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Oral nitrate supplementation to enhance pulmonary rehabilitation in COPD: ON-EPIC a multicentre, double-blind, placebo-controlled, randomised parallel group study.
Pavitt, MJ, Tanner, RJ, Lewis, A, Buttery, S, Mehta, B, Jefford, H, Curtis, KJ, Banya, WAS, Husain, S, Satkunam, K, et al
Thorax. 2020;(7):547-555
Abstract
RATIONALE Dietary nitrate supplementation has been proposed as a strategy to improve exercise performance, both in healthy individuals and in people with COPD. We aimed to assess whether it could enhance the effect of pulmonary rehabilitation (PR) in COPD. METHODS This double-blind, placebo-controlled, parallel group, randomised controlled study performed at four UK centres, enrolled adults with Global Initiative for Chronic Obstructive Lung Disease grade II-IV COPD and Medical Research Council dyspnoea score 3-5 or functional limitation to undertake a twice weekly 8-week PR programme. They were randomly assigned (1:1) to either 140 mL of nitrate-rich beetroot juice (BRJ) (12.9 mmol nitrate), or placebo nitrate-deplete BRJ, consumed 3 hours prior to undertaking each PR session. Allocation used computer-generated block randomisation. MEASUREMENTS The primary outcome was change in incremental shuttle walk test (ISWT) distance. Secondary outcomes included quality of life, physical activity level, endothelial function via flow-mediated dilatation, fat-free mass index and blood pressure parameters. RESULTS 165 participants were recruited, 78 randomised to nitrate-rich BRJ and 87 randomised to placebo. Exercise capacity increased more with active treatment (n=57) than placebo (n=65); median (IQR) change in ISWT distance +60 m (10, 85) vs +30 m (0, 70), estimated treatment effect 30 m (95% CI 10 to 40); p=0.027. Active treatment also impacted on systolic blood pressure: treatment group -5.0 mm Hg (-5.0, -3.0) versus control +6.0 mm Hg (-1.0, 15.5), estimated treatment effect -7 mm Hg (95% CI 7 to -20) (p<0.0005). No significant serious adverse events or side effects were reported. CONCLUSIONS Dietary nitrate supplementation appears to be a well-tolerated and effective strategy to augment the benefits of PR in COPD. TRIAL REGISTRATION NUMBER ISRCTN27860457.
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A randomized multicentre trial to compare revascularization with optimal medical therapy for the treatment of chronic total coronary occlusions.
Werner, GS, Martin-Yuste, V, Hildick-Smith, D, Boudou, N, Sianos, G, Gelev, V, Rumoroso, JR, Erglis, A, Christiansen, EH, Escaned, J, et al
European heart journal. 2018;(26):2484-2493
Abstract
AIMS: The clinical value of percutaneous coronary intervention (PCI) for chronic coronary total occlusions (CTOs) is not established by randomized trials. This study should compare the benefit of PCI vs. optimal medical therapy (OMT) on the health status in patients with at least one CTO. METHOD AND RESULTS Three hundred and ninety-six patients were enrolled in a prospective randomized, multicentre, open-label, and controlled clinical trial to compare the treatment by PCI with OMT with a 2:1 randomization ratio. The primary endpoint was the change in health status assessed by the Seattle angina questionnaire (SAQ) between baseline and 12 months follow-up. Fifty-two percent of patients have multi-vessel disease in whom all significant non-occlusive lesions were treated before randomization. An intention-to-treat analysis was performed including 13.4% failed procedures in the PCI group and 7.3% cross-overs in the OMT group. At 12 months, a greater improvement of SAQ subscales was observed with PCI as compared with OMT for angina frequency [5.23, 95% confidence interval (CI) 1.75; 8.71; P = 0.003], and quality of life (6.62, 95% CI 1.78-11.46; P = 0.007), reaching the prespecified significance level of 0.01 for the primary endpoint. Physical limitation (P = 0.02) was also improved in the PCI group. Complete freedom from angina was more frequent with PCI 71.6% than OMT 57.8% (P = 0.008). There was no periprocedural death or myocardial infarction. At 12 months, major adverse cardiac events were comparable between the two groups. CONCLUSION Percutaneous coronary intervention leads to a significant improvement of the health status in patients with stable angina and a CTO as compared with OMT alone. TRIAL REGISTRATION NCT01760083.
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Plasma Nitrate and Incidence of Cardiovascular Disease and All-Cause Mortality in the Community: The Framingham Offspring Study.
