Pathophysiology of peripheral muscle wasting in cardiac cachexia Gerasimos S. Filippatosa, Stefan D. Ankerb,c and Dimitrios T. Kremastinosa Purpose of review Many different mechanisms have been proposed to explain muscle wasting in patients with heart failure; however, the pathogenesis remains largely obscure. This manuscript looks at current developments concerning the pathophysiology of skeletal muscle wasting in cardiac cachexia. Recent findings Many studies have shown that malnutrition, malabsorption, metabolic dysfunction, anabolic/catabolic imbalance, inflammatory and neurohormonal activation, and cell death play an important role in the pathogenesis of wasting in cardiac cachexia. However, the aetiology of the muscle changes is not entirely clear. In biopsies of skeletal muscles from animals with cardiac cachexia increased rates of protein degradation have been observed, with increased activity of the ubiquitin–proteasome proteolytic pathway. Skeletal muscle apoptosis may also play a role in muscle atrophy and wasting and can be partly prevented by neurohormonal inhibition, but it has recently been reported that in cachectic patients with chronic heart failure apoptosis is not the main pathway of cell death and muscle loss. Summary Many hypotheses have been used to explain the pathogenesis of muscle wasting in cardiac cachexia. Cardiac cachexia is a multifactorial disorder, and the targeting of different pathways will be necessary for effective treatment. The immune and neurohormonal abnormalities present in chronic heart failure may play a significant role in the pathogenesis of the wasting process. It has been suggested that common pathogenetic mechanisms underlie the loss of muscle mass in different cachectic states. More studies are needed to show whether there is a common pathway in cardiac cachexia and the other cachectic states. Keywords apoptosis, cachexia, cytokines, heart failure, skeletal muscles, wasting Curr Opin in Clin Nutr Metab Care 8:249–254. # 2005 Lippincott Williams & Wilkins. a 2nd University Department of Cardiology, Atticon University Hospital, Athens, Greece; bDivision of Applied Cachexia Research. Department of Cardiology, Charité, Campus Virchow-Klinikum, Berlin, Germany; and cClinical Cardiology, National Heart and Lung Institute, Imperial College School of Medicine, London, UK Correspondence to Gerasimos S. Filippatos, 2nd University Department of Cardiology, Atticon University Hospital, Rimini 1, Haidari 12461, Athens, Greece Tel: +30 210 8048427; fax: +30 210 8104367; e-mail: email@example.com Current Opinion in Clinical Nutrition and Metabolic Care 2005, 8:249–254 Abbreviations ACE CHF GH IGF TNF angiotensin-converting enzyme chronic heart failure growth hormone insulin-like growth factor tumour necrosis factor # 2005 Lippincott Williams & Wilkins 1363-1950 Introduction Cachexia is a syndrome of tissue wasting, which was first described in chronic heart failure (CHF) by Hippocrates 2300 years ago, and is associated with significant morbidity and mortality . However, there is still no widely accepted definition of cardiac cachexia. In the past most clinicians used low body weight to define cachexia, but a constitutionally low body weight should not automatically qualify a patient as cachectic. In other studies patients were classified according to body fat content, lean body tissue or by anthropometric measurements . Kotler  defined cachexia as ‘accelerated loss of skeletal muscle in the context of a chronic inflammatory response’. This definition cannot be used in research or in clinical practice, but it is important because it shows that the development of cachexia in CHF is a dynamic process that can only be proved by documented non-intentional weight loss measured in a non-oedematous state. It has thus been suggested that in patients with CHF, cardiac cachexia can be diagnosed when non-intentional weight loss greater than 6% of the previous normal weight is observed . Although the cut-off value of 6% weight loss for the definition of cardiac cachexia remains arbitrary, it is very simple and quickly applicable in clinical practice. The frequency of body wasting in CHF is 12 –16% in outpatients [4,5], but it is up to 50% in patients with severe CHF . In patients with a myocardial infarct complicated by congestive heart failure, low body weight is also a detrimental sign . This article discusses recent advances in the pathogenesis of skeletal muscle wasting in patients with cardiovascular