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Cardiac cachexia is a co-morbidity of heart failure (HF) defined by a non-edematous weight loss of ≥6% within the previous 6-12 months. Cachexia affects about 10-39% patients with HF and occurs typically in advanced stages of HF, especially in the presence of congestive right ventricular dysfunction. This review elucidates the approaches and pitfalls in the diagnosis of cachexia. It summarizes the prevalence and impact of cardiac cachexia. It also discusses changes in body composition over the course of HF and provides an overview of the mechanisms involved in wasting in HF., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure., Methods: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 μg/L, or 100-299 μg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed., Findings: Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62-1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64-1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70-1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58-0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66-0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47-0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group., Interpretation: In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death., Funding: Vifor Pharma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Bachground: Postprandial hyperlipaemia impairs endothelial function, possibly via oxidative-stress-mediated mechanisms. The aim of this study was to evaluate the acute effects of an oral triglyceride load (OTGL) on peripheral endothelial function in heart failure patients with reduced ejection fraction (HFrEF) compared to healthy controls., Design: Prospective cross-sectional., Methods: We enrolled 47 patients with HFrEF and 20 healthy controls. Peripheral endothelial function was assessed with EndoPAT2000 technology using a reactive hyperaemia index (RHI) and pulse wave amplitude (PWA) at baseline (after 8-h overnight fasting) as well as 1, 2, 3 and 4-h post-OTGL consumption (250-ml cream drink). Pulse wave amplitude index (PWAI) was calculated as a ratio of PWA at each time point to the baseline PWA., Results: RHI at baseline was lower in HFrEF patients compared to controls (1.7 ± 0.3 and 2.3 ± 0.6, respectively; P = 0.001). The OTGL accounted for a physiologic increase in PWA in healthy controls (p = 0.01), but this change was not observed in HFrEF patients. After 4 h, vasodilator response was significantly increased in healthy controls but not patients with HFrEF (2.3 ± 1.3 vs. 1.3 ± 0.8 respectively, P < 0.05)., Conclusions: The main finding of this study was the impaired postprandial dynamic changes in peripheral endothelial function in patients with HFrEF compared to healthy controls. A high-fat load that caused acute hypertriglyceridaemia significantly increased resting blood flow and peak flow at reactive hyperaemia in healthy subjects. By contrast, patients with HFrEF exhibited impaired dynamic changes in peripheral endothelial function after oral triglyceride load., Competing Interests: Declaration of Competing Interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Study Objectives: Aim of the study was to investigate the association between obstructive sleep apnoea (OSA) and cardiovascular morbidity and mortality in a cohort of patients with cardiovascular risk factors., Methods: In this prospective study, 378 patients of the DIAST-CHF cohort were screened for OSA by home polygraphy. Inclusion criteria were risk factors for diastolic heart failure, such as hypertension, diabetes mellitus, atherosclerotic disease, or history of chronic heart failure. Patients were followed up after 1, 2, 5, 9 and 10 years for the occurrence of major adverse cardiac and cerebrovascular events (MACE and MACCE)., Results: 344 patients were included in the analysis, of which 60% were diagnosed with OSA (apnoea-hypopnoea index ≥5/h). Overall mortality was higher in the OSA group (14.9% vs. 5.9%; p = 0.007), but significance disappeared after adjustment for age and sex (hazard ratio (HR) 1.89, 95% confidence interval (CI) 0.86-4.16, p = 0.12). There was no significant difference in the occurrence of MACE or MACCE in patients with OSA compared to those without OSA (MACE: 31% vs. 30%; p = 0.61; MACCE: 32% vs. 30%; p = 0.53)., Conclusion: We did not find evidence of an adverse effect of OSA on cardiovascular morbidity and mortality in a cohort of patients with cardiovascular risk factors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Iron deficiency is an extremely common comorbidity in patients with heart failure, affecting up to 50% of all ambulatory patients. It is associated with reduced exercise capacity and physical well-being and reduced quality of life. Cutoff values have been identified for diagnosing iron deficiency in heart failure with reduced ejection fraction as serum ferritin, <100 μg/l, or ferritin, 100 to 300 μg/l, with transferrin saturation of <20%. Oral iron products have been shown to have little efficacy in heart failure, where the preference is intravenous iron products. Most clinical studies have been performed using ferric carboxymaltose with good efficacy in terms of improvements in 6-min walk test distance, peak oxygen consumption, quality of life, and improvements in New York Heart Association functional class. Data from meta-analyses also suggest beneficial effects for hospitalization rates for heart failure and reduction in cardiovascular mortality rates. A prospective trial to investigate effects on morbidity and mortality is currently ongoing. This paper highlights current knowledge of the pathophysiology of iron deficiency in heart failure, its prevalence and clinical impact, and its possible treatment options., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cachexia in the context of heart failure (HF) has been termed cardiac cachexia, and represents a progressive involuntary weight loss. Cachexia is mainly the result of an imbalance in the homeostasis of muscle protein synthesis and degradation due to a lower activity of protein synthesis pathways and an over-activation of protein degradation. In addition, muscle wasting leads to of impaired functional capacity, even after adjusting for clinical relevant variables in patients with HF. However, there is no sufficient therapeutic strategy in muscle wasting in HF patients and very few studies in animal models. Exercise training represents a promising intervention that can prevent or even reverse the process of muscle wasting, and worsening the muscle function and performance in HF with muscle wasting and cachexia. The pathological mechanisms and effective therapeutic approach of cardiac cachexia remain uncertain, because of the difficulty to establish animal cardiac cachexia models, thus novel animal models are warranted. Furthermore, the use of improved animal models will lead to a better understanding of the pathways that modulate muscle wasting and therapeutics of muscle wasting of cardiac cachexia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Approximately 40-50% of the population over 80years of age suffers from sarcopenia making this condition a major geriatric clinical disorder and a key challenge to healthy aging. The hallmark symptom of sarcopenia is the loss of muscle mass