The importance of tumor necrosis factor and lipoproteins in the pathogenesis of chronic heart failure

Elevated levels of proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-6 (IL-6), have been demonstrated in patients with chronic heart failure (CHF). Evidence suggests that cytokines such as these may play a central role in the pathogenesis of this syndrome. TNF has several properties that are particularly detrimental in CHF, such as negatively inotropic effects, the promotion of left ventricular remodelling, and the induction of dilated cardiomyopathy in humans. Furthermore, TNF can cause skeletal muscle wasting and apoptosis, and, therefore, may be important in the development of cardiac cachexia. Although the precise stimulus for immune activation in CHF is unknown, one hypothesis is that endotoxin may be a significant trigger for cytokine release. This is supported by the finding that decompensated CHF patients have elevated endotoxin levels that normalize on diuretic therapy. The factors that influence endotoxin responsiveness in patients with CHF, in particular the potential importance of serum lipoproteins, will be discussed in this review.     

Inducible nitric oxide synthase (iNOS) in muscle wasting syndrome, sarcopenia, and cachexia

Muscle atrophy-also known as muscle wasting-is a debilitating syndrome that slowly develops with age (sarcopenia) or rapidly appears at the late stages of deadly diseases such as cancer, AIDS, and sepsis (cachexia). Despite the prevalence and the drastic detrimental effects of these two syndromes, there are currently no widely used, effective treatment options for those suffering from muscle wasting. In an attempt to identify potential therapeutic targets, the molecular mechanisms of sarcopenia and cachexia have begun to be elucidated. Growing evidence suggests that inflammatory cytokines may play an important role in the pathology of both syndromes. As one of the key cytokines involved in both sarcopenic and cachectic muscle wasting, tumor necrosis factor α (TNFα) and its downstream effectors provide an enticing target for pharmacological intervention. However, to date, no drugs targeting the TNFα signaling pathway have been successful as a remedial option for the treatment of muscle wasting. Thus, there is a need to identify new effectors in this important pathway that might prove to be more efficacious targets. Inducible nitric oxide synthase (iNOS) has recently been shown to be an important mediator of TNFα-induced cachectic muscle loss, and studies suggest that it may also play a role in sarcopenia. In addition, investigations into the mechanism of iNOS-mediated muscle loss have begun to reveal potential therapeutic strategies. In this review, we will highlight the potential for targeting the iNOS/NO pathway in the treatment of muscle loss and discuss its functional relevance in sarcopenia and cachexia.     

The syndrome of cardiac cachexia

Cachexia, i.e. body wasting, has long been recognised as a serious complication of chronic illness. The occurrence of wasting in chronic heart failure (CHF) has been known for many centuries, but it has not been investigated extensively until recently. Cardiac cachexia is a common complication of CHF which is associated with poor prognosis, independently of functional disease severity, age, measures of exercise capacity, and left ventricular ejection fraction. Patients with cardiac cachexia suffer from generalised loss of lean tissue, fat tissue, as well as bone tissue. Cachectic CHF patients are weaker and fatigue earlier. This is due to both reduced skeletal muscle mass and impaired skeletal muscle quality. Concerning the pathophysiology of cardiac cachexia, there is increasing evidence that neurohormonal and immune abnormalities may play a crucial role. Cachectic CHF patients have raised plasma levels of norepinephrine, epinephrine, and cortisol, and they show high plasma renin activity and increased plasma aldosterone levels. A number of studies have also shown that cardiac cachexia is linked to raised plasma levels of inflammatory cytokines, such as tumor necrosis factor alpha. The available evidence suggests that cardiac cachexia is a multifactorial neuroendocrine and metabolic disorder with a poor prognosis. A complex imbalance of different body systems, termed catabolic/anabolic imbalance, is likely to be responsible for the development of the wasting process. It is hoped that a better understanding of the pathophysiological mechanisms involved in cardiac cachexia will lead to novel therapeutic strategies in the (near) future.     

