Cachexia In Chronic Heart Failure Research Articles

Polymorphism of the ITGAM gene (rs7193943) and bioelectric impedance analysis as potential predictors of cachexia in chronic heart failure

Cardiac cachexia (CC) is an unfavorable metabolic syndrome leading to exacerbation of chronic heart failure (CHF) and a higher risk of death. The main factor contributing to the development of cachexia is the ongoing inflammatory process mediated by genes (e.g. Integrin Subunit Alpha M—ITGAM). The study aimed to assess the relationship between a single nucleotide polymorphism (SNP) -323G > A of the ITGAM and the occurrence of nutritional disorders in patients with CHF. 157 CHF patients underwent clinical and nutritional screening. Body composition was evaluated by bioelectrical impedance analysis (BIA). Patients with cachexia were characterized by significantly lower weight, body mass index (BMI), lower fat mass (FM), albumin, and hemoglobin. Lower values of BIA parameters: capacitance of membrane (Cm), phase angle (PA), and impedance ratio (Z200/Z5) were noted in women. Those patients demonstrated significantly higher values of creatinine, c-reactive protein (CRP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and pulmonary artery systolic pressure (PASP). A significantly higher risk of cachexia was reported in patients: aged ≥ 74 years (OR 3.55), with renal failure (OR 3.75), New York Heart Association classification (NYHA) III-IV (OR 2.83), with moderate or severe malnutrition according to the score of subjective global assessment (SGA) (OR 19.01) and AA genotype of ITGAM gene (OR 2.03). Determination of the -323G > A SNP in the ITGAM may prove to be a useful marker (after confirmation in further studies and appropriate validation) in the assessment of the risk of nutritional disorders in patients with CHF.

Associations between cachexia and metalloproteinases, haemodynamics and mortality in heart failure.

Addressing cachexia in chronic heart failure (CHF) patients is an urgent issue in Japan, the most aged country in the world. We investigated the possible relationships between cachexia and, metalloproteinases and haemodynamics assessed by the cardiac catheterization. We also clarified the prognostic value of cardiac cachexia in the Japanese CHF population. A total of 370 participants (median age, 69years; 35% women) were included. The haemodynamic effects of cachexia were analysed by right heart catheterization. The serum levels of matrix metalloproteinase (MMP) and tissue inhibitors of MMP (TIMP), as myocardial collagen turnover markers, were also assessed. Cachexia was present in 88 patients (31%). Overall, 59 patients (16%) had all-cause death. Serum MMP-2 and TIMP-2 levels were higher in cachectic patients than in noncachectic patients (797.5 [649.0-1066.8] vs 610.0 [461.8-756.8] ng/mL; P=.004 and 39.0 [28.0-49.0] vs 24.0 [19.0-37.0] ng/mL; P=.008, respectively). Cachectic patients had greater values of pulmonary vascular resistance (PVR) (161.9 [119.4-225.4] vs 127.8 [90.7-164.8] dynes/sec/cm-5 , P=.020). Kaplan-Meier survival analysis demonstrated higher probabilities of all-cause death in the cachexia group (log-rank P=.010). Cox proportional hazards modelling showed cachexia was an independent predictor of mortality (hazard ratio, 1.89; 95% confidence interval, 1.06-3.37; P=.029). The random forest model showed that C-reactive protein, age, haemoglobin, PVR and MMP-2 were predictors of cardiac cachexia. Cachexia, applying the globally accepted definition, was associated with adverse outcomes in the Japanese CHF population and accompanied by increased activity of MMP species and PVR.

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

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. 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. 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.

