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(Circulation. 1997;96:526-534.)
© 1997 American Heart Association, Inc.

Articles

Hormonal Changes and Catabolic/Anabolic Imbalance in Chronic Heart Failure and Their Importance for Cardiac Cachexia

Stefan D. Anker, MD; Tuan Peng Chua, MD; Piotr Ponikowski, MD; Derek Harrington, MRCP; Jon W. Swan, MD; Wolfgang J. Kox, MD, PhD; Philip A. Poole-Wilson, MD; ; Andrew J. S. Coats, DM

From Cardiac Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London, UK (S.D.A., T.P.C., P.P., D.H., J.W.S., P.A.P.-W., A.J.S.C.); the Department of Internal Medicine III/Cardiology, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany (S.D.A.); and the Department of Anesthesiology and Intensive Care Medicine, University Hospital Charité, Humboldt University Berlin, Germany (W.J.K.).

	Abstract

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Background The role of hormonal and cytokine abnormalities in the development of cardiac cachexia remains obscure.

Methods and Results Healthy control subjects (n=16) and patients with chronic heart failure (CHF), classified clinically as cachectic (8% to 35% weight loss over 6 months before study, n=16) or noncachectic (n=37), were assessed for markers of disease severity (maximal oxygen consumption, left ventricular ejection fraction, NYHA functional class). These markers were compared with plasma concentrations of potentially important anabolic and catabolic factors. The degree of neurohormonal activation and catabolic/anabolic imbalance was closely related to wasting but not to conventional measures of the severity of heart failure. Compared with control subjects and noncachectic patients, cachectic patients had reduced plasma sodium and increased norepinephrine, epinephrine (all P<.0001), cortisol, tumor necrosis factor (TNF)- (both P<.002), and human growth hormone (P<.05). Insulin-like growth factor-1, testosterone, and estrogen were similar in all groups. Insulin was increased only in the noncachectic patients (P<.005 versus control subjects). Dehydroepiandrosterone was reduced in the cachectic patients (P<.02 versus control subjects). Insulin, cortisol, TNF-, and norepinephrine correlated independently with wasting in CHF (P<.05; multiple regression of these four factors versus percent ideal weight, R²=.50, P<.0001).

Conclusions Cachexia is more closely associated with hormonal changes in CHF than conventional measures of the severity of CHF. This study suggests that the syndrome of heart failure progresses to cardiac cachexia if the normal metabolic balance between catabolism and anabolism is altered.

Key Words: heart failure • hormones • metabolism • catecholamines • cachexia

	Introduction

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Chronic heart failure is a heterogeneous syndrome with an overall adverse prognosis. Two particular predictors of adverse prognosis are neurohormonal abnormalities¹ and the development of cachexia.²

The syndrome of cardiac cachexia has been recognized for many centuries,³ but little is known about the mechanisms of the transition from heart failure to cardiac cachexia. Even the definition of cachexia and the characteristics of the cachectic patient are controversial. More than 30 years ago, the pathogenesis of cardiac cachexia was linked to dietary and metabolic factors.⁴ In 1990, Levine et al⁵ and subsequently others^{6 7} showed that TNF- in plasma is increased in patients with severe heart failure and coexisting cardiac cachexia, as in other wasting disorders. The plasma concentrations of TNF- partly reflect the local tissue concentration, which is more closely related to muscle wasting.⁸ Cytokine activation is a potential causal mechanism for the development of cachexia.

Cardiac cachectic patients suffer from loss of both muscle (ie, protein reserves) and fat tissue (ie, energy reserves), indicative of increased catabolism. An increased resting metabolic rate, regulated primarily by thyroid hormones⁹ and catecholamines,¹⁰ has been reported in CHF patients.¹¹ Cortisol, another catabolic hormone, is also increased in untreated severe congested heart failure patients.¹² Less is known about anabolic metabolism in heart failure. Anand et al¹² found hGH to be greatly increased (10-fold) in untreated patients with severe heart failure. To date, these results have not been confirmed by others. Increased plasma insulin levels and insulin resistance occur in patients with CHF.¹³

The neurohormonal hypothesis¹ postulates that heart failure progresses because 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,^{14 15 16} but different hormones correlate only weakly with each other.¹⁵ Norepinephrine and plasma renin activity were found not to be related to peak oxygen consumption (peak O₂) or LVEF.¹⁶ Left ventricular function, exercise capacity, clinical status, and sympathetic activation were independently related to the progression of CHF.¹⁶

No previous study has assessed the spectrum of catabolic and anabolic abnormalities in patients with CHF with different degrees of body wasting. We undertook the present study to compare the hormonal changes linked to catabolism and anabolism that occur in the presence and absence of cachexia in patients with CHF. We sought to determine whether neurohormonal changes in CHF were more closely related to the onset of cachexia than to other conventional markers of the severity of heart failure.