diseases. Pathogenesis of wasting in cardiac cachexia Many different mechanisms have been proposed for the pathogenesis of wasting in cardiac cachexia. It has been suggested that malnutrition, malabsorption, metabolic dysfunction, anabolic/catabolic imbalance and the 249 250 Anabolic and catabolic signals loss of nutrients via the urinary or digestive tracts are important for the development of wasting, but the mechanisms of the transition from heart failure to cardiac cachexia are not known. Ajayi et al.  found that in patients with CHF, tricuspid regurgitation is associated with protein losing enteropathy, hypoalbuminemia and a greater reduction in skinfold thickness. It has been reported that right ventricular failure and tricuspid regurgitation are more common in patients with heart failure and cardiac cachexia, and increased right atrial pressure was the only predictor of malnutrition observed in patients with severe CHF but this was not confirmed in all studies . Simple starvation and anorexia are often considered to be responsible for cardiac cachexia. It is known that patients with symptomatic heart failure and nausea from intestinal oedema can be anorectic. In these patients oral intake is usually inadequate as a result of early satiety also caused by a lowered gastric volume secondary to hepatomegalia and ascites. In addition, anorexia may be exaggerated by drug therapy and sodium-restricted diets. However, starvation would lead to reduced plasma albumin levels. In most CHF studies there is evidence of a general wasting process, and cachectic patients suffer from fat, muscle, and bone tissue loss, but albumin is not decreased in most of these patients . Moreover, increased nutritional intake does not reverse cardiac cachexia. This would argue against a major contribution of starvation, anorexia and gastrointestinal malabsorption in cardiac cachexia. However, it has been reported that acetate provided by the oxidation of free fatty acid increases the consumption of amino acids in the tricarboxylic acid cycle, leading to muscular wasting and cachexia. The optimization of substrate and the administration of a specific formulation of amino acids (mainly branched-chained with elevated amounts of leucine), calculated for matching energetic needs, has been suggested to prevent wasting  by inducing the hepatic synthesis of anabolic molecules such as growth hormone (GH) and insulin-like growth factor (IGF), and by modulating the catabolic neurohormonal-mediated effects. Cytokine and neuroendocrine activation In CHF, neurohormones and cytokines are activated, as a response to the impaired cardiac function. These systems are acting, initially, as compensatory mechanisms, but eventually they contribute to the progression of heart failure, haemodynamic deterioration and ventricular remodelling. Elevated plasma levels of neurohormones and cytokines predict mortality in patients with CHF  and they interrelate . Cachectic CHF patients have markedly increased plasma levels of tumour necrosis factor (TNF), IL-6, IL-1, norepinephrine, epinephrine, cortisol, angiotensin II and aldosterone, with non-cachectic CHF patients having near-normal levels [14,15]. Cytokine activation plays a central role in the pathogenesis of muscle wasting in cardiac cachexia. TNF is one of the key cytokines important to the development of catabolism, together with IL-1, IL-6 and transforming growth factor beta . In-vivo experiments have shown that IL-6 is capable of inducing proteolysis, muscle atrophy and weight loss, all of which can be prevented by IL-6 antibody therapy. TNF is increased in patients in cardiac cachexia, and is the strongest predictor of the degree of previous weight loss . The site of production and action of TNF modifies its effect. In animals, when TNF-producing cells are implanted into skeletal muscle cachexia occurs, whereas TNF-producing cells implanted in the brain cause profound anorexia. TNF can also induce skeletal muscle wasting, modulate collagen synthesis, and induce IL-1 release and apoptosis in many cell types . It has recently been reported that TNF could induce different signals within the same cell type . The main stimulus for the immune activation in CHF is not known. It has been suggested that hypoxia is the stimulus for increased proinflammatory cytokine production in CHF patients, and the failing heart itself may be the main source of TNF . Moreover, bowel wall oedema, which occurs in CHF, may be responsible for bacterial