Studies on apoptosis and fibrosis in skeletal musculature: a comparison of heart failure patients with and without cardiac cachexia

Apoptosis has been found in skeletal muscles of patients with chronic heart failure (CHF) and has been associated with exercise intolerance. In CHF, cachexia is characterized by neurohormonal activation and muscle wasting. Neurohormonal activation can lead to cell death and fibrosis. The purpose of the study was to determine the severity of apoptosis and fibrosis in skeletal muscles of patients with CHF and cachexia and its relationship to exercise intolerance in these patients. Skeletal muscle biopsies of 21 patients with CHF (eight with cachexia) and four healthy controls of similar age have been studied by in situ end labeling (ISEL) for apoptosis and by the Picrosirius Red technique for collagen. Apoptosis in skeletal muscles was detected by ISEL in 52% of the patients with CHF (11 out of 21) and in none of the controls. CHF patients with apoptosis-positive skeletal muscles had impaired exercise tolerance (peak oxygen consumption 11.4+/-5.7 vs. 16.91+/-6.6, P=0.029). Increased collagen was detected by Picrosirius Red in eight out of 21 patients with CHF and in none of the controls. Increased collagen (fibrosis) was detected in six out of eight patients with cachexia and in two out of 13 patients without cachexia (P=0.01). Peak oxygen consumption and apoptosis were similar in cachectic and non-cachectic patients. Thus, the skeletal musculature of patients with cardiac cachexia is characterised by the presence of fibrosis. Apoptosis was not found to be more frequent in cachectic CHF patients. Our data support the hypothesis that cachexia contributes by a different mechanism to skeletal muscle myopathy of CHF patients and different mechanisms are implicated in deterioration of exercise tolerance and progression to cardiac cachexia.     

Chronic heart failure and skeletal muscle catabolism: effects of exercise training

Although the clinical picture of cardiac cachexia is well-known in patients with advanced chronic heart failure (CHF) the factors that determine who is at risk for this progressive catabolic syndrome and who is not remain unclear. Different endocrine systems have been accused of being involved in this process: an imbalance between catabolic and anabolic steroids with an elevated cortisol/dihydroepiandrosterone ratio, an increased resting metabolic rate due to high levels of circulating catecholamines, various cytokines are activated in CHF (i.e. TNF-alpha, IL-6, IL-1beta and others), and elevated levels of growth hormone (GH) with inappropriately normal or low serum levels of insulin-like growth factor-I (IGF-I) have been described in cardiac cachexia. These catabolic factors contribute to peripheral muscle atrophy, augment the expression of the inducible nitric oxide synthase (iNOS), which in turn inhibits the aerobic cellular metabolism. The present review examines whether the catabolic factors can be influenced by a classical anabolic intervention: regular physical exercise training. Long-term training programs increase skeletal muscle cytochrome c oxidase activity and are associated with reduced local expression of pro-inflammatory cytokines as well as iNOS, and augment local IGF-I production. In concert, these beneficial effects of exercise training may help to retard the catabolic process in CHF finally leading to cardiac cachexia and death.     

The role of inflammatory mediators in chronic heart failure: cytokines, nitric oxide, and endothelin-1

There is now considerable evidence to suggest that neurohormonal and immune mechanisms may play a central role in the pathogenesis of chronic heart failure (CHF), which is likely to have important implications for the management of this condition. It has been proposed that CHF is a state of immune activation with inflammatory cytokines contributing to both the central and the peripheral manifestations of this syndrome. The immune system is the body's natural defence mechanism against infection and other stresses, which has several different components that interact with each other in a complex manner. The main components which are thought to be relevant to the pathogenesis of CHF are: cytokines, adhesion molecules, autoantibodies, nitric oxide, and endothelin-1, and this review will concentrate on these factors. This article will also discuss the potential role of anti-cytokine therapies in the treatment of CHF.     