	Methods

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Patient Population and Characteristics
Measurements were made in 53 male patients with mild to severe CHF and 16 male healthy control subjects of similar age (range, 46 to 68 years). The diagnosis of CHF was based on a history of congestive heart failure of at least 6 months (range, 1 to 20 years) with symptoms, reduced exercise tolerance, cardiomegaly, and objective left ventricular functional impairment. At the time of investigation, all CHF patients were clinically stable. The patients had no clinical signs of acute infection or other primary cachectic states (such as cancer, thyroid disease, or severe liver disease), had no residual signs of peripheral or pulmonary edema, and were studied when free of ascites. No patient was limited by exertional angina. Patients with chronic lung disease, hemodynamically important valve disease, neuromuscular disorders, myocardial infarction within the previous 12 weeks, renal failure, peripheral vascular disease, or excessive alcohol intake were excluded.

Thirty-seven CHF patients were not cachectic (age range, 49 to 75 years). Sixteen CHF patients (age range, 40 to 77 years, P=.08 versus noncachectic patients) had signs of clinical cardiac cachexia. Cardiac cachexia was defined clinically as documented nonintentional dry weight loss of 5 kg (all >7.5% of their previous normal weight) over a period of at least 6 months. To exclude patients with intentional weight loss, a second criterion of a body mass index (weight/height²) of <24 kg/m² was used. All cachectic patients also complained of their weight loss. The weight loss amounted to 6 to 30 kg (mean, 11.8±1.5 kg, or 8% to 36% loss of previous body weight) in the preceding 0.75 to 11 years (ie, 6.0±0.9 kg/y).

All subjects performed a maximal treadmill exercise test (modified Bruce protocol, Amis 2000¹⁷ ) for estimation of peak O₂ (in mL·kg^-1·min^-1). In patients, the LVEF was measured with radionuclide ventriculography. The protocol was approved by the Ethics Committee of the Royal Brompton Hospital, London. All patients gave written informed consent before the study.

Hormonal Measurements
Blood samples were collected in the morning, between 9 and 10 AM, after a fasting period of 12 hours. An antecubital polyethylene catheter was inserted, and after supine rest for at least 20 minutes, 25 mL of venous blood was drawn. After immediate centrifugation, aliquots were stored at -70°C until analysis. IGF-1 (Medgenix; sensitivity, 0.25 ng/mL), hGH (Nichols Institute Diagnostics; sensitivity, 0.02 ng/mL), thyroid stimulating hormone (Bering Diagnostics; sensitivity, 0.3 mU/L), reverse T₃ (Biodata; sensitivity, 0.014 nmol/L), PRA (Biodata SPA; sensitivity, 0.039 ng·mL^-1·h^-1), and aldosterone (DPC; sensitivity, 16 pg/mL) were measured by radioimmunoassay. Epinephrine and norepinephrine were measured with high-performance liquid chromatography (sensitivity, 0.1 ng/mL for both). TNF- was measured with an ELISA with a lower limit of detectability of 3.0 pg/mL (Medgenix). This test uses three antibodies directed against distinct epitopes of TNF- and is not influenced by soluble TNF receptors,¹⁸ ie, it measures the total TNF concentration, bound or unbound. All other parameters (including steroid hormones and insulin) were analyzed by routine analysis in our hospital.

Statistical Analysis
All results are presented as mean±SEM. When ANOVA showed significant differences, Fisher's post hoc test was applied. To analyze relationships between variables, simple linear regression (least-squares method), multivariate analysis, and stepwise regressions were performed (StatView 4.5, Abacus Concepts Inc). To take account of multiple analyses, a probability value of <.01 was considered statistically significant. For multiple and stepwise regression analysis, a value of P<.05 was used to indicate statistical significance. If blood results were below the limit of detectability of a test, the lower limit of detection was recorded. Log-transformed values were used for statistical analysis of basal insulin levels.

