrate confers several cardiovascular beneficial effects on blood pressure, platelets, endothelial function, mitochondrial efficiency and exercise. Having described key twists and turns in the elucidation of the pathway and the underlying mechanisms in Part I, we explore the more recent developments which have served to confirm mechanisms, extend our understanding, and discover new properties and potential therapeutic uses of the pathway in Part II. Even the established dependency on low oxygen states for bioactivation of nitrite has recently been challenged. Dietary nitrate appears to be an important component of 'healthy diets', such as the DASH diet to lower blood pressure and the Mediterranean diet, with its potential to lower cardiovascular risk, possibly through beneficial interactions with a range of other constituents. The World Cancer Research Foundation report strong evidence for vegetables including spinach and lettuce (high nitrate-containing) decreasing cancer risk (mouth, pharynx, larynx, oesophagus and stomach), summarized in a 'Nitrate-Cancer Risk Veg-Table'. The European Space Agency recommends that beetroot, lettuce, spinach and rocket (high-nitrate vegetables) are grown to provide food for long-term space missions. Nitrate, an ancient component of rocket fuel, could support sustainable crops for healthy humans.

Dietary nitrate (found in green leafy vegetables such as rocket and in beetroot) is now recognised to be an important source of nitric oxide, via the nitrate-nitrite-NO pathway. Dietary nitrate confers several cardiovascular beneficial effects on blood pressure, platelets, endothelial function, mitochondrial efficiency and exercise. Having described key twists and turns in the elucidation of the pathway and the underlying mechanisms in Part I, we explore the more recent developments which have served to confirm mechanisms, extend our understanding, and discover new properties and potential therapeutic uses of the Pathway in Part II. Even the established dependency on low oxygen states for bioactivation of nitrite has recently been challenged. Dietary nitrate appears to be an important component of 'healthy diets', such as the DASH diet to lower blood pressure and the Mediterranean diet, with its potential to lower cardiovascular risk, possibly through beneficial interactions with a range of other constituents. The World Cancer Research Foundation report strong evidence for vegetables including spinach and lettuce (high nitrate-containing) decreasing cancer risk (mouth, pharynx, larynx, oesophagus and stomach), summarised in a 'Nitrate-Cancer Risk Veg-Table'. The European Space Agency recommends beetroot, lettuce, spinach and rocket (high-nitrate vegetables) are grown to provide food for long term space missions. Nitrate, an ancient component of rocket fuel, could support sustainable crops for healthy humans. This article is protected by copyright. All rights reserved.

Anthropometric and Biochemical Characteristics of Subjects (meanâ Âąâ SD). Table S2. Univariate Association of CAVI and various cardiovascular risk factors. Table S3. Univariate Association of Aortic PWV and various cardiovascular risk factors. Table S4. Univariate Association of heart-ankle PWV and various cardiovascular risk factors. (DOC 94 kb)