and strength without the loss of overall body weight. Sarcopenic patients are likely to have worse clinical outcomes and higher mortality compared to healthy individuals. This review will focus on animal models designed to study sarcopenia including hind-limb unloading, de-nervation, and immobilization by using casts or wire strategies, as well as using aged rodents. Currently there are no registered treatments for sarcopenia. Most sarcopenic individuals show signs of physical frailty, which leads to increases the prevalence of balance disorders, falls, fractures and pain. Therefore, is it essential to develop and use relevant animal models to further the research on sarcopenia therapy?, (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cachexia is defined as a complex metabolic syndrome associated with underlying illness that is characterized by the loss of body weight consisting of muscle and fat mass wasting. Sarcopenia is defined as the ageing related loss of muscle mass in health and disease that may not have an effect on body weight. As millions of patients are in cachectic or sarcopenic states, both conditions contribute to high numbers to death worldwide. A number of treatments have been proposed for cachexia and sarcopenia, but these are either in the preclinical stage or in clinical trials and hence not available to the general population. Particularly in cachexia there is a massive problem of recruiting patients for trials and also with the follow-up, due to the seriousness of the disease. This underlines the importance of well-characterized animal models. Obviously, most of the widely used cachexia and sarcopenia animal models have limitations in reproducibility of the condition and novel models are warranted in this context. The key findings of developing models in the field of cachexia and sarcopenia are that more types of the conditions have been taken into the researchers' interest. In cardiac cachexia, technical issues, which limit the preciseness and reproducibility in surgical heart failure models, have been overcome by a combination of surgery and the use of transgenic mouse models or salt sensitive rat models. Fatigue is the most pronounced symptom of cachexia and may be caused by reduced cardiac function independent of the underlying disease. Sarcopenia models often suffer from the use of young animals, due to the limited availability and very high costs of using aged animals. This review will focus on rodent models designed to mimic cachexia and sarcopenia including co-morbidities such as cancer, heart failure, as well as other diseases and conditions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Skeletal muscle wasting, also known as sarcopenia, has recently been identified as a serious comorbidity in patients with heart failure (HF). We aimed to assess the impact of sarcopenia on endothelial dysfunction in patients with HF with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF)., Design: Cross-sectional study., Setting: Ambulatory patients with HF were recruited at Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany., Participants: We assessed peripheral blood flow (arm and leg) in 228 patients with HF and 32 controls who participated in the Studies Investigating Comorbidities Aggravating HF (SICA-HF)., Measurements: The appendicular skeletal muscle mass of the arms and the legs combined was assessed by dual energy x-ray absorptiometry (DEXA). Sarcopenia was defined as the appendicular muscle mass two standard deviations below the mean of a healthy reference group of adults aged 18 to 40 years, as suggested for the diagnosis of muscle wasting in healthy aging. All patients underwent a 6-minute walk test and spiroergometry testing. Forearm and leg blood flow were measured by venous occlusion plethysmography. Peak blood flow was assessed after a period of ischemia in the limbs to test endothelial function., Results: Sarcopenia was identified in 37 patients (19.5%). Patients with sarcopenia presented with lower baseline forearm blood flow (2.30 ± 1.21 vs. 3.06 ± 1.49 vs. 4.00 ± 1.66 mL min -1 100 mL -1 ; P = .02) than those without sarcopenia or controls. The group of patients with sarcopenia showed similar baseline leg blood flow (2.06 ± 1.62 vs. 2.39 ± 1.39 mL min -1 100 mL -1 ; P = .11) to those without but lower values when compared to controls (2.06 ± 1.62 vs. 2.99 ± 1.28 mL min -1 100 mL -1 ; P = .03). In addition, patients with and without sarcopenia presented with lower peak flow in the forearm when compared to controls (18.37 ± 7.07 vs. 22.19 ± 8.64 vs. 33.63 ± 8.57 mL min -1 100 mL -1 ; P < .001). A similar result was observed in the leg (10.89 ± 5.61 vs. 14.66 ± 7.19 vs. 21.37 ± 13.16 mL min -1 100 mL -1 ; P < .001). Peak flow in the forearm showed a significant correlation with exercise capacity (relative peak VO 2 : R = 0.47; P < .001; absolute peak VO 2 : R = 0.35; P < .001; and 6-min walk distance: R = 0.20; P < .01). Similar correlations were observed between peak flow in the leg and exercise capacity (absolute peak VO 2 : R = 0.42, P < .001; relative peak VO 2 : R = 0.41, P < .001; and 6-min walk test: R = 0.33; P < .001). Logistic regression showed peak flow in the leg to be independently associated with the 6-min walk distance adjusted for age, hemoglobin level, albumin, creatinine, presence of sarcopenia, and coronary artery disease (hazard ratio, 0.903; 95% confidence interval, 0.835-0.976; P = .01)., Conclusion: Patients with HF associated with sarcopenia have impaired endothelial function. Lower vasodilatation had a negative impact on exercise capacity, particularly prevalent in patients with sarcopenia., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Hemiparetic stroke leads to structural and metabolic alterations of skeletal muscle tissue, thereby contributing to functional impairment associated with stroke. In situ metabolic processes at tissue level in skeletal muscle have not been investigated. We hypothesize that muscular metabolic capacity is limited after hemiparetic stroke, and that changes affect rather the paretic than non-paretic limb., Methods: Nine male hemiparetic stroke survivors (age, 62±8years; BMI, 28±4kg/m 2 ; median stroke latency, 23months ranging from 7 to 34months poststroke) underwent dynamic in situ measurements of carbohydrate and lipid metabolism at fasting condition and during oral glucose tolerance testing, using bilateral microdialysis. Results were compared to 8 healthy male subjects of similar age and BMI., Results: Tissue perfusion, fasting and postprandial profiles of interstitial metabolites glucose, pyruvate, lactate and glycerol did not differ between paretic and non-paretic muscle. Patients displayed higher fasting and postprandial dialysate glycerol levels compared to controls (P<0.001) with elevated plasma FFA (fasting FFA; 0.63±0.23 vs. 0.29±0.17mmol/L; P=0.004). Glycolytic activity was higher in patients vs. controls, with increased lactate production upon glucose load (P<0.001)., Conclusions: An elevated lipolytic and glycolytic activity on tissue level suggests an impaired substrate metabolism with blunted oxidative metabolism in bilateral skeletal muscle in patients after hemiparetic stroke. Muscular metabolic properties did not differ between paretic and non-paretic leg. Further work is needed to investigate the clinical impact