Muscle wasting as an independent predictor of survival in patients with chronic heart failure

Background: Skeletal muscle wasting is an extremely common feature in patients with heart failure, affecting approximately 20% of ambulatory patients with even higher values during acute decompensation. Its occurrence is associated with reduced exercise capacity, muscle strength, and quality of life. We sought to investigate if the presence of muscle wasting carries prognostic information. Methods: Two hundred sixty‐eight ambulatory patients with heart failure (age 67.1 ± 10.9 years, New York Heart Association class 2.3 ± 0.6, left ventricular ejection fraction 39 ± 13.3%, and 21% female) were prospectively enrolled as part of the Studies Investigating Co‐morbidities Aggravating Heart Failure. Muscle wasting as assessed using dual‐energy X‐ray absorptiometry was present in 47 patients (17.5%). Results During a mean follow‐up of 67.2 ± 28.02 months, 95 patients (35.4%) died from any cause. After adjusting for age, New York Heart Association class, left ventricular ejection fraction, creatinine, N‐terminal pro‐B‐type natriuretic peptide, and iron deficiency, muscle wasting remained an independent predictor of death (hazard ratio 1.80, 95% confidence interval 1.01–3.19, P = 0.04). This effect was more pronounced in patients with heart failure with reduced than in heart failure with preserved ejection fraction. Conclusions: Muscle wasting is an independent predictor of death in ambulatory patients with heart failure. Clinical trials are needed to identify treatment approaches to this co‐morbidity

The role of the epidermal growth factor receptor in the Moraxella catarrhalis- induced proinflammatory immune response in the pulmonary epithelium

Die chronisch obstruktive Lungenerkrankung (COPD) ist mit weltweit zunehmender Inzidenz eine der größten Herausforderungen in der Gesundheitsfürsorge. Chronische Entzündung in den unteren Atemwegen wird als ein Hauptfaktor für die Pathogenese und Progression der Erkrankung angesehen. Moraxella catarrhalis ist ein COPD-assoziierter Erreger, der Exazerbationen und bakterielle Kolonisierung der unteren Atemwege verursacht, welche im Verdacht steht zu chronischer Entzündung beizutragen. Der epidermale Wachstumsfaktor- Rezeptor (EGFR) ist in der COPD oft überexprimiert und wird assoziiert mit muköser Hypersekretion, welche zur Atemwegsobstruktion beiträgt. In letzter Zeit gibt es vermehrte Hinweise, dass EGFR auch proinflammatorische Prozesse reguliert. Das Ziel dieser Arbeit war es, zu untersuchen, welche Bedeutung EGFR für die M. catarrhalis-induzierte proinflammatorische Immunantwort in Atemwegsepithelzellen hat. Die Ergebnisse zeigen, dass eine Infektion mit M. catarrhalis die Expression und Aktivierung des EGFR induziert. In Versuchen mit dem EGFR-Inhibitor AG1478 und siRNA wies ich nach, dass die Aktivierung des EGFR für die Produktion des proinflammatorischen IL-8 von großer Bedeutung ist. Mittels Western-Blot stellte ich bei einer Inhibition des EGFR eine Minderung der Aktivierung von ERK fest. Außerdem konnte ich zeigen, dass eine Inhibition von EGFR bzw. ERK jeweils zu einer verminderten DNA-Bindung des Transkriptionsfaktors NF-κB führte. Durch Chromatin-Immunopräzipitation (ChIP) wies ich eine verminderte Bindung von aktivem NF-κB an den IL-8-Promotor in AG1478-behandelten Zellen nach. Zusammenfassend konnte ich zeigen, dass eine Infektion mit Moraxella catarrhalis in Atemwegsepithelzellen eine erhöhte Expression und Aktivierung des EGFR verursacht. Über einen EGFR/ERK/NF-κB- abhängigen Signalweg wird die Produktion von proinflammatorischem IL-8 induziert. Die Inhibition der EGFR-Signalübermittlung in der COPD könnte ein wichtiger Angriffspunkt nicht nur zur Behandlung der mukösen Hypersekretion sondern auch zur Minderung der von bakteriellen Erregern ausgelösten Atemwegsentzündung sein.Chronic obstructive lung disease (COPD) is a worldwide health care burden with increasing incidence. Chronic lower airway inflammation is considered a major cause for pathogenesis and disease progression. Moraxella catarrhalis is a COPD associated pathogen leading to exacerbations and bacterial colonization in the lower airways, which may contribute to chronic inflammation. The epidermal growth factor receptor (EGFR) is often overexpressed in COPD and is associated with mucous hypersecretion leading to airway obstruction. Increasing evidence reveals EGFR also to be a regulator of inflammatory processes. The goal of this study was to investigate the role of EGFR in the Moraxella catarrhalis induced proinflammatory immune response in airway epithelial cells. The results show, that an infection with M. catarrhalis leads to the expression and activation of EGFR. In investigations with the EGFR inhibitor AG1478 and siRNA I could demonstrate, that activation of EGFR is essential for the production of proinflammatory IL-8. Using Western-Blot analysis, I observed a decrease in ERK activation in response to EGFR inhibition. Moreover, I found that inhibition of EGFR or ERK leads to a decrease in DNA binding activity of transcription factor NF-κB. By chromatin immunoprecipitation (ChIP) I detected reduced binding of active NF-κB to the IL-8 promotor in AG1478-treated cells. In conclusion, I could show that an infection of airway epithelial cells with Moraxella catarrhalis leads to increased EGFR expression and activation. Via an EGFR/ERK/NF-κB dependent pathway production of proinflammatory IL-8 is induced. The inhibition of EGFR signaling in COPD could be an important target not only for treatment of mucous hypersecretion but also to reduce airway inflammation caused by bacterial pathogens

