Objective: Glucagon-like-peptide-1 (GLP-1) receptor analogues have been shown to reduce cardiovascular events in patients with type 2 diabetes. However, the mechanism behind is still unknown. The aim of the study was to investigate the effect of intact GLP-1 (7-36) on coronary microcirculation in overweight adults. Design and methods: A double-blinded randomized cross-over study was performed, with 12 overweight participants. Effects of intact GLP-1 (7-36) infusion were compared with a saline infusion on separate days. A DPP-4 inhibitor was administered to block degradation of intact GLP-1 (7-36) to the GLP-1 metabolite (9-36). Coronary microcirculation was assessed by Doppler coronary flow velocity reserve (CFVR) before and after 2 h of infusion. Peripheral endothelial function was assessed by flow mediated dilation (FMD) before and after one hour of infusion. Results: CFVR was 3.77 +/- 1.25 during GLP-1 infusion and 3.85 +/- 1.32 during saline infusion, endothelial function was 16.3 +/- 15.5 % during GLP-1 infusion and 7.85 +/- 7.76 % during saline infusion. When adjusting for baseline values no significant differences in CFVR (Delta CFVR 0.38 +/- 0.92 vs. Delta CFVR 0.71 +/- 1.03, p = 0.43) and no difference in peripheral endothelial function (Delta FMD 7.34 +/- 11.5 % vs. Delta FMD-1.25 +/- 9.23%, p=0.14) was found. Conclusions: We found no effect of intact GLP-1 (7-36), protected from DPP4 mediated degradation on coronarymicrocirculation in overweight adults. (c) 2019 The Authors. Published by Elsevier B.V.

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.

PURPOSE:We investigated whether impaired flow-mediated dilation (FMD) and plasma biomarkers reflecting endothelial dysfunction are associated with coronary microvascular dysfunction (CMD) in women with angina and no obstructive coronary artery disease (CAD).METHODS:Patients (n = 194) were randomly selected women with angina pectoris and no obstructive CAD (<50% stenosis). A reference population of asymptomatic women without CAD (n = 25) was included. We measured FMD in the brachial artery by high-resolution ultrasound. Coronary flow velocity reserve (CFVR) was assessed by transthoracic Doppler flow echocardiography (TTDE) of the left anterior descending artery during rest and high-dose dipyridamole infusion. CMD was defined as CFVR <2.RESULTS:FMD and CFVR were measured in 128 patients and 21 controls. Mean (SD) age was 64.5 (8.9) years, mean CFVR was 2.3 (2.0-2.7), and mean FMD was 8.4% (4.8%) in angina patients. Angina patients had a higher risk factor burden compared with the reference population. Measures of peripheral endothelial dysfunction and endothelial plasma biomarkers did not differ according to angina or CFVR. CFVR and FMD did not correlate (Spearman ρ = -0.07, p = 0.45).CONCLUSIONS:FMD and biomarkers of endothelial dysfunction did not identify individuals with CMD assessed as impaired CFVR by TTDE in women with angina and no obstructive CAD.

AimsStable angina is the most common presentation of heart disease and has a good prognosis. With declining coronary artery disease (CAD), rates a diagnostic approach balancing costs and benefits is a challenge, particularly in women. This study describes the real-life diagnostic workup in a large hospital to explore whether the diagnostic approach may be improved.Methods and resultsWe identified 4028 patients free of CAD, referred for and assessed with non-invasive (NIT) or invasive test for stable suspected CAD in 2012-15. In both the sexes, the majority (>85%) presented with chest pain as primary symptom. Women had more non-angina (60.2 vs. 54.5%) and less typical angina (8.2 vs. 11.8%, P < 0.001). Despite a mean pretest probability of 20.9% in women and 45.1% in men (P < 0.001), only 69 (3.1%) women and 190 men (10.4%) were diagnosed with obstructive CAD. In all, 93% underwent a NIT and 80% of these were normal. Among the 1238 men and 1595 women with non-angina or dyspnoea, only 6.1% and 2.9%, respectively, had positive NIT. After multiple adjustments, women remained less likely to have positive NIT [odds ratio (OR) 0.42 95% confidence interval (95% CI 0.32-0.56)] and given a positive test also less likely to have obstructive CAD [OR 0.30 (0.17-0.52)]. The C-statistics for predicting positive NIT was 0.77 (0.72-0.82) in women and 0.77 (0.74-0.80) in men.ConclusionThese data confirm the very low diagnostic yield of non-invasive and invasive assessment of CAD in current clinical practice, particularly in women and in patients with atypical symptoms. Data call for a more rational approach to avoid unnecessary testing.