of this impaired muscular metabolic capacity in post-stroke patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Neuromuscular electrical stimulation (NMES) seems to be safe and beneficial in improvement in functional capacity, muscle strength, and quality of life when compared with conventional aerobic exercise, while the change in muscle fiber composition and muscle size was conflicting in patients with heart failure (HF). Moreover, NMES studies seem to have beneficial effects on pro-inflammatory cytokine, oxidative enzyme activity, and protein anabolic and catabolic metabolism that are the key molecular mechanism of muscle wasting in patients with HF. We review specific issues related to the effects of NMES on muscle wasting in patients with HF, whether NMES seems to be an alternative exercise modality preventing or improving in muscle wasting for HF patients who are unable or unwilling to engage in conventional exercise training; however no established strategies currently exist to focus on the patients with HF accompanied by muscle wasting., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: To describe the prevalence of sarcopenia in ambulatory patients with heart failure with preserved ejection fraction (HFpEF) and its relation to reduced exercise capacity, muscle strength, and quality of life (QoL)., Methods and Results: A total of 117 symptomatic outpatients with HFpEF were prospectively enrolled in Germany, England, and Slovenia as part of the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF). Appendicular skeletal muscle (ASM) mass (the sum of muscle mass in both arms and legs) was assessed by DEXA. Echocardiography, 6-minute walk testing (6-MWT), muscle strength assessment, spiroergometry and QoL evaluation using EQ-5D Questionnaire were performed. Sarcopenia was defined as ASM 2 standard deviations below the mean of a healthy reference group aged 18-40years. Patients were divided into 3 groups according to the E/e' value: ≤8, 9-14, and ≥15. Sarcopenia was detected in 19.7% of all patients. These patients performed worse during 6-MWT (404±116 vs. 307±145m, p=0.003) and showed lower absolute peak oxygen consumption (1579±474 vs. 1211±442mL/min, p<0.05). Both ASM and muscle strength were lowest in patients with E/e' >15 (p<0.05). Higher values of muscle strength/ASM were associated with a better QoL (r=0.5, p<0.0005). Logistic regression showed ASM to be independently associated with reduced distance walked during the 6-MWT adjusted for NYHA, height, left atrium diameter, ferritin and forced expiratory volume in 1s (FEV1) (odds ratio 1.2, p=0.02)., Conclusion: Sarcopenia affects a clinically relevant proportion of patients with HFpEF. Low ASM is strongly linked to reduced muscle strength, exercise capacity and QoL in these patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background/objectives: To evaluate whether biomarkers reflecting pathophysiological pathways and selected single nucleotide polymorphisms differ between patients (pts) with heart failure (HF)., Methods: 110 pts with were involved, including HF pts with preserved ejection fraction (HFpEF, n=51) with hypertensive origin, HF pts with reduced ejection fraction (HFrEF) with ischemic aetiology (ICM) (n=32) and HFrEF with dilated cardiomyopathy (DCM) (n=27). We assessed selected HF biomarkers, echocardiographic examinations and functional polymorphisms selected from six candidate genes: CYP27B1, NOS3, IL-6, TGF beta, TNF alpha, and PPAR gamma., Results: Higher concentrations of TNF alpha were observed in pts with hypertensive HFpEF compared to pts with DCM (p=0.008). Pts with HFpEF had higher concentrations of TGF beta 1 compared to DCM and ICM (p=0.0001 and p=0.0003, respectively). For the NOS3 -786 C/T rs2070744 polymorphism in DCM there were significantly more CT heterozygotes than in ICM and HFpEF. In multivariate analysis TGF beta 1 (p=0.001) and syndecan 4 (p=0.001) were the only factors distinguishing HFrEF pts with DCM vs HFpEF and also TGF beta 1 (p=0.001) and syndecan 4 (p=0.023) were the only factors distinguishing HFrEF pts with ICM vs HFpEF pts., Conclusions: Inflammation mediated through TNF alpha and TGF beta 1 may represent an important component of an inflammatory response that partially drives the pathophysiology of HFpEF. NOS3 -786 C/T rs2070744 polymorphism in DCM may serve as a marker for more rapid progression of heart failure. The only biomarkers independently distinguishing HFpEF and HFrEF are syndecan 4 and TGF beta 1., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Natriuretic peptides play an important role in the diagnosis and risk stratification of patients with acute and chronic heart failure. Multiple studies have shown that these peptides are liable to the influence of individual factors. For N-terminal-pro-B-type natriuretic peptide (NT-proBNP) some of these confounding factors have been evaluated over the years such as age, gender, New York Heart Association (NYHA) class and body mass index (BMI). The aim of this study was to establish confounding factors of mid-regional pro-atrial natriuretic peptide (MR-proANP) assessment., Methods and Results: We studied 684 patients (94% male, age 61.2±11.2, left ventricular ejection fraction [LVEF]<35%-45%, NYHA class (I/II/III/IV: 8.4/45.8/39.5/6.3%), ischaemic aetiology 71%, body mass index [BMI] 26.5±4.3kg/m(2), mean MR-proANP 296.0±281.0pmol/L, mean NT-proBNP 2792.0±5328.6pg/mL, mean creatinine level 110.2±38.0μmol/L and mean haemoglobin 13.9±1.5g/dL) with clinically stable chronic heart failure. MR-proANP levels increased with increasing NYHA class (p<0.0001) and an increasing BMI category was associated with decreasing values of MR-proANP (p<0.0001). We found MR-proANP to be independently associated with BMI, creatinine, ischaemic aetiology, LVEF and NYHA class. Meanwhile, NT-proBNP was independently associated with BMI, creatinine, haemoglobin, LVEF and NYHA class., Conclusion: MR-proANP is subject to the almost identical influencing factors like NT-proBNP. The effects of anaemia warrant further study., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Background: Erythropoietin administration, which is clinically used in cancer patients with cancer-induced anemia, has also potentially beneficial effects on nonhematopoietic organs. We assessed the effects of erythropoietin on cancer cachexia progression and cardiac wasting compared with placebo using the Yoshida hepatoma model., Methods: Wistar rats were divided in a sham group (n=10) and a tumor-bearing group (n=60). The tumor-bearing group was further randomized to placebo (n=28), 500Unit/kg/day (n=16) or 5000Unit/kg/day of erythropoietin (n=16). Body composition was measured using nuclear magnetic resonance spectroscopy, cardiac function using echocardiography, physical activity using infrared monitoring system., Results: Tumor-bearing rats with high dose erythropoietin led to a significant improvement on survival compared with placebo (hazard ratio: 0.43, 95%CI: 0.20-0.92, p=0.030), though low dose erythropoietin did not reach significance (hazard ratio: 0.46, 95%CI: 0.22-1.02, p=0.056). Loss of body weight, wasting of lean mass, fat mass, and reduced physical activity were ameliorated in rats treated with both low and high doses of erythropoietin (p<0.05, all). Moreover, reduced left ventricular mass and left