8-Isoprostanes and Asymmetric Dimethylarginine as Predictors of Mortality in Patients Following Coronary Bypass Surgery: A Long-Term Follow-Up Study

Background: We previously demonstrated that enhanced oxidative stress and reduced nitric oxide bioavailability are associated with unfavorable outcomes early after coronary artery bypass grafting. It is not known whether these processes may impact long-term results. We sought to assess whether during long-term follow-up, markers of oxidative stress and nitric oxide bioavailability may predict cardiovascular mortality following bypass surgery. Methods: We studied 152 consecutive patients (118 men, age 65.2 ± 8.3 years) who underwent elective, primary, isolated on-pump bypass surgery. We measured plasma 8-iso-prostaglandin F2α and asymmetric dimethylarginine before surgery and twice after surgery (18–36 h and 5–7 days). We assessed all-cause and cardiovascular death in relation to these two biomarkers during a mean follow-up time of 11.7 years. Results: The overall mortality was 44.7% (4.7 per 100 patient-years) and cardiovascular mortality was 21.0% (2.2 per 100 patient-years). Baseline 8-iso-prostaglandin F2α was associated with cardiovascular mortality (HR 1 pg/mL 1.010, 95% CI 1.001–1.021, p = 0.036) with the optimal cut-off ≤ 364 pg/mL for higher survival rate (HR 0.460, 95% CI 0.224–0.942, p = 0.030). Asymmetric dimethylarginine > 1.01 μmol/L measured 18–36 h after surgery also predicted cardiovascular death (HR 2.467, 95% CI 1.140–5.340, p = 0.020). Additionally, elevated 8-iso-prostaglandin F2α measured at the same time point associated with all-cause mortality (HR 1 pg/mL 1.007, 95% CI 1.000–1.014, p = 0.048). Conclusions: Our findings indicate that in advanced coronary disease, increased oxidative stress, reflected by 8-iso-prostaglandin F2α before bypass surgery and enhanced asymmetric dimethylarginine accumulation just after the surgery are associated with cardiovascular death during long-term follow-up

Effect of food sources of nitrate, polyphenols, L-arginine and L-citrulline on endurance exercise performance: a systematic review and meta-analysis of randomised controlled trials

Background Increasing nitric oxide bioavailability may induce physiological effects that enhance endurance exercise performance. This review sought to evaluate the performance effects of consuming foods containing compounds that may promote nitric oxide bioavailability. Methods Scopus, Web of Science, Ovid Medline, EMBASE and SportDiscus were searched, with included studies assessing endurance performance following consumption of foods containing nitrate, L-arginine, L-citrulline or polyphenols. Random effects meta-analysis was conducted, with subgroup analyses performed based on food sources, sex, fitness, performance test type and supplementation protocol (e.g. duration). Results One hundred and eighteen studies were included in the meta-analysis, which encompassed 59 polyphenol studies, 56 nitrate studies and three L-citrulline studies. No effect on exercise performance following consumption of foods rich in L-citrulline was identified (SMD=-0.03, p=0.24). Trivial but significant benefits were demonstrated for consumption of nitrate and polyphenol-rich foods (SMD=0.15 and 0.17, respectively, p<0.001), including performance in time-trial, time-to-exhaustion and intermittent-type tests, and following both acute and multiple-day supplementation, but no effect of nitrate or polyphenol consumption was found in females. Among nitrate-rich foods, beneficial effects were seen for beetroot, but not red spinach or Swiss chard and rhubarb. For polyphenol-rich foods, benefits were found for grape, (nitrate-depleted) beetroot, French maritime pine, Montmorency cherry and pomegranate, while no significant effects were evident for New Zealand blackcurrant, cocoa, ginseng, green tea or raisins. Considerable heterogeneity between polyphenol studies may reflect food-specific effects or differences in study designs and subject characteristics. Well-trained males (V̇O2max ≥65 ml.kg.min-1) exhibited small, significant benefits following polyphenol, but not nitrate consumption. Conclusion Foods rich in polyphenols and nitrate provide trivial benefits for endurance exercise performance, although these effects may be food dependent. Highly trained endurance athletes do not appear to benefit from consuming nitrate-rich foods but may benefit from polyphenol consumption. Further research into food sources, dosage and supplementation duration to optimise the ergogenic response to polyphenol consumption is warranted. Further studies should evaluate whether differential sex-based responses to nitrate and polyphenol consumption are attributable to physiological differences or sample size limitations. Other The review protocol was registered on the Open Science Framework (https://osf.io/u7nsj) and no funding was provided.

Relationship between endothelin and nitric oxide pathways in the onset and maintenance of hypertension in children and adolescents

The mechanisms that regulate blood pressure are numerous and complex; one mechanism that plays an important role in this scenario is represented by the balance between the vasoconstrictor effect of endothelin-1 and the vasodilator effect of nitric oxide. While there is agreement on the fact that increased endothelin-1 activity and decreased nitric oxide bioavailability are present in hypertensive adults, the situation is less clear in children and adolescents. Not all studies agree on the finding of an increase in plasma endothelin-1 levels in hypertensive children and adolescents; in addition, the picture is often confused by the concomitant presence of obesity, a condition that stimulates the production of endothelin-1. Furthermore, there is recent evidence that, in younger obese and hypertensive subjects, there is an overproduction of nitric oxide, rather than a reduction. This condition may change over time, causing endothelial dysfunction due to a reduced availability of nitric oxide in hypertensive adolescents. The purpose of this review is to address the main biochemical and pathophysiological aspects of endothelin and nitric oxide involvement in hypertension and to summarize the available scientific evidence on their role in the onset and maintenance of high blood pressure in children and adolescents.

A Low-Sodium Diet Boosts Ang (1–7) Production and NO-cGMP Bioavailability to Reduce Edema and Enhance Survival in Experimental Heart Failure

Sodium restriction is often recommended in heart failure (HF) to block symptomatic edema, despite limited evidence for benefit. However, a low-sodium diet (LSD) activates the classical renin-angiotensin-aldosterone system (RAAS), which may adversely affect HF progression and mortality in patients with dilated cardiomyopathy (DCM). We performed a randomized, blinded pre-clinical trial to compare the effects of a normal (human-equivalent) sodium diet and a LSD on HF progression in a normotensive model of DCM in mice that has translational relevance to human HF. The LSD reduced HF progression by suppressing the development of pleural effusions (p < 0.01), blocking pathological increases in systemic extracellular water (p < 0.001) and prolonging median survival (15%, p < 0.01). The LSD activated the classical RAAS by increasing plasma renin activity, angiotensin II and aldosterone levels. However, the LSD also significantly up-elevated the counter-regulatory RAAS by boosting plasma angiotensin converting enzyme 2 (ACE2) and angiotensin (1–7) levels, promoting nitric oxide bioavailability and stimulating 3′-5′-cyclic guanosine monophosphate (cGMP) production. Plasma HF biomarkers associated with poor outcomes, such as B-type natriuretic peptide and neprilysin were decreased by a LSD. Cardiac systolic function, blood pressure and renal function were not affected. Although a LSD activates the classical RAAS system, we conclude that the LSD delayed HF progression and mortality in experimental DCM, in part through protective stimulation of the counter-regulatory RAAS to increase plasma ACE2 and angiotensin (1–7) levels, nitric oxide bioavailability and cGMP production.