Maas, R, Xanthakis, V, Göen, T, Müller, J, Schwedhelm, E, Böger, RH, Vasan, RS
Journal of the American Heart Association. 2017;(11)
Abstract
BACKGROUND Nitrate is a dietary component as well as an endogenously formed metabolite and source of the signaling molecule nitric oxide. Harmful as well as beneficial effects of nitrate have been advocated. Data regarding the prognostic relevance of plasma nitrate are limited. The aim of this study was to evaluate the prospective association of plasma nitrate with cardiovascular disease (CVD) and all-cause mortality. METHODS AND RESULTS We assayed plasma nitrate in 2855 Framingham Offspring Study participants (mean age 59 years, 54% women) by gas chromatography-mass spectrometry and evaluated its association with all-cause mortality and incident CVD. On follow-up (median 17.3 years), 775 participants died and 522 developed new-onset CVD (of 2546 participants free of CVD at baseline). In multivariable models adjusting for standard risk factors, plasma nitrate was associated with an increased risk of death in participants (hazard ratio per unit increase in log-nitrate 1.21; 95% confidence interval, 1.04-1.40 [P=0.015]). The strength of the association was attenuated by additional adjustment for estimated glomerular filtration rate (hazard ratio, 1.16; 95% confidence interval, 1.00-1.35 [P=0.057]). In contrast, no evidence was found for an association of plasma nitrate with incident CVD (multivariable-adjusted hazard ratio per unit increase log-nitrate 1.08; 95% confidence interval, 0.89-1.31 [P=0.42]). CONCLUSIONS In our prospective community-based investigation, a higher plasma nitrate concentration was associated with all-cause mortality but not with incident CVD. The association of nitrate with mortality may at least in part be attributable to its association with renal function.
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Placental protein tyrosine nitration and MAPK in type 1 diabetic pre-eclampsia: Impact of antioxidant vitamin supplementation.
Johnston, PC, Powell, LA, McCance, DR, Pogue, K, McMaster, C, Gilchrist, S, Holmes, VA, Young, IS, McGinty, A
Journal of diabetes and its complications. 2013;(4):322-7
Abstract
AIM: To examine the role of placental protein tyrosine nitration and p38-Mitogen-Activated Protein Kinase α (p38-MAPKα), Extra Cellular-Signal Regulated Kinase (ERK) and c-Jun NH2-Terminal Kinase (JNK) activity, in the pathogenesis of type 1 diabetic pre-eclampsia, and the putative modulation of these indices by maternal vitamin C and E supplementation. METHODS Placental samples were obtained from a sub-cohort of the DAPIT trial: a randomised placebo-controlled trial of antioxidant supplementation to reduce pre-eclampsia in type 1 diabetic pregnancy. Placenta from placebo-treated: normotensive (NT) [n=17], gestational hypertension (GH) [n=7] and pre-eclampsia (PE) [n=6] and vitamin-treated: NT (n=20), GH (n=4) and PE (n=3) was analysed. Protein tyrosine nitration was assessed by immunohistochemistry in paraffin-embedded tissue. Catalytic activities of placental p38-MAPKα, ERK and JNK were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS Nitrotyrosine immunostaining was present in placebo-treated NT, GH and PE placentae, with no significant difference observed between the groups. There was a non-significant trend towards decreased p38-MAPKα activity in PE vs NT control placentae. ERK and JNK were similar among the three outcome placebo groups and vitamin supplementation did not significantly alter their activity. CONCLUSION Nitrotyrosine immunopositivity in normotensive diabetic placentae indicates some degree of tyrosine nitration in uncomplicated diabetic pregnancy, possibly due to inherent oxidative stress and peroxynitrite production. Our results suggest that p38-MAPKα, ERK and JNK are not directly involved in the pathogenesis of type 1 diabetic pre-eclampsia and are not modulated by vitamin-supplementation.
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Diuretic, opiate and nitrate use in severe acidotic acute cardiogenic pulmonary oedema: analysis from the 3CPO trial.
