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Cardiac Cachexia*: A Syndrome With Impaired Survival and Immune and Neuroendocrine Activation FREE TO VIEW

Stefan D. Anker, MD, PhD; Andrew J. S. Coats, DM
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*From the Department of Cardiac Medicine (Dr. Anker and Mr. Coats), National Heart & Lung Institute, London, UK; and the Franz-Volhard-Klinik am Max Delbrück Centrum (Dr. Anker), Charité, Campus Berlin-Buch, Berlin, Germany.



Chest. 1999;115(3):836-847. doi:10.1378/chest.115.3.836
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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.

Abbreviations: ACE = angiotensin-converting enzyme; CHF = chronic heart failure; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; TNF-α = tumor necrosis factor-α; V̇o2 = oxygen consumption

Figures in this Article

The average life span of humans in modern civilization is about 80 years. Death is often preceded by disease. It is known that there are common patterns of response to disease in humans, including inflammation and fever; weight loss is frequently observed. The term cachexia is of Greek origin, derived from the words kakos (ie, bad) and hexis (ie, condition). Cachexia is one of the most visible and devastating consequences of human disease, seen in several chronic diseases, including cancer, AIDS, thyrotoxicosis, and rheumatoid arthritis. In malignant cancer and AIDS, cachexia is known to be a sign of very poor prognosis. In general, it is thought to be related to loss of appetite (anorexia), anemia, and metabolic abnormalities, which in turn are influenced by altered hormones and cytokines.

It has long been recognized that significant weight loss and wasting are also important features of severe chronic heart failure (CHF). This dates back 2,300 years to the time of classical Greece and the school of medicine of Hippocrates (about 460–370 BC) on the island of Cos:“ The flesh is consumed and becomes water, … the shoulders, clavicles, chest and thighs melt away. This illness is fatal… .” 1In 1785, Withering2 wrote about a patient with heart failure: “his countenance was pale, his pulse quick and feeble, his body greatly emaciated, except his belly, which was very large.” The presence of general weight loss in heart failure patients has somewhat misleadingly been termed cardiac cachexia. Whether the process of weight loss is accompanied by a loss of cardiac muscle tissue has never been studied, and whether the distinction between peripheral and cardiac cachexia is necessary remains unknown. Considering the general problem of weight homeostasis in humans, this article will focus on the available knowledge concerning the presence of general weight loss in CHF patients, its clinical implications, and the potential importance of immunologic and neurohormonal abnormalities in its development and progression.

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.3Starvation 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 healthy subjects is more complicated, and it cannot be clearly said whether it matters if weight changes over time.8Over shorter periods (a few years), a substantial weight loss and significant weight variation may be harmful, but a smaller degree of weight gain is not.9,,10 Over the longer term, between early and middle adulthood, weight changes of up to± 10 kg are not related to altered mortality, but weight gain of> 10 kg is related to increased mortality in men and women,9,,10 whereas weight loss of > 10 kg in women (initial weight at age 18, follow-up 16 years) has been shown to be related to somewhat, although not significantly, reduced mortality.10

Physiologic aging is accompanied by body composition changes. Starting between ages 20 and 30, lean body mass can decline by approximately 0.3 kg/yr,9,,10 but this is more than offset by an increase of fat stores at least until age 65 to 70.9,,11 These processes lead to highest body weights between ages 40 and 60, weight stability until age 70, and then small decreases after age 70 to 75 years.12Body wasting is often thought to be simply a consequence of old age and normal; certainly, studies in this area are difficult, because it is often unclear whether weight loss results from physical inactivity, subclinical disease, or aging itself. Interestingly, two longitudinal studies of very healthy elderly subjects suggest that only 0.1 to 0.2 kg weight loss/yr (ie,≤ 1 kg in 5 years) appeared to be related to normal aging.13,,14 Another commonly held belief is that intentional and nonintentional weight loss need to be distinguished when the clinical implications of body wasting are discussed. This seems doubtful, as weight loss in the elderly, whether voluntary or not, is similarly related to increased mortality15,,16; also, in obese subjects, in whom probably all weight loss is regarded as welcome by the patient (and the doctor), “successful” dieters are on average persons who are losing weight and keep it off because of underlying illness.17It has been shown that older subjects, after experimentally induced underfeeding leading to weight loss, did not adjust their energy intake appropriately to fully regain weight, unlike younger participants.18 Therefore, perhaps the most important impact of the aging process itself on weight homeostasis is that, in the elderly, the ability to recover previously lost weight is impaired.