Cardiac cachexia: a syndrome with impaired survival and immune and neuroendocrine activation

Chronic heart failure (CHF) is a complex syndrome affecting many body systems. Body wasting (ie, cardiac cachexia) is a serious complication of CHF long known but little investigated. Although no specific diagnostic criteria have been established, we have suggested that cardiac cachexia be defined on the basis of the presence of documented nonintentional and nonedematous weight loss > 7.5% of the premorbid normal weight, occurring over a time period of > 6 months. Using this definition, 16% of an unselected CHF outpatient population was found to be cachectic. The cachectic state is predictive of impaired prognosis independently of age, functional disease classification, left ventricular ejection fraction, and peak oxygen consumption. The mortality in the cachectic cohort is 50% at 18 months. Analyzing body composition in detail, it has been found that patients with cardiac cachexia suffer from a general loss of fat tissue (ie, energy reserves), lean tissue (ie, skeletal muscle), and bone tissue (ie, osteoporosis). Cachectic CHF patients are weaker and fatigue earlier, which is due to both reduced skeletal muscle mass and impaired muscle quality. The pathophysiologic alterations leading to cardiac cachexia remain unclear, but initial cross-sectional studies have suggested that humoral neuroendocrine and immunologic abnormalities are linked, independently of established heart failure severity markers, to the presence of body wasting. Comparing the features of cachectic and noncachectic CHF patients with those of healthy control subjects, it is mainly the cachectic CHF patients who show raised plasma levels of epinephrine, norepinephrine, and cortisol; the highest plasma renin activity and aldosterone plasma concentrations; and the lowest plasma sodium level. Several studies have shown that cardiac cachexia is linked to raised plasma levels of tumor necrosis factor-ac. The degree of body wasting is strongly correlated with neurohormonal and immune abnormalities. The available evidence suggests that cardiac cachexia is a multifactorial neuroendocrine and metabolic disorder with a poor prognosis. A complex imbalance of different body systems may cause the development of body wasting.     

Cachexia in rheumatoid arthritis

Rheumatoid arthritis is a debilitating, chronic, systemic, autoimmune disease of unknown etiology that causes destruction of joint cartilage and bone. It generally occurs between the fourth and sixth decades of life, and affects two to three times more women than men. It is characterized by joint stiffness, pain, and swelling, and is accompanied by a loss of body cell mass. This loss of cell mass, known as rheumatoid cachexia, predominates in skeletal muscle, but also occurs in the viscera and immune system. Thus, rheumatoid cachexia leads to muscle weakness and a loss of functional capacity, and is believed to accelerate morbidity and mortality in rheumatoid arthritis. Currently there is no established mechanism for rheumatoid cachexia, but it is accompanied by elevated resting energy expenditure, accelerated whole-body protein catabolism, and excess production of the inflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta. Tumor necrosis factor-alpha is probably the central mediator of muscle wasting in rheumatoid arthritis, and is known to act synergistically with interleukin-1beta to promote cachexia. In general, tumor necrosis factor-alpha and interleukin-1beta are thought to alter the balance between protein degradation and protein synthesis in rheumatoid arthritis to cause muscle wasting. The precise mechanism by which they do this is not known. Reduced peripheral insulin action and low habitual physical activity are important consequences of rheumatoid arthritis, and have also been implicated as mediators of rheumatoid cachexia. Insulin inhibits muscle protein degradation. Consequently, reduced peripheral insulin action in rheumatoid arthritis is thought to be permissive to cytokine-driven muscle loss. The cause of reduced peripheral insulin action in rheumatoid arthritis is not known, but tumor necrosis factor-alpha has been shown to interfere with insulin receptor signaling and is probably an important contributor. Low habitual physical activity has consistently been observed in rheumatoid arthritis and is an important consequence of, and contributor to, muscle wasting. In addition, low physical activity predisposes to fat gain and is believed to precipitate a negative reinforcing cycle of muscle loss, reduced physical function, and fat gain in rheumatoid arthritis, which leads to 'cachectic obesity'. To date, there is no standard treatment for rheumatoid cachexia. However, physical exercise is currently believed to be the most important and clinically relevant countermeasure against rheumatoid cachexia. In general, a combination of skeletal muscle strength training and aerobic exercise is recommended, but must be prescribed with the patient's disease status, overall health, and safety in mind. Future studies should investigate the safety, efficacy, and required dose of anti-cytokine therapy for the treatment of rheumatoid cachexia. In this review, we outline the current definition of rheumatoid cachexia, and discuss the etiology, pathogenesis, and treatment of rheumatoid cachexia.     

