The neuregulin-1 (NRG-1)/receptor tyrosine-protein kinase erbB (ErbB) system is an endothelium-controlled paracrine system modulating cardiac performance and adaptation. Recent studies have indicated that NRG-1 has antifibrotic effects in the left ventricle, which were explained by direct actions on cardiac fibroblasts. However, the NRG-1/ErbB system also regulates the function of macrophages. In this study, we hypothesized that the antifibrotic effect of NRG-1 in the heart is at least partially mediated through inhibitory effects on macrophages. We also hypothesized that the antifibrotic effect of NRG-1 may be active in other organs, such as the skin and lung. First, in a mouse model of angiotensin II (ANG II)-induced myocardial hypertrophy and fibrosis, NRG-1 treatment (20 µg·kg −1 ·day −1 ip) significantly attenuated myocardial hypertrophy and fibrosis and improved passive ventricular stiffness (4 wk). Interestingly, 1 wk after exposure to ANG II, NRG-1 already attenuated myocardial macrophage infiltration and cytokine expression. Furthermore, mice with myeloid-specific deletion of the ErbB4 gene ( ErbB4 F/F LysM-Cre +/− ) showed an intensified myocardial fibrotic response to ANG II. Consistently, NRG-1 activated the ErbB4 receptor in isolated macrophages, inhibited phosphatidylinositide 3-kinase/Akt and STAT3 signaling pathways, and reduced the release of inflammatory cytokines. Further experiments showed that the antifibrotic and anti-inflammatory effects of NRG-1 were reproducible in mouse models of bleomycin-induced dermal and pulmonary fibrosis. Overall, this study demonstrates that the antifibrotic effect of NRG-1 in the heart is linked to anti-inflammatory activity NRG-1/ErbB4 signaling in macrophages. Second, this study shows that NRG-1 has antifibrotic and anti-inflammatory effects in organs other than the heart, such as the skin and lung. NEW & NOTEWORTHY Our study contributes to the understanding of the antifibrotic effect of neuregulin-1 during myocardial remodeling. Here, we show that the antifibrotic effect of neuregulin-1 is at least partially mediated through anti-inflammatory activity, linked to receptor tyrosine-protein kinase erbB-4 activation in macrophages. Furthermore, we show that this effect is also present outside the heart. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/nrg-1-inhibits-macrophage-activation-during-tissue-fibrosis/ .
ABSTRACT Objectives: Data on Helicobacter pylori (HP) resistance in Belgium are largely based on the patient population of Brussels and Wallonia. Notably Brussels harbours a large proportion of patients with a migration background which might not be representative for other parts of the country. Methods: An observational cross-sectional study was performed in the province of West Flanders, Belgium for collecting gastric biopsies to examine the resistance of HP. The study population consisted of patients who underwent a gastroduodenoscopy for any medically indicated purpose. Rapid urease testing (RUT) was performed on all biopsies and cultures were only started if the RUT showed positive. Results: 512 patients participated of whom 495 were eligible for analysis: 438 in first line testing and 57 in second line. The growth of HP was successful in 88.9% (n = 88/99) of which 52.3% (n = 46/88) resulted in an antibiogram. The resistance rate in first line was based on 37 succeeded antibiograms and showed 13.5% resistance for clarithromycin (95% confidence interval; 2.5% to 24.5%); 29.7% for metronidazole; 29.7% for levofloxacin; 11.4% for rifampicin; 2.7% for amoxicillin and 0% for tetracycline. Conclusion: The primary clarithromycin resistance rate of HP could still be slightly under 15% in West Flanders, Belgium. This might implicate a clarithromycin-based triple therapy is an option for first line empiric eradication in this region according to the Maastricht V/Florence consensus although conclusions must be interpreted with caution due to the rather small sample size. Further testing in Flanders is recommended to confirm these results.
