Jochen Springer

Cardiac cachexia: A systematic overview

Cardiac cachexia as a terminal stage of chronic heart failure carries a poor prognosis. The definition of this clinical syndrome has been a matter of debate in recent years. This review describes the ongoing discussion about this issue and the complex pathophysiology of cardiac cachexia and chronic heart failure with particular focus on immunological, metabolic, and hormonal aspects at the intracellular and extracellular level. These include regulators such as neuropeptide Y, leptin, melanocortins, ghrelin, growth hormone, and insulin. The regulation of feeding is discussed as are nutritional aspects in the treatment of the disease. The mechanisms of wasting in different body compartments are described. Moreover, we discuss several therapeutic approaches. These include appetite stimulants like megestrol acetate, medroxyprogesterone acetate, and cannabinoids. Other drug classes of interest comprise angiotensin-converting enzyme inhibitors, beta-blockers, anabolic steroids, beta-adrenergic agonists, anti-inflammatory substances, statins, thalidomide, proteasome inhibitors, and pentoxifylline.

Localization of the Peptide Transporter PEPT2 in the Lung: Implications for Pulmonary Oligopeptide Uptake

Pulmonary delivery of peptidomimetic antibiotics is frequently used for local drug therapy in pulmonary infections. Identification of transport pathways into airway epithelia can lead to new strategies of therapy. Here we describe the distribution of the beta-lactam-transporting high-affinity proton-coupled peptide transporter PEPT2 in mammalian lungs. Using reverse transcriptase-polymerase chain reaction and Northern blot analysis, PEPT2-mRNA was detected in lung extracts. The expression of PEPT2-mRNA and protein was localized to alveolar type II pneumocytes, bronchial epithelium, and endothelium of small arteries of rat lung by nonisotopic in situ hybridization and immunohistochemistry. In addition, transport studies using murine whole-organ preparations revealed transporter-mediated uptake of a fluorophore-conjugated dipeptide derivative into bronchial epithelial cells and type II pneumocytes. This transport was competitively inhibited by cephalosporins and dipeptides that are reported as PEPT2-carried substrates. Cell specificity of the PEPT2-mediated uptake pattern was confirmed by double labeling with Lycopersicon esculentum lectin. Together these data suggest that PEPT2 is the molecular basis for the transport of peptides and peptidomimetics in pulmonary epithelial cells. In conclusion PEPT2 may be an interesting target for pulmonary delivery of peptides and peptidomimetics.

The role of myostatin in muscle wasting: an overview

Myostatin is an extracellular cytokine mostly expressed in skeletal muscles and known to play a crucial role in the negative regulation of muscle mass. Upon the binding to activin type IIB receptor, myostatin can initiate several different signalling cascades resulting in the upregulation of the atrogenes and downregulation of the important for myogenesis genes. Muscle size is regulated via a complex interplay of myostatin signalling with the insulin-like growth factor 1/phosphatidylinositol 3-kinase/Akt pathway responsible for increase in protein synthesis in muscle. Therefore, the regulation of muscle weight is a process in which myostatin plays a central role but the mechanism of its action and signalling cascades are not fully understood. Myostatin upregulation was observed in the pathogenesis of muscle wasting during cachexia associated with different diseases (i.e. cancer, heart failure, HIV). Characterisation of myostatin signalling is therefore a perspective direction in the treatment development for cachexia. The current review covers the present knowledge about myostatin signalling pathways leading to muscle wasting and the state of therapy approaches via the regulation of myostatin and/or its downstream targets in cachexia.

Overweight and obesity are associated with improved survival, functional outcome, and stroke recurrence after acute stroke or transient ischaemic attack: observations from the TEMPiS trial

