Objective: The pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) impairs insulin action in insulin-sensitive tissues, such as fat, muscle and endothelium, and causes endothelial dysfunction. We hypothesized that TNF-α blockade with etanercept could reverse vascular and metabolic insulin resistance. Method and Results: Twenty obese patients with type 2 diabetes were randomized to etanercept treatment (25 mg subcutaneously twice weekly for 4 weeks) or used as controls in an open parallel study. Forearm blood flow and glucose uptake were measured during intra-arterial infusions of serotonin, sodium nitroprusside and insulin co-infused with serotonin. β-Cell function was assessed with oral and intra-venous glucose tolerance tests and whole-body insulin sensitivity by hyperinsulinemic euglycemic clamps. Plasma levels of C-reactive protein and interleukin-6 decreased significantly with etanercept (C-reactive protein from 9.9 ± 3.1 to 4.8 ± 1.4 mg l^–1, p = 0.04; interleukin-6 from 3.1 ± 0.4 to 1.9 ± 0.2 ng l^–1, p = 0.03). Vasodilatory responses to serotonin and sodium nitroprusside infusions remained unchanged. Insulin effect on vasodilatation and on whole-body and forearm glucose uptake remained unchanged as well. β-Cell function tended to improve. Conclusion: Although short-term etanercept treatment had a significant beneficial effect on systemic inflammatory markers, no improvement of vascular or metabolic insulin sensitivity was observed.

Aims We hypothesized that the modified Diamond–Forrester (D-F) prediction model overestimates probability of coronary artery disease (CAD). The aim of this study was to update the prediction model based on pre-test information and assess the model’s performance in predicting prognosis in an unselected, contemporary population suspected of angina. Methods and results We included 3903 consecutive patients free of CAD and heart failure and suspected of angina, who were referred to a single centre for assessment in 2012–15. Obstructive CAD was defined from invasive angiography as lesion requiring revascularization, >70% stenosis or fractional flow reserve <0.8. Patients were followed (mean follow-up 33 months) for myocardial infarction, unstable angina, heart failure, stroke, and death. The updated D-F prediction model overestimated probability considerably: mean pre-test probability was 31.4%, while only 274 (7%) were diagnosed with obstructive CAD. A basic prediction model with age, gender, and symptoms demonstrated good discrimination with C-statistics of 0.86 (95% CI 0.84–0.88), while a clinical prediction model adding diabetes, family history, and dyslipidaemia slightly improved the C-statistic to 0.88 (0.86–0.90) (P for difference between models <0.0001). Quartiles of probability of CAD from the clinical prediction model provided good diagnostic and prognostic stratification: in the lowest quartiles there were no cases of obstructive CAD and cumulative risk of the composite endpoint was less than 3% at 2 years. Conclusion The pre-test probability model recommended in current ESC guidelines substantially overestimates likelihood of CAD when applied to a contemporary, unselected, all-comer population. We provide an updated prediction model that identifies subgroups with low likelihood of obstructive CAD and good prognosis in which non-invasive testing may safely be deferred.

Coronary allograft vasculopathy is a well-known longterm complication after cardiac transplantation. Endothelial dysfunction is involved and may be prevented by aerobic exercise. The purpose of this study was to examine whether high intensity aerobic exercise improves peak oxygen uptake (VO 2 peak ) and endothelial function in heart transplant (HT) recipients. Twentyseven long-term HT recipients were randomized to either 8-weeks high intensity aerobic exercise or no training. Flow mediated dilation of the brachial artery (FMD) was measured by ultrasound and VO 2 peak by the analysis of expired air. Blood pressure and biomarkers were measured before and after 8 weeks. VO 2 peak increased significantly in the exercise group (VO 2 peak 23.9 ± 1.79 to 28.3 ± 1.63 mL/kg/min compared to controls (VO 2 peak 24.6 ± 1.38 to 23.4 ± 1.58, p < 0.001 exercise vs. control).FMD increased in the exercise group compared to controls (8.3 ± 1.1% to 11.4 ± 1.2% vs. 5.6 ± 1.0% to 5.3 ± 1.7%, p = 0.024). No increase in nitroglycerin-induced vasodilation was observed. Systolic blood pressure fell in the exercise group (142 ± 4.2 mmHg to127 ± 3.4 mmHg, p = 0.01) and was unchanged in controls (141 ± 4.2 mmHg to 142 ± 6.4 mmHg, NS). High intensity aerobic exercise reduces systolic blood pressure and improves endothelial function in HT recipients.Key words: Blood pressure, endothelial dysfunction, exercise, exercise testing, heart transplantation Abbreviations: ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CRP, C-reactive protein; FMD, flow mediated vasodilation; HT, heart transplant; IHD, ischemic heart disease; DCM, dilated cardiomyopathy; NTG, nitroglycerin; TNF-alfa, tumor necrosis factor-alfa; VO 2peak , peak oxygen uptake.

Background-Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-␣ inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans. Methods and Results-Healthy, lean male volunteers were studied. On each study day, 3 acetylcholine (ACh) or sodium nitroprusside (SNP) dose-response studies were performed by infusion into the brachial artery. Before and during the last 2 dose-response studies, insulin and/or TNF-␣ were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220Ϯ44%. This increase was completely inhibited during coinfusion of TNF-␣ (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF-␣ inhibited the ACh forearm blood flow response (PϽ0.001), and this inhibition was larger during insulin infusion (Pϭ0.01) but not further increased by N G -monomethyl-L-arginine acetate (Pϭ0.2). Insulin potentiated the SNP response less than the ACh response and the effect of TNF-␣ was smaller (PϽ0.001); TNF-␣ had no effect on the SNP response without insulin infusion. Thus, TNF-␣ inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production. Conclusion-These results support the concept that TNF-␣ could play a role in the development of insulin resistance in humans, both in muscle and in vascular tissue.