Introduction: The neuregulin-1 (NRG-1)/ErbB system emerges as an endothelium-controlled cardioprotective system, indispensable for cardiac development and function. Treatment with NRG-1 of animal models with heart failure has been shown to impede LV remodeling and to reduce mortality. Phase III clinical trials in patients are currently performed. The underlying mechanisms of NRG-1 in heart failure are however incompletely understood. Here, we tested whether NRG-1 interferes with the cardiac actions of angiotensin II.
The JAK2 V617F mutation, the thrombopoietin receptor MPL W515K/L mutation and calreticulin (CALR) mutations are mutually exclusive in essential thrombocythemia and support a novel molecular categorization of essential thrombocythemia. CALR mutations account for approximately 30% of cases of essential thrombocythemia. In a retrospective study, we examined the frequency of MPL and CALR mutations in JAK2 V617F-negative cases of essential thrombocythemia (n=103). In addition, we compared the clinical phenotype and outcome of CALR mutant cases of essential thrombocythemia with a cohort of JAK2 V617F-positive essential thrombocythemia (n=57). CALR-positive cases represented 63.7% of double-negative cases of essential thrombocythemia, and most carried CALR type 1 or type 2 indels. However, we also identified one patient who was positive for both the JAK2 V617F and the CALR mutations. This study revealed that CALR mutant essential thrombocythemia is associated with younger age, higher platelet counts, lower erythrocyte counts, leukocyte counts, hemoglobin, and hematocrit, and increased risk of progression to myelofibrosis in comparison with JAK2 V617F-positive essential thrombocythemia. Analysis of the CALR mutant group according to indel type showed that CALR type 1 deletion is strongly associated with male gender. CALR mutant patients had a better overall survival than JAK2 V617F-positive patients, in particular patients of age 60 years or younger. In conclusion, this study in a Belgian cohort of patients supports and extends the growing body of evidence that CALR mutant cases of essential thrombocythemia are phenotypically distinct from JAK2 V617F-positive cases, with regards to clinical and hematologic presentation as well as overall survival.
Introduction: Diabetic cardiomyopathy (DCMP) is a leading cause of cardiac morbidity and mortality. DCMP is characterized by left ventricular (LV) tissue remodeling and by LV diastolic dysfunction, causing LV filling disturbances. Dipeptidyl peptidase-IV (DPP-IV) is a membrane-bound protease, expressed in cardiac microvascular endothelial cells, responsible for the breakdown of several cardio-active peptides. DPP-IV inhibitors are novel drugs for the treatment of type II diabetes. This study investigates the effects of sitagliptin (SITA), an orally active inhibitor of DPP-IV, on LV structure and function in obese diabetic mice. Results: Obese male type II diabetic mice (Leprdb/db, n=24) were treated with SITA (300 mg/kg/day in drinking water) or vehicle during 8 weeks. SITA impaired more than 85% of serum DPP-IV activity but had no effect on fasting glucose levels. SITA reduced cardiomyocyte size (p<0.05) and minimally affected LV collagen fraction. Invasive hemodynamic cardiac recordings in anesthetized diabetic mice at varying preloads showed that SITA increased LV stroke volume (p<0.005), cardiac output (p<0.005), LV stroke work (p<0.001) and LV compliance (p<0.05), whereas LV end-systolic elastance and preload-recruitable stroke work remained unchanged. In addition, in vitro analyses showed that the resting tension of cardiomyocytes in SITA-treated diabetic mice was lower than in vehicle-treated diabetic mice. This observation was consistent with the intensified phosphorylation of the cytoskeletal protein titin (p<0.001), the significantly increased myocardial concentrations of cGMP, and the increased activity of protein kinase G (PKG) in myocardial samples of SITA-treated diabetic mice. Finally, activation of PKG in samples of control diabetic mice decreased the resting tension of cardiomyocytes from vehicle-treated diabetic mice, but had no effect on cardiomyocytes from SITA-treated mice. Conclusion: In obese diabetic mice, in absence of hypoglycaemic effects, DPP-IV inhibition by SITA improves global LV performance and LV compliance. These effects seem at least partially mediated by stimulatory effects of SITA on the myocardial cGMP-PKG pathway and, hence, on the phosphorylation status of titin and the hereto coupled cardiomyocyte stiffness modulus.
