Meta-Analysis

Authors: Weibing Liu, Zhuoran Meng, Ge Wang...

Background

Although some studies have found that nitrates were beneficial for bone health, the findings are inconsistent. To assess the efficacy of nitrates for bone health, we conducted a meta-analysis.

Methods

PubMed, EMBASE databases, Cochrane Library for relevant articles published before December 2021 were searched. All observational and randomized controlled studies that reporting bone mineral density (BMD), fractures with nitrates use were included. A meta-analysis was performed to calculate risk ratios (RRs) for fractures, change differences for bone mineral density.

Results

Four cohort studies and two case-control studies examining the association between nitrates use and fractures were identified. The nitrates use was not associated with any fracture risk (RR = 0.97; 95% CI, 0.94-1.01; = 31.5%) and hip fracture (RR = 0.88; 95% CI, 0.76-1.02; = 74.5%). Subgroup analyses revealed no differences in fracture risk, whereas two cohort studies revealed a reduced risk of hip fracture (RR = 0.71, 95% CI, 0.58-0.86, = 0.0%). There were no statistically significant differences in BMD percent changes at lumbar spine (WMD = -0.07, 95% CI,-0.78-0.65; = 0.0%), total hip (WMD = -0.42, 95% CI,-0.88-0.04; = 0.0%), femoral neck (WMD = -0.38, 95% CI,-1.02-0.25; = 0.0%), or total body (WMD = -0.17, 95% CI,-0.51-0.17; = 0.0%) in two randomized controlled trials (RCTs) compared with a placebo. Another two RCTs compared nitrates with alendronate. Nitrates were comparable to alendronate in increasing bone mineral density at lumbar spine (WMD = 0.00, 95% CI,-0.01-0.02; = 0.0%). Besides, the most common adverse effect was headache, contributing to low adherence to therapy.

Conclusion

Our meta-analysis showed no association between nitrates use and fractures in observational studies. The results of RCTs on the usage of nitrates and their effects on BMD were inconsistent. High-quality, long-term studies are needed to clarify the efficacy of nitrates for bone health.

Topics: Bone Density; Bone and Bones; Female; Fractures, Bone; Humans; Isosorbide Dinitrate; Male; Nitrates; Nitric Oxide Donors; Nitroglycerin; Risk Factors

PubMed: 35222289
DOI: 10.3389/fendo.2022.833932

Probabilistic risk and benefit assessment of nitrates and nitrites by integrating total diet study-based exogenous dietary exposure with endogenous nitrite formation using toxicokinetic modeling.

Authors: Cheng-Jih Cheng, Yuh-Ting Kuo, Jein-Wen Chen...

The impacts of dietary nitrates and nitrites on human health have been a controversial topic for many years. However, the risk and benefit assessment of nitrates and nitrites is complicated by the large variation in nitrate and nitrite intake among people and the endogenous nitrite formation in the body. This study conducted a probabilistic risk-benefit assessment of dietary nitrates and nitrites based on internal dose by integrating exogenous and endogenous exposures with human trial data on cardiovascular benefits. A total diet study was carried out to quantify the age-specific dietary intakes of nitrates and nitrites. A previously well-validated human toxicokinetic model was used to predict internal doses for different age groups. In addition, the integrated approach was applied to different populations from different countries/regions based on reported exposure estimates to conduct a comprehensive risk-benefit assessment of dietary nitrates and nitrites. The results demonstrated that vegetable consumption was the main contributor to the internal nitrate and nitrite levels in all age groups. Exposure to nitrates and nitrites exceeding acceptable daily intakes in a variety of foods showed cardiovascular benefits. The probabilistic risk assessment showed that the exposure to nitrates and nitrites did not pose an appreciable health and safety risk. Therefore, the present results suggest that dietary nitrates and nitrites have clear cardiovascular benefits that may outweigh potential risks. Our analysis contributes significantly to addressing the controversy regarding risks and benefits from dietary nitrates and nitrites, and our approach could be applied to other dietary constituents with the potential for both risks and benefits.

Topics: Diet; Dietary Exposure; Humans; Nitrates; Nitrites; Toxicokinetics

PubMed: 34418847
DOI: 10.1016/j.envint.2021.106807

Authors: Melina Lopez, Pedro F Malacarne, Anna Gajos-Draus...

BACKGROUND AND PURPOSE

Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here.