Gray, A, Goodacre, S, Seah, M, Tilley, S
QJM : monthly journal of the Association of Physicians. 2010;(8):573-81
Abstract
BACKGROUND Drug treatments for acute cardiogenic pulmonary oedema (ACPO) have not been rigorously evaluated and recent observational data suggests some agents are related to poorer outcome. AIM: We aimed to examine the effect of treatment with diuretics, nitrates and opiates on 7-day mortality, acidosis and respiratory distress in UK Emergency Department (ED) patients with severe acidotic pulmonary oedema. DESIGN Analysis of data from the 3CPO trial; a multicentre randomized controlled trial. METHODS Data were analysed from patients recruited with severe acidotic pulmonary oedema to the 3CPO trial in 26 UK EDs between 2003 and 2007. The effects of these treatments on 7-day mortality, improvement in acidosis (pH change between baseline and 1 h) and improvement in respiratory distress (patient measured breathlessness using a Visual Analogue Score between baseline and 1 h) were tested using univariate logistic regression analysis, and a regression model used to adjust for confounding baseline differences. RESULTS Nitrates were given to 947/1048 (90.4%) patients, diuretics to 934/1049 (89.0%) patients and opiates to 541/1052 patients (51.4%). Adjusted analysis showed that opiate treatment was associated with less improvement in acidosis [difference in improvement in pH -0.022, 95% confidence interval (CI) -0.014 to -0.030, P < 0.001], but no difference in mortality or improvement in respiratory distress. We found no evidence that nitrate or diuretic use were associated with any difference in mortality, improvement in acidosis or respiratory distress. CONCLUSION Opiate use is associated with less improvement in acidosis during initial treatment and may attenuate effective treatment of severe acidotic ACPO.
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Impact of an initial strategy of medical therapy without percutaneous coronary intervention in high-risk patients from the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial.
Maron, DJ, Spertus, JA, Mancini, GB, Hartigan, PM, Sedlis, SP, Bates, ER, Kostuk, WJ, Dada, M, Berman, DS, Shaw, LJ, et al
The American journal of cardiology. 2009;(8):1055-62
Abstract
We explored the safety and quality-of-life consequences of treating patients with stable coronary disease and high-risk features initially with optimal medical therapy (OMT) alone compared to OMT plus percutaneous coronary intervention. This was a post hoc analysis of Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial patients. We defined high risk as the onset of Canadian Cardiovascular Society class III angina within 2 months or stabilized acute coronary syndrome within 2 weeks of enrollment. The primary end point was death or myocardial infarction after 4.6 years. Of the 2,287 patients enrolled in the COURAGE trial, 264 (12%) were high risk and had a relative risk of 1.56 for death or myocardial infarction (p = 0.0008) compared to those with non-high-risk features. A total of 35 primary events occurred in the OMT group and 32 in the percutaneous coronary intervention plus OMT group (hazard ratio 1.11, 95% confidence interval 0.69 to 1.79; p = 0.68). No significant difference was found in the prevalence of angina between the 2 groups at 1 year. During the first year of follow-up, 30% of the OMT patients crossed over to the revascularization group. In conclusion, an initial strategy of OMT alone for high-risk patients in the COURAGE trial did not result in increased death or myocardial infarction at 4.6 years or worse angina at 1 year, but it was associated with a high rate of crossover to revascularization.
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Nitric oxide metabolites, nitrates and nitrites in the cerebrospinal fluid in children with west syndrome.
Vanhatalo, S, Riikonen, R
Epilepsy research. 2001;(1):3-13
Abstract
Nitric oxide (NO) has been implicated in the mediation of the neuronal excitotoxic cascade. In order to estimate brain NO production, cerebrospinal fluid (CSF) levels of NO metabolites, nitrates and nitrites (NN(x)) were measured in 31 children with west syndrome (WS) and in 12 controls. There was no age-related change in the NN(x) levels during the first year of life. The mean of the NN(x) levels was significantly higher in patients with WS than in controls (8.43 vs. 5.27 microM; P=0.01). Analysis of the etiological subgroups showed that the patients with a symptomatic etiology of WS had significantly higher NN(x) levels than controls (P<0.005) or than the patients with a cryptogenic etiology. The cryptogenic cases, in turn, did not differ from the controls (P=0.48). Levels of NN(x) were also significantly higher in children with focal brain abnormalities (infarction, atrophy or previous infection) than in those with other abnormalities or with normal neuroradiological findings (P<0.005). No correlation was found between the NN(x) levels and the duration of the symptoms, while paired samples obtained from eight children with WS showed that the NN(x) levels rose significantly (P=0.02) within the first 40 days of symptoms. The levels of NN(x) did not correlate with the CSF levels of neuronal growth factor or with the later decline in mental performance. This study demonstrates that the production of NO can be measured in human epileptic conditions and supports the idea gained from experimental studies that NO is involved in the pathophysiology of epilepsy. However, normal levels of NN(x) in patients with cryptogenic infantile spasms suggest that an increase in NO production be due to the concomitant neuronal damage rather than seizure activity per se. The findings suggest that there are no age-related changes in the NN(x) levels during the first year of life, and that children with symptomatic WS have elevated levels of NN(x), which rise during the first 40 days of symptoms. Although the NN(x) levels cannot be used to estimate the duration of symptoms or to predict the prognosis of mental development, they may support the differentiation of symptomatic from cryptogenic etiologies of WS.