ventricular systolic function were also ameliorated in rats treated with low and high doses of erythropoietin (p<0.05, respectively)., Conclusions: Overall, the present data support that cardiac wasting induced by cancer cachexia plays an important role which leads to impaired survival, provided that the erythropoietin could be an effective therapeutic approach for cancer cachexia progression and cardiac wasting., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Sleep-disordered breathing (SDB) is a common comorbidity in a number of cardiovascular diseases, and mounting clinical evidence demonstrates that it has important implications in the long-term outcomes of patients with cardiovascular disease (CVD). While recognition among clinicians of the role of SDB in CVD is increasing, it too often remains neglected in the routine care of patients with CVD, and therefore remains widely undiagnosed and untreated. In this article, we provide an overview of SDB and its relationship to CVD, with the goal of helping cardiovascular clinicians better recognize and treat this important comorbidity in their patients. We will describe the two major types of SDB and discuss the pathophysiologic, diagnostic, and therapeutic considerations of SDB in patients with CVD., (Copyright © 2015 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Body wasting in the context of chronic illness is associated with reduced quality of life and impaired survival. Recent clinical trials have investigated different approaches to improve patients' skeletal muscle mass and strength, exercise capacity, and survival in the context of cachexia and body wasting, many of them in patients with cancer. The aim of this article is to summarise clinical trials published over the last two years. Therapeutic approaches discussed here include appetite stimulants like megestrol acetate, l-carnitine, or melatonin, anti-inflammatory drugs like thalidomide, pentoxyphylline, or a monoclonal antibody against interleukin-1α as well as ghrelin and the ghrelin agonist anamorelin, nutritional support, and anabolics like enobosarm and testosterone., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Background/objectives: Iron deficiency (ID) may be an important, treatable co-morbidity complicating cardiovascular diseases, but considerable uncertainty exists about the diagnostic accuracy of blood tests. Accordingly, we investigated the relationship between blood tests for ID and iron stores in bone marrow aspirates, the diagnostic gold-standard for ID, in patients with stable coronary artery disease (CAD)., Methods: Bone marrow aspirates were obtained from 65 patients with stable CAD undergoing cardiac surgery and 10 healthy controls. ID was defined as depleted extracellular iron stores (0-1 grade according to Gale scale) accompanied by ≤10% of erythroblasts containing iron., Results: Bone marrow ID was found in 31 (48%) patients with CAD but in none of the controls (p<0.01). Amongst patients with CAD, ID was present in 10 of 16 (63%) with and 21 of 49 (43%) without anaemia (p=0.17). The clinical profiles of patients with and without ID were similar. Of circulating biomarkers of ID, serum soluble transferrin receptor had the strongest association with bone marrow ID (area under curve: 0.876±0.048, 95% confidence interval: 0.762-0.948, for cut-off of ≥1.32mg/L-sensitivity: 67%, specificity: 97%)., Conclusions: Almost half of patients with stable CAD have profound bone marrow iron depletion that can be accurately assessed non-invasively using serum soluble transferrin receptor., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: We evaluated the prognostic value of mid-regional proadrenomedullin (MR-proADM) in atrial fibrillation (AF) patients undergoing radiofrequency ablation., Methods: Plasma concentrations of MR-proADM were measured at baseline and after 12months in 87 AF patients in whom radiofrequency ablation was performed. The association between MR-proADM and AF recurrence was tested by univariable and multivariable Cox models., Results: In all 87 patients radiofrequency ablation was successfully performed. Of the total population 54% had paroxysmal AF. The mean left ventricular ejection fraction was 54% (minimum 25%). After 12months of follow-up, 71% of the patients were free of AF recurrence. At baseline, mean MR-proADM in the total population was 0.72nmol/l±0.22. Patients with AF recurrence had significantly higher baseline MR-proADM (0.89nmol/l±0.29) as compared with patients without AF recurrence (0.65nmol/l±0.14; p<0.001). After 12months, mean MR-proADM plasma concentration remained higher in patients with AF recurrence (0.81nmol/l±0.22 as compared with patients free of AF 0.54nmol/l±0.20; p<0.001). Receiver operating characteristic (ROC) curve analysis for MR-proADM yields a specificity of 98% and a sensitivity of 64% with an optimal cut-off value of 0.82nmol/l to predict recurrence of AF after catheter ablation. In the logistic regression analysis only MR-proADM remained independently predictive for AF recurrence., Conclusion: This is the first study revealing the association between MR-proADM elevation before ablation and poor outcomes after ablation of AF. Larger studies are needed to validate these results., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Body wasting in the context of chronic illness is associated with reduced quality of life and impaired survival. Recent clinical trials have investigated different approaches to improve patients' skeletal muscle mass and strength, exercise capacity, and survival in the context of cachexia and body wasting, many of them in patients with cancer. The aim of this article was to summarize clinical trials published over the past 2 years. Therapeutic approaches discussed include appetite stimulants, such as megestrol acetate, L-carnitine, or melatonin, anti-inflammatory drugs, such as thalidomide, pentoxyphylline, or a monoclonal antibody against interleukin-1α as well as ghrelin and the ghrelin agonist anamorelin; nutritional support, and anabolics, such as enobosarm and testosterone., (Copyright © 2014 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Serum phosphorus abnormalities may pose a risk on the cardiovascular system. In heart failure (HF) phosphorus homeostatic mechanisms are altered and may be modified by modern HF therapy. The impact of therapy optimization on phosphorus abnormalities and related outcome remains unknown. In 722 patients with HF subjected to treatment up-titration we analyzed the prevalence of serum phosphorus abnormalities and their relation to HF severity on top of optimal treatment, and we assessed adjusted risk of phosphorus abnormalities at different stages of HF. We analyzed predictors of hypo- and hyperphosphatemia and relation to prognosis. Hypophosphatemia was associated with better response to therapy, was more prevalent in milder HF, and the association was independent of age, sex, BMI, etiology of HF, kidney function and the use of diuretics. Hypophosphatemic patients lost more phosphorus into urine. They had also less catabolic profile. Patients with hyperphosphatemia on top of optimal therapy responded worse to treatment. Hyperphosphatemia was more prevalent in advanced HF, but the effect was attenuated after adjustment for potential confounders. Clinical and biochemical profiles of hyperphosphatemics suggested domination of catabolism. Neither hypophosphatemia nor hyperphosphatemia modifies the outcome Serum phosphorus abnormalities are related to HF severity on top of optimal therapy. Hypophosphatemia occurring on HF up-titration therapy likely has a multifactorial pathophysiology comprising of urinary phosphorus wasting and refeeding effects. Hyperphosphatemia is linked to the catabolic profile but the effect of renal impairment can't be ruled out. The prognostic impact of serum phosphorus abnormalities remain to be established., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