	Results

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Clinical Details
The clinical details and results of the treadmill exercise tests of the patients and control subjects are shown in Tables 1 and 2. The age, body mass index, and percent ideal weight¹⁹ of the 53 patients with CHF were similar to those of the 16 control subjects. The healthy control subjects had a significantly higher treadmill exercise time and exercise capacity. The cachectic and noncachectic patients with CHF had similar peak O₂, LVEF, NYHA functional class, disease pathogenesis, drug medication, mean furosemide equivalent dose (106±18 mg versus and 103±19 mg), and duration since onset of heart failure (both patient groups: mean, 5±1 years; median, 3 years) but differed significantly in weight, body mass index, and percent ideal weight (Table 1). Patients with cardiac cachexia (44.9±0.9 g/L) had similar and normal albumin levels compared with control subjects (45.1±0.6 g/L) and noncachectic CHF patients (43.2±0.4 g/L, P<.05 for noncachectic CHF versus control and cachectic subjects). Total protein levels were highest in cachectic CHF patients (72.1±0.9 g/L) compared with noncachectic (69.2±0.7 g/L, P<.05 versus cachectic) and control subjects (66.9±0.7, P=.0004 versus cachectic, P=.053 versus noncachectic subjects). Mean bilirubin levels (ANOVA P=.18) and aspartate aminotransferase activity (ANOVA P=.07, trend for higher levels in noncachectic CHF) did not differ significantly between groups.

View this table: [in this window] [in a new window]   Table 1. Characteristics of cCHF and ncCHF Patients Compared With Healthy Control Subjects

View this table: [in this window] [in a new window]   Table 2. Characteristics of 16 Cachectic and 37 Noncachectic CHF Patients

Hormonal Determinations
All CHF patients. Compared with control subjects, the total group of CHF patients had increased creatinine, PRA, reverse T₃, basal insulin levels, and lowered plasma sodium (all P<.005, Table 3). In addition, trends for increased norepinephrine, epinephrine, and aldosterone as well as for reduced DHEA (P=.01 to .06) were found.

View this table: [in this window] [in a new window]   Table 3. Results of Hormone Analysis in Healthy Control Subjects and Patients With CHF: Heart Failure Patients Subgrouped by Cachectic State

Cachectic patients. The results for cachectic and noncachectic CHF patients are shown in Table 3. The plasma sodium concentration was decreased, and epinephrine, norepinephrine, cortisol, and TNF- were substantially increased in cachectic CHF patients (all P.0002 versus noncachectic CHF patients, all P.0015 versus control subjects). In cachectic patients, aldosterone and hGH were increased compared with noncachectic patients (both P<.01), and aldosterone, PRA, reverse T₃, and creatinine were increased compared with control subjects (all P<.005). Individual values varied from normal to greatly elevated levels in the cachectic patients. There were trends for increased hGH and reduced DHEA in cachectic patients compared with control subjects (both .01<P<.05). This trend reached statistical significance for DHEA, when the cachectic patients with <85% of normal weight (n=9; mean, 6.4±1.5 nmol/L) were compared with the control subjects (P=.008).

Noncachectic patients. Compared with control subjects, the noncachectic patients had significantly increased insulin (P<.005) and trends toward increased creatinine, reverse T₃, and PRA (all .01<P<.05). The noncachectic patients had levels of epinephrine, norepinephrine, TNF-, cortisol, and hGH similar to the control subjects (all P>.20).

No significant differences between groups were seen for albumin, potassium, IGF-1, thyroid-stimulating hormone, testosterone, or estrogen (ANOVA P>.05 for each).

Relation between hGH and IGF-1. Because IGF-1 is the anabolic mediator of hGH, the relation between the two hormones was studied. The IGF-1/hGH ratio was approximately four times higher in noncachectic CHF patients and control subjects than in cachectic subjects. Because this ratio has a skewed distribution, the log-transformed ratios were compared statistically (control subjects, 2.89±0.25; noncachectic, 3.00±0.16; cachectic, 2.03±0.22, P=.014 versus control subjects and P=.0014 versus noncachectic subjects).