EXPERIMENTAL APPROACH

As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell-specific, inducible knockout mouse of POR (smcPOR ) to investigate the contribution of POR/CYP to vascular biotransformation of organic nitrates.

KEY RESULTS

Microsomes containing recombinant CYPs expressed in human vascular tissues released nitrite from NTG and PETN with CYP2C9 and CYP2C8 being most efficient. SFK525, a CYP suicide inhibitor, blocked this effect. smcPOR mice exhibited no obvious cardiovascular phenotype (normal cardiac weight and endothelium-dependent relaxation) and plasma and vascular nitrite production was similar to control (CTL) animals. NTG- and PETN-induced relaxation of isolated endothelium-intact or endothelium-denuded vessels were identical between CTL and smcPOR . Likewise, nitrite release from organic nitrates in aortic rings was not affected by deletion of POR in smooth muscle cells (SMCs). In contrast, inhibition of ALDH2 by benomyl (10 μM) inhibited NTG-induced nitrite production and relaxation. Deletion of POR did not modulate this response.

CONCLUSIONS AND IMPLICATIONS

Our data suggest that metabolism by vascular CYPs does not contribute to the pharmacological function of organic nitrates.

Topics: Animals; Biotransformation; Cytochrome P-450 Enzyme System; Mice; Nitrates; Nitroglycerin; Pentaerythritol Tetranitrate

PubMed: 33450066
DOI: 10.1111/bph.15362

Randomized Controlled Trial

Authors: Ashraf Hamarneh, Andrew Fu Wah Ho, Heerajnarain Bulluck...

Remote ischaemic preconditioning (RIPC) using transient limb ischaemia failed to improve clinical outcomes following cardiac surgery and the reasons for this remain unclear. In the ERIC-GTN study, we evaluated whether concomitant nitrate therapy abrogated RIPC cardioprotection. We also undertook a post-hoc analysis of the ERICCA study, to investigate a potential negative interaction between RIPC and nitrates on clinical outcomes following cardiac surgery. In ERIC-GTN, 185 patients undergoing cardiac surgery were randomized to: (1) Control (no RIPC or nitrates); (2) RIPC alone; (3); Nitrates alone; and (4) RIPC + Nitrates. An intravenous infusion of nitrates (glyceryl trinitrate 1 mg/mL solution) was commenced on arrival at the operating theatre at a rate of 2-5 mL/h to maintain a mean arterial pressure between 60 and 70 mmHg and was stopped when the patient was taken off cardiopulmonary bypass. The primary endpoint was peri-operative myocardial injury (PMI) quantified by a 48-h area-under-the-curve high-sensitivity Troponin-T (48 h-AUC-hs-cTnT). In ERICCA, we analysed data for 1502 patients undergoing cardiac surgery to investigate for a potential negative interaction between RIPC and nitrates on clinical outcomes at 12-months. In ERIC-GTN, RIPC alone reduced 48 h-AUC-hs-cTnT by 37.1%, when compared to control (ratio of AUC 0.629 [95% CI 0.413-0.957], p = 0.031), and this cardioprotective effect was abrogated in the presence of nitrates. Treatment with nitrates alone did not reduce 48 h-AUC-hs-cTnT, when compared to control. In ERICCA there was a negative interaction between nitrate use and RIPC for all-cause and cardiovascular mortality at 12-months, and for risk of peri-operative myocardial infarction. RIPC alone reduced the risk of peri-operative myocardial infarction, compared to control, but no significant effect of RIPC was demonstrated for the other outcomes. When RIPC and nitrates were used together they had an adverse impact in patients undergoing cardiac surgery with the presence of nitrates abrogating RIPC-induced cardioprotection and increasing the risk of mortality at 12-months post-cardiac surgery in patients receiving RIPC.

Topics: Cardiac Surgical Procedures; Humans; Ischemic Preconditioning; Ischemic Preconditioning, Myocardial; Myocardial Infarction; Nitrates; Treatment Outcome; Troponin T

PubMed: 35727392
DOI: 10.1007/s00395-022-00938-3

Authors: Carmine Massarelli, Daniela Losacco, Marina Tumolo...