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 (usually using data of the Metropolitan Life Insurance Tables from 195919or the Build Study from 197920); scores including serum albumin concentrations, cell-mediated immunity changes, weight/height index or body mass index (weight/height2), and the history of weight loss.21 In heart failure studies, patients were classified as “malnourished” when the body fat content was < 22% in women and < 15% for men or when the percentage of ideal weight was< 90%.22Other groups defined CHF patients prospectively as “cachectic” when the body fat content was < 29% (women) or < 27% (men),23or when the ideal body weight was < 85%24or even < 80%.25 Additionally, it is possible to characterize the lean tissue by studying urinary creatinine excretion rates, skeletal muscle protein turnover (using labeled amino acids), bioelectrical impedance, or total body potassium content, or by measuring the skeletal muscle size by means of MRI and CT or body densitometry. Freeman and Roubenoff26 suggested in 1994 that a documented loss of at least 10% of lean tissue should be used as the criteria to define cardiac cachexia. The disadvantages of such a definition are: (1) many physicians may not have easy access to facilities that allow prospective measurement of lean body mass; (2) such measurement would involve fairly large additional costs; and (3) this definition is muscle-focused without considering first that fat tissue replacement may be intact with no general weight loss, and second that some patients may mainly suffer from fat tissue loss but little or no lean tissue loss.

It is important to note that the development of the cachectic state in CHF is a process that can only be proven by a documented weight loss measured in a nonedematous state. Including weight loss as a criterion excludes patients who constitutionally have a low body weight. We suggest the use of a relatively wide definition of “clinical cardiac cachexia”: In patients with CHF of at least 6 months’ duration without signs of other primary cachectic states (eg, cancer, thyroid disease, or severe liver disease), cardiac cachexia can be diagnosed when weight loss of > 7.5% of the previous normal weight is observed. This weight loss should usually be obeserved over a period of > 6 months. Massive weight loss over a shorter time period might be cardiac cachexia, but obviously other causes of wasting (such as cancer and infection) need to be considered carefully.

This definition is simple and quickly applicable. In general, the previous normal weight of a heart failure patient would be the average weight prior to the onset of heart disease (ie, before a myocardial infarction, before the diagnosis of idiopathic dilated cardiomyopathy, etc); and on the time axis, it would be important to note the last time point when the patient had this weight without being edematous. In some cases, particularly when patients suffer from mild-to-moderate heart failure over longer time periods, a few patients may develop obesity after the onset of heart failure, and one would need to take this (higher) weight as the previous normal weight. Nevertheless, in our experience, these patients have been seen infrequently and did not subsequently develop cardiac cachexia.

In practice, when applying the above definition, it is necessary to take a careful weight history. Although physicians may need to rely on previous weight measurements by others potentially using different sets of scales, and although those assessments may have been performed at different times of the day and with the patient wearing different clothing, we feel these problems are minor, particularly when it is the aim to identify a definite state of cachexia, rather then the precise degree of body wasting. Over the past years, we have personally evaluated about 40 cachectic CHF patients who all had a weight loss of more than 7.5%, and all these patients had a body mass index of < 24 kg/m2 and more than 5 kg of documented nonedematous weight loss. Certainly, some of these patients do not present in the dramatically wasted condition (like so many cachectic cancer patients) that many cardiologists have in mind when first discussing cardiac cachexia. Our definition of cardiac cachexia is fairly broad, and it is one of the major goals of this review to show that these patients with smaller amounts of weight loss can already be differentiated from CHF patients with no weight loss.

If the aim is to take the severity of the wasting process itself into account, it is possible to study the patients’ pathophysiology in relation to the amount of weight loss. In this regard, we have found it useful to further classify cachectic patients into those with severe cachexia (defined as > 15% weight loss, or > 7.5% weight loss and< 85% of ideal body weight) and those with early or moderate cachexia (defined as > 7.5 to ≤ 15% weight loss, or > 7.5% weight loss and ≥ 85% of ideal body weight). To standardize the assessment of cardiac cachexia, we have developed a simple questionnaire that is freely available from us. This questionnaire has recently been included in substudies of major heart failure intervention trials (ELITE 2, captopril vs losartan; COPERNICUS, carvedilol vs placebo). Finally, as with any other available definition, it is our understanding that the given definition of cardiac cachexia has not yet been validated in large-scale registries, and the cut-off value of a 7.5% weight loss remains arbitrary. Theoretically, the degree of weight loss that most strongly predicts impaired survival could be considered the most clinically relevant cut-off value. Such studies are underway.

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.27 It 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 morbidity or mortality in cardiac cachexia.29Cardiac cachexia also occurs in childhood, related to malnutrition and/or malabsorption diseases such as kwashiorkor or marasmus.30 Nevertheless, to date there is no comprehensive large-scale study on the frequency and degree of body wasting in CHF.