Predictors of Muscle Wasting
Weight loss. Only in cachectic patients could the documented weight loss be correlated with physiological measures and humoral parameters. Significant correlates of weight loss (in kilograms) in simple regression analysis were TNF- (r=.78, P=.0003), reverse T₃ (r=.61, P=.012), peak O₂ (r=-.54, P=.032). Independent predictors of documented weight loss in a multivariate model with age, TNF-, reverse T₃, cortisol, norepinephrine, and insulin were TNF- (P=.006) and reverse T₃ (P=.044). Predictors of documented weight loss in a stepwise regression model with age, peak O₂, and 12 humoral factors were TNF- in the first step (F value, 22.24; P<.001) and testosterone in the second step (F value, 4.13; P<.025). Similar results were found when the weight loss was normalized for the previous normal weight (TNF- versus percent weight loss, r=.80, P=.0002). When the derived measure of the ratio of IGF-1 and hGH was analyzed together with TNF- and testosterone, these three variables predicted 83.5% of the variation of the documented weight loss (in kilograms) and 84.7% of the variation of the relative weight loss (in percent) in 16 cachectic CHF patients (see Table 4). It is important to note that neither testosterone nor log IGF-1/hGH significantly correlated with the body mass index or measures of weight loss but that both became (independently of each other) important after adjustment for the effect of TNF.

View this table: [in this window] [in a new window]   Table 4. Stepwise and Multiple Regression Analysis of the Association Between TNF- and Testosterone Levels and the Ratio of IGF-1 and hGH Levels (log IGF-1/hGH) on Documented Weight Loss in 16 Cachectic CHF Patients

Ideal body weight. In Table 5, we present the results of correlation analysis for percent ideal weight. Significant correlates of lower weight (ie, percent ideal weight) in 53 CHF patients were epinephrine, cortisol, norepinephrine, TNF-, log IGF-1/hGH (P<.001), hGH, and basal insulin (both P<.01) but also reverse T₃ (r=-.34), age (r=-.32), and plasma sodium (r=-.31, all P<.05). Predictors of reduced weight in a multivariate model with these 10 parameters were insulin (P=.036) and to a lesser extent cortisol (P=.10), TNF- (P=.13), and norepinephrine (P=.20). In a smaller multivariate model with only these four humoral factors, it was found that they predicted weight changes independently of each other in our CHF population: insulin and cortisol (both P<.01), TNF-, and norepinephrine (both P<.05). Stepwise regression showed that, one after another, these factors contributed significantly to the variation of the weight (all four factors together versus percent ideal weight: R²=.501, P<.0001). The inclusion of testosterone did not change the principal outcome of the multivariate and the stepwise regression models for percent ideal weight.

View this table: [in this window] [in a new window]   Table 5. Relation Between Age and Resting Humoral Factors and Body Weight (Measured in % Ideal Body Weight): Results of Univariate Linear Regression Analysis

Influence of Other Clinical Markers
To investigate the best discriminators for explaining the variations in the degree of neurohormonal activation, patients were subgrouped according to peak O₂, NYHA functional class, and LVEF. The main results of these analyses are presented in Fig 1 (catecholamines, cortisol, and TNF-) and Fig 2 (hGH, IGF, insulin, DHEA) compared with the earlier grouping according to the cachectic state.

View larger version (32K): [in this window] [in a new window]   Figure 1. Levels of catabolic factors (norepinephrine, epinephrine, cortisol, and TNF-) in 16 healthy control subjects and 53 patients with CHF. Heart failure patients were subgrouped by cachectic state (noncachectic [nc], n=37; cachectic [cach], n=16), peak O2 (<14 [n=17] vs 14 to 20 [n=24] vs >20 mL·kg-1·min-1 [n=12]), functional NYHA class (class 1/2 [n=16] vs class 3/4 [n=37]), and LVEF (<20 [n=24] vs 20 to 35 [n=17] vs >35% [n=12]). Probability values for Fisher's test are given if ANOVA showed significant intergroup variation. Data are mean±SEM. *P<.05 for intergroup comparison; ***P<.001 for intergroup comparison; P<.05 vs control subjects; P<.01 vs control subjects; and P<.001 vs control subjects.

View larger version (34K): [in this window] [in a new window]   Figure 2. Levels of anabolic hormones (hGH, IGF-1, insulin, DHEA) in 16 healthy control subjects and 53 patients with CHF. Data are mean±SEM. Subgrouping of heart failure patients and statistical presentation as in legend of Fig 1.

Peak O₂. The CHF patients were stratified according to their peak O₂ (<14, 14 to 20, and >20 mL·kg^-1·min^-1). The only significant intergroup difference was observed for creatinine (P<.01 for peak O₂ <14 [146±14 µmol/L] versus peak O₂ 14 to 20 mL·kg^-1·min^-1 [117±12 µmol/L]).

NYHA class. The influence of clinical status as assessed by the functional NYHA classification was analyzed comparing patients in NYHA class 1 or 2 with patients in NYHA class 3 or 4. No significant alterations at the P<.01 level could be detected for any of the hormones studied.