Chronic heart failure: an example of a systemic chronic inflammatory disease resulting in cachexia

Chronic heart failure is no longer a mere cardiac entity, but involves several, initially adaptive and later detrimental, neurohumoral compensatory mechanisms. Peripheral manifestations of the disease, such as endothelial dysfunction, skeletal muscle changes, and disturbances in ventilatory control, are major determinants of symptoms. The independent prognostic value and the relevance of cachexia on morbidity of patients with chronic heart failure have only recently been recognised. Altered body composition in heart failure patients is reflected in the early loss of muscle tissue but affects all tissue compartments in case of cardiac cachexia. Recently, a new portfolio of biologically active molecules, termed cytokines, have been shown to play an important role in the development and progression of both cardiac and peripheral abnormalities. Similar to other chronic illnesses, covered in the remainder of this issue, a low-grade chronic inflammatory process may be of particular relevance in the development of tissue wasting in these patients. Whereas the presence of immune activation in chronic heart failure is now widely accepted, as well as the prognostic relevance of chronic inflammation, the site and the source of cytokine production remain the object of intense research. Although the inciting event is located in the heart, cross-talk between the myocardium on the one hand, and the immune system, peripheral tissues and organs on the other hand, will lead to the overproduction of proinflammatory cytokines and, inevitably, to their detrimental effects. The specific problems related to heart failure progression and inflammatory activation are described in this review.     

The role of tumour necrosis factor-α in acquired immunodeficiency syndrome

Abstract. Tumour necrosis factor-α (TNF) is a primary mediator in the pathogenesis of infection, tissue injury and inflammation. It is synthesised by various activated, phagocytic and non-phagocytic cells, and a wide variety of infectious or inflammatory stimulae are capable of triggering TNF biosynthesis. Recent studies indicate that overproduction of TNF in septicaemia is a critical step in triggering septic shock and multiple organ damage. Intravenous administration of recombinant human TNF induced the same types of derangement in cardiovascular homatologic, inflammatory and metabolic homeostasis that are found with endotoxic or septic shock. Chronic TNF production causes a potentially lethal syndrome of cachexia, anaemia, and protein and lipid wasting. Several investigators have recently demonstrated elevated levels of serum TNF in patients with acquired immunodeficiency syndrome (AIDS), these levels being closely correlated with the severity of the disease. This review discusses the role of TNF in the pathophysiology of AIDS and of several disorders associated with the latter. In addition, it discusses the interactions between TNF and several agents used in AIDS therapy, and suggests the use of TNF-antagonists in combination as a therapeutic regimen for AIDS patients.     

The complex pathophysiology of cardiac cachexia: A review of current pathophysiology and implications for clinical practice

Cardiac cachexia is a muscle wasting process that often develops in those with chronic heart failure resulting in weight loss, low levels of physical activity, reduced quality of life, and is associated with a poor prognosis. The pathology of cardiac cachexia is complex with new evidence emerging that implicates several body systems. This review describes the pathophysiology associated with cardiac cachexia and addresses: 1) hormonal changes- neurohormonal abnormalities and metabolic hormone imbalance; 2) mechanisms of muscle wasting in cardiac cachexia, and the integral mechanisms between changed hormones due to cardiac cachexia and muscle wasting processes, and 3) associated abnormalities of gastrointestinal system that contribute to cardiac cachexia. These pleiotropic mechanisms demonstrate the intricate interplay between the affected systems and account for why cardiac cachexia is difficult to manage clinically. This review summarises current pathophysiology of cardiac cachexia and highlights symptoms of cardiac cachexia, implications for clinical practice and research gaps.     