In our clinic, between June 1993 and May 1995, we performed the first prospective study31 of the frequency and prognostic importance of cachexia in CHF patients using the definition given above. We assessed 171 consecutive CHF patients with a mean age (±SD) of 60 ± 11 years; 17 were women. The patients’ mean treadmill peak oxygen consumption (V̇o2) was 17.5 ± 6.8 mL/kg/min. Twenty-one were in functional NYHA class I, 63 in class II, 68 in class III, and 19 in class IV. Of these 171 patients, we identified 28 as being cachectic, ie, 16% of our CHF outpatient population had cardiac cachexia.,31 The observed weight loss in these patients amounted to 9 to 36% (6 to 30 kg) within the previous 0.5 to 13 years (average weight loss/yr, 6.0 ± 3.7 kg). The cachectic patients were slightly older and had a reduced exercise capacity, reduced exercise time, and lower sodium levels than the noncachectic cohort, but the left ventricular ejection fraction (LVEF) was similar in cachectic and noncachectic patients. This study focused on all-cause mortality (follow-up > 18 months), and all 49 observed deaths could be attributed to cardiovascular causes or were of a sudden nature. Significant predictors of mortality included peak V̇o2, NYHA class, and exercise time (each p < 0.0001), percentage of ideal weight (p = 0.0002), LVEF (p = 0.0004), cachectic state (p = 0.0029), and age (p = 0.028). The cachectic state was predictive of mortality at 18 months independently of age, NYHA class, LVEF, peak V̇o2, and sodium levels. The mortality in the cachectic patients was very high: 18% at 3 months, 29% at 6 months, 39% at 12 months, and 50% at 18 months; these rates are very similar to the mortality in patients with a peak V̇o2 of < 14 mL/kg/min (mortality after 18 months, 51%; Fig 1 ) or in NYHA class IV (18-month mortality, 63% based on analysis of patients in our previous study,31). Patients who had a peak V̇o2 of < 14 mL/kg/min and were defined as cachectic (ie, with the presence of two risk factors) had an 18-month survival of 23% (95% confidence interval, 0 to 46%), compared with 93% (95% confidence interval, 88 to 98%) in patients with neither of these two risk factors (p < 0.0001).,31The unfavorable subgroup prognosis of cachectic CHF patients may largely contribute to the overall adverse prognosis of CHF patients.32 In fact, in our study,31 one third of all deaths occurred with cardiac cachexia being present.

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,35but some studies did not find it.36Muscle 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,37or in cachectic subjects.38It has been found that it is incompatible with life to lose > 40% of lean tissue.39The loss of lean tissue predicts a poor prognosis in cancer and AIDS.40Such a direct relationship has not yet been documented in CHF. A study of 27 patients with CHF and a mean weight 21% lower than normal subjects (weight loss itself was not documented) failed to show loss of fat tissue, but documented an average total body potassium decrease of 35% (measure of lean tissue independent of body water content).41In patients undergoing cardiac transplantation or awaiting transplantation, osteoporosis has been documented.42 In these studies, no clinical data, drug intake, or humoral factors have yet been found to predict loss of muscle and fat tissue or reduced bone mineral density in any group of heart failure patients.

When using documented weight loss as criterion to dichotomize the CHF patients, we have shown that cachectic CHF patients not only suffer from significant loss of lean tissue (ie, skeletal muscle; Fig 2 ) but also show a grossly reduced fat tissue mass (ie, energy reserves) and evidence of decreased bone mass (ie, osteoporosis) when leg cross-sectional areas are analyzed by CT.38 Using dual energy x-ray absorptiometry, we43and others44could confirm that cachectic CHF patients show reduction of total body fat and lean tissue mass compared with noncachectic patients or healthy control subjects, and that bone density is significantly reduced in cachectic patients.45 Considering the loss of muscle tissue (muscle quantity), it is certainly not surprising that cachectic CHF patients showed greater muscle weakness than noncachectic patients (both legs, 39% lower strength; Fig 2), but they also demonstrated 16% reduced strength per unit muscle, ie, impaired muscle quality was found (Fig 2).,38 Additionally, the loss of muscle tissue is important as it contributes, together with the impaired peripheral blood flow seen in CHF patients,46 to the decreased oxidative capacity, which is the main cause of the impaired exercise capacity of patients with heart failure.

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 intermediary metabolism, therefore producing increased catabolism (protein loss) and reduced anabolism. Additionally, they suggested anorexia and increased basal metabolic rate to be closely related and possibly the result, in part, of a lack of oxygen.

Little is known about the mechanisms of the transition from heart failure to cardiac cachexia. Anorexia can be related to heart failure via its main symptoms (ie, fatigue and dyspnea) or via intestinal edema causing nausea and/or a protein-losing gastroenteropathy. Additionally, anorexia may be iatrogenic as a side effect of digitalis, sodium-restricted diets, and some angiotensin-converting enzyme (ACE) inhibitors. To test this hypothesis, in 1977 Buchanan and colleagues48performed a study in 11 cachectic patients (NYHA class IV, mitral valve disease, preoperative and postoperative assessment). Most commonly, they found marked, reversible anorexia to be the cause of the cachectic state. Neither malabsorption (D-xylose absorption test) nor cellular hypoxia (assessed by lactate and pyruvate concentration) was of importance in their patients. In contrast, it was recently demonstrated that elderly ambulatory patients with cardiac cachexia (mean age, 76 years) showed evidence of fat malabsorption.49It could be argued that cachexia in heart failure is due to gastrointestinal protein loss, but in 5-day stool collections, the recovery radioactivity indicative of protein excretion (chromic chloride test) was similar in cachectic CHF patients compared with healthy age- and sex-matched subjects (p = 0.9).50 It is not clear to what degree these results hold true for younger patients with cardiac cachexia.