Multiple myeloma is one of the most common hematologic malignancies. Acquired factor X deficiencies are often observed in primary (AL) amyloidosis and rarely in multiple myeloma.We report a case of an acquired factor X deficiency in a patient with a newly diagnosed IgA lambda multiple myeloma, without any evidence of concomitant amyloidosis.We present the patient's medical history, clinical and physical examinations, laboratory analysis, and outcome.A 76-year-old male presented at the emergency department with ongoing gingival bleeding. Several analytical problems with blood sample analysis arose, which eventually led to the diagnosis of a multiple myeloma. Further exploration revealed an acquired factor X deficiency, explaining the ongoing bleeding. There was no evidence of concomitant amyloidosis. The multiple myeloma was treated, leading to complete remission of the malignancy and bleeding tendency.While coagulopathy is rarely observed in patients diagnosed with multiple myeloma, considering an acquired factor X deficiency becomes relevant when such patient present with bleeding diathesis.
There is a need for animal models of plaque rupture. We previously reported that elastin fragmentation, due to a mutation (C1039G+/−) in the fibrillin-1 (Fbn1) gene, promotes atherogenesis and a highly unstable plaque phenotype in apolipoprotein E deficient (ApoE−/−) mice on a Western-type diet (WD). Here, we investigated whether plaque rupture occurred in ApoE−/−Fbn1C1039G+/− mice and was associated with myocardial infarction, stroke, and sudden death. Female ApoE−/−Fbn1C1039G+/− and ApoE−/− mice were fed a WD for up to 35 weeks. Compared to ApoE−/− mice, plaques of ApoE−/−Fbn1C1039G+/− mice showed a threefold increase in necrotic core size, augmented T-cell infiltration, a decreased collagen I content (70 ± 10%), extensive neovascularization, intraplaque haemorrhage, and a significant increase in matrix metalloproteinase-2, -9, -12, and -13 expression or activity. Plaque rupture was observed in 70% of ascending aortas and in 50% of brachiocephalic arteries of ApoE−/−Fbn1C1039G+/− mice. In ApoE−/− mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE−/−Fbn1C1039G+/− mice died suddenly, whereas all ApoE−/− mice survived. ApoE−/−Fbn1C1039G+/− mice showed coronary plaques and myocardial infarction (75% of mice). Furthermore, they displayed head tilt, disorientation, and motor disturbances (66% of cases), disturbed cerebral blood flow (73% of cases; MR angiograms) and brain hypoxia (64% of cases), indicative of stroke. Elastin fragmentation plays a key role in plaque destabilization and rupture. ApoE−/−Fbn1C1039G+/− mice represent a unique model of acute plaque rupture with human-like complications.
Summary Introduction The CellaVision Advanced Red Blood Cell ( RBC ) Software Application is a new software for advanced morphological analysis of RBC , which automatically performs a preliminary characterization and grouping of RBC into 21 morphological categories, including schistocytes. Upon automated classification, the software offers the possibility of reclassification of RBC by the operator. The aim of this study was to evaluate the schistocyte analysis by the CellaVision Advanced RBC Application. Methods Schistocyte counts were evaluated comparing the automated count on a CellaVision DM 96, both before and after reclassification, with the reference manual microscopic method according to the ICSH criteria. Thirty‐six samples of hospitalized patients and 40 samples of controls were analyzed. Results Within‐run, between‐run and between‐observer coefficients of variation were lower when counted with the CellaVision compared to the manual microscopic count. The very high sensitivity but rather poor specificity implicates the need for reclassification by the operator, following automated analysis. After reclassification, method comparison studies revealed good agreement with the manual microscopic method, with however slightly higher values of schistocytes for the automated analysis. Conclusion The CellaVision Advanced RBC Software Application provides a sensitive and reproducible measurement of schistocytes in peripheral blood, but still requires manual revision. Furthermore, it is an easy‐to‐use software and an excellent teaching tool that might contribute to standardization in the investigation of schistocyte‐related conditions.