Nitrogen is a vital nutrient helpful to plants and crop growth. However, among the leading causes of water resources pollution is the excess nitrogen from agricultural sources. In European Union countries, the Nitrates Directive has been approved to reduce this problem monitoring of water bodies with regard to nitrate concentrations, designation of Nitrate Vulnerable Zones (NVZs), and establishing codes of good agricultural practices and measures to prevent and reduce water pollution from nitrates. In light of this, we propose an integrated methodological approach to better manage a environmental issue as the perimeter of NVZs with the prospective that our approach could be used in the future by other member states representing a Best Practice in that direction. The methodology is based on data integration applied in a GIS environment. Different available data representing the knowledge of the territory were harmonised, systematised and georeferenced, in order to increase the environmental framework, preserve the contamination of the water resource and give indications on the measures to be implemented to apply in the best way possible the Nitrates Directive. Finally, it was also possible to overcome the infringement procedure in progress for Italy and the Puglia region and proceed to new designation of NVZs.

Topics: Agriculture; Environmental Monitoring; European Union; Nitrates; Prospective Studies; Water Pollutants, Chemical; Water Pollution; Water Resources

PubMed: 34948931
DOI: 10.3390/ijerph182413323

Authors: Tetsuro Tsujimoto, Hiroshi Kajio

OBJECTIVE

To assess the association of nitrate use with cardiovascular events in patients with heart failure with preserved ejection fraction (HFpEF).

PATIENTS AND METHODS

Patient data were collected from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist trial, which had been conducted at 233 sites in 6 countries from August 10, 2006, through January 31, 2012. The primary outcome was the occurrence of a major adverse cardiovascular event (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) or heart failure hospitalization. The association between nitrate use and cardiovascular risk was evaluated using Cox proportional hazards analysis. In addition, we verified the results using propensity score-matched patients.

RESULTS

A total of 3417 patients with HFpEF were evaluated over a mean follow-up of 3.1 years, and 778 experienced a primary outcome event. The risk of primary outcome events was significantly higher in patients taking nitrates than in those not taking nitrates (hazard ratio [HR], 1.21; 95% CI, 1.01-1.46, P=.04). The risk of major adverse cardiovascular events was significantly higher in patients taking nitrates than in those not taking nitrates (HR, 1.32; 95% CI, 1.05-1.66, P=.01). Furthermore, the risk of hospitalization for heart failure was higher in patients taking nitrates (HR, 1.25; 95% CI, 0.99-1.60, P=.06), with propensity score-matched analyses revealing similar findings. In addition, a similar association was observed in various subgroups.

CONCLUSION

This study reported that nitrate use in patients with HFpEF was associated with a significantly increased risk of cardiovascular events.

Topics: Aged; Female; Heart Failure; Humans; Male; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Nitrates; Randomized Controlled Trials as Topic; Risk Assessment; Spironolactone; Stroke; Stroke Volume; Ventricular Function, Left

PubMed: 31272569
DOI: 10.1016/j.mayocp.2018.11.032

Authors: Lidiya Vysotskaya, Leylya Timergalina, Guzel Akhiyarova...

Changes in root elongation are important for the acquisition of mineral nutrients by plants. Plant hormones, cytokinins, and abscisic acid (ABA) and their interaction are important for the control of root elongation under changes in the availability of ions. However, their role in growth responses to supra-optimal concentrations of nitrates and phosphates has not been sufficiently studied and was addressed in the present research. Effects of supra-optimal concentrations of these ions on root elongation and distribution of cytokinins between roots and shoots were studied in ABA-deficient barley mutant Az34 and its parental variety, Steptoe. Cytokinin concentration in the cells of the growing root tips was analyzed with the help of an immunohistochemical technique. Increased concentrations of nitrates and phosphates led to the accumulation of ABA and cytokinins in the root tips, accompanied by a decline in shoot cytokinin content and inhibition of root elongation in Steptoe. Neither of the effects were detected in Az34, suggesting the importance of the ability of plants to accumulate ABA for the control of these responses. Since cytokinins are known to inhibit root elongation, the effect of supra-optimal concentration of nitrates and phosphates on root growth is likely to be due to the accumulation of cytokinins brought about by ABA-induced inhibition of cytokinin transport from roots to shoots.

Topics: Abscisic Acid; Biological Transport; Cytokinins; Hordeum; Nitrates; Phosphates; Plant Roots; Plant Shoots; Plant Transpiration

PubMed: 34831337
DOI: 10.3390/cells10113110

Authors: Lorenzo Rambaldo, Héctor Ávila, Mònica Escolà Casas...