Background: Angina pectoris is the most common symptom of coronary artery disease (CAD) among women but large studies have indicated low diagnostic yield of invasive coronary angiography (ICA). It is well accepted that women have more atypical symptoms and that some tests perform less well in women. Purpose: To examine whether symptoms and non-invasive test result (NIT) are less predictive of obstructive CAD in women compared to men in a large city hospital. Methods: Patients referred for assessment of stable CAD in 2012-2014 in a single center were included. Information on symptoms, risk factors, results of NIT and ICA was gathered from registries and patient records. Ability of symptoms and NIT result to predict obstructive CAD in men and women was compared in multiple adjusted logistic regression models by testing for statistical interaction. Results: A total of 2763 patients were included, 1462 (53%) women. Women were older (59.1 vs 56.4 years, p<0.0001), more likely to have non-anginal chest pain and...

Coronary allograft vasculopathy is a well-known long-term 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. Twenty-seven 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.

BACKGROUND:Carvedilol has been shown to be superior to metoprolol tartrate to improve clinical outcomes in patients with heart failure (HF), yet the mechanisms responsible for these differences remain unclear. We examined if there were differences in endothelial function, insulin stimulated endothelial function, 24 hour ambulatory blood pressure and heart rate during treatment with carvedilol, metoprolol tartrate and metoprolol succinate in patients with HF.METHODS:Twenty-seven patients with mild HF, all initially treated with carvedilol, were randomized to a two-month treatment with carvedilol, metoprolol tartrate or metoprolol succinate. Venous occlusion plethysmography, 24-hour blood pressure and heart rate measurements were done before and after a two-month treatment period.RESULTS:Endothelium-dependent vasodilatation was not affected by changing from carvedilol to either metoprolol tartrate or metoprolol succinate. The relative forearm blood flow at the highest dose of serotonin was 2.42 ± 0.33 in the carvedilol group at baseline and 2.14 ± 0.24 after two months continuation of carvedilol (P = 0.34); 2.57 ± 0.33 before metoprolol tartrate treatment and 2.42 ± 0.55 after treatment (p = 0.74) and in the metoprolol succinate group 1.82 ± 0.29 and 2.10 ± 0.37 before and after treatment, respectively (p = 0.27). Diurnal blood pressures as well as heart rate were also unchanged by changing from carvedilol to metoprolol tartrate or metoprolol succinate.CONCLUSION:Endothelial function remained unchanged when switching the beta blocker treatment from carvedilol to either metoprolol tartrate or metoprolol succinate in this study, where blood pressure and heart rate also remained unchanged in patients with mild HF.TRIAL REGISTRATION:Current Controlled Trials NCT00497003.

Aim: Chronic heart failure is associated with endothelial dysfunction and insulin resistance. The aim of this investigation was to study insulin-stimulated endothelial function and glucose uptake in skeletal muscles in patients with heart failure in comparison to patients with type 2 diabetes.Methods: Twenty-three patients with systolic heart failure and no history of diabetes, seven patients with both systolic heart failure and type 2 diabetes, 19 patients with type 2 diabetes, and ten healthy controls were included in the study. Endothelial function was studied by venous occlusion plethysmography. Insulin-stimulated endothelial function was assessed after intra-arterial infusion of insulin followed by co-infusion with serotonin in three different dosages. Forearm glucose uptake was measured during the insulin infusion.Results: Patients with systolic heart failure had impaired insulin-stimulated endothelial function. The percentage increase in blood flow during co-infusion with insulin and serotonin dose response study was 24.74% +/- 6.16%, 23.50% +/- 8.32%, and 22.29% +/- 10.77% at the three doses respectively, compared to the healthy control group 45.96% +/- 11.56%, 67.40% +/- 18.11% and 84.57% +/- 25.73% (P = 0.01). Insulin-stimulated endothelial function was similar in heart failure patients and patients with type 2 diabetes, while it was further deteriorated in patients suffering from both heart failure and diabetes with a percentage increase in blood flow of 19.15% +/- 7.81%, -2.35% +/- 11.76%, and 5.82% +/- 17.70% at the three doses of serotonin, -respectively. Forearm glucose uptake was impaired in patients with heart failure compared to healthy controls (P = 0.03) and tended to be further impaired by co-existence of diabetes (P = 0.08).Conclusion: Systolic heart failure and type 2 diabetes result in similar vascular insulin resistance and reduced muscular insulin-stimulated glucose uptake. The effects of systolic heart failure and type 2 diabetes appear to be additive.

Studies of beta blockade in patients with type 2 diabetes have shown inferiority of metoprolol treatment compared to carvedilol on indices of insulin resistance. The aim of this study was to examine the effect of metoprolol versus carvedilol on endothelial function and insulin-stimulated endothelial function in patients with type 2 diabetes.