In 1984, Braunwald51 suggested that patients with cardiac cachexia might have biventricular heart failure, and that a predominant right ventricular component could be more common in these patients. Interestingly, increased right atrial pressure was the only independent predictor of malnutrition observed in 24 out of 48 investigated patients with severe CHF; in this study, cardiac index and pulmonary capillary wedge pressure had been similar in malnourished and well-nourished CHF patients.22 In contrast, in their comparison of nine cachectic and nine noncachectic patients who were considered for heart transplantation (75 ± 7% vs 105 ± 16% of ideal weight), MacGowan and colleagues52 found no differences in right atrial pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, and pulmonary and peripheral vascular resistance, but cardiac output (p < 0.05) and cardiac index were worse in the cachectics (1.9 ± 0.4 vs 2.2 ± 0.5 L/min/m2; p = 0.08).

Simple starvation and anorexia are often considered to be the main cause of cardiac cachexia, but they would mainly lead to a loss of fat tissue. They would also cause reduced plasma albumin levels. Yet, cachectic CHF patients suffer from fat, muscle, and bone tissue loss (indicating the presence of a general wasting process), and albumin and liver enzyme plasma levels were not decreased in these patients.53 This would argue against a major contribution of starvation, anorexia, gastrointestinal malabsorption, or liver synthetic dysfunction in these patients. The latter would also be expected to be present if right heart failure were indeed dominant in cachectic CHF patients.

Physical inactivity and deconditioning have been suggested to be important for the muscle atrophy observed in many patients with CHF,35 but histologic evidence suggests that the atrophy in states of reduced activity is significantly different from the muscle atrophy observed in CHF.54,,55 Therefore, it seems unlikely that physical inactivity is of great importance in the genesis of cardiac cachexia. In 1994, Poehlman et al56 demonstrated increased resting metabolic rates in stable CHF patients compared with control subjects. When the same group recently compared cachectic CHF with noncachectic patients and healthy control subjects, they found no evidence of increased resting metabolic rate in cachectic patients that could cause cachexia per se.,44 Rather, they found a reduced resting metabolic rate in cachectics (−9.1% vs control subjects), and they confirmed an increased resting energy expenditure in noncachectic patients (+10.9% vs control subjects).44 Total daily energy expenditure and physical activity energy expenditure were also lower in the cachectic patients, but in this study relatively old cachectic patients were investigated (mean age, 73 years). Interestingly, the resting metabolic rates have been shown to correlate with increasing concentrations of catecholamines in older individuals57; whether this is true for heart failure patients is not known, but it seems likely.

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 level might be involved in the development of cardiac cachexia. In 1990, Levine and colleagues24 reported that tumor necrosis factor-α (TNF-α) is increased in patients in cardiac cachexia. This was subsequently confirmed by other groups.23,,59 Using our definition of cardiac cachexia, we found also that TNF-α plasma levels were increased mainly in cachectic CHF patients (Fig 3 ); these were the strongest predictors of the degree of previous weight loss.,53 TNF-α is one of the key cytokines important to the development of catabolism, together with interleukin-1 (IL-1), IL-6, interferon-γ, and transforming growth factor-β. These cytokines are produced primarily by monocytes/macrophages,60,,61 but also endothelial cells and (particularly relevant to heart failure) the myocardium have been found to produce cytokines such as TNF-α.62,,63 At the myocardial level, a chronic repetitive stress is thought to induce TNF-α production.64Whether our endotoxin hypothesis—that bowel wall edema occurs in heart failure and leads to bacterial or endotoxin translocation with subsequent immune activation65—holds true and whether it is of relevance for the immune activation in cardiac cachexia remain to be seen.

