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Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome’s functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation.

Background Patients with cirrhosis suffer from a complex multiorgan disturbance and their prognosis is influenced by the development of portal hypertension and systemic circulatory dysfunction. Although non-invasive techniques such as transient elastography aid in early detection, there is an unmet need for reliable markers of these clinically significant complications. Methods We conducted an exploratory single-center study investigating dipeptidyl peptidase-3 (DPP3) concentrations in various vascular beds in a cohort of 48 patients with cirrhosis and 16 healthy controls. Liver vein catheterisation with sampling from femoral artery and femoral, renal and hepatic veins as well as measurement of hepatic pressure and liver function via indocyanine green and galactose elimination tests were performed. Results DPP3 concentrations were higher in cirrhotic patients compared to controls (12.6 vs. 7.4 ng/mL, p = 0.006) and increased according to the severity of cirrhosis. DPP3 associated with MELD-Na score, Child class, indocyanine green clearance, increased DPP3 with the increased hepatic venous pressure gradient (p = 0.015) as well as increased heart rate and reduced systemic vascular resistance. DPP3 concentrations predicted the presence of clinically significant portal hypertension in cirrhotic patients (AUROC 0.78, 95% CI 0.65-0.9). Conclusion DPP3 is a promising marker for portal hypertension and systemic hemodynamic changes in cirrhosis.

Background: Somatostatin inhibits intestinal motility and hormonal secretion and is a potent arterial vasoconstrictor of the splanchnic blood flow. It is unknown if somatostatin concentrations are associated with central hemodynamic measurements in patients with advanced heart failure (HF). Methods: A prospective study of HF patients with a left ventricular ejection fraction (LVEF) 45% referred to right heart catheterization (RHC) for evaluation for heart transplantation (HTX) or left ventricular assist device (LVAD). Results: Fifty-Three patients were included with mean LVEF 18 ± 8% and majority in NYHA-class III-IV (79%). Median plasma somatostatin concentration was 18 pmol/L. In univariable regression analysis, log(somatostatin) was associated with increased central venous pressure (CVP; r2 = 0.14, p = 0.003) and a reduced cardiac index (CI; r2 = 0.15, p = 0.004). When adjusted for selected clinical variables (age, gender, LVEF, eGFR and BMI), log(somatostatin) remained a significant predictor of CVP (p = 0.044). Increased somatostatin concentrations predicted mortality in multivariable models (hazard ratio: 5.2 [1.2-22.2], p = 0.026) but not the combined endpoint of death, LVAD implantation or HTX. Conclusions: Somatostatin concentrations were associated with CVP and CI in patients with HF. The pathophysiological mechanism may be related to congestion and/or hypoperfusion of the intestine. Somatostatin was an independent predictor of mortality in advanced HF.

Background: Takotsubo cardiomyopathy (TTC) is a syndrome of acute non-coronary heart failure with similar symptoms and electrocardiograms to acute anterior ST-elevation myocardial infarction (STEMI). Little is known about the pathophysiology of TTC. We assessed admission plasma concentrations of biomarkers reflecting neuroendocrine response (copeptin, mid-regional-pro-adrenomedullin, pro-atrial-natriuretic-peptide, soluble thrombomodulin (sTM), syndecan-1) and inflammation (suppression-of-tumorigenicity 2 (ST2), high-sensitive C-reactive-protein) in TTC patients and compared to patients with acute anterior STEMI.Materials and methods: Twenty TTC patients were matched with 40 STEMI patients by age, gender and left ventricular ejection fraction. Blood was sampled upon hospital admission immediately before acute coronary angiography.Results: The groups had similar comorbidities. TTC patients had higher plasma concentrations of sTM: 7.94 (5.89;9.61) vs. 6.42 (5.50;7.82)ng/ml, p = 0.04 and ST2 (53 (32;157) vs. 45 (31;55)ng/ml, p = 0.008) and higher heart rate: 101 ([Formula: see text]33) vs. 76([Formula: see text]14)bpm, p = 0.0001, but lower concentrations of copeptin (10.4 (7.6;39) vs. 92.3 (13;197)pmol/l, p < 0.05) and troponin T (348 (98;759) vs. 1190 (261;4105)ng/l, p = 0.04).Conclusion: TTC patients had higher plasma concentrations of sTM and ST2, higher heart rate and lower copeptin and troponin T concentrations compared to acute anterior STEMI patients. This study contributes to the hypothesis that TTC patients have endothelial cell damage and are hemodynamically more stable than patients with acute anterior STEMI on admission.

Aims Patients with type 1 diabetes have a high risk of cardiovascular disease. Yet, the importance of routine assessment of myocardial function in patients with type 1 diabetes is not known. Thus, we examined the prognostic importance of NT-proBNP and E/e', an echocardiographic measure of diastolic function, in type 1 diabetes patients with preserved left ventricular ejection fraction (LVEF) and without known heart disease. Methods and Results Type 1 diabetes patients without known heart disease and LVEF ≥ 45% enrolled in the Thousand and1 study were included and followed through nationwide registries. The risk of major cardiovascular events (MACE) and death associated with levels of NT-proBNP and E/e' was examined. Of 960 patients, median follow-up of 6.3 years (Q1-Q3: 5.7-7.0), 121 (12%) experienced MACE and 51 (5%) died. Increased levels of both NT-proBNP and E/e' were associated with worse outcomes (adjusted hazard ratios for MACE = 1.56 (1.23-1.98) and 4.29 (2.25-8.16) per Loge increase for NT-proBNP and E/e', respectively). NTproBNP and E/e' combined significantly improved the discrimination power of the Steno T1D risk engine (MACE, C-index: 0.813 (0.779-0.847) vs 0.779 (0.742-0.816); P=0.0001; All-cause mortality, C-index 0.855 (0.806-0.903) vs 0.828 (0.776-0.880); P=0.03). Conclusion In patients with type 1 diabetes, preserved ejection fraction, and no known heart disease, NT-proBNP and E/e' were associated with increased risk of MACE and all-cause mortality. The risks associated with NT-proBNP and E/e' combined identified patients at remarkably high risk.

Von Willebrand disease (VWD) is an inherited bleeding disorder with abnormal primary haemostasis due to defects in, or decreased concentration of the glycoprotein von Willebrand factor. In Denmark, the estimated prevalence of VWD is 1% corresponding to approximately 50,000 patients, but only a few hundred have been diagnosed, mostly due to prolonged bleeding after a trauma or during surgery. Thus, VWD is underdiagnosed in the general population. Improved anamnestic screening for bleeding disorders such as VWD in certain high-risk groups can facilitate institution of prophylactic treatment.

Plasma concentrations of pro-Atrial natriuretic peptide, proANP, are decreased in obesity and diabetes. Decreased proANP concentrations have also been noted after meal intake, and recently, a glucose-mediated regulation of ANP gene expression was reported. Hence, we evaluated the effects of insulin, glucagon and glucose on plasma proANP in a series of observational and experimental studies. Six healthy men underwent seven days of bed rest. Before and after the bed rest, hyperinsulinemic euglycemic clamps with serial plasma measurements of proANP were performed. Moreover, plasma proANP was quantified in 65 individuals with normal or impaired glucose regulation. Finally, the effects of infusion-induced hyperglucagonemia were examined in ten healthy men. Bed rest decreased insulin sensitivity and plasma proANP. The decrease in proANP was not associated with insulin sensitivity and the peptide concentrations remained constant during euglycemic hyperinsulinemia and hyperglycemic hyperglucagonemia. Impaired glucose regulation was not associated with decreased proANP concentrations. Bed rest per se induces a marked decrease in plasma proANP concentrations whereas insulin resistance and impaired glucose regulation was not associated with lower proANP concentrations. Neither acute hyperinsulinemia nor hyperglucagonemia seems to affect plasma proANP. Our findings thus suggest that decreased plasma proANP concentrations occur late in the development of insulin resistance.

The natriuretic peptides (NPs), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), have vasoactive functions that concern humans and most animals, but their specific effects on cerebral circulation are poorly understood. We therefore examined the responsiveness of cerebral arteries to different doses of the natriuretic peptides in animals and humans. We conducted a dose-response experiment in guinea pigs (in vitro) and a double-blind, three-way cross-over study in healthy volunteers (in vivo). In the animal experiment, we administered cumulative doses of NPs to pre-contracted segments of cerebral arteries. In the main study, six healthy volunteers were randomly allocated to receive two intravenous doses of ANP, BNP or CNP, respectively, over 20 min on three separate study days. We recorded blood flow velocity in the middle cerebral artery (VMCA) by transcranial Doppler. In addition, we measured temporal and radial artery diameters, headache response and plasma concentrations of the NPs. In guinea pigs, ANP and BNP but not CNP showed significant dose-dependent relaxation of cerebral arteries. In healthy humans, NP infusion had no effect on mean VMCA, and we found no difference in hemodynamic responses between the NPs. Furthermore, natriuretic peptides did not affect temporal and radial artery diameters or induce headache. In conclusion, natriuretic peptides in physiological and pharmacological doses do not affect blood flow velocity in the middle cerebral artery or dilate extracerebral arteries in healthy volunteers.

Free diving is associated with extreme hypoxia. This study evaluated the combined effect of maximal static breath holding and underwater swimming on plasma biomarkers of tissue hypoxemia: erythropoietin, neuron-specific enolase and S100B, C-reactive protein, pro-atrial natriuretic peptide, and troponin T. Venous blood samples were obtained from 17 competing free divers before and 3 h after sessions of static apnea and underwater swimming. The heart was evaluated by echocardiography. Static apnea for 293 ± 78 s (mean ± SD) and subsequent 88 ± 21 m underwater swimming increased plasma erythropoietin from 10.6 ± 3.4 to 12.4 ± 4.1 mIU/L (P = 0.013) and neuron-specific enolase from 14.5 ± 5.3 to 24.6 ± 6.4 ng/mL (P = 0.017); C-reactive protein decreased from 0.84 ± 1.0 to 0.71 ± 0.67 mmol/L (P = 0.013). In contrast, plasma concentrations of S100B (P = 0.394), pro-atrial natriuretic peptide (P = 0.549), and troponin T (P = 0.125) remained unchanged and, as assessed by echocardiography, the heart was not affected. In competitive free divers, bouts of static and dynamic apnea increase plasma erythropoietin and neuron-specific enolase, suggesting that renal and neural tissue, rather than the heart, is affected by the hypoxia developed during apnea and underwater swimming.

The antihypertensive actions of glucagon-like peptide-1 (GLP1) receptor agonists have been linked to the release of atrial natriuretic peptide (ANP) in mice. Whether a GLP1-ANP axis exists in humans is unknown. In this study, we examined 12 healthy young males in a randomized, controlled, double-blinded, single-day, cross-over study to evaluate the effects of a 2-h native GLP1 infusion. Plasma proANP concentrations were measured by an automated mid-region-directed proANP immunoassay and N-terminal pro B-type natriuretic peptide (BNP) on Roche Modular E170. Urine was collected for measurements of sodium excretion. Although GLP1 infusion increased the urinary sodium excretion markedly, there were no significant changes in either proANP or proBNP concentrations. When GLP1 infusion was stopped, sodium excretion declined rapidly. As proANP concentration reflects ANP secretion, our data could not confirm the existence of a GLP1-ANP axis in humans. Especially, the natriuretic effects of GLP1 seem unlikely to be mediated exclusively via ANP.

Copeptin, a stable fragment of the vasopressin prohormone, has been shown to be a significant biomarker for morbidity and mortality in heart failure. The aims of this study were to evaluate the influence of plasma sodium on the prognostic significance of copeptin concentrations in heart failure outpatients and to determine whether increased copeptin concentrations predict future development of hyponatremia.

Our aim was to assess the prognostic impact of a high-sensitivity cardiac troponin T (hs-cTnT) assay in an outpatient population with chronic systolic left ventricular heart failure (HF). Four hundred sixteen patients with chronic HF and left ventricular ejection fraction ≤ 45% were enrolled in a prospective cohort study. In addition to hs-cTnT, plasma amino-terminal pro-B-type natriuretic peptide was measured at baseline. Mean age was 71 years, 29% were women, 62% had coronary artery disease (CAD), mean left ventricular ejection fraction was 31%, and 57% had abnormal level of hs-cTnT. During 4.4 years of follow-up, 211 (51%) patients died. In multivariate Cox regression models, hs-cTnT was categorized as quartiles or dichotomized by the 99th percentile of a healthy population. Adjusted hazard ratios for all-cause mortality for quartiles 2 to 4, with quartile 1 as reference, were 1.4 (95% confidence interval 0.9 to 2.4, p = 0.16) for quartile 2, 1.7 (0.9 to 2.5, p = 0.12) for quartile 3, and 2.6 (1.6 to 4.4, p