LVEF. Stratification of patients according to LVEF was studied (<20% versus 20% to 35% versus >35%). Significant intergroup differences were found only for aldosterone (LVEF <20% [989±177 pmol/L] versus 20% to 35% [462±66 pmol/L] and versus >35% [456±78 pmol/L], both P<.01).

It is important to note that for only 2 of the 17 humoral factors (aldosterone and creatinine) were comparisons between groups of CHF patients divided according to NYHA class, LVEF, or peak O₂ significant at the P<.01 level. If the more stringent Bonferroni correction was applied (17 humoral parameters analyzed; P<.05/17, or .00294, considered significant), no significant difference could be found for any comparison. In contrast, the classification into cachectic and noncachectic patients led to substantial differences in many neurohormonal and anabolic/catabolic factors (Table 3, Figs 1 and 2). The results of regression analysis of several hormones and TNF- versus markers of disease severity in the CHF patients are shown in Table 6 compared with the relation to percent ideal weight.

View this table: [in this window] [in a new window]   Table 6. Univariate Regression Coefficients for the Relation Between Hormones and Cytokines vs Conventional Markers of Severity of CHF and Normalized Body Weight in 53 Patients With CHF

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The major finding of this study is that cachexia is associated with hormonal changes in CHF and more conventional measures of severity of CHF are not. Patients with cardiac cachexia demonstrate severe hormonal changes consistent with sympathetic activation and catabolic/anabolic imbalance. These hormonal changes are most clearly demonstrated when patients are subgrouped on the basis of their cachectic status. Several humoral factors are independently related to weight changes in these patients. Subgrouping by cachexia is more predictive of the neurohormonal status than conventional classifications of severity of CHF. These findings suggest that the catabolic/anabolic disturbance leading to cachexia and the neurohormonal activation are related and of greater importance than the degree of hemodynamic or functional disturbance. Much of the variability in the association of conventional measures of the severity of heart failure and neurohormonal activation, and indeed much of the neurohormonal activation itself, is attributable to cachexia and to the small group of patients with cachexia who are included in many studies.

Definition of Cardiac Cachexia
No agreed-upon definition of cachexia exists, but body fat estimation, anthropometric measurements, predicted percent ideal mass, weight/height index, body mass index, serum albumin, and cell-mediated immunity changes, and especially a weight loss of >10% of the previous normal (ie, "usual") weight, have all been used. Patients have been classified as "malnourished" when the body fat content was <22% in women and <15% in men or when the percentage of ideal weight was <90%.²⁰ Other groups have defined CHF patients prospectively as "cachectic" when the body fat content was <29% (women) or <27% (men)⁶ or when the body weight was <85%⁵ or even <80% of ideal.²¹

The development of the cachectic state in CHF could be demonstrated by a longitudinal study in which body weight is measured in a nonedematous state. Including the weight loss as a criterion excludes patients who are constitutionally underweight. Equally, patients initially overweight may be mistakenly classified as cachectic. We used a broad definition of "clinical cardiac cachexia," ie, documented weight loss of 5 kg over a period of 6 months and a body mass index of 24 kg/m² observed in patients with CHF without signs of other primary cachectic states. All patients had a weight loss of >7.5% of their previous normal nonedematous body weight. A body mass index of <24 excludes previously obese patients who could merely have lost weight as a consequence of intentional dieting. Because all such definitions are arbitrary, it is important to note that our findings do not differ when the analysis uses different cutoff values for defining cachexia, such as >10% premorbid weight loss (14 patients) or weight loss 5 kg and weight <85% of ideal (9 patients).

Development of Cardiac Cachexia
In 1964, Pittman and Cohen,⁴ writing about the pathogenesis of cardiac cachexia, stressed the importance of cellular hypoxia to the initiation of less efficient intermediary metabolism, thereby increasing catabolism (protein loss) and reducing anabolism. In addition, they suggested anorexia and increased basal metabolic rate to be the result of a lack of oxygen. Buchanan and colleagues²² found anorexia that was reversible after mitral valve replacement to be the cause of the cachexia in 11 patients. Neither malabsorption nor cellular hypoxia was of importance. Starvation and anorexia in otherwise healthy persons led to a preferential loss of fat tissue. A study in 27 CHF patients (mean weight, 21% lower than normal)²³ failed to show fat tissue loss but documented an average total body potassium decrease of 35% (a measure of lean tissue independent of body water content). Another study¹¹ demonstrated increased resting metabolic rates in CHF patients compared with control subjects, a feature of interest given that resting metabolic rate has been shown to correlate with increasing concentrations of catecholamines,¹⁰ and we have now shown catecholamines to be increased markedly in cardiac cachexia. Physical inactivity and deconditioning have been suggested to be important for the muscle atrophy observed in many CHF patients,²⁴ but recent histological evidence suggests that the atrophy in states of reduced activity is different from the muscle atrophy observed in CHF.^{25 26} This is also supported by the finding that the duration of heart failure was not different in cachectic and noncachectic patients. In contrast to the commonly held belief, albumin levels were not decreased in the cachectic patients. This would argue against a major contribution of gastrointestinal malabsorption or liver synthetic dysfunction in these patients.