Multiple factors can modify the biological effects of TNF-α, which itself can exert a variety of effects. Many of them can directly or indirectly contribute to body wasting in CHF. In animal experiments it has been shown that skeletal muscle cachexia occurs when TNF-α-producing tumor cells are implanted into skeletal muscle, and TNF-α-producing cells implanted in the brain cause profound anorexia.66This shows that the site of the production and action of TNF-α modifies its effect, and also that increased levels of TNF-α may indeed play a causative role in the genesis of cachexia. TNF-α also can induce apoptosis,67,,68 which might be important in cachectic patients. Apoptosis has not been assessed in any tissue of cachectic CHF patients. TNF-α also exerts effects on endothelial cells, including rearrangement of the cytoskeleton, increased permeability to albumin and water, enhanced expression of activation antigens, induction of surface procoagulant activity, and IL-1 release.69TNF-α is known to reduce constitutive nitric oxide synthase mRNA in vascular endothelial cells.70These actions could all impair endothelial function. The strong inverse relationship between maximal peripheral blood flow and TNF-α levels in CHF patients could support the idea of detrimental effects of long-term increased TNF-α effects.71

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 systems are thought to be beneficial, but eventually they contribute to increased vascular resistance and afterload, and ventricular enlargement and remodeling.72

The neurohormonal hypothesis73postulates that heart failure progresses because the activated endogenous neurohormonal systems exert a deleterious effect on the heart and circulation. Several studies have found neurohormonal activation to be strongly related to mortality,74,,75,,76 but different hormones correlate only weakly with each other.75Norepinephrine and plasma renin activity were found not to be related to either peak exercise capacity or LVEF.76Many studies have investigated catecholamine levels in CHF patients. Plasma norepinephrine may reflect overall sympathetic activity77 and both norepinephrine and epinephrine can cause a catabolic metabolic shift.57,,78

Since the original observation in 1962 of increased catecholamines in CHF,79 until recently no study had investigated catecholamine levels specifically in cachectic CHF patients. When we stratified 53 CHF patients for presence of cachexia, peak V̇o2, LVEF, and NYHA class, we found that cachectic CHF patients showed markedly increased norepinephrine and epinephrine levels, with noncachectic CHF patients having near-normal levels.,53 None of the other subclassifications revealed significant differences between groups of CHF patients (Fig 3). Also, aldosterone plasma levels and plasma renin activity were increased in cardiac cachexia, although treatment with ACE inhibitors and diuretics and the time since diagnosis of CHF were similar.,53 This suggests a specific association between cachexia and sympathetic activation in CHF. Another hormone considered to be part of the general stress response with a catabolic action is cortisol.80In untreated, severely diseased CHF patients, Anand and colleagues81demonstrated a 2.5-fold increase of cortisol, probably due to an increase in the release of adrenocorticotropic hormone.82 The cachectic patients in our study53 had a 2-fold increase of cortisol levels. No other subgrouping of the CHF patients revealed any significant effect on mean cortisol levels. In addition, the anabolic steroid dehydroepiandrosterone was lowest in cachectic CHF patients, suggestive of a catabolic/anabolic imbalance.53 Interestingly, the abnormalities of sex steroid metabolism in CHF are strongly and directly related to the immune activation seen particularly in the cachectic CHF patients.83

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 and interactions.84,,85 In a smaller number of cachectic patients, anorexia and liver dysfunction may have a role, but in the majority of cases, we believe, cardiac cachexia is due to a systemic wasting process. Neuroendocrine and immunologic abnormalities may be of particular importance for its development. Both neurohormones86and cytokines87,,88 can predict survival in CHF and are related to the presence of cardiac cachexia. The intensity of neurohormonal and immunologic alterations in CHF patients varies, and it is not clear what plasma concentration is important in a particular patient. The onset of weight loss may indicate sensitively that these changes have reached a clinically relevant level, and the subsequent prognosis of the patient is thus impaired.

Importantly, in heart failure, cachexia is independent of not only age and functional status, but also ejection fraction and peak V̇o2—to date, the most commonly used prognostic characteristics. These characteristics are included in virtually all studies of survival, whether analyzed from a pathophysiologic point of view or analyzed as the response to a therapeutic intervention. Studies often exclude patients with severe acute weight loss in order to exclude cancer or acute infection, but the presence of chronic wasting seems to be an important indicator of the severity of heart failure. We therefore would like to suggest that the assessment of cachectic status should be included in heart transplant assessment programs and in other studies of survival in heart failure.

It is not difficult to detect this wasting process if one looks for it. We would like to emphasize the importance of a carefully documented weight history (weight taken regularly in a nonedematous state) for all CHF patients that are under follow-up. It is also important to document the weight changes during in-hospital stays in discharge letters. This is an easy, time-effective, and cost-effective task.

