Nicole Ebner

Muscle wasting in patients with chronic heart failure: results from the studies investigating co-morbidities aggravating heart failure (SICA-HF)

AIMS To assess the prevalence and clinical impact of reductions in the skeletal muscle mass of patients with chronic heart failure (HF). Chronic HF is accompanied by co-morbidities that influence the quality of life and outcomes. METHODS AND RESULTS We prospectively enrolled 200 patients with chronic HF. The appendicular skeletal muscle mass of the arms and the legs combined, was assessed by dual energy X-ray absorptiometry. We analysed the muscle strength in arms and legs, and all patients underwent a 6-min walk test, a 4-m walk test, and spiroergometry testing. Muscle wasting was defined as the appendicular muscle mass 2 SD below the mean of a healthy reference group of adults aged 18-40 years, as suggested for the diagnosis of muscle wasting in healthy ageing (sarcopenia). Muscle wasting was detected in 39 (19.5%) subjects. Patients with muscle wasting had significantly lower values for handgrip and quadriceps strength as well as lower total peak oxygen consumption (peakVO2, 1173 ± 433 vs. 1622 ± 456 mL/min), lower exercise time (7.7 ± 3.8 vs. 10.22 ± 3.0 min, both P < 0.001), and lower left ventricular ejection fraction (LVEF, P = 0.05) than patients without. The distance walked during 6 min and the gait speed during the 4-m walk were lower in patients with muscle wasting (both P < 0.05). Serum levels of interleukin-6 were significantly elevated in patients with muscle wasting (P = 0.001). Logistic regression showed muscle wasting to be independently associated with reduced peak VO2 adjusted for age, sex, New York Heart Association class, haemoglobin, LVEF, distance walked in 6 minutes, and the number of co-morbidities (odds ratio 6.53, p = 0.01). CONCLUSION Muscle wasting is a frequent co-morbidity among patients with chronic HF. Patients with muscle wasting present with reduced exercise capacity and muscle strength, and advanced disease.

Loss of muscle mass: current developments in cachexia and sarcopenia focused on biomarkers and treatment.

Loss of muscle mass arises from an imbalance of protein synthesis and protein degradation. Potential triggers of muscle wasting and function are immobilization, loss of appetite, dystrophies, and chronic diseases as well as aging. All these conditions lead to increased morbidity and mortality in patients, which makes it a timely matter to find new biomarkers to get a fast clinical diagnosis and to develop new therapies. This mini‐review covers current developments in the field of biomarkers and drugs on cachexia and sarcopenia. Here, we reported about promising markers, e.g. tartate‐resistant acid phosphatase 5a, and novel substances like epigallocatechin‐3‐gallate. In summary, the progress to combat muscle wasting is in full swing, and perhaps diagnosis of muscle atrophy and of course patient treatments could be soon support by improved and more helpful strategies.

Highlights from the 7th Cachexia Conference: muscle wasting pathophysiological detection and novel treatment strategies

This article highlights preclinical and clinical studies in the field of wasting disorders that were presented at the 7th Cachexia Conference held in Kobe, Japan, in December 2013. This year, the main topics were the development of new methods and new biomarkers in the field of cachexia and wasting disorders with particular focus on inflammatory pathways, growth differentiation factor-15, myostatin, the ubiquitin proteasome-dependent pathway, valosin and the regulation of ubiquitin-specific protease 19 that is involved in the differentiation of myogenin and myosin heavy chain. This article presents highlights from the development of drugs that have shown potential in the treatment of wasting disorders, particularly the ghrelin receptor agonist anamorelin, the myostatin antagonist REGN1033, the selective androgen receptor modulators enobosarm and TEI-E0001, and the anabolic catabolic transforming agent espindolol. In addition, novel data on the prevalence and detection methods of muscle wasting/sarcopenia are presented, including the D3-creatine dilution method and several new biomarkers.

