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Purpose As life expectancy increases, muscle wasting is becoming a more and more important public health problem. This review summarizes the current knowledge of pathophysiological mechanisms underlying muscle loss in ageing and chronic diseases such as heart failure and discusses evolving interventional strategies. Recent findings Loss of skeletal muscle mass and strength is a common phenomenon in a wide variety of disorders associated with ageing and morbidity-associated catabolic conditions such as chronic heart failure. Muscle wasting in ageing but otherwise healthy human beings is referred to as sarcopenia. Unlike cachexia in advanced stages of chronic heart failure, muscle wasting per se is not necessarily associated with weight loss. In this review, we discuss pathophysiological mechanisms underlying muscle loss in sarcopenia and cachexia, highlight similarities and differences of both conditions, and discuss therapeutic targets and possible treatments, such as exercise training, nutritional support, and drugs. Candidate drugs to treat muscle wasting disease include myostatin antagonists, ghrelin agonists, selective androgen receptor molecules, megestrol acetate, activin receptor antagonists, espindolol, and fast skeletal muscle troponin inhibitors. Summary Present approaches to muscle wasting disease include exercise training, nutritional support, and drugs, although particularly the latter remain currently restricted to clinical studies. Optimizing skeletal muscle mass and function in ageing and chronic illness including heart failure is one of the chapters that are far from finished and gains future potential for new therapeutic interventions to come. Open-Access Publikationsfonds 2015 peerReviewed

BACKGROUND: C-terminal Agrin Fragment (CAF) has been proposed as a novel biomarker for sarcopenia originating from the degeneration of the neuromuscular junctions. In patients with stroke muscle wasting is a common observation that predicts functional outcome. We aimed to evaluate agrin sub-fragment CAF22 as a marker of decreased muscle mass and physical performance in the early phase after acute stroke. METHODS: Patients with acute ischaemic or haemorrhagic stroke (n = 123, mean age 70 ± 11 y, body mass index BMI 27.0 ± 4.9 kg/m(2)) admitted to inpatient rehabilitation were studied in comparison to 26 healthy controls of similar age and BMI. Functional assessments were performed at begin (23 ± 17 days post stroke) and at the end of the structured rehabilitation programme (49 ± 18 days post stroke) that included physical assessment, maximum hand grip strength, Rivermead motor assessment, and Barthel index. Body composition was assessed by bioelectrical impedance analysis (BIA). Serum levels of CAF22 were measured by ELISA. RESULTS: CAF22 levels were elevated in stroke patients at admission (134.3 ± 52.3 pM) and showed incomplete recovery until discharge (118.2 ± 42.7 pM) compared to healthy controls (95.7 ± 31.8 pM, p

Background Chronic heart failure (CHF) is associated with insulin resistance, indicating impairment in the control of energy metabolism. Insulin resistance in CHF relates to symptomatic status and independently predicts poor prognosis. We sought to determine whether insulin sensitivity is related to skeletal muscle strength in patients with CHF, taking into account muscle size and perfusion. Methods Quadriceps muscle size (square centimetre cross-sectional area at mid-femur level, computed tomography), isometric quadriceps muscle strength [absolute (in N) and strength per unit muscle area (N/cm2)], resting-leg blood flow (plethysmography) and maximal oxygen consumption (treadmill exercise test) were measured in 33 patients with CHF (left ventricular ejection fraction 28 ± 3.2%, mean ± Standard Error of the mean (SEM)) and 20 healthy controls. Insulin sensitivity was assessed by intravenous glucose tolerance tests and minimal modelling analysis. Results Right quadriceps strength (−27.0%, P

AIMS Skeletal muscle wasting affects 20% of patients with chronic heart failure and has serious implications for their activities of daily living. Assessment of muscle wasting is technically challenging. C-terminal agrin-fragment (CAF), a breakdown product of the synaptically located protein agrin, has shown early promise as biomarker of muscle wasting. We sought to investigate the diagnostic properties of CAF in muscle wasting among patients with heart failure. METHODS AND RESULTS We assessed serum CAF levels in 196 patients who participated in the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF). Muscle wasting was identified using dual-energy X-ray absorptiometry (DEXA) in 38 patients (19.4%). Patients with muscle wasting demonstrated higher CAF values than those without (125.1 ± 59.5 pmol/L vs. 103.8 ± 42.9 pmol/L, P = 0.01). Using receiver operating characteristics (ROC), we calculated the optimal CAF value to identify patients with muscle wasting as >87.5 pmol/L, which had a sensitivity of 78.9% and a specificity of 43.7%. The area under the ROC curve was 0.63 (95% confidence interval 0.56-0.70). Using simple regression, we found that serum CAF was associated with handgrip (R = - 0.17, P = 0.03) and quadriceps strength (R = - 0.31, P

