Birgit Heinisch

Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol

Objective Non-selective β-blockers or endoscopic band ligation (EBL) are recommended for primary prophylaxis of variceal bleeding in patients with oesophageal varices. Additional α-adrenergic blockade (as by carvedilol) may increase the number of patients with haemodynamic response (reduction in hepatic venous pressure gradient (HVPG) of ≥20% or to values <12 mm Hg). Design Patients with oesophageal varices undergoing measurement of HVPG before and under propranolol treatment (80–160 mg/day) were included. HVPG responders were kept on propranolol (PROP group), while non-responders were placed on carvedilol (6.25–50 mg/day). Carvedilol responders continued treatment (CARV group), while non-responders to carvedilol underwent EBL. The primary aim was to assess haemodynamic response rates to carvedilol in propranolol non-responders. Results 36% (37/104) of patients showed a HVPG response to propranolol. Among the propranolol non-responders 56% (38/67) eventually achieved a haemodynamic response with carvedilol, while 44% (29/67) patients were finally treated with EBL. The decrease in HVPG was significantly greater with carvedilol (median 12.5 mg/day) than with propranolol (median 100 mg/day): −19±10% versus −12±11% (p<0.001). During a 2 year follow-up bleeding rates for PROP were 11% versus CARV 5% versus EBL 25% (p=0.0429). Fewer episodes of hepatic decompensation (PROP 38%/CARV 26% vs EBL 55%; p=0.0789) and significantly lower mortality (PROP 14%/CARV 11% vs EBL 31%; p=0.0455) were observed in haemodynamic responders compared to the EBL group. Conclusions Carvedilol leads to a significantly greater decrease in HVPG than propranolol. Using carvedilol for primary prophylaxis a substantial proportion of non-responders to propranolol can achieve a haemodynamic response, which is associated with improved outcome with regard to prevention of variceal bleeding, hepatic decompensation and death.

Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis

BACKGROUND & AIMS We evaluated the gastrointestinal permeability and bacterial translocation in cirrhotic patients with portal hypertension (PHT) prior to and after non-selective betablocker (NSBB) treatment. METHODS Hepatic venous pressure gradient (HVPG) was measured prior to and under NSBB treatment. Gastroduodenal and intestinal permeability was assessed by the sucrose-lactulose-mannitol (SLM) test. Anti-gliadin and anti-endomysial antibodies were measured. Levels of LPS-binding protein (LBP) and interleukin-6 (IL-6) were quantified by ELISA, and NOD2 and toll-like receptor 2 (TLR2) polymorphisms were genotyped. RESULTS Fifty cirrhotics were included (72% male, 18% ascites, 60% alcoholic etiology). Abnormal gastroduodenal and intestinal permeability was found in 72% and 59% of patients, respectively. Patients with severe portal hypertension (HVPG ≥20 mm Hg; n=35) had increased markers of gastroduodenal/intestinal permeability (urine sucrose levels p=0.049; sucrose/mannitol ratios p=0.007; intestinal permeability indices p=0.002), and bacterial translocation (LBP p=0.002; IL-6 p=0.025) than patients with HVPG <20 mm Hg. A substantial portion of patients showed elevated levels of anti-gliadin antibodies (IgA: 60%, IgG: 34%) whereas no anti-endomysial antibodies were detected. A significant correlation of portal pressure (i.e., HVPG) with all markers of gastroduodenal/intestinal permeability and with LBP and IL-6 levels was observed. NOD2 and TLR2 risk variants were associated with abnormal intestinal permeability and elevated markers of bacterial translocation. At follow-up HVPG measurements under NSBB, we found an amelioration of gastroduodenal/intestinal permeability and a decrease of bacterial translocation (LBP - 16% p=0.018; IL-6 - 41% p<0.0001) levels, which was not limited to hemodynamic responders. Abnormal SLM test results and higher LBP/IL-6 levels were associated with a higher risk of variceal bleeding during follow-up but not with mortality. CONCLUSIONS Abnormal gastroduodenal/intestinal permeability, anti-gliadin antibodies, and bacterial translocation are common findings in cirrhotic patients and are correlated with the degree of portal hypertension. NSBB treatment ameliorates gastroduodenal/intestinal permeability and reduces bacterial translocation partially independent of their hemodynamic effects on portal pressure, which may contribute to a reduced risk of variceal bleeding.

