Chest
Volume 115, Issue 3, March 1999, Pages 836-847
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Cardiac Cachexia: A Syndrome With Impaired Survival and Immune and Neuroendocrine Activation

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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-α. 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.

Section snippets

Human Weight Homeostasis

The homeostasis of weight in humans is complex and body weight and mortality are related. Extreme obesity is related to a shortened lifespan, but this is to some degree modified by race, sex, and correlated risk factors.3 Starvation leads to death at 66% of ideal body weight.4,5 Within the “normal” range of weight and looking at all age groups, the relation between weight and mortality is not close in either male or female subjects.6,7 The relationship between weight changes and mortality in

Definition of Cardiac Cachexia

The problems of research into cardiac cachexia start with its definition. Although research groups have extensively investigated different cachectic conditions, there is still no accepted definition of cachexia. Different approaches are possible. Methods used include: 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

Epidemiology

Studies of CHF suggest that CHF increases in frequency with an increasing proportion of elderly people in the population, reaching a prevalence of up to 30% in those older than 80 years.27It has been shown that up to 50% of CHF patients are to some degree malnourished.22 In patients with cardiac cachexia, the natural and perioperative morbidity and mortality are increased compared with noncachectic CHF patients.25,28 The New York Heart Association (NYHA) class does not correlate with disease

Body Composition Alterations

Muscle atrophy has long been known to occur in CHF patients,33,34 and it has been found in up to 68% of CHF patients,35 but some studies did not find it.36 Muscle weakness and early fatigue are two of the main symptoms of CHF patients, and in the largest series of CHF patients reported to date (n = 101), we found muscle weakness and fatigue to occur mainly in patients with NYHA class III and IV,37 or in cachectic subjects.38 It has been found that it is incompatible with life to lose > 40% of

Views on the Causes of Cardiac Cachexia

Historically, three categories of mechanisms were thought to be responsible for the development of cardiac cachexia: (1) malabsorption and metabolic malfunction, (2) dietary deficiency, and (3) loss of nutrients via the urinary or digestive tracts. Pittman and Cohen47 in 1964 were the first to analyze extensively the pathogenesis of the syndrome of cardiac cachexia. In general, they thought the development of cellular hypoxia to be the leading pathogenic factor causing less efficient

Immune Abnormalities

Interestingly, as early as 1934 the existence of an unexplained pyrogen as a product of anaerobic metabolism in cases of fever in heart failure was suggested.58 Unexplained episodes of pyrexia are commonly seen in the setting of acute heart failure and particularly in cardiogenic shock, but this has never been studied in detail. Could low-grade fever, increased basal metabolic rate, local hypoxia, and anorexia still be related by common factors? Several immunologic interactions at the cellular

Neuroendocrine Abnormalities

A variety of secondary changes occur when heart failure becomes chronic (ie, after 3 or 6 months). These secondary changes are mainly a response to the impaired cardiac function, although some of these changes may develop consequent to 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

Clinical Implications

Because of these many strikingly different views and findings and the many interactions, it appears unlikely that a single physical or biochemical disorder causing cardiac cachexia will be found. We view cardiac cachexia as a multifactorial neuroendocrine and metabolic disorder in which a complex imbalance of different body systems may cause the development of body wasting. Potentially, advanced mathematic modeling methods (eg, factor analysis) are necessary to account for the multiple factors

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    Dr. Anker is supported with a postgraduate fellowship of the Max Delbrück Centrum für Melekulare Medizin.

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