Background: Blood flow in the intestinal arteries is reduced in patients with stable heart failure (HF) and relates to gastrointestinal (GI) symptoms and cardiac cachexia. Objectives: The aims of this study were to measure arterial intestinal blood flow and assess its role in juxtamucosal bacterial growth, GI symptoms, and cachexia in patients with HF. Methods: A total of 65 patients and 25 controls were investigated. Twelve patients were cachectic. Intestinal blood flow and bowel wall thickness were measured using ultrasound. GI symptoms were documented. Bacteria in stool and juxtamucosal bacteria on biopsies taken during sigmoidoscopy were studied in a subgroup by fluorescence in situ hybridization. Serum lipopolysaccharide antibodies were measured. Results: Patients showed 30% to 43% reduced mean systolic blood flow in the superior and inferior mesenteric arteries and celiac trunk (CT) compared with controls (p < 0.007 for all). Cachectic patients had the lowest blood flow (p < 0.002). Lower blood flow in the superior mesenteric artery and CT was correlated with HF severity (p < 0.04 for all). Patients had more feelings of repletion, flatulence, intestinal murmurs, and burping (p < 0.04). Burping and nausea or vomiting were most severe in patients with cachexia (p < 0.05). Patients with lower CT blood flow had more abdominal discomfort and immunoglobulin A–antilipopolysaccharide (r = 0.76, p < 0.02). Antilipopolysaccharide response was correlated with increased growth of juxtamucosal but not stool bacteria. Patients with intestinal murmurs had greater bowel wall thickness of the sigmoid and descending colon, suggestive of edema contributing to GI symptoms (p < 0.05). In multivariate regression analysis, lower blood flow in the superior mesenteric artery, CT (p < 0.04), and inferior mesenteric artery (p = 0.056) was correlated with the presence of cardiac cachexia. Conclusions: Intestinal blood flow is reduced in patients with HF. This may contribute to juxtamucosal bacterial growth and GI symptoms in patients with advanced HF complicated by cachexia.

