High concentrations of nitrite present in saliva (derived from dietary nitrate) may, upon acidification, generate nitrogen oxides in the stomach in sufficient amounts to provide protection from swallowed pathogens. We now show that, in the rat, reduction of nitrate to nitrite is confined to a specialized area on the posterior surface of the tongue, which is heavily colonized by bacteria, and that nitrate reduction is absent in germ-free rats. We also show that in humans increased salivary nitrite production resulting from nitrate intake enhances oral nitric oxide production. We propose that the salivary generation of nitrite is accomplished by a symbiotic relationship involving nitrate-reducing bacteria on the tongue surface, which is designed to provide host defence against microbial pathogens in the mouth and lower gut. These results provide further evidence for beneficial effects of dietary nitrate.

SummaryBackgroundRemote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months.MethodsWe did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed.FindingsBetween Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91–1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed.InterpretationRemote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI.FundingBritish Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden.

Aims  A fractional flow reserve (FFR) value ≥0.90 after percutaneous coronary intervention (PCI) is associated with a reduced risk of adverse cardiovascular events. TARGET-FFR is an investigator-initiated, single-centre, randomized controlled trial to determine the feasibility and efficacy of a post-PCI FFR-guided optimization strategy vs. standard coronary angiography in achieving final post-PCI FFR values ≥0.90. Methods and results  After angiographically guided PCI, patients were randomized 1:1 to receive a physiology-guided incremental optimization strategy (PIOS) or a blinded coronary physiology assessment (control group). The primary outcome was the proportion of patients with a final post-PCI FFR ≥0.90. Final FFR ≤0.80 was a prioritized secondary outcome. A total of 260 patients were randomized (131 to PIOS, 129 to control) and 68.1% of patients had an initial post-PCI FFR <0.90. In the PIOS group, 30.5% underwent further intervention (stent post-dilation and/or additional stenting). There was no significant difference in the primary endpoint of the proportion of patients with final post-PCI FFR ≥0.90 between groups (PIOS minus control 10%, 95% confidence interval −1.84 to 21.91, P = 0.099). The proportion of patients with a final FFR ≤0.80 was significantly reduced when compared with the angiography-guided control group (−11.2%, 95% confidence interval −21.87 to −0.35], P = 0.045). Conclusion  Over two-thirds of patients had a physiologically suboptimal result after angiography-guided PCI. An FFR-guided optimization strategy did not significantly increase the proportion of patients with a final FFR ≥0.90, but did reduce the proportion of patients with a final FFR ≤0.80.

ObjectivePrimary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) is insufficiently implemented in many countries. We investigated patient and hospital characteristics associated with PPCI utilisation.MethodsWhole country registry data (MINAP, Myocardial Ischaemia National Audit Project) comprising PPCI-capable National Health Service trusts in England (84 hospital trusts; 92 350 hospitalisations; 90 489 patients), 2003–2013. Multilevel Poisson regression modelled the relationship between incidence rate ratios (IRR) of PPCI and patient and trust-level factors.ResultsOverall, standardised rates of PPCI increased from 0.01% to 86.3% (2003–2013). While, on average, there was a yearly increase in PPCI utilisation of 30% (adjusted IRR 1.30, 95% CI 1.23 to 1.36), it varied substantially between trusts. PPCI rates were lower for patients with previous myocardial infarction (0.95, 0.93 to 0.98), heart failure (0.86, 0.81 to 0.92), angina (0.96, 0.94 to 0.98), diabetes (0.97, 0.95 to 0.99), chronic renal failure (0.89, 0.85 to 0.90), cerebrovascular disease (0.96, 0.93 to 0.99), age >80 years (0.87, 0.85 to 0.90), and travel distances >30 km (0.95, 0.93 to 0.98). PPCI rates were higher for patients with previous percutaneous coronary intervention (1.09, 1.05 to 1.12) and among trusts with >5 interventional cardiologists (1.30, 1.25 to 1.34), more visiting interventional cardiologists (1–5: 1.31, 1.26 to 1.36; ≥6: 1.42, 1.35 to 1.49), and a 24 h, 7-days-a-week PPCI service (2.69, 2.58 to 2.81). Half of the unexplained variation in PPCI rates was due to between-trust differences.ConclusionsFollowing an 8 year implementation phase, PPCI utilisation rates stabilised at 85%. However, older and sicker patients were less likely to receive PPCI and there remained between-trust variation in PPCI rates not attributable to differences in staffing levels. Compliance with clinical pathways for STEMI is needed to ensure more equitable quality of care.