The syndrome of cachexia, i.e. involuntary weight loss in patients with underlying diseases, sarcopenia, i.e. loss of muscle mass due to ageing, and general muscle atrophy from disuse and/or prolonged bed rest have received more attention over the last decades. All lead to a higher morbidity and mortality in patients and therefore, they represent a major socio-economic burden for the society today. This mini-review looks at recent developments in basic research that are relevant to the loss of skeletal muscle. It aims to cover the most significant publication of last three years on the causes and effects of muscle wasting, new targets for therapy development and potential biomarkers for assessing skeletal muscle mass. The targets include 1) E-3 ligases: TRIM32, SOCS1 and SOCS3 by involving the elongin BC ubiquitin-ligase, Cbl-b, culling 7, Fbxo40, MG53 (TRIM72) and the mitochondrial Mul1, 2) the kinase MST1 and 3) the G-protein Gαi2. D(3)-creatine has the potential to be used as a novel biomarker that allows to monitor actual change in skeletal muscle mass over time. In conclusion, significant development efforts are being made by academic groups as well as numerous pharmaceutical companies to identify new targets and biomarkers muscle, as muscle wasting represents a great medical need, but no therapies have been approved in the last decades., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: Adiponectin (ADPN) as an adipose tissue hormone contributes to regulation of energy metabolism and body composition and is associated with cardiovascular risk profile parameters. Cardiac cachexia may develop as a result of severe catabolic derangement in chronic heart failure (CHF). We aimed to determinate an abnormal ADPN regulation as a link between catabolic signalling, symptomatic deterioration and poor prognosis., Methods and Results: We measured plasma ADPN in 111 CHF patients (age 65 ± 11, 90% male, left ventricular ejection fraction (LVEF) 36 ± 11%, peak oxygen consumption (peakVO2) 18.1 ± 5.7 l/kg*min, body mass index (BMI) 27 ± 4 kg/m(2), all mean ± standard deviation) and 36 healthy controls of similar age and BMI. Body composition was assessed by dual energy X-ray absorptiometry, insulin sensitivity was evaluated by homoeostasis model assessment, exercise capacity by spiroergometry. Plasma ADPN did not differ between CHF vs. controls (13.5 ± 11.0 vs. 10.5 ± 5.3 mg/l, p > 0.4), but increased stepwise with NYHA functional class (I/II/III: 5.7 ± 1.4/10.7 ± 8.3/19.2 ± 14.0 mg/l, ANOVA p < 0.01). Furthermore, ADPN correlated with VO2 at anaerobic threshold (r = -0.34, p < 0.05). ADPN was highest in cachectic patients (cCHF, 16%) vs. non-cachectic (ncCHF) (18.7 ± 15.0 vs. 12.5 ± 9.9 mg/l; p < 0.05). ADPN indicated mortality risk independently of established prognosticators (HR: 1.04 95% CI: 1.02-1.07; p < 0.0001). ADPN above the mean (13.5 mg/l) was associated with a 3.4 times higher mortality risk in CHF vs. patients with ADPN levels below the mean., Conclusion: Circulating ADPN is abnormally regulated in CHF. ADPN may be involved in impaired metabolic signalling linking disease progression, tissue wasting, and poor outcome in CHF., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Stroke is the second leading cause of death and the leading cause of disability in Western countries. More than 60% of patients remain disabled, 50% of patients suffer from hemiparesis and 30% remain unable to walk without assistance. The skeletal muscle is the main effector organ accountable for disability in stroke. This disability is primarily attributed to the brain lesion; however less attention is paid to structural, metabolic and functional alterations of muscle tissue after stroke. Hemiparetic stroke leads to various muscle abnormalities: A combination of denervation, disuse, inflammation, remodelling and spasticity accounts for a complex pattern of muscle tissue phenotype change and atrophy. The molecular mechanisms of muscle degradation after stroke are only incompletely understood. Reinnervation, fibre-type shift, disuse atrophy, and local inflammatory activation are only some of the key features yet to be explained. Only limited data is available today on clinical muscle changes after stroke that results from few studies in a mere 500 patients. Despite its importance for optimum post stroke recovery, stroke-related sarcopenia is not considered in current guidelines for stroke therapy or rehabilitation and measurement tools to address sarcopenia are infrequently used. This lack of robust evidence on muscle pathology after stroke and on treatment strategies needs to be addressed in an interdisciplinary integrated approach. This review provides an overview on current pathophysiologic insights and on clinical relevance of sarcopenia in stroke patients and on measurement tools to address the problem in the clinical setting., (© 2013.)

Background: Cancer cachexia is thought to be the cause of >20% of cancer related deaths. Symptoms of cancer cachexia patients include depression and anorexia significantly worsening their quality of life. Moreover, in rodent models of cancer cachexia atrophy of the heart has been shown to impair cardiac function. Here, we characterize the effects of the antidepressant and anxiolytic drug tandospirone on wasting, cardiac function and survival in experimental cancer cachexia., Methods: The well-established Yoshida hepatoma rat model was used and tumor-bearing rats were treated with 1mg/kg/d (LD), 10mg/kg/d (HD) tandospirone or placebo. Weight, body composition (NMR), cardiac function (echocardiography), activity and food intake were assessed. Noradrenalin and cortisol were measured in plasma and caspase activity in skeletal muscle., Results: Ten mg/kg/d tandospirone decreased the loss of body weight (p=0.0003) compared to placebo animals, mainly due to preservation of muscle mass (p<0.001), while 1mg/kg/d tandospirone was not effective. Locomotor activity (p=0.0007) and food intake (p=0.0001) were increased by HD tandospirone. The weight (p=0.0277) and function of heart (left ventricular mass, fractional shortening, stroke volume, ejection fraction, all p<0.05) were significantly improved. In the HD tandospirone group, plasma levels of noradrenalin and cortisol were significantly reduced by 49% and 52%, respectively, which may have contributed to the lower caspase activity in the gastrocnemius muscle. Most importantly, HD tandospirone significantly improved survival compared to placebo rats (HR: 0.34; 95% CI: 0.13-0.86; p=0.0495)., Conclusion: Tandospirone showed significant beneficial effects in the Yoshida hepatoma cancer cachexia model and should be further examined as a prospective drug for this syndrome., (© 2013.)