Intestinal congestion and right ventricular dysfunction: a link with appetite loss, inflammation, and cachexia in chronic heart failure

AIMS Mechanisms leading to cachexia in heart failure (HF) are not fully understood. We evaluated signs of intestinal congestion in patients with chronic HF and their relationship with cachexia. METHODS AND RESULTS Of the 165 prospectively enrolled outpatients with left ventricular ejection fraction ≤40%, 29 (18%) were cachectic. Among echocardiographic parameters, the combination of right ventricular dysfunction and elevated right atrial pressure (RAP) provided the best discrimination between cachectic and non-cachectic patients [area under the curve 0.892, 95% confidence interval (CI): 0.832-0.936]. Cachectic patients, compared with non-cachectic, had higher prevalence of postprandial fullness, appetite loss, and abdominal discomfort. Abdominal ultrasound showed a larger bowel wall thickness (BWT) in the entire colon and terminal ileum in cachectic than in non-cachectic patients. Bowel wall thickness correlated positively with gastrointestinal symptoms, high-sensitivity C-reactive protein, RAP, and truncal fat-free mass, the latter serving as a marker of the fluid content. Logistic regression analysis showed that BWT was associated with cachexia, even after adjusting for cardiac function, inflammation, and stages of HF (odds ratio 1.4, 95% CI: 1.0-1.8; P-value = 0.03). Among the cardiac parameters, only RAP remained significantly associated with cachexia after multivariable adjustment. CONCLUSION Cardiac cachexia was associated with intestinal congestion irrespective of HF stage and cardiac function. Gastrointestinal discomfort, appetite loss, and pro-inflammatory activation provide probable mechanisms, by which intestinal congestion may trigger cardiac cachexia. However, our results are preliminary and larger studies are needed to clarify the intrinsic nature of this relationship.

Mechanism and novel therapeutic approaches to wasting in chronic disease

Cachexia is a multifactorial syndrome defined by continuous loss of skeletal muscle mass - with or without loss of fat mass - which cannot be fully reversed by conventional nutritional support and which may lead to progressive functional impairment and increased death risk. Its pathophysiology is characterized by negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. Muscle wasting is encountered in virtually all chronic disease states in particular during advanced stages of the respective illness. Several pre-clinical and clinical studies are ongoing to ameliorate this clinical problem. The mechanisms of muscle wasting and cachexia in chronic diseases such as cancer, chronic heart failure, chronic obstructive pulmonary disease and chronic kidney disease are described. We discuss therapeutic targets and such potential modulators as appetite stimulants, selective androgen receptor modulators, amino acids and naturally occurring peptide hormones.

The impact of iron deficiency and anaemia on exercise capacity and outcomes in patients with chronic heart failure. Results from the Studies Investigating Co-morbidities Aggravating Heart Failure.

UNLABELLED Anaemia and iron deficiency (ID) are important co-morbidities in patients with chronic heart failure (HF) and both may lead to reduced exercise capacity. METHODS We enrolled 331 out-patients with stable chronic HF (mean age: 64 ± 11 years, 17% female, left ventricular ejection fraction [LVEF] 35 ± 13%, body mass index [BMI] 28.5 ± 5.2 kg/m(2), New York Heart Association [NYHA] class 2.2 ± 0.7, chronic kidney disease 35%, glomerular filtration rate 61.7 ± 20.1 mL/min). Anaemia was defined according to World Health Organization criteria (haemoglobin [Hb] < 13 g/dL in men, < 12 g/dL in women). ID was defined as serum ferritin < 100 μg/L or ferritin < 300 μg/L with transferrin saturation (TSAT) < 20%. Exercise capacity was assessed as peak oxygen consumption (peak VO2) by spiroergometry and 6-minute walk test (6MWT). RESULTS A total of 91 (27%) patients died from any cause during a mean follow-up of 18 months. At baseline, 98 (30%) patients presented with anaemia and 149 (45%) patients presented with ID. We observed a significant reduction in exercise capacity in parallel to decreasing Hb levels (r = 0.24, p < 0.001). In patients with anaemia and ID (n = 63, 19%), exercise capacity was significantly lower than in patients with ID or anaemia only. Cox regression analysis showed that after adjusting for NYHA, age, hsCRP and creatinine anaemia is an independent predictor of mortality in patients with HF (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.33-0.97, p = 0.04). CONCLUSION The impact of anaemia on reduced exercise capacity and on mortality is stronger than that of ID. Anaemia remained an independent predictor of death after adjusting for clinically relevant variables.

Detection of muscle wasting in patients with chronic heart failure using C-terminal agrin fragment: results from the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF).

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.

Muscle wasting and cachexia in heart failure: mechanisms and therapies.