The role and regulation of Moraxella catarrhalis-induced human beta-defensin 3 expression in human pulmonary epithelial cells

Background: Bacterial colonisation with Moraxella catarrhalis may partly sustain chronic inflammation in the lower airways of patients with chronic obstructive pulmonary disease (COPD). In addition, this bacterium causes infectious exacerbations of COPD, which often necessitate treatment with antibiotics. Antimicrobial peptides are the body's own antibiotic substances with bactericidal and bacteriostatic, as well as immunomodulatory function. In particular, human beta-defensin 3 (hBD-3) exerts an antimicrobial effect against an extraordinarily broad spectrum of pathogens. We therefore investigated the role of hBD-3 in infections of pulmonary epithelial cells with M. catarrhalis. Methods: The antimicrobial activity of hBD-3 vs. M. catarrhalis was evaluated in an antimicrobial susceptibility assay. We analyzed hBD-3 secretion of M. catarrhalis-infected pulmonary epithelial cells using ELISA. The role of M. catarrhalis-specific virulence factors, toll-like receptors (TLR) 2 and 4, MAPK pathways, and transcription factors AP-1 and NF-kappa B in the induction and regulation of hBD-3 expression were explored with specific inhibitors, small interference RNA, Western Blot, and chromatin immunoprecipitation (ChIP) assays. Results: HBD-3 exhibited a strong bactericidal effect against M. catarrhalis. M. catarrhalis induced hBD-3 expression in pulmonary epithelial cells, which was dependent on M. catarrhalis membranous lipoolygosaccharide (LOS), while the surface proteins UspA1 and UspA2 were not involved. Gene silencing of TLR2, but not TLR4, led to a reduced hBD-3 secretion after stimulation with M. catarrhalis or M. catarrhalis LOS. Inhibition of MAPKs ERK1/2 and JNK, but not p38, reduced hBD-3 secretion. HBD-3 expression was mediated through the recruitment of AP-1 to the hBD-3 gene promoter and was independent of NF-kappa B. Conclusion: The immune response of pulmonary epithelial cells towards M. catarrhalis involves secretion of hBD-3, which has a bactericidal effect against this pathogen. Binding of M. catarrhalis virulence factor LOS to TLR2 causes an ERK1/2- and JNK-dependent induction of AP-1-related transcription of the hBD-3 gene, resulting in the production and secretion of hBD-3. (C) 2015 Published by Elsevier Inc

Effects of varenicline on sympatho-vagal balance and cue reactivity during smoking withdrawal: a randomised placebo-controlled trial

Introduction Varenicline is an effective smoking cessation medication. Some concern has been raised that its use may precipitate adverse cardiovascular events although no patho-physiological mechanism potentially underlying such an effect has been reported. The aim of this study was to test the hypothesis that varenicline impacts on sympatho-vagal balance during smoking withdrawal. Material and Methods In this randomised, placebo-controlled trial, muscle sympathetic nerve activity (MSNA), baroreflex sensitivity (BRS), heart rate, and blood pressure were assessed in 17 smokers four weeks before a quit attempt (baseline) and again on the third day of that quit attempt (acute smoking withdrawal). Results Regarding the primary endpoint of our study, we did not find a significant effect of varenicline compared to placebo on changes in MSNA burst incidence between baseline and acute smoking withdrawal (−3.0 ± 3.3 vs.−3.9 ± 5.0 bursts/100 heart beats; p = 0.308). However, heart rate and systolic blood pressure significantly decreased in the placebo group only, while no significant changes in these parameters were observed in the varenicline group. Exposure to smoking cues during acute withdrawal lead to a significant increase of heart rate in the placebo group, while heart rate decreased in the varenicline group, and the difference in these changes was significant between groups (+2.7 ± 1.0 vs.−1.8 ± 0.5 1/min; p = 0.002). In all 17 participants combined, a significant increase in heart rate during smoking cue exposure was detected in subjects who relapsed in the course of six weeks after the quit date compared to those who stayed abstinent (+2.5 ± 1.2 vs.−1.1 ± 0.7; p = 0.018). Six-week abstinence rates were higher in the varenicline group compared to placebo (88 vs. 22 % p = 0.015). Conclusions We did not find evidence of adverse effects of varenicline on sympatho-vagal balance. Varenicline probably blunts the heart rate response to smoking cues, which may be linked to improved cessation outcome