Prevalence of cachexia in chronic heart failure and characteristics of body composition and metabolic status

The prevalence of cardiac cachexia has previously been estimated to 8-42 %. However, novel treatment strategies for chronic heart failure (CHF) have improved and decreased morbidity and mortality. Therefore, we aimed to reassess the prevalence of cachexia in an outpatient CHF clinic and to characterize a CHF population with and without cachexia with respect to body composition and related biomarkers. From 2008 to 2011, we screened 238 optimally treated, non-diabetic CHF patients for cardiac cachexia, defined as unintentional non-oedematous weight loss of >5 % over ≥6 months. CHF patients (LVEF <45 %) with cachexia (n = 19) and without (n = 19) were compared to controls with prior myocardial infarction and left ventricular ejection fraction (LVEF) >45 % (n = 19). The groups were matched for age, sex, and kidney function. Body composition was assessed by dual energy X-ray absorptiometry. The prevalence of cachexia was 10.5 %. Abdominal fat ± SD (%) was reduced in cachectic CHF: 27.4 ± 10.0 versus 37.5 ± 10.6 % (CHF, no cachexia) and 40.6 ± 8.0 % (controls), (P < 0.001). NT-proBNP levels were inversely correlated to abdominal fat in a multivariate linear regression analysis adjusted for known predictors of NT-proBNP (LVEF and NYHA); (β = -0.28; P = 0.018). Myostatin levels were reduced in cachectic CHF compared to controls (P = 0.013). The prevalence of cachexia in stable CHF, treated according to recent guidelines, is lower than previously anticipated. Body alterations in cachexia consist mainly of reduced abdominal fat mass, and its inverse correlation to NT-proBNP suggests involvement of abdominal lipolysis. Our data do not support a role of circulating myostatin as a biomarker for muscle wasting.

Clinical Application of Ghrelin

Ghrelin as a human natural hormone is involved in fundamental regulatory processes of eating and energy balance. Ghrelin signals the nutrient availability from the gastrointestinal tract to the central nervous system, up-regulates food intake and lowers energy expenditure mainly through hypothalamic mediators acting both centrally and peripherally including the gastrointestinal tract (motility, epithelium), promotes both neuro-endocrine and inflammatory signals to increase skeletal muscle growth and decrease protein breakdown, and increases lipolysis while body fat utilization is reduced. Ghrelin does more to exert its probably sentinel role around "human energy": it influences through mainly extra-hypothalamic actions the hedonic and incentive value of food, mood and anxiety, sleep-wake regulation, learning and memory, and neurogenesis. Recently numerous ghrelin gene-derived peptides were discovered, demonstrating the complexity within the ghrelin/ghrelin receptor axis. For clinical applications, not only the natural ghrelin and its slice variants, but also several modified or artificial molecules acting at ghrelin-associated receptors were and are developed. Current clinical applications are limited to clinical studies, focusing mainly on cachexia in chronic heart failure, COPD, cancer, endstage- renal-disease or cystic fibrosis, but also on frailty in elderly, gastrointestinal motility (e.g., gastroparesis, functional dyspepsia, postoperative ileus), after curative gastrectomy, anorexia nervosa, growth hormone deficient patients, alcohol craving, sleep-wake regulation (e.g. major depression), or sympathetic nervous activity in obesity. The results of completed, preliminary studies support the clinical potential of ghrelin, ghrelin gene-derived peptides, and artificial analogues, suggesting that larger clinical trials are demanded to move ghrelin towards an available and reimbursed pharmaceutical intervention.

Cachexia in chronic heart failure: endocrine determinants and treatment perspectives

It is well documented in the current literature that chronic heart failure is often associated with cachexia, defined as involuntary weight loss of 5% in 12month or less. Clinical studies unraveled that the presence of cachexia decreases significantly mean survival of the patient. At the molecular level mainly myofibrillar proteins are degraded, although a reduced protein synthesis may also contribute to the loss of muscle mass. Endocrine factors clearly regulate muscle mass and function by influencing the normally precisely controlled balance between protein breakdown and protein synthesis The aim of the present article is to review the knowledge in the field with respect to the role of endocrine factors for the regulation of cachexia in patients with CHF and deduce treatment perspectives.

The Secret Life of Fat Suggests New Therapeutic Targets

Not so many years ago, most considered fat a passive recipient of our indulgence. But since the discovery of leptin in 1994,1 it has become ever clearer that fat is more than a storage site for excess calories. Rather, fat plays an active, communicative role in metabolism that research is beginning to uncover. Two recent studies not only represent our rapidly changing grasp of the biology of fat but also suggest potential treatments for one of the world's most intractable chronic health conditions: obesity. A paper in Nature 2 in January 2012 from the laboratory of Bruce Spiegelman, PhD, of the Dana-Farber Cancer Institute in Boston, MA, reported the discovery of a new hormone released by muscle that converts white fat deposits into thermogenic brown fat. Whereas white fat acts as a repository for excess, mitochondria-rich brown fat cells burn ordinary fat as energy to produce heat. Once thought to only exist in rodents and infants, several groups have confirmed brown fat in humans. It is found in small patches along the spine, in the upper back, on the sides of the neck, and between the collarbone and shoulder. A few weeks after Spiegelman's Nature paper was published, a publication3 in the Journal of Clinical Investigation from the laboratory of Shelia Collins, PhD, of the Sanford-Burnham Medical Research Institute in Orlando, FL, revealed the heart plays a role in the regulation of fat burning. Collins, first author Marica Bordicchia, and colleagues reported that cardiac natriuretic peptides increased browning of white fat, elevating uncoupling protein 1 (UCP1)–dependent energy expenditure. C. Ronald Kahn, MD, chief academic officer at the Joslin Diabetes Center in Boston, MA, says the recent discoveries are likely just the opening act in our growing knowledge about fat metabolism. “Right now we're looking at the first things …

The effects of a high‐caloric protein‐rich oral nutritional supplement in patients with chronic heart failure and cachexia on quality of life, body composition, and inflammation markers: a randomized, double‐blind pilot study

The prevalence of cardiac cachexia in chronic heart failure is approximately 5% to 15% and 18-month mortality rates can reach 50%. Treatment with angiotensin-converting enzyme inhibitors and beta-blockers may confer some benefit but no proven therapy exists. We tested the effects of an oral nutritional supplement in cachectic patients with heart failure. This was a prospective, randomized, double-blind, placebo-controlled pilot study which randomized 29 patients to a high-caloric (600 kcal) high-protein (20 g) oral nutritional supplement or placebo for a duration of 6 weeks in addition to the patients’ usual food intake. At baseline, 6 weeks, and 18 weeks, we measured body weight, quality of life, body composition, heart function, laboratory parameters, and exercise performance. Edema-free body weight increased in 19 of 20 patients receiving intervention at 6 weeks and in 17 of 19 patients at 18 weeks with an average weight gain of 2.0 ± 1.7 kg (3.1 ± 2.4%, p = 0.0001) and 2.3 ± 3.1 kg (3.6 ± 4.7%, p = 0.007) at 6 and 18 weeks, respectively. Most of the weight gain was fat tissue with an absolute gain of 1.5 ± 1.7 kg (p = 0.003) and 1.6 ± 2.7 kg (p = 0.008). A significant improvement in quality of life and decrease in serum levels of tumor necrosis factor-α were observed (p < 0.05 for both). We demonstrated the feasibility of oral nutritional supplement in cachectic patients with heart failure and significant clinical benefit in terms of body size and body composition, laboratory parameters, and quality of life (www.clinicaltrials.gov identifier NCT00654719).

Myostatin

Cachexia in chronic heart failure (HF) is a major clinical problem that is still underestimated for its impact on morbidity, mortality, and healthcare expenditures. The pathophysiology of cardiac cachexia is characterized by a catabolic/anabolic imbalance. An important player in the development of muscle wasting and cachexia in HF may be myostatin. Article see p 419 Myostatin, also known as growth differentiation factor-8 (GDF-8), is a member of the transforming growth factor-β superfamily and was identified in 1997.1 In humans, myostatin is expressed almost exclusively in skeletal muscle and is essential for normal regulation of muscle mass through its actions as a negative regulator of muscle bulk.2 Gene disruption, either natural or by targeted mutation, leads to a marked increase in muscle mass due to hypertrophy and hyperplasia.1 This was clearly evident in a child with a mutation in the myostatin gene who had the ability to hold two 3-kg dumbbells at the age of 4 years.3 Myostatin has been shown to be upregulated in human immunodeficiency virus– and cancer-associated cachexia,4 with advanced age,5 and in chronic HF.6 In each of these conditions, a loss of skeletal muscle mass occurs that leads to a disproportionate loss of exercise tolerance and an early increase in muscle fatigue. Human cardiovascular studies concerning myostatin are generally lacking. Before the report by Heineke et al7 in this issue of Circulation , 2 animal studies reported increased myostatin expression in the peri-infarct zone in sheep8 and in a rat model of volume overload induced by an aortocaval shunt.9 Importantly, the expression remained increased after 4 weeks in the shunt model. In 2008, Hoenig10 presented a hypothesis that myostatin acts as a mediator of cardiac cachexia, insulin resistance, and osteoporosis in chronic HF. To date, it …

Disturbance of circulating ghrelin and obestatin in chronic heart failure patients especially in those with cachexia

Plasma ghrelin was elevated in chronic heart failure (CHF) patients with cachexia. Obestatin, a sibling of ghrelin, opposes several actions of ghrelin. We, therefore, investigated plasma obestatin and ghrelin levels in patients with CHF. Total plasma ghrelin and obestatin levels were measured in 65 patients with CHF (22 with cardiac cachexia) and 15 controls. Ghrelin levels were significantly higher in patients with cachexia (1237.8 ± 47.9 pg/ml) than those without cachexia ( P = 0.041) and controls ( P < 0.01). Obestatin levels correlated positively with ghrelin levels, and obestatin levels were significantly increased in patients with cachexia (282.3 ± 13.0 pg/ml) than patients without cachexia and controls (both P < 0.01). However, the ghrelin to obestatin ratios (4.5 ± 0.2) were significantly lower in CHF patients with cachexia than controls ( P < 0.01). Ghrelin and ratio of ghrelin to obestatin were independent predictors of the development of cardiac cachexia. No association was found between ghrelin, obestatin and New York Heart Association functional class, brain natriuretic peptide. There was disturbance of circulating ghrelin and obestatin in the CHF patients especially those with cachexia, which may have a role in the pathogenesis of cardiac cachexia in CHF.

Von der Herzinsuffizienz zur kardialen Kachexie: Klinik und pathophysiologische Mechanismen

Cachexia develops in the course of many chronic diseases such as malign tumours, chronic heart failure, chronic kidney failure, rheumatoid arthritis, or AIDS. In most cases, the development of cachexia worsens morbidity and mortality of the underlying disease. Unfortunately, the term „cachexia” is still not routinely used by clinicians, although the clinical impact of cachexia is difficult to overestimate. The reasons include the difficult question of a uniform definition of cachexia, but also the absence of specific therapies. The aim of this article is to provide an overview of the pathophysiology and potential therapeutic approaches to cachexia in chronic heart failure. We particularly discuss the role of inflammation and the regulation of appetite.

Recent insights on chronic heart failure, cachexia and nutrition

To provide recent observations on the interrelation between chronic heart failure (CHF), cachexia and human nutrition and updating epidemiological issues in CHF. Present evidence suggests that impairment in cardiac muscle energetics plays an important role in the pathogenesis of heart failure. New concepts such as microRNA expression are emerging as potential agents in heart failure. Recent research suggests mechanisms by which inflammatory catabolic states may persist in the presence of adequate growth factors and nutrition. A consensus panel has recently designed a definition for general cachexia and its stratification. Together with classicals, new nutrients and substrates are showing efficacies in the malnutrition associated with CHF. Although still promising, ghrelin, growth factors and other biological compounds maintain emergent therapeutical positions for heart failure or associated catabolic states or both. Altered intestinal function as an agent for CHF is rising in evidence. New techniques to well diagnose and stratify malnutrition and cardiac cachexia in CHF are needed. Treatment of cachexia in CHF appears to be a combination of different approaches, in which metabolic, nutritional, immunological and hormonal strategies may play an important role. Although the current experimental research is of great help, well designed randomized controlled trials are needed to test these hypothesis and generate clinical evidence.

P-46 Neurohormonal Blockade is Associated with Prevention of Cachexia in Chronic Heart Failure

P-46 Neurohormonal Blockade is Associated with Prevention of Cachexia in Chronic Heart Failure

Nutrition, metabolism, and the complex pathophysiology of cachexia in chronic heart failure

Chronic heart failure is a complex catabolic state that carries a devastating prognosis. The transition from stable disease to cardiac cachexia is not well understood. Mechanisms that maintain the wasting process involve neurohormones and pro-inflammatory cytokines, which contribute to an imbalance in anabolic and catabolic pathways. A decrease in food intake alone rarely triggers the development of a wasting process, but dietary deficiencies in micronutrients and macronutrients contribute to the progression of the disease. Malabsorption from the gut as a result of bowel wall edema and decreased bowel perfusion also plays an important role. This article describes the complex interplay of hormonal systems in energy balance in patients with chronic heart failure as well as other factors such as malabsorption and dietary deficiencies that contribute to the wasting process. Finally, therapeutic approaches are discussed. These include dietary advice, ongoing studies, and future possibilities.

Therapeutic Potential of Ghrelin in the Treatment of Heart Failure

Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, which has been identified as an endogenous ligand for the GH secretagogues receptor. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated, not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. Considering the haemodynamic and anabolic effects of GH, ghrelin may have beneficial effects on cardiac function and energy metabolism in heart failure through GH-dependent mechanisms. On the other hand, ghrelin has some GH-independent actions: ghrelin stimulates food intake and induces adiposity. Interestingly, ghrelin acts directly on the CNS to decrease sympathetic nerve activity. It also inhibits apoptosis of cardiomyocytes and endothelial cells. An experimental study has shown that repeated administration of ghrelin improves cardiac structure and function, and attenuates the development of cardiac cachexia in chronic heart failure (CHF). These results suggest that ghrelin has cardiovascular effects and regulates energy metabolism through GH-dependent and -independent mechanisms. Thus, administration of ghrelin may be a new therapeutic strategy for the treatment of severe CHF.

Cachexia in chronic heart failure: Prognostic implications and novel therapeutic approaches

Cachexia in patients with chronic heart failure (CHF) has been recognized for a long time; however, it has not received much attention until recently. Cardiac cachexia, a common and serious complication of CHF, is associated with very poor prognosis. Several studies have demonstrated that increased neurohormonal and immune abnormalities may play a crucial role in the pathophysiology of cardiac cachexia. Hormonal and catabolic/anabolic imbalances of the body are likely to be responsible for the development of cachexia in CHF. Recently, ghrelin, a novel growth hormone-releasing peptide, has been widely noticed to have potential in the treatment of severe CHF and cardiac cachexia. However, further research will be necessary to identify the exact pathways involved and to find the best therapeutic strategies of using ghrelin to fight the wasting process.

The importance of the gastrointestinal system in the pathogenesis of heart failure

Chronic heart failure (CHF) is a multi-organ disease with increasing evidence for the involvement of the gastrointestinal (GI) system in this syndrome. In recent research, the gut has received very little attention from cardiologists as its role in the pathogenesis of cardiovascular disease is poorly understood. Intestinal ischaemia may play an important role in bacterial translocation by increasing bowel permeability. Decreased cardiac function can reduce bowel perfusion and so clearly impairs the function of the intestinal barrier. There is an increasing evidence to suggest that a 'leaky' bowel wall may lead to translocation of bacteria and/or endotoxin, which may be an important stimulus for inflammatory cytokine activation in CHF. Impaired functioning of the GI system may also contribute to malnutrition and cachexia in CHF. It is hoped that by improving our understanding of the role of the gut in cardiac disease will lead to the development of novel therapeutic strategies in the future.

Muscle wasting in cardiac cachexia

Cardiac cachexia is a serious complication of chronic heart failure which is characterized by complex changes that overall lead to a catabolic/anabolic imbalance resulting in body wasting and a poor prognosis. The wasting process affects all body components, but particularly the skeletal musculature, causing extreme fatigue and weakness, especially in cachectic heart failure patients. Available evidence suggests that several pathophysiologic pathways play a role in the muscle wasting process. Metabolic, neurohormonal, and immune abnormalities lead to an altered regulation of proliferation, differentiation, apoptosis, and metabolism in skeletal muscle, finally resulting in deterioration of the underlying cause with symptomatic exercise intolerance. Possible treatment strategies against muscle wasting and cachexia in chronic heart failure are also described here. As there is no validated therapy for cardiac cachexia yet, further research is necessary to find more therapeutic options for the wasting process.

Body mass index obtained before discharge is a powerful long-term prognostic marker in patients with decompensated heart failure

Background: In the general population, obesity is associated with an increased risk of adverse outcomes. However, cachexia in chronic heart failure carries a poor prognosis. In addition, little is known about the influence of body mass index (BMI) on the prognosis of a non-selected population after hospitalization for worsening heart failure. Objectives: To evaluate the prognostic role of nutritional state and BMI obtained before discharge in stabilized patients after admission for acutely decompensated heart failure (ADHF). Methods: Clinical, echocardiographic, and laboratory data were prospectively obtained in 139 patients admitted for ADHF. Before discharge, anthropometric measurements and bioelectrical impedance parametres (Digital Tetrapolar Bioimpedanciometer Maltron VF®) were obtained. Height and weight were measured according to a standardized protocol and BMI was calculated. The end point was all cause mortality during a mean follow-up of 169±97 days. Results: Mean age was 64.9±13.7, 56% were male and 42% of ischemic etiology. During follow-up 15 (11%) patients died. From all the anthropometric variables, the brachial circumference, the subescapular fold and the BMI were associated with mortality in univariated analysis. However, BMI was the only independent predictor of events (HR = 0.88, 95% CI = 0.79–0.97). The area under the ROC curve was 0.69 and the cut-off of 24.6 showed a sensitivity of 73% and specificity of 73% to predict death. According to BMI ≤ o >24.6 the population was classified in group 1 (43%) and 2, respectively. Groups 1 and 2 differed in history of hypertension (38% vs. 59%, p = 0.053), hemoglobin leves (12.1 vs. 12.8 g/L, p = 0.087). white cell count (7000 vs. 7900, p = 0.037), serum sodium (137 vs. 139 mEq/L, p = 0.058), ejection fraction (34% vs. 41%, p = 0.033), and refractoriness to treatment during index hospitalization (39% vs. 19%, p = 0.009). One-year cumulative survival was 74% and 89% (p = 0.005) in patients with BMI lower or higher than cut-off. A BMI ≤24.6 was associated to an increase in long-term mortality (HR = 4.4, 95%CI = 1.4–13.9), even after the adjustment for basal differences (HR = 4.3, 95%CI = 1.13–13.4). Conclusion: BMI obtained previous discharge, in patients hospitalized by ADHF, is a powerful prognostic marker of poor outcome. A value ≤24.6 was associated with an 4-fold increase of the risk of one-year mortality.

1345 Evidence for distinct mechanisms of reduced exercise capacity versus cardiac cachexia in chronic heart failure

1345 Evidence for distinct mechanisms of reduced exercise capacity versus cardiac cachexia in chronic heart failure