The syndrome of cardiac cachexia

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Abstract

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.

Introduction

It has very long been recognised that significant weight loss and wasting are important features of advanced chronic heart failure (CHF). This dates back 2300 years to the school of medicine of Hippocrates (about 460–370 BC) on the island of Cos, when it was stated that: “The flesh is consumed and becomes water,…, the shoulders, clavicles, chest and thighs melt away. This illness is fatal,…” [1]. The term cachexia is of Greek origin, derived from the words kakos (meaning: bad) and hexis (meaning: condition). Cachexia is a process of muscle wasting and weight loss that occurs in several different chronic disorders and is also part of the ageing process [2], being almost always associated with a poor prognosis.

Cardiac cachexia is a serious complication of CHF which, until relatively recently, has been little investigated [3]. The available knowledge concerning the presence of general weight loss in CHF patients, its pathogenesis—with particular emphasis on the immunological and neurohormonal abnormalities present in this condition—and the potential treatment strategies for cardiac cachexia will be reviewed.

Section snippets

Definition of cardiac cachexia

The problems of research into cardiac cachexia start with the definition of cardiac cachexia. Research groups have extensively investigated the wasting process in different conditions, but there is still no consensus with regard to the best definition of cachexia. Body composition analyses with body fat and lean tissue estimation and anthropometric measurements (skinfold thickness, arm muscle circumference), calculations of predicted percent ideal mass matched for sex, age and height (e.g.

Epidemiology

It is widely recognised that the prevalence of chronic heart failure (CHF) is increasing. This has been attributed to improved survival in patients with coronary artery disease, the use of drug therapy prolonging life in patients with established CHF, and a strong correlation between CHF and age in populations with increasing longevity [12]. The natural and perioperative morbidity and mortality of patients with cardiac cachexia is higher than that of non-cachectic patients [9], [13]. The New

Etiology

Historically, three distinct mechanisms were thought to be responsible for the development of cardiac cachexia: (a) malabsorption and metabolic dysfunction, (b) dietary deficiency and (c) loss of nutrients via the urinary or digestive tracts. Pittman and Cohen in 1964 were the first to analyse extensively the pathogenesis of the syndrome of cardiac cachexia [16]. They proposed the development of cellular hypoxia as being the principal pathogenic factor leading to less efficient intermediary

Inflammatory cytokine activation

There is now considerable evidence to suggest that neurohormonal and immune mechanisms may play a central role in the pathogenesis of cardiac cachexia, which is likely to have a dramatic effect on the way that this condition is managed in the future [3], [28], [29], [30]. The immune system is the body’s natural defence mechanism against infection and other stresses. There are several different components to this system which interact with each other in a complex manner and may be involved in

Neuroendocrine abnormalities

A variety of secondary changes occur when heart failure becomes chronic (i.e. after 3 or 6 months) and are a response predominantly to the impaired cardiac function, although some of these secondary changes may develop consequent upon the drugs used in the treatment of heart failure. These secondary changes include general neurohormonal activation with stimulation of the sympathetic nervous system, the renin–angiotensin–aldosterone-axis, and the natriuretic peptide system. Initially, these

Body composition alterations

Patients with CHF characteristically have evidence of muscle atrophy [76], [77], being present in up to 68% of patients in certain studies [22]. Muscle weakness and early fatigue are two of the main symptoms experienced by CHF patients, and in the largest series reported to date (n=101) we found muscle weakness and fatigue to occur mainly in patients with NYHA class 3 and 4 [78], and cachectic subjects [79]. A loss of lean body mass is known to predict prognosis in cancer and AIDS [80].

Clinical implications

The detection of wasting in a CHF patient is an ominous sign. As cardiac cachexia is a multifactorial disorder characterised by an imbalance of catabolic and anabolic body systems (Fig. 4), it is unlikely that any single agent will be completely effective in treating this condition and the targeting of different pathways will be necessary.

Conclusions

Diseases that have a high priority in national health care programmes need to be: (i) common, (ii) detectable, and (iii) effectively treatable. Chronic heart failure has a prevalence of about 1–2% in the population [12], [124] which appears to be on the increase. Cachectic CHF patients represent a significant proportion of CHF patients (about 10–15%), with this condition being readily detectable. A long-term aim is to be able to predict the development of cardiac cachexia and to stop the

Acknowledgements

SDA is supported with a postgraduate fellowship from the Max Delbrück Centrum for Molecular Medicine, Berlin, Germany.

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