Body wasting is a serious complication that affects a large proportion of patients with heart failure. Muscle wasting, also known as sarcopenia, is the loss of muscle mass and strength, whereas cachexia describes loss of weight. After reaching guideline-recommended doses of heart failure therapies, the most promising approach to treating body wasting seems to be combined therapy that includes exercise, nutritional counselling, and drug treatment. Nutritional considerations include avoiding excessive salt and fluid intake, and replenishment of deficiencies in trace elements. Administration of omega-3 polyunsaturated fatty acids is beneficial in selected patients. High-calorific nutritional supplements can also be useful. The prescription of aerobic exercise training that provokes mild or moderate breathlessness has good scientific support. Drugs with potential benefit in the treatment of body wasting that have been tested in clinical studies in patients with heart failure include testosterone, ghrelin, recombinant human growth hormone, essential amino acids, and β2-adrenergic receptor agonists. In this Review, we summarize the pathophysiological mechanisms of muscle wasting and cachexia in heart failure, and highlight the potential treatment strategies. We aim to provide clinicians with the relevant information on body wasting to understand and treat these conditions in patients with heart failure.

Elevated plasma levels of neuropeptide proenkephalin a predict mortality and functional outcome in ischemic stroke.

OBJECTIVES The purpose of this study was to investigate neuropeptides in patients presenting with symptoms of acute cerebrovascular disease. BACKGROUND The precursor neuropeptides proenkephalin A (PENK-A) and protachykinin (PTA) are markers of blood-brain barrier integrity and have been recently discussed in vascular dementia and neuroinflammatory disorders. METHODS In a prospective observational study, we measured plasma PENK-A and PTA concentrations in 189 consecutive patients who were admitted with symptoms of acute stroke. Plasma concentrations were determined by sandwich immunoassay; lower detection limits were 15.6 pmol/l (PENK-A) and 22 pmol/l (PTA). Clinical outcome was assessed at 3 months for mortality, major adverse cerebro/cardiovascular events, and functional outcome (modified Rankin scale). RESULTS PENK-A was significantly elevated in patients with ischemic stroke (n = 124; 65.6%) compared to patients with transient ischemic attack (n = 16; 8.5%) and to patients with nonischemic events (n = 49; 25.9%): median (interquartile range), stroke 123.8 pmol/l (93 to 160.5); transient ischemic attack 114.5 pmol/l (85.3 to 138.8); and nonischemic event 102.8 pmol/l (76.4 to 137.6; both groups vs. stroke p < 0.05). High concentrations of PENK-A, but not PTA, were related to severity of stroke as assessed by National Institutes of Health Stroke Scale (NIHSS [r = 0.225; p = 0.002]) and to advanced functional disability (modified Rankin Scale score 3 to 6 vs. 0 to 2: 135.1 pmol/l [99.2 to 174.1] vs. 108.9 pmol/l [88.6 to 139.5]; p = 0.014). After adjusting for age, NIHSS, and brain lesion size (computed tomography), PENK-A predicted mortality (hazard ratio [HR] for log-10 PENK-A in pmol/l: 4.52; 95% confidence interval [CI]: 1.1 to 19.0; p < 0.05) and major adverse cerebro/cardiovascular events (HR: 6.65; 95% CI: 1.8 to 24.9; p < 0.05). Patients in the highest quartile of PENK-A (cutoff >153 pmol/l) had an increased risk of mortality (HR: 2.40; 95% CI: 1.02 to 5.40; p < 0.05) and of major adverse cerebro/cardiovascular events (HR: 2.23; 95% CI: 1.10 to 4.54; p < 0.05). CONCLUSIONS PENK-A is a prognostic biomarker in the acute phase of ischemic stroke. Elevated PENK-A concentrations are associated with ischemic stroke, severity of cerebral injury, and may have prognostic value for fatal and nonfatal events.

Iron Deficiency in Heart Failure: A Practical Guide

Iron is an element necessary for cells due to its capacity of transporting oxygen and electrons. One of the important co-morbidities in heart failure is iron deficiency. Iron has relevant biological functions, for example, the formation of haemoglobin, myoglobin and numerous enzymatic groups. The prevalence of iron deficiency increases with the severity of heart failure. For a long time, the influence of iron deficiency was underestimated especially in terms of worsening of cardiovascular diseases and of developing anaemia. In recent years, studies with intravenous iron agents in patients with iron deficiency and cardiovascular diseases indicated new insights in the improvement of therapy. Experimental studies support the understanding of iron metabolism. Many physicians remain doubtful of the use of intravenous iron due to reports of side effects. The aim of this review is to describe iron metabolism in humans, to highlight the influence of iron deficiency on the course and symptoms of heart failure, discuss diagnostic tools of iron deficiency and provide guidance on the use of intravenous iron.