Background: The mechanisms involved in cardiac cachexia remain poorly understood. We examined the association of right ventricular (RV) and hepatic dysfunction with cardiac cachexia., Methods: We prospectively enrolled 118 patients with left ventricular ejection fraction (LVEF) ≤40%, which were subgrouped as follows: New York Heart Association (NYHA) class II (n=59), NYHA class III without cachexia (n=41) and NYHA class III with cachexia (n=18). All patients underwent blood collection, echocardiography and exercise testing., Results: Reduced systolic RV function (tricuspid annular plane systolic excursion [TAPSE] ≤15 mm), was present in 80% of cachectic patients. When comparing NYHA class II patients vs. non-cachectic and cachectic NYHA class III patients we found a stepwise decrease in systolic RV function (TAPSE 19 [16-23] vs. 16 [13-19] vs. 14 [9-15] mm, respectively; p<0.001) and an increase in right atrial pressure (RAP; >10 mm Hg: 6.8 vs. 27.5 vs. 75.0%, respectively; p<0.001), indicating a higher degree of congestive right HF in cardiac cachexia. Systolic and diastolic function of the left ventricle did not differ between non-cachectic and cachectic patients in NYHA class III. Serum alkaline phosphatase and direct bilirubin correlated with TAPSE and RAP, and were highest in cachectic patients (all p ≤ 0.002), suggesting cholestatic dysfunction due to liver congestion. In multivariable regression analysis, RV dysfunction, cholestatic liver parameters and albumin were independently associated with the presence of cardiac cachexia., Conclusion: Patients with cardiac cachexia display a more pronounced degree of right HF, cholestatic liver dysfunction and hypoalbuminemia compared to non-cachectic patients of similar LVEF and NYHA class., (© 2013.)

Objectives: Muscle wasting is common in patients with chronic heart failure (HF) and worsens functional status. Protein catabolism is characteristic of muscle wasting and contributes to resting energy expenditure (REE). Glucagonlike peptide 1 (GLP-1) is linked to REE in healthy individuals. We aimed to evaluate (1) whether REE is elevated in patients with HF with muscle wasting, and (2) whether basal GLP-1 levels are linked to REE in HF., Design: Cross-sectional study., Setting: Ambulatory patients with HF were recruited at the Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany., Participants: A total of 166 patients with HF and 27 healthy controls participating in the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) were enrolled. GLP-1 was measured in 55 of these patients., Measurements: Body composition was measured by dual-energy X-ray absorptiometry (DEXA). Muscle wasting was defined as appendicular lean mass of at least 2 SDs below values of a healthy young reference group. REE was measured by indirect calorimetry. GLP-1 was assessed by ELISA., Results: Thirty-four of 166 patients (mean age 67.4 ± 10.2 years, 77.7% male, New York Heart Association class 2.3 ± 0.6) presented with muscle wasting. REE in controls and patients with muscle wasting was significantly lower than in patients without muscle wasting (1579 ± 289 and 1532 ± 265 vs 1748 ± 359 kcal/d, P = .018 and P = .001, respectively). REE normalized for fat-free mass (FFM) using the ratio method (REE/FFM) and analysis of covariance was not different (P = .23 and .71, respectively). GLP-1 did not significantly correlate with REE (P = .49), even not after controlling for FFM using multivariable regression (P = .15)., Conclusions: Differences in REE are attributable to lower FFM. GLP-1 does not relate to REE in patients with HF, possibly because of HF-related effects on REE., (Copyright © 2013 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The six-minute walk test (6MWT) is an established measure of functional exercise capacity associated with clinical prognosis in Chronic Heart Failure (CHF). The aim of this study is to evaluate the employment of tele-accelerometry for the remote assessment of 6MWT in CHF., Methods: 155 patients were subjected to tele-accelerometry in form of monthly 6MWTs in their home surroundings. Accelerometer output included steps/6 min and walking speed. Data was directly transferred via mobile network to the Telemedicine Centre subsequent to test completion. 6MWT distance was measured by hand wheel and steps were counted with a digital hand-counter at baseline (Test 1) and at 12 months follow-up (Test 2)., Results: Accelerometer accuracy was within the 99th percentile. There was a significant correlation between step count, walking speed and measured 6MWT distance (Test 1: steps: r=0.80, P<0.001; Test 2: steps: r=0.90, P<0.001 and Walking Speed Test 1: r=0.80, P<0.001; Walking Speed Test 2: r=0.86, P<0.001). The reproducibility of tele-accelerometry was within 95% margin for all performance parameters, which showed stronger associations to quality of life questionnaire (Short Form - 36) Physical Component Score (PCS) than New York Heart Association (NYHA) functional class., Conclusion: Tele-accelerometry is feasible in patients with CHF and output parameters are indicative of exercise capacity. The benefit of this approach lies in its simplicity under every day circumstances by enabling routine performance testing to assess patients' functional status., (© 2013.)

Background: Functional iron deficiency (FID) is an independent risk factor for poor outcome in advanced heart failure with reduced EF, but its role in heart failure with preserved EF (HFPEF) remains unclear. We aimed to investigate the impact of FID on cardiac performance determined by pressure-volume loop analysis in HFPEF., Methods: 26 HFPEF patients who showed an increase in LV stiffness by pressure-volume (PV) loop analysis obtained by conductance-catheterization, performed exercise testing, echocardiographic examination including tissue Doppler and determination of iron metabolism: serum iron, ferritin and transferrin saturation. HFPEF patients who provided ferritin <100 μg/l or ferritin of 100-299 μg/l in combination with transferrin saturation <20% were defined as having FID. In 14 patients the expression of transferrin receptor was determined from available endomyocardial biopsies., Results: Fifteen out of 26 HFPEF patients showed FID without anemia. Compared to control subjects and HFPEF patients without FID, HFPEF patients with FID showed an up-regulation of the myocardial transferrin receptor expression (p<0.05). No differences between HFPEF patients with and without iron deficiency were found in heart dimensions, systolic and diastolic function obtained by PV-loop and echocardiography analysis. According to the linear regression analysis, LV stiffness was correlated with peak oxygen uptake (r=-0.636, p<0.001) but not with the ferritin level or transferrin saturation. No relation was found between FID and exercise capacity. The association of LV stiffness with exercise performance was independent from the level of iron deficiency., Conclusion: In non-anemic HFPEF patients, cardiac dysfunction and impaired exercise capacity occur independently of FID., (© 2013.)