Cancer cachexia—pathophysiology and management

About half of all cancer patients show a syndrome of cachexia, characterized by anorexia and loss of adipose tissue and skeletal muscle mass. Cachexia can have a profound impact on quality of life, symptom burden, and a patient’s sense of dignity. It is a very serious complication, as weight loss during cancer treatment is associated with more chemotherapy-related side effects, fewer completed cycles of chemotherapy, and decreased survival rates. Numerous cytokines have been postulated to play a role in the etiology of cancer cachexia. Cytokines can elicit effects that mimic leptin signaling and suppress orexigenic ghrelin and neuropeptide Y (NPY) signaling, inducing sustained anorexia and cachexia not accompanied by the usual compensatory response. Furthermore, cytokines have been implicated in the induction of cancer-related muscle wasting. Cytokine-induced skeletal muscle wasting is probably a multifactorial process, which involves a protein synthesis inhibition, an increase in protein degradation, or a combination of both. The best treatment of the cachectic syndrome is a multifactorial approach. Many drugs including appetite stimulants, thalidomide, cytokine inhibitors, steroids, nonsteroidal anti-inflammatory drugs, branched-chain amino acids, eicosapentaenoic acid, and antiserotoninergic drugs have been proposed and used in clinical trials, while others are still under investigation using experimental animals. There is a growing awareness of the positive impact of supportive care measures and development of promising novel pharmaceutical agents for cachexia. While there has been great progress in understanding the underlying biological mechanisms of cachexia, health care providers must also recognize the psychosocial and biomedical impact cachexia can have.     

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.     

Insights into the pathogenesis of chronic heart failure: immune activation and cachexia.

Body wasting, i.e, cardiac cachexia, is a complication of chronic heart failure (CHF). The authors have suggested that cardiac cachexia should be diagnosed when nonedematous weight loss of more than 7.5% of the premorbid normal weight occurs over a time period of more than 6 months. In an unselected CHF outpatient population, 16% of patients were found to be cachectic. The cachectic state is predictive of poor survival independently of age, functional class, ejection fraction, and exercise capacity. Patients with cardiac cachexia suffer from a general loss of fat, lean, and bone tissue. Cachectic CHF patients are weaker and fatigue earlier. The pathophysiologic causes of body wasting in patients with CHF remain unclear, but initial studies have suggested that humoral neuroendocrine and immunologic abnormalities may be of importance. Cachectic CHF patients show increased plasma levels of catecholamines, cortisol, and aldosterone. Several studies have shown that cardiac cachexia is linked to increased plasma levels of tumor necrosis factor alpha. The degree of body wasting is strongly correlated with neurohormonal and immune abnormalities. Some investigators have suggested that endotoxin may be important in triggering immune activation in CHF patients. Available studies suggest that cardiac cachexia is a multifactorial neuroendocrine and immunologic disorder that carries a poor prognosis. A complex catabolic-anabolic imbalance in different body systems may cause body wasting in patients with CHF.     

Pathophysiology and treatment options for cardiac anorexia

The anorexia–cachexia syndrome (ACS) occurs in many chronic illnesses, such as cancer, AIDS, and chronic obstructive pulmonary disease in addition to chronic congestive heart failure (CHF). Comparable to other chronic states, the ACS complicates CHF and impacts its prognosis; however, the available treatment options for this syndrome remain unsatisfactory. This review article focuses on the complex pathophysiology of cardiac anorexia. We focus on the recent data demonstrating the relationships between central appetite-regulating structures, inflammatory processes, and neurohormonal activation, and their respective roles in the development of anorexia. We then describe the different treatment options and discuss some future prospects for the management for cardiac anorexia.     

Regulation of food intake by inflammatory cytokines in the brain

A number of inflammatory cytokines are synthesized and released after activation of the immune system. In addition to other biological effects, these cytokines can potently inhibit food intake. Cytokine-mediated inhibition of food intake is of particular importance because excessive production of peripheral inflammatory cytokines is often associated with the cachexia-anorexia syndrome seen in some chronic diseases. The weight loss in cachexia is associated with an increase in morbidity and mortality. Understanding how cytokines regulate food intake may be crucial in enhancing quality of life and facilitating recovery in patients exhibiting cachexia. This review describes the main inflammatory cytokines that influence food intake and explores how peripheral cytokines communicate with hypothalamic nuclei to influence feeding.     