AIMS The aim of the study was to evaluate the association of the body mass index (BMI) with mortality and with non-fatal functional outcome in patients with acute stroke or transient ischaemic attack (TIA). Obesity is an established risk factors in primary cardiovascular disease prevention including stroke. The impact of overweight in patients with stroke or TIA on secondary fatal and non-fatal functional outcomes is less well established. METHODS AND RESULTS Data from 4428 patients with acute stroke or transient ischaemic attack (TIA) from the Telemedical Project for Integrative Stroke Care (TEMPiS) were studied in this post hoc analysis. The body mass index was available in 1521 patients. Patients were categorized as underweight (BMI <18.5), normal (BMI 18.5 to <25) overweight (BMI 25 to <30), obesity (BMI 30 to <35), advanced obesity (BMI ≥35 all kg/m(2)), and no body weight assessed. Outcome measures after 30 months were all-cause mortality and non-fatal outcomes: recurrent stroke, need for institutional care, and functional impairment (Barthel index <60, modified Rankin score >3). Mortality risk was lower in overweight patients [hazard ratio (HR): 0.69, 95% confidence interval (CI): 0.56-0.86) and lowest in obese (HR: 0.50, 95% CI: 0.35-0.71) and very obese patients (HR: 0.36, 95% CI: 0.20-0.66] compared with normal BMI. Functional, non-fatal outcomes, and recurrent stroke followed the same inverse pattern: underweight patients had the worst outcomes but obese patients had better outcomes than patients with normal BMI (all P < 0.01). After adjustment for multiple confounding factors, obese patients had a lower risk of the combined endpoints of death or institutional care (OR: 0.60, 95% CI: 0.38-0.92), death or high dependency (OR: 0.60, 95% CI: 0.39-0.91) and death or recurrent stroke (OR: 0.56, 95% CI: 0.37-0.86). Mortality was significantly lower in obese patients (all BMI >30 kg/m(2)) than patients with normal weight (HR: 0.70; 95% CI: 0.50-0.98). Underweight patients had consistently the highest risks for all endpoints. CONCLUSION Overweight and obese patients with stroke or TIA have better survival and better combined outcomes of survival and non-fatal functional status than patients with the BMI <25 kg/m(2).

Calcitonin gene-related peptide as inflammatory mediator.

Sensory neuropeptides have been proposed to play a key role in the pathogenesis of a number of respiratory diseases such as asthma, chronic obstructive pulmonary disease or chronic cough. Next to prominent neuropeptides such as tachykinins or vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) has long been suggested to participate in airway physiology and pathophysiology. CGRP is a 37 amino-acid peptide which is expressed by nerve fibers projecting to the airways and by pulmonary neuroendocrine cells. The most prominent effects of CGRP in the airways are vasodilatation and in a few instances bronchoconstriction. A further pulmonary effect of CGRP is the induction of eosinophil migration and the stimulation of beta-integrin-mediated T cell adhesion to fibronectin at the site of inflammation. By contrast, CGRP inhibits macrophage secretion and the capacity of macrophages to activate T-cells, indicating a potential anti-inflammatory effect. Due to the complex pulmonary effects of CGRP with bronchoconstriction and vasodilatation and diverse immunomodulatory actions, potential anti-asthma drugs based on this peptide have not been established so far. However, targeting the effects of CGRP may be of value for future strategies in nerve modulation.

Muscle wasting in heart failure: An overview.

Patients with heart failure are frequently limited in their exercise capacity. Although this clinical phenomenon is mostly attributed to the failing myocardium, the effects of skeletal muscle wasting should not be underestimated. Muscle wasting may present in the form of loss of muscle mass and function, termed sarcopenia in healthy aging, or in the form of cachexia. Only cachexia is associated with loss of body weight. The mechanisms involved embrace an anabolic-/catabolic imbalance with increased degradation of myofibrils and myocyte apoptosis. Clinical effects include reduced muscle mass, strength and consequently reduced exercise capacity. This article describes the terminology, molecular pathways, prevalence, clinical implications and possible treatment approaches to muscle wasting in patients with heart failure. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Prognosis and therapy approaches of cardiac cachexia

Purpose of review This review focuses on the prognostic implications and therapeutic approaches in cardiac cachexia – a syndrome that has been recognized for a long time, although it has only received increased attention lately. Recent findings Cardiac cachexia is a common and serious complication of chronic heart failure and associated with very poor prognosis, yet is often recognized by the clinicians only at late stage. Approximately 15% of heart failure patients will develop cardiac cachexia, defined by a 6% non-edematous, non-voluntary weight loss over a period of 6 months. Several studies have demonstrated that cardiac cachexia is a multi-factorial disease, which involves increased neurohormonal activity and immune abnormalities, resulting in hormonal and metabolic catabolic/anabolic imbalance of the body, leading to the loss of fat and lean mass and ultimately death. So far, there are no standardized therapies available for this disease. Summary Cardiac cachexia in heart failure patients is under-recognized and there is currently no causal therapy available. Several interesting treatment options exist, however, which have emerged recently, including appetite stimulants, hormones and ‘classical’ drugs, such as beta-blockers and ACE inhibitors.

Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure

BACKGROUND Small intestinal function may be altered in decompensated chronic heart failure (CHF) and translocating LPS may contribute to systemic inflammation observed in CHF. METHODS We measured intestinal permeability (melibiose and rhamnose), active (3-O-methyl-d-glucose (3-OMG)) and passive (d-xylose) carrier-mediated absorption in 20 CHF patients (12 edematous and 8 non-edematous) and 8 controls by saccharide absorption technique assessing urinary recovery of orally administered sugars. We additionally measured LPS concentrations in 42 patients with decompensated heart failure and after recompensation. RESULTS CHF patients had a 54% reduction of active carrier-mediated intestinal transport compared to controls (p<0.0001). This reduction was strongest in edematous compared to non-edematous patients and controls (recovery in urine: 13.2±2.0% vs. 20.8±2.4% vs. 36.0 ± 3.7%, all p ≤ 0.05). Patients showed a 34% reduction of passive carrier-mediated transport, strongest in edematous patients (p=0.006). A greater impairment of active carrier-mediated transport remained significant after adjustment for non-mucosal factors in CHF (p=0.0004). Non carrier-mediated intestinal permeability was not altered. Data from 42 decompensated patients showed a decrease in LPS after recompensation (p=0.004). Edematous patients had highest blood concentrations of LPS, TNF and sTNF-R1 (p<0.04). CHF patients with abnormal LPS concentrations >0.50EU/mL (n=7) had the highest concentrations of TNF (7.0 ± 1.6 vs. 3.1 ± 0.3pg/mL, p<0.02), and sTNF-R1 (3499 ± 52 vs. 1599±219 pg/mL, p=0.02). CONCLUSION Active carrier-mediated intestinal transport is reduced in decompensated CHF indicating epithelial dysfunction possibly as a consequence of intestinal ischemia. Higher LPS concentrations in edematous CHF relate to inflammation. LPS decreased after recompensation. This suggests a cause/effect relationship between edematous gut wall, epithelial dysfunction and translocating LPS.

SMAD-signaling in chronic obstructive pulmonary disease: transcriptional down-regulation of inhibitory SMAD 6 and 7 by cigarette smoke.

Abstract Transforming growth factor-β1 is a potent mediator of fibrosis stimulating the secretion of extracellular matrix proteins and is involved in airway remodeling in chronic obstructive pulmonary disease (COPD). Signals from the TGF superfamily are mediated by the SMAD group of transcription factors. Here, the expression of the regulatory SMAD2, 3, the co-SMAD4 and the inhibitory SMAD6 and 7 was assessed in bronchial biopsies of COPD patients and controls by quantitative RTPCR. While SMAD2 was not expressed and SMAD3 and 4 displayed no change, the inhibitory SMAD6 and 7 were significantly downregulated in COPD. To reveal the molecular basis of tobacco smoke-induced airway remodeling and to test whether it may interfere with intracellular SMAD signaling, the airway epithelial cell line A549 was incubated with cigarette smoke extract (1% and 10%) for 48 hours, which led to down-regulation of SMAD6 and 7 at both concentrations tested. It can be concluded that TGF-β-mediated effects in COPD are influenced by a disturbed intracellular feedback mechanism of inhibitory SMADs. Also, the effects of non-volatile components in tobacco smoke may partly be regulated via a smoke-induced down-regulation of inhibitory SMADs.

Prevention of liver cancer cachexia-induced cardiac wasting and heart failure

AIMS Symptoms of cancer cachexia (CC) include fatigue, shortness of breath, and impaired exercise capacity, which are also hallmark symptoms of heart failure (HF). Herein, we evaluate the effects of drugs commonly used to treat HF (bisoprolol, imidapril, spironolactone) on development of cardiac wasting, HF, and death in the rat hepatoma CC model (AH-130). METHODS AND RESULTS Tumour-bearing rats showed a progressive loss of body weight and left-ventricular (LV) mass that was associated with a progressive deterioration in cardiac function. Strikingly, bisoprolol and spironolactone significantly reduced wasting of LV mass, attenuated cardiac dysfunction, and improved survival. In contrast, imidapril had no beneficial effect. Several key anabolic and catabolic pathways were dysregulated in the cachectic hearts and, in addition, we found enhanced fibrosis that was corrected by treatment with spironolactone. Finally, we found cardiac wasting and fibrotic remodelling in patients who died as a result of CC. In living cancer patients, with and without cachexia, serum levels of brain natriuretic peptide and aldosterone were elevated. CONCLUSION Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer.