Background: The beneficial cardiovascular effects of vegetables may be underpinned by their high inorganic nitrate content.Objective: We sought to examine the effects of a 6-wk once-daily intake of dietary nitrate (nitrate-rich beetroot juice) compared with placebo intake (nitrate-depleted beetroot juice) on vascular and platelet function in untreated hypercholesterolemics.Design: A total of 69 subjects were recruited in this randomized, double-blind, placebo-controlled parallel study. The primary endpoint was the change in vascular function determined with the use of ultrasound flow-mediated dilatation (FMD).Results: Baseline characteristics were similar between the groups, with primary outcome data available for 67 patients. Dietary nitrate resulted in an absolute increase in the FMD response of 1.1% (an ∼24% improvement from baseline) with a worsening of 0.3% in the placebo group (P < 0.001). A small improvement in the aortic pulse wave velocity (i.e., a decrease of 0.22 m/s; 95% CI: −0.4, −0.3 m/s) was evident in the nitrate group, showing a trend (P = 0.06) to improvement in comparison with the placebo group. Dietary nitrate also caused a small but significant reduction (7.6%) in platelet-monocyte aggregates compared with an increase of 10.1% in the placebo group (P = 0.004), with statistically significant reductions in stimulated (ex vivo) P-selectin expression compared with the placebo group (P < 0.05) but no significant changes in unstimulated expression. No adverse effects of dietary nitrate were detected. The composition of the salivary microbiome was altered after the nitrate treatment but not after the placebo treatment (P < 0.01). The proportions of 78 bacterial taxa were different after the nitrate treatment; of those taxa present, 2 taxa were responsible for >1% of this change, with the proportions of Rothia mucilaginosa trending to increase and Neisseria flavescens (P < 0.01) increased after nitrate treatment relative to after placebo treatment.Conclusions: Sustained dietary nitrate ingestion improves vascular function in hypercholesterolemic patients. These changes are associated with alterations in the oral microbiome and, in particular, nitrate-reducing genera. Our findings provide additional support for the assessment of the potential of dietary nitrate as a preventative strategy against atherogenesis in larger cohorts. This trial was registered at clinicaltrials.gov as NCT01493752.

Aims Plasma volume (PV) expansion hallmarks worsening chronic heart failure (CHF) but no non‐invasive means of quantifying volume status exists. Because weight and haematocrit are related to PV, they can be used to calculate relative PV status (PVS). We tested the validity and prognostic utility of calculated PVS in CHF patients. Methods and results First, we evaluated the agreement between calculated actual PV (aPV) and aPV levels measured using 125Iodine‐human serum albumin. Second, we derived PVS as: [(calculated aPV – ideal PV)/ideal PV] × 100%. Third, we assessed the prognostic implications of PVS in 5002 patients from the Valsartan in Heart Failure Trial (Val‐HeFT), and validated this in another 246 routine CHF outpatients. On analysis, calculated and measured aPV values correlated significantly in 119 normal subjects and 30 CHF patients. In the Val‐HeFT cohort, mean (+SD) PVS was –9 ± 8% and related to volume biomarkers such as brain natriuretic peptide (BNP). Over 2 years, 977 (20%) patients died. Plasma volume status was associated with death and first morbid events in a ‘J‐shaped’ fashion with the highest risk seen with a PVS > –4%. Stratification into PVS quartiles confirmed that a PVS > –4% was associated with increased mortality (unadjusted hazard ratio 1.65, 95% confidence interval 1.44–1.88, χ2 = 54, P < 0.001) even after adjusting for 22 variables, including brain natriuretic peptide. These results were mirrored in the validation cohort. Conclusions Relative PVS calculated from simple clinical indices reflects the degree to which patients have deviated from their ideal PV and independently relates to outcomes. The utility of PVS‐driven CHF management needs further evaluation.

BACKGROUND. Cardiovascular disease occurs at lower incidence in premenopausal females compared with age-matched males. This variation may be linked to sex differences in inflammation. We prospectively investigated whether inflammation and components of the inflammatory response are altered in females compared with males.METHODS. We performed 2 clinical studies in healthy volunteers. In 12 men and 12 women, we assessed systemic inflammatory markers and vascular function using brachial artery flow-mediated dilation (FMD). In a further 8 volunteers of each sex, we assessed FMD response to glyceryl trinitrate (GTN) at baseline and at 8 hours and 32 hours after typhoid vaccine. In a separate study in 16 men and 16 women, we measured inflammatory exudate mediators and cellular recruitment in cantharidin-induced skin blisters at 24 and 72 hours.RESULTS. Typhoid vaccine induced mild systemic inflammation at 8 hours, reflected by increased white cell count in both sexes. Although neutrophil numbers at baseline and 8 hours were greater in females, the neutrophils were less activated. Systemic inflammation caused a decrease in FMD in males, but an increase in females, at 8 hours. In contrast, GTN response was not altered in either sex after vaccine. At 24 hours, cantharidin formed blisters of similar volume in both sexes; however, at 72 hours, blisters had only resolved in females. Monocyte and leukocyte counts were reduced, and the activation state of all major leukocytes was lower, in blisters of females. This was associated with enhanced levels of the resolving lipids, particularly D-resolvin.CONCLUSIONS. Our findings suggest that female sex protects against systemic inflammation-induced endothelial dysfunction. This effect is likely due to accelerated resolution of inflammation compared with males, specifically via neutrophils, mediated by an elevation of the D-resolvin pathway.TRIAL REGISTRATION. ClinicalTrials.gov NCT01582321 and NRES: City Road and Hampstead Ethics Committee: 11/LO/2038.FUNDING. The authors were funded by multiple sources, including the National Institute for Health Research, the British Heart Foundation, and the European Research Council.