Die chronische Herzinsuffizienz geht mit einer chronischen sytemischen Inflammation und einem katabolen/anabolen Ungleichgewicht einher, welche zu einer prognoserelevanten kardialen Kachexie im fortgeschrittenen Stadium der Erkrankung führen können. Ziel dieser Arbeit war es, die Bedeutung des Darm- Traktes für die Entstehung von systemischer Inflammation und Kachexie bei Patienten mit chronischer Herzinsuffizienz zu charakterisieren. Wir konnten zeigen, dass Patienten mit chronischer Herzinsuffizienz einen reduzierten intestinalen Blutfluss haben und ein Darmwandödem ausprägen. Diese Veränderungen gehen einher mit erschwerter intestinaler Absorptionsfunktion, erlauben eine Ausbreitung des Wachstums der Darmbakterien innerhalb des Schleimhautbiofilms, die dadurch mit der Dickdarmmukosa in Kontakt treten können. Unsere Arbeiten zeigen zudem, dass die Konzentration der adhärenten Darmbakterien mit der systemisch nachweisbaren LPS-Antikörper-antwort bei Herzinsuffizienz korreliert. Damit sind eine Interaktion zwischen den Darmbakterien und dem Immunsystem des Wirtes sowie eine lokale Entzündung und Permeabilitätserhöhung der Darmschleimhaut wahrscheinlich. Die Tatsache, dass höhere LPS-Konzentrationen im Serum ödematöser Patienten mit höheren Entzündungswerten assoziiert waren und die höheren LPS-Konzentrationen nach Rekompensation sanken, unterstreicht diese Ursache-Wirkungsbeziehung zwischen ödematöser Darmwand, epithelialer Dysfunktion und translozierendem LPS. Dies deutet auf einen circulus vitiosus hin, innerhalb dessen die durchblutungsabhängige Schrankenstörung der Darmschleimhaut zu verstärkter Auseinandersetzung mit Darmbakterien und lokaler Inflammation führt, die wiederum die Darmbarriere weiter schwächen. Als Ausdruck einer systemischen Relevanz dieser Veränderungen bestand in unseren Untersuchungen eine Korrelation einer höheren Darmwanddicke des Sigmoids mit CrP-Werten im Serum als Kennzeichen systemischer Entzündung. Zudem korrelierte eine höhere Darmwanddicke auch des aufsteigenden Kolons als Hinweis auf ein Ödem der Darmwand mit einer höheren Leukozytenkonzentration im Blut der Patienten. Auch ein geringer Blutfluss in Truncus coeliacus und in der oberen Mesenterialarterie korrelierte mit einer erhöhten Konzentration von C-reaktivem Protein im Serum. Diese Resultate sind vereinbar mit einer Beteiligung der intestinalen Hämodynamik an der prognoserelevanten systemischen Inflammation. Eine stärkere Betonung des immunologischen Status der Patienten mit Herzschwäche sollte als Reflektor auch der Veränderungen am Darm die Risikostratifizierung verbessern. Wir konnten mit dem 4 Faktoren- Modell aus sTNF-R1, Harnsäure, LVEF und der NYHA-Klasse ein hochprognostisches Risikostratifizierungsmodell für die zugrundeliegende Patientenkohorte erstellen und eine Abbildbarkeit auch der Veränderungen an anderen Organsystemen wie z.B. dem Darm durch Parameter der systemischen Immunaktivierung wie sTNF-R 1 integrieren. Ein geringer intestinaler arterieller Blutfluss, eine Rechtsherzdysfunktion, eine kongestive Leberdysfunktion und eine geringe Albuminkonzentration im Serum sind in unseren multivariaten Modellen mit naturgemäß limitierter statistischer Aussage bei kleinen Kohorten für das Vorhandensein einer Kachexie prädiktiv. Interventionsstudien an größeren Patientenkohorten müssen zeigen, ob eine gezielte Verbesserung des mesenterialen Blutflusses das Wachstum der Darmbakterien unmittelbar an der Dickdarmschleimhaut hemmen, die chronische Entzündung und intestinale Symptome reduzieren und kardiale Kachexie bei Patienten mit fortgeschrittener Herzinsuffizienz und kardiointestinalem Syndrom verhindern kann. Die vorgelegten Untersuchungen zur nachgewiesenen Barrierestörung des Darmes bei Herzinsuffizienz ebnen den Weg für hierauf aufbauende Interventionsstudien, die auf die Darmbakterien als Quelle systemischer Inflammation und kardiovaskulärer Pathogenese zielen., Chronic heart failure is associated with low-grade systemic inflammation and anabolic-catabolic imbalance, that may lead to prognostically relevant cardiac cachexia in advanced stages of the disease. Aim of this work was to characterize the role of the gastrointestinal tract for the development of systemic inflammation and cachexia in patients with chronic heart failure.We found that patients with chronic heart failure have a reduced intestinal blood flow and an edema of the intestinal wall. These alterations are accompanied by a decreased specific intestinal absorption function, permit bacterial overgrowth in the mucus layer adjacent to the apical surface of the colonic mucosa. Furthermore, our studies show that the concentration of adherent juxtamucosal gut bacteria correlates with blood lipopolysaccharide(LPS)-antibodies indicating a systemic response to bacteria in heart failure. Thus, interaction between gut bacteria and immune system of the host, local Inflammation and an increase in intestinal permeability of the intestinal mucosa are conceivable. The fact that higher blood concentrations of LPS were associated with higher degree of inflammation in edematously decompensated patients and that these inflammatory markers decreased after recompensation suggests a cause/effect relationship between edematous gut wall, epithelial dysfunction and translocating LPS.This points to a vicious circle where increased permeability due to lower blood supply leads to an augmented interaction with gut bacteria and local Inflammation again weakening intestinal barrier. As an indicator of systemic relevance of these alterations, we found a correlation of a greater bowel wall thickness of the sigmoid with higher blood C-reactive Protein (CrP) as a hallmark of systemic Inflammation. Furthermore, a greater bowel wall thickness of the ascending colon suggestive of a bowel wall edema, correlated with a higher concentration of blood leucocytes in these patients with heart failure. Low intestinal blood flow in celiac trunk and upper mesenteric artery, correlated with higher blood CrP, too. These results are consistent with a contribution of intestinal hemodynamics to prognostically relevant systemic inflammation. An implementation of the immunological status of the patients should improve risk stratification in heart failure. We were able to show a risk stratification model including 4 factors (soluble tumor necrosis factor-receptor 1 (sTNF-R 1), uric acid, left ventricular ejection fraction and NYHA class) to be highly prognostic in our cohort and therefore integrated intestinal alterations through markers of systemic Inflammation such as sTNF-R 1. In multivariate Regression analysis with limited statistical power, low intestinal arterial blood flow, right ventricular dysfunction, congestive liver dysfunction and low serum albumin were predictive of the presence of cachexia. Research is needed to determine whether interventions that specially increase mesenteric blood flow inhibit the growth of juxtamucosal bacteria, reduce inflammation and GI symptoms, and ameliorate cardiac cachexia in patients with advanced HF. Our studies of intestinal barrier dysfunction in heart failure pave the way for interventional studies that target gut bacteria as source of systemic Inflammation and cardiovascular pathogenesis.