Groundwater pollution has increased in recent years due to the intensification of agricultural and livestock activities. This results in a significant reduction in available freshwater resources. Here, we have studied the long term assessment of a green technology (1-4 L/day) based on a photobioreactor (PBR) containing immobilised microalgae-bacteria in polyurethane foam (PF) followed by a cork filter (CF) for removing nitrates, pesticides (atrazine and bromacil), and antibiotics (sulfamethoxazole and sulfacetamide) from groundwater. The prototype was moderately effective for removing nitrates (58%) at an HRT of 8 days, while its efficiency decreased at a HRT of 4 and 2 days (<20% removal). The combined use of PBR-CF enabled antibiotics and pesticides to be attenuated by up to 95% at an HRT of 8 days, but their attenuation decreased with shorter HRT, with pesticides being the compounds most affected (reducing from 97 to 98% at an HRT of 8 days to 23-45% at an HRT of 2 days). Pesticide transformation products were identified after the CF, supporting biodegradation as the main attenuation process. A gene-based metataxonomic assessment linked the attenuation of micropollutants to the presence of specific pesticide biodegradation species (e.g. genus Phenylobacterium, Sphingomonadaceae, and Caulobacteraceae). Therefore, the results highlighted the potential use of microalgae and cork to treat polluted groundwater.

Topics: Anti-Bacterial Agents; Biodegradation, Environmental; Groundwater; Microalgae; Nitrates; Nitrogen Oxides; Pesticides; Photobioreactors; Water Pollutants, Chemical

PubMed: 35500629
DOI: 10.1016/j.chemosphere.2022.134777

Authors: Jimmy T Efird, Charulata Jindal, Andy C Kiser...

Background Postoperative atrial fibrillation (POAF) is a frequent complication of coronary artery bypass graft (CABG) surgery. This arrhythmia occurs more frequently among patients who receive perioperative inotropic therapy (PINOT). Administration of nitrates with antiplatelet agents reduces the conversion rate of cyclic guanosine monophosphate to guanosine monophosphate. This process is associated with increased concentrations of free radicals, catecholamines, and blood plasma volume. We hypothesized that patients undergoing CABG surgery who receive PINOT may be more susceptible to POAF when nitrates are administered with antiplatelet agents. Methods Clinical records were examined from a prospectively maintained cohort of 4,124 patients undergoing primary isolated CABG surgery to identify POAF-associated factors. Results POAF risk was increased among patients receiving PINOT, and the greatest effect was observed when nitrates were administered with antiplatelet therapy. Adjustment for comorbidities did not substantively change the study results. Conclusions Administration of nitrates with certain antiplatelet agents was associated with an increased POAF risk among patients undergoing CABG surgery. Additional studies are needed to determine whether preventive strategies such as administration of antioxidants will reduce this risk.

Topics: Adult; Atrial Fibrillation; Cardiovascular Agents; Coronary Artery Bypass; Coronary Artery Disease; Female; Humans; Male; Middle Aged; Nitrates; Platelet Aggregation Inhibitors; Retrospective Studies; Risk Factors

PubMed: 29808744
DOI: 10.1177/0300060518773934

Review

Authors: Zhu Meng, Weili Gai, Dalin Song...

Early reperfusion remains the key therapy to salvage viable myocardium and must be applied as soon as possible following an acute myocardial infarction (AMI) to attenuate the ischemic insult. However, reperfusion injury may develop following reintroduction of blood and oxygen to vulnerable myocytes, which results in more severe cell death than in the preceding ischemic episode. Ischemic postconditioning (I-PostC) provides a cardioprotective effect in combination with pharmacological agents. Although nitrates have been tested in many experimental and clinical studies of acute AMI to evaluate the cardioprotective effect, few investigations have been focused on nitrates postconditioning in patients undergoing percutaneous coronary intervention (PCI). This review presents the manifestations of myocardial reperfusion injury (RI) and potential mechanisms underlying it, and provides the mechanisms involved in the cardioprotection of I-PostC. We also present a new therapeutic approach to attenuate RI by use of an 'old' agent - nitrates - in AMI patients.

Topics: Animals; Humans; Ischemia; Ischemic Postconditioning; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Nitrates; Percutaneous Coronary Intervention

PubMed: 32516304
DOI: 10.12659/MSM.923129