Nutritional Support

The detection of cardiac cachexia in a CHF patient means that the patient has only a 50% chance to survive for > 18 months. This is mainly because there is no specific therapy for cachectic CHF patients. Theoretically, it seems clear that the nutritional status has to be improved to regain energy reserves (fat tissue), the muscle tissue must be increased to improve exercise capacity, and possibly anticytokine therapy is feasible. Except for preoperative and postoperative nutritional support of cardiac cachectic patients, there are no controlled studies for the outcome of therapeutic strategies in cardiac cachexia. In stable CHF patients with no signs of severe malnutrition, nutritional support alone had no significant effect on the clinical status of heart failure.89Intensive nutritional support could increase the body’s oxidative demands, but it has been shown that nutritional support is safe in cardiac cachectic patients and can lead to an increased amount of lean tissue.90 This strategy is of great importance in the preoperative and postoperative phases when surgery has to be performed. Immediate postoperative IV hyperalimentation alone did not improve survival in one study,28 whereas in another study, cachectic patients with heart failure who received preoperative support (5 to 8 weeks’ duration, IV up to 1,200 kcal/d) had lower mortality than did patients not given nutritional support (17 vs 57%; p < 0.05).25 Others have suggested the provision of 40 to 50 kcal/m2 body surface/h, including 1.5 to 2 g/kg/h protein, and the restriction of supplementation of sodium (2 g/d) and fluid (1,000 to 1,500 mL/d) using high-density continuous feeding.,28 In any case (especially for ambulant cachectic but stable patients), the consultation of dietitians could be very helpful. Otherwise, in view of the side effect of anorexia, digitalis should be used carefully (if at all) and levels monitored frequently. Also, some ACE inhibitors, captopril in particular, are known to impair taste and exacerbate anorexia.

Exercise

Muscular metabolic abnormalities, atrophy, impaired peripheral blood flow, and neurohormonal abnormalities can all be reversed by exercise rehabilitation training, resulting in increased exercise capacity and anaerobic threshold.91,,92 From our experience, it can be suggested that moderate exercise training could safely be applied to cachectic CHF patients in NYHA class I to III, too. This would certainly increase the status of daily physical activity. We have previously shown that peak leg blood flow, rather than muscle size and strength, is the best correlate of impaired exercise capacity in cachectic CHF patients, whereas strength and age are the best predictors of exercise intolerance in noncachectic patients.38 Whether this has implications for a potential systematic rehabilitation program (eg, use of physiotherapeutic procedures to increase peripheral perfusion before the start of any exercise training) has not been studied yet.

Drugs

In sepsis and rheumatoid arthritis, nonspecific (corticosteroids, pentoxifylline, and hydralazine sulfate) and specific drugs (monoclonal antibody or soluble TNF-α receptors and IL-1 receptor antagonist) have been shown to reduce cytokine activity and partly inhibit its biological effects. Fish oil (n-3 polyunsaturated fatty acids) has been shown to reduce TNF-α and IL-1 in healthy volunteers93 and patients with rheumatic disease.94To achieve sufficient dosing, high-concentration formulations are necessary, but this has not been studied in CHF. In animal experiments of sepsis, the administration of soluble TNF receptors improved hemodynamic performance and could reduce cytokine induction.95Except for a pilot study using a TNF receptor fusion protein in stable CHF patients,96no study has investigated the potential of specific anticytokine therapy. Recently, Sliwa et al97 reported that pen-toxiphylline (a phosphodiesterase inhibitor) given for 6 months significantly reduced TNF-α plasma concentrations in CHF patients (and improved LVEF and symptoms), yet the mean reduction of TNF-α plasma concentrations (ie, the treatment effect) was virtually identical in the two treatment groups: −4.4 pg/mL in the pentoxiphylline group (significant within this group of patients) compared to −4.3 pg/mL in the placebo group. On the anabolic side, recombinant human growth hormone can been considered an option for treatment of cardiac cachexia, although normal doses (2 IU/d) did not produce significant clinical benefits after 3 months of treatment when compared with placebo.98 Two case reports involving a total of three cachectic patients with CHF99,,100 demonstrated that short periods (1 week to 3 months) of high-dose growth hormone therapy (70 to 98 IU/wk) resulted in profound increases of muscle mass and strength and improvement of exercise capacity with no reported side effects. The use of anabolic steroids to increase muscle mass may be an option, but their effects on kidney function and potential to induce prostate hyperplasia may limit their use unless substances are used with (nearly) no androgenic action.

Diseases that have a high priority in national health-care programs need to be (1) common, (2) detectable, and (3) effectively treatable. Chronic heart failure has a prevalence of about 1 to 2% in the population.27,,101 Because of general improvements in health care, an increasing proportion of elderly people in the population, and improved survival after myocardial infarction, the incidence of new CHF cases is likely to increase further. If 10% of the heart failure population would suffer from cardiac cachexia (16% documented in our unit), at least 600,000 to 1,200,000 patients may suffer from this condition in North America and Europe. Cardiac cachexia seems to contribute substantially to heart failure-related mortality, and it can be detected easily. There is certainly much more that needs to be learned about the pathophysiology of wasting in CHF. Studies will very likely be driven by the remaining task: to develop an effective treatment for cardiac cachexia. A long-term aim may be to be able to predict the development of cardiac cachexia and to stop the wasting process before the onset of significant weight loss. Enhancing the prognosis of cardiac cachexia or even reversing the cachectic process will have significant influence on the quality of life of many patients and may improve the long-term prognosis of CHF overall. We regard this area of heart research as one of the most interesting fields, as it requires a joint effort from cardiologists, endocrinologists, and immunologists. Studying cardiac cachexia is studying metabolic cardiology.