B-Type Natriuretic Peptide Modulates Ghrelin, Hunger, and Satiety in Healthy Men

Chronic heart failure is accompanied by anorexia and increased release of B-type natriuretic peptide (BNP) from ventricular cardiomyocytes. The pathophysiological mechanisms linking heart failure and appetite regulation remain unknown. In this study, we investigated the impact of intravenous BNP administration on appetite-regulating hormones and subjective ratings of hunger and satiety in 10 healthy volunteers. Participants received in a randomized, placebo-controlled, crossover, single-blinded study (subject) placebo once and 3.0 pmol/kg/min human BNP-32 once administered as a continuous infusion during 4 h. Circulating concentrations of appetite-regulating peptides were measured hourly. Subjective ratings of hunger and satiety were evaluated by visual analog scales. BNP inhibited the fasting-induced increase in total and acylated ghrelin concentrations over time (P = 0.043 and P = 0.038, respectively). In addition, BNP decreased the subjective rating of hunger (P = 0.009) and increased the feeling of satiety (P = 0.012) when compared with placebo. There were no significant changes in circulating peptide YY, glucagon-like peptide 1, oxyntomodulin, pancreatic polypeptide, leptin, and adiponectin concentrations. In summary, our results demonstrate that BNP exerts anorectic effects and reduces ghrelin concentrations in men. These data, taken together with the known cardiovascular properties of ghrelin, support the existence of a heart–gut–brain axis, which could be therapeutically targeted in patients with heart failure and obesity.

Evaluation of a new balloon occlusion catheter specifically designed for measurement of hepatic venous pressure gradient

Despite the important clinical value of hepatic venous pressure gradient (HVPG) and its increasing use, no specific balloon occlusion catheters have been designed to cannulate liver veins. The aim of the study was to evaluate the clinical applicability of a novel balloon (NC) occlusion catheter specifically designed for HVPG measurement.

The effect of erythropoietin on platelet and endothelial activation markers: A prospective trial in healthy volunteers

Erythropoietin (EPO) enhances formation of red blood cells and also affects thrombopoiesis and platelet function. We hypothesized that the effect of EPO may be reflected by changes in thromboxane B2 (TXB2) and endothelial cell function. Six male and six female subjects received recombinant human epoetin alpha (Erypo®) intravenously (300 U/kg). Biomarker levels were assessed at baseline and 4, 24, 48 and 72 hours after infusion. Epoetin alpha increased TXB2 levels by 140%, which reached significance at 48 hours (6.6 ± 5 ng/ml vs. 15 ± 9 ng/ml; p = 0.044) and remained at that level at 72 hours. In line, epoetin alpha increased E-selectin levels by 25% already at 24 hours (39 ± 21 ng/ml vs. 49 ± 26 ng/ml; p < 0.001) which stayed at this level until 72 hours (p < 0.001). The raise in platelet activation markers corresponded to an 88% increase in reticulocyte count (43 ± 10 × 109/l vs. 81 ± 17 × 109/l; p < 0.001) and a 9% increase in platelet count at 72 hours (224 ± 45 × 109/l vs. 244 ± 52 × 109/l; p = 0.005). Thrombomodulin and von Willebrand factor concentrations were not significantly altered by epoetin alpha. Interestingly, gender differences in the baseline levels of E-selectin and thrombomodulin were observed. E-selectin and thrombomodulin levels were doubled in men compared to women (51 ± 24 and 28 ± 10 ng/ml; p = 0.025 and 30 ± 5 ng/ml vs. 16 ± 5 ng/ml; p = 0.002, respectively). EPO increases TXB2 serum levels and soluble E-selectin. Further studies are needed to investigate whether these markers might be useful for estimation of thromboembolic risk during EPO-therapy and whether inhibition of thromboxane formation may lower thrombotic complications during EPO treatment: NCT01392612.

Randomised clinical study: the effects of oral taurine 6g/day vs placebo on portal hypertension

The amino sulphonic acid taurine reduces oxidative endoplasmatic reticulum stress and inhibits hepatic stellate cell activation, which might lead to reduction of portal pressure in cirrhosis.

S-ibuprofen effectively inhibits thromboxane B2 levels and platelet function in an experimental model of lipopolysaccharide-stimulated and non-stimulated whole blood.

Objective: The present study aimed at testing the effect of S- and R-ibuprofen on thromboxane B2 (TXB2), collagen-epinephrine closure time (CEPI-CT) and collagen-adenosine 5′-diphosphate closure time (CADP-CT) in lipopolysaccharide (LPS)-stimulated and non-stimulated human whole blood. Materials and Methods: Whole blood was incubated with S- or R-ibuprofen with and without prior stimulation with LPS. To verify ibuprofen’s potential effects on TXB2, varying ratios of concentrations of S- and R-ibuprofen ranging from 0 to 100% were used. TXB2 levels were measured by ELISA. The effects of S- and R-ibuprofen enantiomers on platelet aggregability were tested utilizing a PFA-100 apparatus. Results: In non-stimulated and LPS-stimulated whole blood, S-ibuprofen markedly decreased TXB2 levels at concentrations ranging from 10 to 200 µg/ml. R-ibuprofen showed its inhibiting effect at concentrations >100 µg/ml. In inflammatory and non-inflammatory conditions, CEPI-CT was prolonged at concentrations of 12.5 and 75 µg/ml for S-ibuprofen and at a concentration of 150 µg/ml of combined R- and S-ibuprofen. S-ibuprofen was significantly more effective than R-ibuprofen (p < 0.05). The combined use of S- and R-ibuprofen did not additively or synergistically prolong CEPI-CTs. CADP-CTs remained unaffected by both enantiomers. Conclusions: S-ibuprofen was more effective than the R-ibuprofen enantiomer in inhibiting TXB2 plasma levels and aggregability of thrombocytes in non-inflammatory and inflammatory conditions.