Des-acyl ghrelin exhibits pro-anabolic and anti-catabolic effects on C2C12 myotubes exposed to cytokines and reduces burn-induced muscle proteolysis in rats

Although ghrelin and GHRP-2 have been shown to inhibit skeletal muscle proteolysis in rats with burn injury, the effects of des-acyl ghrelin (DAG) have not been reported. In this paper, we demonstrate that continuous 24h administration of DAG attenuated burn-induced EDL muscle proteolysis, and normalized elevated TNFα mRNA. Combined treatment of cultured C2C12 myotubes with TNFα and IFN-γ (TNF+IFN) inhibited protein synthesis and increased protein breakdown; DAG abolished both effects. PI3 kinase inhibition by LY294002 and mTOR inhibition by rapamycin blocked the reversal of the anti-anabolic effects of TNF+IFN-treated myotubes by DAG. DAG also reversed or attenuated the TNF+IFN-induced reduction in phosphorylation of Akt, FOXO1, 4E-BP-1, and GSK-3β in myotubes. Furthermore, DAG attenuated the atrophy signal, phospho-NF-κB, and the mRNA expression of MAFbx and MuRF1, upregulated by TNF+IFN in C2C12 myotubes. We conclude that DAG reduces muscle cachexia produced by injury and proinflammatory cytokines, and that DAG or DAG-based compounds may be useful in treating wasting disorders.     

The pathological consequences of anaemia.

Many patients with chronic diseases such as chronic renal failure, chronic inflammatory bowel disease and rheumatoid arthritis are anaemic. Recently congestive heart failure (CHF) has also been found to be associated with anaemia. In all these diseases this anaemia or chronic disease is at least partially due to excessive production of cytokines and leukotrines that interfere both with the effect of erythropoietin (EPO) at the bone marrow and the release of stored iron in the reticuloendothelial system. Treating this anaemia with subcutaneous EPO and IV iron improves the weakness, fatigue, cachexia, nutritional state, mood, cognitive function and quality of life. In the case of CHF it also improves cardiac function and patient functional class, prevents deterioration of renal function and markedly reduces hospitalization. Very few agents in medicine improve so many aspects of the patient so well and so quickly. Unfortunately (for the suffering patient) this anaemia is often ignored and goes untreated.     

Testosterone and heart failure

Testosterone deficiency is a generalized phenomenon seen in the course of chronic heart failure (CHF). Reduction in circulating testosterone level is a predictor of deterioration of functional capacity over time, underscoring the role of testosterone deficiency in CHF. Anabolic hormones are determinants of exercise capacity and circulating levels of anabolic hormones strongly determine muscle mass and strength. Testosterone deficiency is involved in the pathophysiology of CHF, contributing to some features of this syndrome, such as the reduced muscle mass, abnormal energy handling, fatigue, dyspnea and, finally, cachexia. This review summarizes current knowledge on the role of testosterone deficiency in the pathophysiology of CHF, gaining insights from the potential implications of testosterone as supplementation therapy.     

The pathological consequences of anaemia

Many patients with chronic diseases such as chronic renal failure, chronic inflammatory bowel disease and rheumatoid arthritis are anaemic. Recently congestive heart failure (CHF) has also been found to be associated with anaemia. In all these diseases this anaemia or chronic disease is at least partially due to excessive production of cytokines and leukotrines that interfere both with the effect of erythropoietin (EPO) at the bone marrow and the release of stored iron in the reticuloendothelial system. Treating this anaemia with subcutaneous EPO and IV iron improves the weakness, fatigue, cachexia, nutritional state, mood, cognitive function and quality of life. In the case of CHF it also improves cardiac function and patient functional class, prevents deterioration of renal function and markedly reduces hospitalization. Very few agents in medicine improve so many aspects of the patient so well and so quickly. Unfortunately (for the suffering patient) this anaemia is often ignored and goes untreated.