Ingestion of glucosinolates has previously been reported to improve endothelial function in spontaneously hypertensive rats, possibly because of an increase in NO availability in the endothelium due to an attenuation of oxidative stress; in our study we tried to see if this also would be the case in humans suffering from essential hypertension. Methods 40 hypertensive individuals without diabetes and with normal levels of cholesterol were examined. The participants were randomized either to ingest 10 g dried broccoli sprouts, a natural donor of glucosinolates with high in vitro antioxidative potential, for a 4 week period or to continue their ordinary diet and act as controls. Blood pressure, endothelial function measured by flow mediated dilation (FMD) and blood samples were obtained from the participants every other week and the content of glucosinolates was measured before and after the study. Measurements were blinded to treatment allocation. Results In the interventional group overall FMD increased from 4% to 5.8% in the interventional group whereas in the control group FMD was stable (4% at baseline and 3.9% at the end of the study). The change in FMD in the interventional group was mainly due to a marked change in FMD in two participants while the other participants did not have marked changes in FMD. The observed differences were not statistically significant. Likewise significant changes in blood pressure or blood samples were not detected between or within groups. Diastolic blood pressure stayed essentially unchanged in both groups, while the systolic blood pressure showed a small non significant decrease (9 mm Hg) in the interventional group from a value of 153 mm Hg at start. Conclusion Daily ingestion of 10 g dried broccoli sprouts does not improve endothelial function in the presence of hypertension in humans. Trial Registration Clinicaltrials.gov NCT00252018

Background/aims. Postprandial hyperglycemia, an independent risk factor for cardiovascular disease, is accompanied by endothelial dysfunction. We studied the effect of oral glucose load on insulin and glucose fluctuations, and on postprandial endothelial function in healthy individuals in order to better understand and cope with the postprandial state in insulin resistant individuals. Methods. We assessed post-oral glucose load endothelial function (flow mediated dilation), plasma insulin, and blood glucose in 9 healthy subjects. Results. The largest increases in delta FMD values (fasting FMD value subtracted from postprandial FMD value) occurred at 3 hours after both glucose or placebo load, respectively: 4.80 +/- 1.41 (P = .009) and 2.34 +/- 1.47 (P = .15). Glucose and insulin concentrations achieved maximum peaks at one hour post-glucose load. Conclusion. Oral glucose load does not induce endothelial dysfunction in healthy individuals with mean insulin and glucose values of 5.6 mmol/L and 27.2 mmol/L, respectively, 2 hours after glucose load. Copyright (C) 2008 A. Major-Pedersen et al.

The aim of the study is to determine if attenuation of postprandial hyperglycemia, by acutely and chronically enhancing postprandial insulin secretion in insulin-resistant individuals, improves the endothelial dysfunction. We assessed postoral glucose-load endothelial function in 56 insulin-resistant subjects with the Flow-Mediated-Dilation (FMD) technique. We randomized subjects to intervention/control group, and examined the acute and chronic effect of nateglinide, an oral antidiabetic drug of rapid action. In the intervention group, postoral glucose-load (post-OGL) FMD delta values deteriorated when compared to pre-OGL values, most significantly at 3 h post-OGL, on the following days: on the first study day termed "Baseline day" (p=0.04); on both days after 3 months of nateglinide treatment [with nateglinide administered on study-day "acute+chronic" (p=0.01); and without nateglinide on study-day "Closing day", p=0.001]. Post-OGL changes in the control group were nonsignificant both at Baseline and on Closing day. After a single dose of nateglinide "Acute day", post-OGL FMD deterioration was abolished. There was an increment in post-OGL FMD delta values most significant at 2 h post-OGL (p=0.02). Insulin concentrations increased while glucose concentrations decreased on study-days with nateglinide when compared to study-days without (p=<0.001 for both insulin and glucose). Comparisons for insulin and glucose concentrations between days with nateglinide, and likewise between days without, showed no significant difference. Postglucose load endothelial dysfunction can be prevented by administration of nateglinide, however, after 3 months of nateglinide treatment, this effect is abolished. Chronically increased insulin secretion could counteract the initial beneficial effect of reduced glucose excursions. We found no relationship between postprandial hyperglycemia and post-OGL FMD.

OBJECTIVEAngiotensin-converting enzyme inhibitors reduce cardiovascular mortality and improve endothelial function in type 2 diabetic patients. We hypothesized that 2 months of quinapril treatment would improve insulin-stimulated endothelial function and glucose uptake in type 2 diabetic subjects and simultaneously increase the expression of genes that are pertinent for endothelial function and metabolism.METHODSTwenty-four type 2 diabetic subjects were randomized to receive 2 months of quinapril 20 mg daily or no treatment in an open parallel study. Endothelium-dependent and -independent vasodilation was studied during serotonin or sodium nitroprusside infusion in the diabetic patients and in 15 healthy subjects. Endothelial function, insulin-stimulated endothelial function, and insulin-stimulated glucose uptake were measured before and after quinapril treatment. Blood flow was measured by venous occlusion plethysmography. Gene expression was measured by real-time PCR.RESULTSQuinapril treatment increased insulin-stimulated endothelial function in the type 2 diabetic subjects (P = 0.005), whereas forearm glucose uptake was unchanged. Endothelial function was also increased by quinapril (P = 0.001). Systolic and diastolic blood pressures were reduced by quinapril (P < 0.001). Quinapril increased adiponectin gene expression in vascular tissue obtained from sc adipose biopsies.CONCLUSIONSQuinapril treatment increases insulin-stimulated endothelial function in patients with type 2 diabetes. Increased vascular adiponectin gene expression may contribute to this beneficial effect.

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.