Effects of B-type natriuretic peptide on cardiovascular biomarkers in healthy volunteers

Cardiovascular biomarkers provide independent prognostic information in the assessment of mortality and cardiovascular complications. However, little is known about possible interactions between these biomarkers. In the present study, we evaluated the influence of B-type natriuretic peptide (BNP) on midregional-proadrenomedullin (MR-proADM), C-terminal-proendothelin-1 (CT-proET-1), growth differentiation factor-15 (GDF-15), midregional-proatrial natriuretic peptide (MR-proANP), copeptin, and procalcitonin in healthy volunteers. Ten healthy male subjects (mean age 24 yr) participating in a randomized, placebo-controlled, single-blinded crossover study received placebo or 3.0 pmol·kg(-1)·min(-1) human BNP 32 during a continuous infusion lasting for 4 h. Effects of BNP on other cardiovascular biomarkers were assessed. BNP did not change concentrations of MR-proADM, copeptin, CT-proET1, GDF-15, or procalcitonin. In contrast, MR-proANP was significantly decreased during BNP infusion. BNP as an established cardiovascular biomarker did not affect plasma concentrations of other cardiovascular biomarkers in a model of healthy volunteers.

B-type natriuretic peptide increases cortisol and catecholamine concentrations in healthy subjects

B-type natriuretic peptide (BNP) is a hormone released by the heart in response to volume load and exerts natriuretic properties. It is clinically used as a diagnostic and prognostic biomarker and investigated as a pharmacological agent in the therapy of heart failure. Here we investigate the changes in pituitary, adrenal, and thyroid hormones in response to BNP administration in a randomized single-blinded crossover study conducted in ten healthy men aged 21-29 yr. Participants received in two study sessions a continuous intravenous infusion during 4 h (once placebo and once 3 pmol·kg-1·min-1 BNP) and remained in supine position throughout the study. Circulating concentrations of pituitary, adrenal, and thyroid hormones, heart rate, and blood pressure were measured at baseline and hourly afterwards. BNP prevented the physiological decrease in cortisol during the late morning hours leading to elevated serum cortisol levels (P = 0.022) and increased circulating epinephrine and norepinephrine concentrations (P = 0.018 and P = 0.036, respectively). These hormone changes were accompanied by an increase in heart rate (P = 0.019) but no differences in blood pressure. Taken together, the impact of BNP on the endocrine system extends beyond the well-known inhibition of the renin-angiotensin-aldosterone system and includes increased adrenergic activity and cortisol concentrations. This neuroendocrine activation might impact the outcome of therapeutical BNP administrations and should be further investigated in conditions associated with increased BNP secretion.NEW & NOTEWORTHY The heart hormone B-type natriuretic peptide (BNP) is increased in patients with heart failure, where it is thought to have beneficial effects by reducing the preload. Here we report that intravenous administration of BNP in men leads to increases in adrenal hormones cortisol, epinephrine, and norepinephrine. Cortisol and catecholamine levels are independent predictors of increased cardiovascular mortality risk; therefore, drugs targeting the BNP system should be evaluated regarding their effects on the neuroendocrine activation accompanying heart failure.

Tumor and patient characteristics of individuals with mismatch repair deficient colorectal cancer

Aims: To investigate tumor and patient characteristics of individuals with mismatch repair (MMR)-deficient colorectal carcinomas. Methods: We immunhistochemically investigated tissue samples of 307 consecutive patients with colorectal cancer for defects in DNA MMR proteins (hMLH1, hMSH2, hMSH6, hPMS2) and those with mutations further for microsatellite instability (MSI) and BRAF V600E mutations. Results: 32/308 (10.4%) tumors showed MMR deficiency. Seventy five percent (n = 24) had loss of hMLH1 and hPMS2 expression, 3% (n = 1) of hPMS2 alone, 18.8% (n = 6) of hMSH6 and hMSH2, 3% (n = 1) of hMSH2 alone. All MMR-deficient tumors showed high MSI. These tumors occurred preferably in the right-sided colon, in women and showed specific histological features. We obtained the family history of 18/32 patients; 2 (11.1%) met Amsterdam Criteria, 5 (27.8%) Bethesda Guidelines and 6 (33.3%) revised Bethesda Guidelines. BRAF V600E mutations were found in 16 (67%) of hMLH1 and none of the hMSH2 deficient tumors. Conclusion: We suggest using immunhistochemical testing of tumor tissues with subsequent MSI analysis, which may be justified as a screening method for MMR deficiency in colorectal cancer, since it identifies patients with possibly hereditary defects and unalike response to chemotherapy.