For related material see page 708.

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

Correspondence to: Stefan D. Anker, MD, PhD, Department of Cardiac Medicine, National Heart & Lung Institute London, Dovehouse St, London SW3 6LY, UK; e-mail: s.anker@ic.ac.uk

Figure Jump LinkFigure 1. Top, survival in ambulatory CHF patients with (n = 28) and without (n = 143) cardiac cachexia, and bottom, survival in these patients grouped by peak V̇o2 < 14 (n = 53) and ≥ 14 mL/kg/min (n = 118). Adapted from data in Anker et al.31Grahic Jump Location
Figure Jump LinkFigure 2.  Isometric quadriceps strength, quadriceps muscle cross-sectional area (CSA [a marker of muscle mass, measured using CT]), and quadriceps strength per unit area of quadriceps muscle (in N/cm2) of left and right leg in cachectic and noncachectic CHF patients. Reprinted with permission from Anker et al.38 N = Newton.Grahic Jump Location
Figure Jump LinkFigure 3.  Plasma levels of norepinephrine, epinephrine, cortisol, and TNF-α in 16 healthy control subjects and 53 patients with CHF. The heart failure patients were grouped by cachectic state (nc = noncachectic, n = 37; cach = cachectic, n = 16); maximal oxygen consumption (peak V̇o2 < 14 mL/kg/min, n = 17; 14 to 20 mL/kg/min, n = 24; and > 20 mL/kg/min, n = 12); functional NYHA class (class I/II, n = 16; class III/IV, n = 37); and LVEF (< 20%, n = 24; 20 to 35%, n = 17; > 35%, n = 12). Data are presented as mean ± SEM; p values for Fisher’s test are given if analysis of variance showed significant intergroup variation. * p < 0.05 for intergroup comparison. ** p < 0.01 for intergroup comparison.*** p < 0.001 for intergroup comparison.• p < 0.05 vs control subjects.•• p < 0.01 vs control subjects.••• p < 0.001 vs control subjects. Reprinted with permission from Anker et al.53Grahic Jump Location
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Kushner, RF Body weight and mortality.Nutr Rev1993;51,127-136. [PubMed]
 
Brozek, J, Wells, S, Keys, A Medical aspects of semistarvation in Leningrad (siege 1941–1942).Am Rev Sov Med1946;4,70-86. [PubMed]
 
Cahill, GF, Jr Starvation in man.N Engl J Med1970;282,668-675. [PubMed]
 
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New weight standards for men and women. Stat Bull Metrop Life Insur Co 1959; 40:1.
 
Society of Actuaries and Association of Life Insurance Medical Directors of America. Build study, 1979. Philadelphia, PA: Recording and Statistical Corporation, 1980.
 
Anker, SD, Coats, AJS The syndrome of cardiac cachexia in chronic heart failure.Poole-Wilson PA, Colucci WS, Massie BM, et al, eds: Heart failure1996,261-267 Churchill-Livingstone. New York, NY:
 
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Figures

Figure Jump LinkFigure 1. Top, survival in ambulatory CHF patients with (n = 28) and without (n = 143) cardiac cachexia, and bottom, survival in these patients grouped by peak V̇o2 < 14 (n = 53) and ≥ 14 mL/kg/min (n = 118). Adapted from data in Anker et al.31Grahic Jump Location
Figure Jump LinkFigure 2.  Isometric quadriceps strength, quadriceps muscle cross-sectional area (CSA [a marker of muscle mass, measured using CT]), and quadriceps strength per unit area of quadriceps muscle (in N/cm2) of left and right leg in cachectic and noncachectic CHF patients. Reprinted with permission from Anker et al.38 N = Newton.Grahic Jump Location
Figure Jump LinkFigure 3.  Plasma levels of norepinephrine, epinephrine, cortisol, and TNF-α in 16 healthy control subjects and 53 patients with CHF. The heart failure patients were grouped by cachectic state (nc = noncachectic, n = 37; cach = cachectic, n = 16); maximal oxygen consumption (peak V̇o2 < 14 mL/kg/min, n = 17; 14 to 20 mL/kg/min, n = 24; and > 20 mL/kg/min, n = 12); functional NYHA class (class I/II, n = 16; class III/IV, n = 37); and LVEF (< 20%, n = 24; 20 to 35%, n = 17; > 35%, n = 12). Data are presented as mean ± SEM; p values for Fisher’s test are given if analysis of variance showed significant intergroup variation. * p < 0.05 for intergroup comparison. ** p < 0.01 for intergroup comparison.*** p < 0.001 for intergroup comparison.• p < 0.05 vs control subjects.•• p < 0.01 vs control subjects.••• p < 0.001 vs control subjects. Reprinted with permission from Anker et al.53Grahic Jump Location