Background: Chronic inflammation is common in cancer cachexia (CC) and directly involved in the atrophy seen in this condition. Recently, several groups have described a form of cardiomyopathy in CC animal models. Hence, we investigated the effect of simvastatin with its known anti-inflammatory and cardioprotective effects in a rat model of CC., Methods: Juvenile Wister Han rats (weight approx. 200 g) were inoculated with Yoshida AH-130 hepatoma cells and treated once daily with 0.1, 1, 10 or 20 mg/kg/d simvastatin or placebo for 14 days. Body weight and body composition (NMR) were assessed at baseline and at the end of the study. Cardiac function was analysed by echocardiography at baseline and day 11., Results: Tumour-bearing, placebo-treated rats lost 47.9±3.8 g of their initial body weight. Treatment with 0.1, 1, 10 or 20 mg/kg/d simvastatin significantly reduced wasting by 39.6%, 47.6%, 28.5% and 35.4%, respectively (all p<0.05 vs. placebo). This was mainly due to reduced atrophy of lean mass, i.e. muscle mass. Cardiac function was significantly improved, e.g. cardiac output (untreated sham: 78.9 mL/min) was severely impaired in tumour-bearing rats (42.4 mL/min) and improved by 1, 10 or 20 mg/kg/d simvastatin (62.2, 59.0 and 57.0 mL/min, respectively, all p<0.05 vs. placebo). Most importantly, 10 or 20 mg/kg/d simvastatin reduced mortality (HR:0.16, 95%CI:0.04-0.76, p=0.021 and HR:0.16, 95%CI:0.03-0.72, p=0.017 vs placebo, respectively)., Conclusion: Simvastatin attenuated loss of body weight as well as muscle mass and improved cardiac function leading to improved survival in this CC model. Simvastatin may be beneficial in a clinical setting to treat CC., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Cachexia is a common complication of cancer and may be responsible for 22% of all cancer-related deaths. The exact cause of death in cancer cachexia patients is unknown. Recently, atrophy of the heart has been described in cancer cachexia animal models, which resulted in impaired cardiac function and is likely to contribute to mortality. In cancer patients hyperuricaemia independent of tumour lysis syndrome is often associated with a worse prognosis. Xanthine oxidase (XO) metabolizes purines to uric acid and its inhibition has been shown to improve clinical outcome in patients with chronic heart failure., Methods: The rat Yoshida AH-130 hepatoma cancer cachexia model was used in this study. Rats were treated with 4 or 40 mg/kg/d oxypurinol or placebo starting one day after tumour-inoculation for maximal 15 days. Cardiac function was analyzed by echocardiography on day 11., Results: Here we show that inhibition of XO by oxypurinol significantly reduces wasting of the heart and preserves cardiac function. LVEF was higher in tumour-bearing rats treated with 4 mg/kg/d (61±4%) or 40 mg/kg/d (64±5%) oxypurinol vs placebo (51±3%, both p<0.05). Fractional shortening was improved by 4 mg/kg/d (43±3%) oxypurinol vs placebo (30±2, p<0.05), while 40 mg/kg/d oxypurinol (41±5%) did not reach statistical significance. Cardiac output was increased in the 4 mg/kg/d dose only (71±11 mL/min vs placebo 38±4 mL/min, p<0.01)., Conclusion: Inhibition of XO with oxypurinol has beneficial effects on cardiac mass and function in a rat model of severe cancer cachexia, suggesting that XO might be a viable drug target in cancer cachexia., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Chronic heart failure (CHF) remains one of the most challenging diseases in terms of numbers and disease management, particularly so, if the CHF patient develops cardiac cachexia. Ghrelin and its analogs have been suggested to improve body weight and cardiac function in heart failure models and exploratory human clinical studies. However, most ghrelin compounds are peptides and need to be injected several times per day, which affects the quality of life of patients. Here, we compared two application routes, three times daily subcutaneous (sc) injections to continuous infusion using osmotic mini-pumps in a rat model of CHF. Moreover, the effects were also compared to three times daily sc injections of growth hormone (GH). Rats were treated for 28 d. The results show that treatment with 50 or 100 nmol/kg/d BIM-28131 (RM-131) potently induces body weight gain, fat and lean mass compared to placebo. The gain of lean mass was equal to the gain of lean mass in the 2mg/kg/d GH group and superior to 250 μg/kg/d GH. Both GH and BIM-28131 increased levels of insulin-like growth factor-1 to a similar extent. Little effect was seen on cardiac function; only cardiac output was improved by either high dose BIM-28131 or GH. Overall the effects of BIM-28131 were similar in both application routes., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: We set out to evaluate the utility of selected heart failure (HF) biomarkers in patients with dilated cardiomyopathy (DCM)., Methods: In a prospective, randomized study, 68 DCM patients with left ventricular ejection fraction (LVEF) ≤ 40% treated optimally were included. They were observed for 5 years. Initial and control tests included full clinical examination, measurement of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and IL-10, syndecan-4, cystatin C (CysC) and N-terminal pro-brain natriuretic peptide (NT-proBNP), echocardiographic examination, and the assessment of exercise capacity in 6-minute walk test (6MWT)., Results: Finally, after 5-year follow-up we analyzed the data of 45 DCM patients. Concentration of syndecan-4 correlated negatively with LVEF (R=-0.36, p=0.02) and positively with LV systolic (R=0.57, p<0.001) and diastolic diameters (R=0.64, p<0.001). A positive correlation between CysC and right ventricular diastolic diameter (R=0.38, p=0.01), and negative correlations between CysC and glomerular filtration rate (R=-0.49, p<0.001), LVEF (R=-0.4, p=0.02), and 6 MWT (R=-0.46, p<0.001) were noted. Patients who had an increase in LVEF during 5 years were characterized by lower levels of CysC (p=0.01) and NT-proBNP (p<0.001). CysC≤95mg/l and NT-proBNP≤32pg/ml were the best predictors of LVEF increase in DCM patients. Multivariate regression analysis showed that 6 MWT was the only independent predictor of HF re-hospitalization (OR 0.989; p<0.001), and NT-proBNP and LV diastolic diameter were the only risk factors of increased mortality (OR 1.001; p=0.007 and OR 2.960; p=0.025, respectively) in DCM patients., Conclusions: CysC correlates negatively with both kidney function and exercise capacity. Syndecan-4 may be a useful biomarker for predicting adverse LV remodeling in DCM patients., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: To test alternative medicine approaches with a specifically designed Tibetan dietary and behavioral program in patients with established coronary artery disease (CAD) and manifest metabolic syndrome., Methods: This was a randomized, controlled, double-blinded, parallel group dietary and behavioral intervention study. Between December 2008 and November 2010, patients were randomly adjudicated either to evidence-based Western diet (usual care), or to Tibetan diet. We evaluated 524 patients undergoing coronary angiography. All patients were white Caucasian, presented with a body mass index (BMI) >25 kg/m(2), and had evidence of metabolic syndrome. The primary endpoint was change in body weight and BMI at 6 months follow-up. Secondary endpoints included blood pressure, heart rate, intima media thickness, lipids, fasting glucose, glycated hemoglobin, fibrinogen, C-reactive protein (CRP) at 6 months follow-up and change in body weight and BMI at 12 months., Results: Both groups of patients showed significantly reduced body weight and BMI compared to baseline (6 months, usual care weight change: -3.2 ± 3.0 kg; BMI change: -1.1 ± 1.0 kg/m(2); Tibetan diet weight change: -6.2 ± 4.4 kg/m(2); BMI change: -2.1 ± 1.5 kg/m(2)), but these changes were more pronounced in Tibetan diet compared to usual care (all, p<0.001). Beneficial effects on weight and BMI were maintained after 12 months of follow-up (p<0.0001). Levels of total and LDL cholesterols, fibrinogen and CRP were decreased in both groups, but more pronounced in Tibetan diet (Tibetan diet vs. usual care (total cholesterol): 176.2 ± 43.7 vs. 185.1 ± 47.8 mg/dL; p=0.024; LDL: 111.6 ± 37.8 vs. 119.4 ± 40.9 mg/dL; p=0.026; fibrinogen: 318.3 ± 90.4 vs. 334.1 ± 87.9 mg/dL; p=0.040; CRP: 1.2 ± 3.0 vs. 2.2 ± 4.5mg/dL; p=0.036)., Conclusions: Tibetan diet reduces body weight and BMI in patients with CAD and metabolic syndrome after 6 months significantly better than Western diet and may induce lipid-modifying and anti-inflammatory effects (ClinicalTrials.gov identifier: NCT00810992)., (© 2013.)

Background: The transcription factor TWIST1 has been described to regulate the microRNA (miR)-199/214 cluster. Genetic disruption of TWIST1 resulted in a cachectic phenotype and early death of the knock-out mice. This might be connected to the activity of the ubiquitin-proteasome-system (UPS), as miR-199a has been suggested to regulate the ubiquitin E2 ligases Ube2i and Ube2g1., Methods: Cardiac tissue from explanted hearts of 42 patients with dilated cardiomyopathy and 20 healthy donor hearts were analysed for protein expression of TWIST1 and its inhibitors Id-1, MuRF-1 and MAFbx, the expression of miR-199a, -199b and -214, as well as the activity of the UPS by using specific fluorogenic substrates., Results: TWIST1 was repressed in patients with dilated cardiomyopathy by 43% (p=0.003), while Id1 expression was unchanged. This was paralleled by a reduced expression of miR-199a by 38 ± 9% (p=0.053), miR-199b by 36 ± 13% (p=0.019) and miR-214 by 41 ± 11% (p=0.0158) compared to donor hearts. An increased peptidylglutamyl-peptide-hydrolysing activity (p<0.0001) was observed in the UPS, while the chymotrypsin-like and trypsin-like activities were unchanged. The protein levels of the rate limiting ubiquitin E3-ligases MuRF-1 and MAFbx were up-regulated (p=0.005 and p=0.0156, respectively). Mechanistically silencing of TWIST1 using siRNA in primary rat cardiomyocytes led to a down-regulation of the miR-199/214 cluster and to a subsequent up-regulation of Ube2i., Conclusion: The TWIST1/miR-199/214 axis is down-regulated in dilated cardiomyopathy, which is likely to play a role in the increased activity of the UPS. This may contribute to the loss of cardiac mass during dilatation of the heart., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

Background: The objective of this study was to elucidate the complex interactions between families of circulating biomarkers representing different biochemical responses to the pathophysiology following complicated acute myocardial infarction (AMI)., Methods: Blood samples, drawn at a median of 3 days post AMI were obtained from 236 patients with complicated AMI and evidence of heart failure or left ventricular dysfunction. Using exploratory factor analysis, 37 biomarkers were grouped according to their collinearity to each other into clusters. The clusters were used as a model to elucidate interdependencies between individual biomarkers. Each cluster defines a specific pathophysiological process, called factor. These factors were used as covariates in multivariable Cox-proportional hazard regression analyses for prediction of all-cause death and the combined endpoint of cardiovascular death and re-infarction., Results: Exploratory factor analysis grouped the biomarkers under 5 factors. The composition of these groups was partially unexpected but biological plausible. In multivariable analysis, only 1 factor proved to be an independent predictor of outcome. Major contributions (factor loadings>0.50) in this cluster came from: mid-regional pro-adrenomedullin, tumor necrosis factor receptor, pro-endothelin-1, growth differentiation factor 15, C-terminal pro arginine vasopressin, uric acid, chromogranin A and procollagen type III N-terminal., Conclusion: Clustering of multiple biomarkers by exploratory factor analysis might prove useful in exploring the biological interactions between different biomarkers in cardiovascular disease and thus increase our understanding of the complicated orchestral interplay at the molecular level., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Frailty is a clinical state in which there is an increase in an individual's vulnerability for developing increased dependency and/or mortality when exposed to a stressor. Frailty can occur as the result of a range of diseases and medical conditions. A consensus group consisting of delegates from 6 major international, European, and US societies created 4 major consensus points on a specific form of frailty: physical frailty. 1. Physical frailty is an important medical syndrome. The group defined physical frailty as "a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual's vulnerability for developing increased dependency and/or death." 2. Physical frailty can potentially be prevented or treated with specific modalities, such as exercise, protein-calorie supplementation, vitamin D, and reduction of polypharmacy. 3. Simple, rapid screening tests have been developed and validated, such as the simple FRAIL scale, to allow physicians to objectively recognize frail persons. 4. For the purposes of optimally managing individuals with physical frailty, all persons older than 70 years and all individuals with significant weight loss (>5%) due to chronic disease should be screened for frailty., (Copyright © 2013 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.)

Worsening renal function (WRF) during the treatment of acute decompensated heart failure (ADHF) occurs in up to a third of patients and is associated with worse survival. Venous congestion is increasingly being recognized as a key player associated with WRF in ADHF. Understanding the hemodynamic effects of venous congestion and the interplay between venous congestion and other pathophysiological factors such as raised abdominal pressure, endothelial cell activation, anemia/ iron deficiency, sympathetic overactivity, and stimulation of the renin-angiotensin-aldosterone system will help in devising effective management strategies. Early recognition of venous congestion through novel techniques such as bioimpedance measurements and remote monitoring of volume status combined with customized diuretic regimens may prevent venous congestion and perhaps avoid significant WRF.