translocation with subsequent endotoxin release and immune activation . It has been proposed that oedema can lead to altered gut permeability for bacteria and endotoxin, which may subsequently enter the circulation and stimulate inflammatory cytokine activation. This hypothesis is supported by the finding that there are elevated concentrations of endotoxin in CHF patients with oedema, which can be normalized by diuretic therapy . In an animal model of gut-derived endotoxaemia, the angiotensin-converting enzyme (ACE) inhibitor enalapril improved survival by reducing bacterial translocation and contributing to a preservation of gastrointestinal functional and structural integrity . As a consequence of the endotoxin hypothesis, lipoproteins may play a beneficial role in patients with CHF by binding to endotoxin and protecting endothelial cells from its toxic effects . It has been shown in patients with CHF that lower serum total cholesterol is independently associated with a worse prognosis, and higher cholesterol levels are related to longer survival in both cachectic and non-cachectic CHF patients . However, it is not known whether cholesterol plays a pathophysiological role in CHF and cardiac cachexia or is only a marker of the severity of the disease. Moreover, the exact role of lowering cholesterol levels is not clear. In mice, lowering cholesterol with 4-aminopyrolo-(3,4-D) pyrimide and with estradiol increased the susceptibility of the mice to lipopolysaccharide . However, in patients with ischaemic and non-ischaemic CHF, statin use was an independent predictor of improved survival although Pathophysiology of peripheral muscle wasting in cardiac cachexia Filippatos et al. 251 the cholesterol levels were similar between treated and non-treated patients . Catecholamines can cause a catabolic metabolic shift, and can lead to a graded increase in resting energy expenditure in patients with CHF . An anabolic hormone that is decreased in cachectic patients is dehydroepiandrosterone, also suggestive of a catabolic/anabolic imbalance . The abnormalities of sex steroid metabolism in CHF are strongly and directly related to the immune activation seen in cachectic CHF patients . Attention has recently focused on ghrelin, which is a novel GHreleasing peptide that has vasodilative effects, inhibits sympathetic nerve activity, and stimulates food intake through GH-independent mechanisms [27,28]. Besides its effects on food intake and body composition , the administration of ghrelin also appears to inhibit proinflammatory cytokine production . In a pilot study in patients with congestive heart failure , ghrelin improved left ventricular function, exercise capacity, and muscle wasting in patients with CHF. Moreover, ghrelin negatively controls the plasma release of leptin and leptin-induced cytokine expression , whereas TNF increases the plasma concentrations of leptin in a dosedependent fashion . Leptin, a product of the ob gene, decreases food intake, increases resting energy expenditure, and upregulates transforming growth factor beta 1, thereby augmenting the fibrogenic response. Plasma levels of leptin have been shown to be elevated in patients with CHF ; however, leptin serum levels are decreased in patients with cardiac cachexia [34,35]. The exact role of leptin in the pathophysiology of cardiac cachexia needs further clarification. are mainly involved in the breakdown of proteins are the lysosomal system, the calpain–calcium-dependent system, and the adenosine triphosphate-dependent ubiquitin proteasome pathway. In cachectic cancer patients, the proteolysis-inducing factor induces the loss of skeletal muscle and this effect is mediated by the upregulation of the ubiquitin–proteasome proteolytic pathway . Moreover, in muscle wasting induced by severe injury and sepsis there is increased gene expression and activity of the calcium/calpain and ubiquitin–proteasome proteolytic pathways. It has recently been proposed that similar transcriptional changes underlie the loss of skeletal muscle in cachexia, and complementary DNA microarrays have been used to compare changes in the content of specific mRNA in muscles atrophying from different causes (fasted mice, rats with cancer cachexia, diabetes mellitus, and renal failure). Animals with cardiac cachexia have not been studied. It has been found that a common set of genes, mainly of the ubiquitin–proteasome pathway (termed atrogins), were induced or suppressed in atrophic muscles in all animals. Different types of muscle atrophy thus share a common transcriptional programme, which is activated in many systemic diseases, and the proteolysis underlying muscle wasting is largely caused by activation of the ubiquitin–proteasome pathway . Ubiquitin levels are increased in rats with CHF, but the system has not been extensively studied in human cardiac cachexia . Moreover, in patients with cardiac cachexia, the proteolysis-inducing factor has not been isolated, and the differential elevation of circulating IL-1, TNF-a, and IL-6 has been found in AIDS-associated cachectic states. Therefore, more studies are urgently needed to show whether there is a common pathway in the different cachectic states. Wasting of skeletal muscle protein According to the muscle hypothesis, changes in the skeletal musculature are at the core of the deterioration of patients with CHF . Fatigue and muscle weakness are two of the main symptoms experienced by CHF patients. The loss of lean body mass, which mainly results from the atrophy of skeletal muscle protein, is one of the characteristics of cardiac cachexia. Muscle atrophy is present in up to 68% of patients with CHF , and it has been shown that skeletal muscle phenotype changes occur during the transition from hypertrophy to heart failure . However, the aetiology of the muscle changes in cardiac cachexia is not entirely clear. It has been suggested that common pathogenetic mechanisms underlie the loss of muscle mass in different cachectic states . In biopsies of skeletal muscle from cachectic cancer patients, both reduced rates of protein synthesis and increased rates of protein degradation have been observed. This imbalance between protein synthesis and degradation is probably an important contributor to muscle wasting in cardiac cachexia. The systems that Muscle cell death in cardiac cachexia Inflammatory cytokine and catabolic hormone levels are known to correlate significantly with the reduction of muscle, fat and bone tissue content in cachectic CHF patients . Insulin also plays a role in regulating the balance between anabolism and catabolism. Experimental models have shown that insulin inhibits protein degradation in skeletal muscle. Moreover, alterations of the GH/IGF-1 axis may play an important role in the pathogenesis of cachexia because patients with low IGF-1 levels have evidence of muscle abnormalities . The levels of GH are elevated and the levels of IGF-1 are inappropriately low in cachectic CHF patients, suggesting the presence of GH resistance, but only local IGF-I expression is significantly correlated with muscle crosssectional area [45,46]. It has been shown that IGF-1 can inhibit a number of apoptotic pathways. The administration of GH at high but not at low doses in rats with heart failure decreased not only muscle atrophy but also serum levels of TNF and the number of apoptotic nuclei, possibly by IGF-1 overexpression . 252 Anabolic and catabolic signals Angiotensin II, which can induce wasting in animal models, reduces circulating IGF-1 levels . The coinfusion of angiotensin II and IGF-I did not prevent muscle loss, suggesting that angiotensin II causes skeletal muscle mass wasting by enhancing protein degradation, probably via its inhibitory effect on the autocrine IGF-1 system . The effects of angiotensin II are mediated via the stimulation of two receptors, named type 1 and type 2. Angiotensin II can also induce apoptosis  and fibrosis through its type 1 receptor. Muscle atrophy and apoptosis can be prevented by using angiotensin II converting enzyme inhibitors and angiotensin II receptor 1 blockers [51,52,53,54–56]. In addition, the administration of the anti-inflammatory cytokine IL-15 completely reversed the apoptosis observed in the skeletal muscle of tumour-bearing animals . Anti-inflammatory effects of statins have also been reported, and have led to the proposal that statins may be useful against cachexia . Apoptosis contributes to cell loss in the failing human heart and to the expansion of fibrotic foci . Apoptosis has also been found in the skeletal myocytes of patients with CHF and cachexia, and has been associated with impaired exercise capacity [60,61]. Moreover, structural alterations and increased collagen content have been found in peripheral skeletal muscles after experimental myocardial infarction. It has been suggested that the apoptosis of muscle nuclei can play a role in muscle atrophy and wasting. It is known that there is a ratio between the size of a muscle fibre and the number of nuclei within a given fibre. Each nucleus regulates metabolism and protein expression within a given muscle fibre volume. The loss of myonuclei through apoptosis thus results in fibre atrophy . However, it has been reported that skeletal muscle apoptosis is not different between CHF patients with and without cachexia, whereas the collagen content is increased in the biopsies of skeletal muscles of patients with cardiac cachexia . Inflammatory cytokine and neurohormonal activation lead to cell death and fibrosis. These systems are particularly activated in CHF patients with cachexia. It can be confirmed that during the disease progression from compensated heart failure to cachexia the form of cell death changes from apoptosis to necrosis and collagen deposition [54–56]. A decrease in the apoptotic index has also been reported in the late stages of cancer cachexia. In rabbits with cancer cachexia, there is an increase in the apoptotic index in the early stages of cachexia but a decrease at higher losses . The expression of Bax, which promotes apoptosis, is also increased in the early stage of weight loss, but thereafter declines. Moreover, it has already been suggested that death involving skeletal muscles may occur by other routes that differ at least morphologically , and the increased proteolytic activity of ‘proapoptotic’ enzymes without evidence of apoptosis has been found in mice with cancer cachexia . In clinical trials in patients with CHF, treatment with an ACE inhibitor reduced the risk of weight loss and bblocker therapy induced weight gain, showing that cardiac cachexia is partly mediated by activation of the renin–angiotensin and sympathetic nervous systems [4,66]. However, cachexia is a complex syndrome, and not only b-blocker therapy but also the administration of the b2-agonist formoterol in animals with cancer cachexia resulted in an important reversal of the musclewasting process . According to the different pathophysiological mechanisms studied, different management strategies have been used to treat muscle wasting [68,69,70] (see Table 1). All these differences could be the result of differences between animal models and human cachexia, differences between different cachexia states, differences in the Table 1. Agents that can be considered for the management of muscle wasting in experimental models and clinical cachexia trials Anabolic agents Recombinant human GH Ghrelin Recombinant IGF-1 IGF–IGFBP3 combinations Testosterone Dehydroepiandrosterone Synthetic anabolic steroids (nandrolone decanoate, oxandrolone) Cytokine inhibition Pentoxifylline Thalidomide Antioxidants Statins Melatonin D-9 Tetrahydrocannabinol L-Carnitine Erythropoietin Antisense therapy directed at NFkB Anti-IL-6 receptor antibody Anti-TNF antibody (infliximab and others) TNF receptor fusion protein (eternacept) Interleukine-15 Interleukine-12 Hypercaloric feeding Appetite stimulants Progestagens Megestrol acetate Medroxyprogesterone Cannabinoids Glucocorticoids Proteasome inhibitors Eicosapentaenoic acid Peptide aldehydes Lactacystin/b-lactone Vinyl sulfones Dipeptide boronic acid analogues Resistance exercise training Metabolic regulators Clenbuterol Formoterol Lipoprotein lipase activators Serotonin type 3 receptor antagonists Inhibition of myostatin pathway GH, Growth hormone; IGF, insulin-like growth factor; IGFBP3, insulinlike growth factor binding protein 3; NFkB, nuclear factor kappa B; TNF, tumour necrosis factor. Some of these agents have never been tested. Many of these agents are in testing in experimental studies or clinical cachexia trials. Very few of these drugs are agency-approved for use in certain types of human cachexia. Most of these agents have never been tested in cardiac cachexia. Modified from Filippatos . Pathophysiology of peripheral muscle wasting in cardiac cachexia Filippatos et al. 253 populations studied, in the definition of cardiac cachexia, or in the time the patients were studied after the ‘beginning’ of cardiac cachexia. Further studies are needed to examine the effect of cachexia in different categories of patients with heart disease . Conclusion Cachectic patients represent a significant proportion of patients with CHF. Cardiac cachexia is a multifactorial disorder, and it is unlikely that any single agent will be completely effective in treating this condition; the targeting of different pathways will be necessary. 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