Efficacy of Electrical Baroreflex Activation Is Independent of Peripheral Chemoreceptor Modulation

Arterial baroreflex activation through electrical carotid sinus stimulation has been developed for the treatment of resistant hypertension. Previous studies suggested that the peripheral chemoreflex is tonically active in hypertensive patients and may inhibit baroreflex responses. We hypothesized that peripheral chemoreflex activation attenuates baroreflex efficacy evoked by electrical carotid sinus stimulation. We screened 35 patients with an implanted electrical carotid sinus stimulator. Of those, 11 patients with consistent acute depressor response were selected (7 men/4 women, age: 67 +/- 8 years, body mass index: 31.6 +/- 5.2 kg/m(2), 6 +/- 2 antihypertensive drug classes). We assessed responses to electrical baroreflex stimulation during normoxia, isocapnic hypoxia (SpO(2): 79.0 +/- 1.5%), and hyperoxia (40% end-tidal O-2 fraction) by measuring heart rate, blood pressure, ventilation, oxygen saturation, end-tidal CO2 and O-2 fractions, and muscle sympathetic nerve activity. During normoxia, baroreflex activation reduced systolic blood pressure from 164 +/- 27 to 151 +/- 25 mm Hg (mean +/- SD, P<0.001), heart rate from 64 +/- 13 to 61 +/- 13 bpm (P=0.002), and muscle sympathetic nerve activity from 42 +/- 12 to 36 +/- 12 bursts/min (P=0.004). Hypoxia increased systolic blood pressure 8 +/- 12 mm Hg (P=0.057), heart rate 10 +/- 6 bpm (P<0.001), muscle sympathetic nerve activity 7 +/- 7 bursts/min (P=0.031), and ventilation 10 +/- 7 L/min (P=0.002). However, responses to electrical carotid sinus stimulation did not differ between hypoxic and hyperoxic conditions: systolic blood pressure: -15 +/- 7 versus -14 +/- 8 mm Hg (P=0.938), heart rate: -2 +/- 3 versus -2 +/- 2 bpm (P=0.701), and muscle sympathetic nerve activity: -6 +/- 4 versus -4 +/- 3 bursts/min (P=0.531). We conclude that moderate peripheral chemoreflex activation does not attenuate acute responses to electrical baroreflex activation therapy in patients with resistant hypertension. These patients provided insight into human baroreflex-chemoreflex interactions that could not be gained otherwise

Present criteria for prophylactic ICD implantation: Insights from the EU-CERT-ICD (Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators in EUrope) project

BACKGROUND. The clinical effectiveness of primary prevention implantable cardioverter defibrillator (ICD) therapy is under debate. It is urgently needed to better identify patients who benefit from prophylactic ICD therapy. The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators (EU-CERT-ICD) completed in 2019 will assess this issue. SUMMARY. The EU-CERT-ICD is a prospective investigator-initiated non-randomized, controlled, multicenter observational cohort study done in 44 centers across 15 European countries. A total of 2327 patients with heart failure due to ischemic heart disease or dilated cardiomyopathy indicated for primary prophylactic ICD implantation were recruited between 2014 and 2018 (>1500 patients at first ICD implantation, >750 patients non-randomized non-ICD control group). The primary endpoint was all-cause mortality, first appropriate shock was co-primary endpoint. At baseline, all patients underwent 12-lead ECG and Holter-ECG analysis using multiple advanced methods for risk stratification as well as documentation of clinical characteristics and laboratory values. The EU-CERT-ICD data will provide much needed information on the survival benefit of preventive ICD therapy and expand on previous prospective risk stratification studies which showed very good applicability of clinical parameters and advanced risk stratifiers in order to define patient subgroups with above or below average ICD benefit. CONCLUSION. The EU-CERT-ICD study will provide new and current data about effectiveness of primary prophylactic ICD implantation. The study also aims for improved risk stratification and patient selection using clinical risk markers in general, and advanced ECG risk markers in particular.peerReviewe