Autonomic and cardiac dysfunction is frequent in cirrhosis, and includes increased sympathetic nervous activity, impaired heart rate variability (HRV) and baroreflex sensitivity (BRS). Quantified 123I-metaiodobenzylguanidine (mIBG) scintigraphy reflects cardiac noradrenaline uptake and in patients with cardiac failure it predicts outcome. In this study we aimed to investigate cardiac sympathetic function in cirrhosis by mIBG scintigraphy in relation to cardiovascular function. Ten patients with cirrhosis and 10 matched healthy controls participated in the study. Heart/mediastinum (H/M) ratios of mIBG uptake were calculated 15 and 230 minutes after intravenous injection of mIBG. Furthermore, washout rate (WOR) of mIBG was calculated. The patients underwent a liver vein catherization with determination of splanchnic and systemic haemodynamics and measurement of HRV and BRS. mIBG-scintigraphy revealed significantly increased WOR in patients with cirrhosis compared to controls (p<0.005), whereas H/M-uptakes were equal in the groups. Forty percent of the patients had reduced uptake of mIBG in the infero-lateral segment of the left ventricle. WOR correlated significantly with central circulation time, an estimate of central hypovolaemia (r=-0.64, P<0.05) and frequency-corrected QTF interval (r=0.71, p=0.01). Patients with cirrhosis had significantly decreased HRV and BRS correlating with indicators of abnormal cathecholamine up-take by mIBG although the catecholamine level was normal in the patients. In conclusion, in alcoholic cirrhosis, mIBG-scintigraphy reveals autonomic dysfunction and impaired myocardial distribution of sympathetic nervous activity. It is associated to indicators of central hypovolaemia, QT-interval, decreased HRV and BRS. Measurement of myocardial catecholamine-uptake by mIBG may add important information on autonomic and cardiac dysfunction in cirrhosis., Autonomic and cardiac dysfunction is frequent in cirrhosis, and includes increased sympathetic nervous activity, impaired heart rate variability (HRV) and baroreflex sensitivity (BRS). Quantified (123)I-metaiodobenzylguanidine (mIBG) scintigraphy reflects cardiac noradrenaline uptake and in patients with cardiac failure it predicts outcome. In this study we aimed to investigate cardiac sympathetic function in cirrhosis by mIBG scintigraphy in relation to cardiovascular function. Ten patients with cirrhosis and 10 matched healthy controls participated in the study. Heart/mediastinum (H/M) ratios of mIBG uptake were calculated 15 and 230 minutes after intravenous injection of mIBG. Furthermore, washout rate (WOR) of mIBG was calculated. The patients underwent a liver vein catherization with determination of splanchnic and systemic haemodynamics and measurement of HRV and BRS. mIBG-scintigraphy revealed significantly increased WOR in patients with cirrhosis compared to controls (p

The aim of this study was to assess the epidemiological features and prognosis of heart failure with preserved ejection fraction (HFPEF) and to compare these findings with those from patients with reduced ejection fraction. Furthermore the effects of N-terminal pro brain natriuretic peptide (NT-proBNP) requirement in the heart failure diagnosis were assessed by repeating the analyses in the subgroup of patients with elevated NT-proBNP.

Purpose. To evaluate the influence of time of day on the circulating concentrations of 14 frequently used clinical biochemical parameters in the Bispebjerg study of diurnal variations. Materials and methods. Venous blood samples were obtained under controlled environmental, activities and food conditions from 24 healthy young men every third hour through 24 hours, nine time points in total. At each time point, the parameters' concentrations were measured. The data were analyzed by rhythmometric statistical methods and in addition the biological variations were calculated. Results. Significant oscillation of melatonin with an amplitude (amp) of 19.84 pg/ml and a peak at 03:34 h confirmed the normal 24-hour rhythms of the participants. Potassium (p

Measurement of plasma concentrations of the biomarker copeptin may help identify patients with heart failure at high and low risk of mortality, although the value of copeptin measurement in elderly patients is not fully known.

BACKGROUND: The N-terminal fragment of cardiac-derived pro–B-type natriuretic peptide is a glycosylated polypeptide. It is unknown whether N-terminal pro–atrial natriuretic peptide (proANP) fragments are also covalently modified. We therefore evaluated the clinical performance of 2 distinctly different proANP assays on clinical outcome. METHODS: We examined 474 elderly patients with symptoms of heart failure presenting in a primary healthcare setting. Samples were analyzed with an automated immunoluminometric midregion proANP (MR-proANP) assay and a new processing-independent assay (PIA) developed in our laboratory. The results were compared with Bland–Altman plots, and clinical performance was assessed by generating ROC curves for different clinical outcomes. RESULTS: Despite linear regression results indicating a good correlation (r = 0.85; P < 0.0001), the PIA measured considerably more proANP than the MR-proANP assay (mean difference, 663 pmol/L; SD, 478 pmol/L). In contrast, the clinical performances of the 2 assays [as assessed by the area under the ROC curve (AUC)] in detecting left ventricular dysfunction were similar [proANP PIA, 0.71 (95% CI, 0.63–0.79); MR-proANP assay, 0.74 (95% CI, 0.66–0.81); P = 0.32]. The prognostic ability to report cardiovascular mortality during a 10-year follow-up revealed AUC values of 0.66 (95% CI, 0.60–0.71) for the proANP PIA and 0.69 (95% CI, 0.63–0.74) for the MR-proANP assay (P = 0.08, for comparing the 2 assays). CONCLUSIONS: Our data suggest that N-terminal proANP fragments in patient plasma differ from the calibrator peptides used but that the difference does not affect ROC curves in an elderly cohort of patients with mild to moderate heart failure. We suggest that human N-terminal proANP fragments can be covalently modified.