Background Mechanisms of postoperative delirium remain poorly understood, limiting development of effective treatments. We tested the hypothesis that intraoperative oxidative damage is associated with delirium and neuronal injury and that disruption of the blood–brain barrier modifies these associations. Methods In a prespecified cohort study of 400 cardiac surgery patients enrolled in a clinical trial of atorvastatin to reduce kidney injury and delirium, we measured plasma concentrations of F2-isoprostanes and isofurans using gas chromatography-mass spectrometry to quantify oxidative damage, ubiquitin carboxyl-terminal hydrolase isozyme L1 to quantify neuronal injury, and S100 calcium-binding protein B using enzyme-linked immunosorbent assays to quantify blood–brain barrier disruption before, during, and after surgery. We performed the Confusion Assessment Method for the Intensive Care Unit twice daily to diagnose delirium. We measured the independent associations between intraoperative F2-isoprostanes and isofurans and delirium (primary outcome) and postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (secondary outcome), and we assessed if S100 calcium-binding protein B modified these associations. Results Delirium occurred in 109 of 400 (27.3%) patients for a median (10th, 90th percentile) of 1.0 (0.5, 3.0) days. In the total cohort, plasma ubiquitin carboxyl-terminal hydrolase isozyme L1 concentration was 6.3 ng/ml (2.7, 14.9) at baseline and 12.4 ng/ml (7.9, 31.2) on postoperative day 1. F2-isoprostanes and isofurans increased throughout surgery, and the log-transformed sum of intraoperative F2-isoprostanes and isofurans was independently associated with increased odds of postoperative delirium (odds ratio, 3.70 [95% CI, 1.41 to 9.70]; P = 0.008) and with increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (ratio of geometric means, 1.42 [1.11 to 1.81]; P = 0.005). The association between increased intraoperative F2-isoprostanes and isofurans and increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 was amplified in patients with elevated S100 calcium-binding protein B (P = 0.049). Conclusions Intraoperative oxidative damage was associated with increased postoperative delirium and neuronal injury, and the association between oxidative damage and neuronal injury was stronger among patients with increased blood–brain barrier disruption. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Early generation β-blockers lower blood pressure and reduce cardiovascular morality in coronary artery disease and congestive heart failure, but worsen glucose homeostasis and fibrinolytic balance. Nebivolol is a third-generation β-blocker which increases the bioavailability of nitric oxide. We compared the effect of nebivolol (5mg/d) and the β1-selective antagonist metoprolol (100mg/d) on glucose homeostasis and markers of fibrinolysis in 46 subjects with metabolic syndrome. Subjects underwent a frequently sampled intravenous glucose tolerance test after 3-week washout and placebo treatment, and following randomized treatment with study drug. After 12-week treatment, nebivolol and metoprolol equivalently decreased systolic blood pressure, diastolic blood pressure, and heart rate. Neither drug affected beta cell function, disposition index, or acute insulin response to glucose. Metoprolol significantly decreased the insulin sensitivity index. In contrast, nebivolol did not affect insulin sensitivity, and the decrease in sensitivity was significantly greater following metoprolol than nebivolol (-1.5±2.5 × 10-4 × min-1 per mU/L versus 0.04±2.19 × 10-4 × min-1 per mU/L after nebivolol, P=0.03). Circulating plasminogen activator inhibitor also increased following treatment with metoprolol (from 9.8±6.8 to 12.3±7.8 ng/mL), but not nebivolol (from 10.8±7.8 to 10.5±6.2 ng/mL, P=0.05 versus metoprolol). Metoprolol, but not nebivolol, increased F2-isoprostane concentrations. In summary, treatment with metoprolol decreased insulin sensitivity and increased oxidative stress and the antifibrinolytic plasminogen activator inhibitor-1in patients with metabolic syndrome, whereas nebivolol lacked detrimental metabolic effects. Large clinical trials are needed to compare effects of nebivolol and the β1 receptor antagonist metoprolol on clinical outcomes in patients with hypertension and the metabolic syndrome.

Aims/hypothesis Obesity is associated with aldosterone excess, hypertension and the metabolic syndrome, but the relative contribution of aldosterone to obesity-related complications is debated. We previously demonstrated that aldosterone impairs insulin secretion, and that genetic aldosterone deficiency increases glucose-stimulated insulin secretion in vivo. We hypothesised that elimination of endogenous aldosterone would prevent obesity-induced insulin resistance and hyperglycaemia. Methods Wild-type and aldosterone synthase-deficient (As−/−) mice were fed a high-fat (HF) or normal chow diet for 12 weeks. We assessed insulin sensitivity and insulin secretion using clamp methodology and circulating plasma adipokines, and examined adipose tissue via histology. Results HF diet induced weight gain similarly in the two groups, but As−/− mice were protected from blood glucose elevation. HF diet impaired insulin sensitivity similarly in As−/− and wild-type mice, assessed by hyperinsulinaemic–euglycaemic clamps. Fasting and glucose-stimulated insulin were higher in HF-fed As−/− mice than in wild-type controls. Although there was no difference in insulin sensitivity during HF feeding in As−/− mice compared with wild-type controls, fat mass, adipocyte size and adiponectin increased, while adipose macrophage infiltration decreased. HF feeding significantly increased hepatic steatosis and triacylglycerol content in wild-type mice, which was attenuated in aldosterone-deficient mice. Conclusions/interpretation These studies demonstrate that obesity induces insulin resistance independently of aldosterone and adipose tissue inflammation, and suggest a novel role for aldosterone in promoting obesity-induced beta cell dysfunction, hepatic steatosis and adipose tissue inflammation.

No abstract

Epoxyeicosatrienoic acids (EETs) reduce blood pressure by acting in the vasculature and kidney, and interventions to increase circulating EETs improve insulin sensitivity and prevent diabetes in animal models. Inhibition of EET hydrolysis with a sEH (soluble epoxide hydrolase) inhibitor is an attractive approach for hypertension and diabetes. We tested the hypothesis that sEH inhibition increases circulating EETs, reduces blood pressure, and improves insulin sensitivity, blood flow, and inflammation in a randomized, double-blind, placebo-controlled crossover study. Sixteen participants with obesity and prediabetes were randomized to GSK2256294 10 mg QD or placebo for 7 days, insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and adipose and muscle tissues biopsies were performed to assess insulin-stimulated Akt phosphorylation. We assessed tissue and plasma EETs and their respective diol concentrations and sEH activity within plasma, muscle, and adipose tissues. GSK2256294 reduced circulating and adipose tissue sEH activity, but blood pressure, circulating EET, and tissue EETs were unchanged. Plasma sEH activity correlated with muscle and adipose tissue sEH activity. Insulin sensitivity assessed during hyperinsulinemic clamps, as well as adipose and muscle phosphorylated-Akt/Akt expression were similar during GSK2256294 and placebo. sEH inhibition with GSK2256294 reduced plasma F2-isoprostanes (50.7±15.8 versus 37.2±17.3 pg/mL; P =0.03) but not IL (interleukin)-6. Resting blood pressure, forearm blood flow, and renal plasma flow were similar during GSK2256294 and placebo. We demonstrate that GSK2256294 administration for 7 days effectively inhibits sEH activity in plasma, muscle, and adipose tissue and reduces F2-isoprostanes—a marker of oxidative stress—but does not improve insulin sensitivity or blood pressure.