Ingestion of vegetables rich in inorganic nitrate has emerged as an effective method, via the formation of a nitrite intermediate, for acutely elevating vascular NO levels. As such a number of beneficial effects of dietary nitrate ingestion have been demonstrated including the suggestion that platelet reactivity is reduced. In this study we investigated whether inorganic nitrate supplementation might also reduce platelet reactivity in healthy volunteers and have determined the mechanisms involved in the effects seen. We conducted two randomised crossover studies each in 24 (12 of each sex) healthy subjects assessing the acute effects of dietary nitrate (250 ml beetroot juice) or potassium nitrate capsules (KNO3, 8 mmol) vs placebo control on platelet reactivity. Inorganic nitrate ingested either from a dietary source or via supplementation raised circulating nitrate and nitrite levels in both sexes and attenuated ex vivo platelet aggregation responses to ADP and, albeit to a lesser extent, collagen but not epinephrine in male but not female volunteers. These inhibitory effects were associated with a reduced platelet P-selectin expression and elevated platelet cGMP levels. In addition, we show that nitrite reduction to NO occurs at the level of the erythrocyte and not the platelet. In summary, our results demonstrate that inorganic nitrate ingestion, whether via the diet or through supplementation, causes a modest decrease in platelet reactivity in healthy males but not females. Our studies provide strong support for further clinical trials investigating the potential of dietary nitrate as an adjunct to current antiplatelet therapies to prevent atherothrombotic complications. Moreover, our observations highlight a previously unknown sexual dimorphism in platelet reactivity to NO and intimate a greater dependence of males on the NO-soluble guanylate cyclase pathway in limiting thrombotic potential.

Rationale: Preclinical evidence demonstrates that inorganic nitrite, after its in situ conversion to nitric oxide, attenuates consequent myocardial reperfusion injury.Objective: We investigated whether intracoronary injection of nitrite during primary percutaneous coronary intervention might improve infarct size in ST-elevated myocardial infarction. Methods and Results:

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Ingestion of fruit and vegetables rich in inorganic nitrate (NO(3)(-)) has emerged as an effective method for acutely elevating vascular nitric oxide (NO) levels through formation of an NO(2)(-) intermediate. As such a number of beneficial effects of NO(3)(-) and NO(2)(-) ingestion have been demonstrated including reductions in blood pressure, measures of arterial stiffness and platelet activity. The pathway for NO generation from such dietary interventions involves the activity of facultative oral microflora that facilitate the reduction of inorganic NO(3)(-), ingested in the diet, to inorganic NO(2)(-). This NO(2)(-) then eventually enters the circulation where, through the activity of one or more of a range of distinct NO(2)(-) reductases, it is chemically reduced to NO. This pathway provides an alternative route for in vivo NO generation that could be utilized for therapeutic benefit in those cardiovascular disease states where reduced bioavailable NO is thought to contribute to pathogenesis. Indeed, the cardiovascular benefits of NO(2)(-) and NO(3)(-) are now starting to be translated in patients in several clinical trials. In this review, we discuss recent evidence supporting the potential utility of delivery of NO(3)(-) or NO(2)(-) for the treatment of cardiovascular diseases.

Background Premenopausal women have a lower incidence of cardiovascular disease, although the exact mechanism underlying this protection is unclear. Both systemic and localised infl ammation have a crucial role in the progression of cardiovascular disease, and much preclinical and observational data in human beings suggest that diff erences in infl ammation between the sexes exist. We investigated whether infl ammation, and which components of the infl ammatory response, might be altered in women compared with men. Methods We performed two clinical studies with 24 and 32 healthy volunteers. In 12 men and 12 women (mean age 26•0 years [SD 5•7] and 24•7 [6•8], respectively), we assessed systemic infl ammatory markers and vascular function using brachial artery fl ow-mediated dilation (FMD) determined with ultrasound. Responses were assessed before administration of typhoid vaccine and then at 8 h and 32 h afterwards. In another study, in 16 male and 16 female volunteers (mean age 27•4 years [SD 1•1] and 26•8 [1•1], respectively), infl ammatory exudate and cellular recruitment were measured at 24 h (acute) and 72 h (resolution) in skin blisters induced with cantharidin. Ethics approval was given by NRES: City Road and Hampstead Ethics Committee (11/LO/2038) for both studies. Both studies are registered with ClinicalTrials.gov, number NCT01582321.