Tables

References

Katz, AM, Katz, PB (1962) Diseases of heart in works of Hippocrates.Br Heart J24,257-264. [PubMed] [CrossRef]
 
Aronson, JK An account of the foxglove and its medical uses.1985,11-100 Oxford University Press. London:
 
Kushner, RF Body weight and mortality.Nutr Rev1993;51,127-136. [PubMed]
 
Brozek, J, Wells, S, Keys, A Medical aspects of semistarvation in Leningrad (siege 1941–1942).Am Rev Sov Med1946;4,70-86. [PubMed]
 
Cahill, GF, Jr Starvation in man.N Engl J Med1970;282,668-675. [PubMed]
 
Iribarren, C, Sharp, DS, Burchfiel, CM, et al Association of weight loss and weight fluctuation in Japanese American men.N Engl J Med1995;333,686-692. [PubMed]
 
Manson JE, Willett WC, Stampfer MJ, et al. Body weight and mortality among women N Engl J Med 1995; 333:677–685.
 
Byers, T Body weight and mortality.N Engl J Med1995;333,723-724. [PubMed]
 
Kuczmarski, RJ Need for body composition information in elderly subjects.Am J Clin Nutr1989;50,1150-1157. [PubMed]
 
Rossman, I Anatomic and body composition changes with aging. Finch, CE Hayflick, L eds.Handbook of the biology of aging1977,189 Von Nostrand Reinhold. New York, NY:
 
Borkan, GA, Hults, DE, Gerzof, SG, et al Age changes in body composition revealed by computed tomography.J Gerontol1983;38,673-677. [PubMed]
 
Wallace, JI, Schwartz, RS Involuntary weight loss in elderly outpatients: recognition, etiologies, and treatment.Clin Geriatr Med1997;13,717-735. [PubMed]
 
Friedlaender, JS, Costa, PT, Jr, Bosse, R, et al Longitudinal physique changes among healthy white veterans at Boston.Hum Biol1977;49,541-558. [PubMed]
 
Chumlea, WC, Garry, PJ, Hunt, WC, et al Distributions of serial changes in stature and weight in a healthy elderly population.Hum Biol1988;60,917-925. [PubMed]
 
Hammond, EC, Garfinkel, L Coronary artery disease, stroke, and aortic aneurysm: factors in the etiology.Arch Environ Health1969;19,167-182
 
Wallace, JI, Schwartz, RS, LaCroix, AZ, et al Involuntary weight loss in older outpatients: incidence and clinical significance.J Am Geriatr Soc1995;43,329-337. [PubMed]
 
Wadden, TA Treatment of obesity by moderate and severe caloric restriction: results of clinical research trials.Ann Intern Med1993;119,688-693. [PubMed]
 
Roberts SB, Fuss P, Heyman MB, et al. Control of food intake in older men. JAMA 1994; 272:1601–1606 (erratum published: JAMA 1995; 273:702).
 
New weight standards for men and women. Stat Bull Metrop Life Insur Co 1959; 40:1.
 
Society of Actuaries and Association of Life Insurance Medical Directors of America. Build study, 1979. Philadelphia, PA: Recording and Statistical Corporation, 1980.
 
Anker, SD, Coats, AJS The syndrome of cardiac cachexia in chronic heart failure.Poole-Wilson PA, Colucci WS, Massie BM, et al, eds: Heart failure1996,261-267 Churchill-Livingstone. New York, NY:
 
Carr, JG, Stevenson, LW, Walden, JA, Heber, D Prevalence and hemodynamic correlates of malnutrition in severe congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.Am J Cardiol1989;63,709-713. [PubMed]
 
McMurray, J, Abdullah, I, Dargie, HJ, et al Increased concentrations of tumor necrosis factor in “cachectic” patients with severe chronic heart failure.Br Heart J1991;66,356-358. [PubMed]
 
Levine, B, Kalman, J, Mayer, L, et al Elevated circulating levels of tumor necrosis factor in severe chronic heart failure.N Engl J Med1990;323,236-241. [PubMed]
 
Otaki, M Surgical treatment of patients with cardiac cachexia: an analysis of factors affecting operative mortality.Chest1994;105,1347-1351. [PubMed]
 
Freeman, LM, Roubenoff, R The nutrition implications of cardiac cachexia.Nutr Rev1994;52,340-347. [PubMed]
 
Kannel, WB, Belanger, AJ Epidemiology of heart failure.Am Heart J1991;121,951-957. [PubMed]
 
Abel, RM, Fischer, J, Buckley, MJ, et al Malnutrition in cardiac surgical patients.Arch Surg1976;111,45-50. [PubMed]
 
Blackburn, GL, Gibbons, GW, Bothe, A, et al Nutritional support in cardiac cachexia.J Thorac Cardiovasc Surg1977;73,489-495. [PubMed]
 
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