Catabolic Factors
In the 1930s, the existence of an unexplained pyrogen as a product of anaerobic metabolism in cases of fever in heart failure was suggested.²⁷ In 1990, Levine and colleagues⁵ reported that TNF- is increased in patients with cardiac cachexia. Increased TNF- has been confirmed by others^{6 7} and in the present study. TNF- is one of the key cytokines important to the development of catabolism. Animal experiments have shown that the implantation of TNF-–producing tumor cells in skeletal muscle causes muscle wasting, whereas TNF-–producing cells in the brain caused marked anorexia.⁸ This shows that increased levels of TNF- may indeed play a causative role in the development of cachexia but also that the site of the production and action of TNF- modifies its effect. The failing human heart can directly produce TNF-.²⁸ Whether this relates to the development of cardiac or general muscle wasting is not known. The new finding of this study is that cytokine activation is only one pathway of those closely related to the degree of wasting and that after adjustment for the influence of TNF, an indirect measure of growth hormone resistance (ie, log IGF-1/hGH) and testosterone levels also seem to be of importance.

Many studies have investigated catecholamine levels in CHF patients. Plasma norepinephrine may reflect overall sympathetic activity,²⁹ and both norepinephrine and epinephrine can cause a catabolic metabolic balance.^{10 30} Since the original observation in 1962 of increased catecholamines in CHF,³¹ no study has investigated catecholamine levels specifically in cachectic CHF patients. Only cachectic CHF patients showed markedly increased norepinephrine and epinephrine levels, with noncachectic CHF patients having near-normal levels (Table 3). None of the three other methods of stratifying the 53 CHF patients revealed significant changes between different groups of CHF patients. 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.³² In untreated severe CHF patients, Anand et al¹² demonstrated a 2.5-fold increase of cortisol, probably due to an increase in the release of adrenocorticotropic hormone.³³ The cachectic patients in our study had a 2-fold increase. No other subgrouping of the CHF patients revealed any significant effect on mean cortisol levels.

Anabolic Hormones
We studied several anabolic hormones such as sex steroids (testosterone, DHEA, and estrogen), hGH, IGF-1, and insulin. We looked for counterregulatory increases of anabolic factors in cachectic CHF patients. Only hGH was increased (Table 3). Anand et al¹² demonstrated such an increase of hGH in untreated patients with severe CHF. The role of hGH in CHF is unclear, because it has both direct and indirect effects. Directly, it acts on lipid metabolism (catabolic), but normally its major (anabolic) effect is indirect via the somatomedins (the main hGH-dependent somatomedin is IGF-1). By this mechanism, hGH acts in an insulin-like manner (ie, anabolic on cell proliferation and protein synthesis) and is opposed to the actions of cortisol.³⁴ Because the increase in hGH in our cachectic patients was not accompanied by an increase of IGF-1, this suggests the presence of growth hormone resistance, and via its direct action, hGH could then even promote increased catabolism. These findings merit further investigation.

Insulin is considered to be the most powerful physiological anabolic hormone. In stable CHF patients, we have previously described the development of insulin resistance along with increases of basal insulin levels.¹³ Cardiac cachectic patients showed slightly reduced insulin levels compared with noncachectic patients but increased levels compared with normal control subjects. There were no significant changes of testosterone or estradiol levels. Interestingly, the mean concentration of the anabolic hormone DHEA was reduced in all heart failure patients as well as in the subgroup of cachectic CHF patients compared with control subjects (both trends with P<.05, Table 3).

Catabolic/Anabolic Imbalance
In cachectic CHF patients, factors that are acting to increase protein and fat tissue degradation and stimulate energy production are increased (norepinephrine, epinephrine, cortisol, TNF-), whereas anabolic factors either respond inadequately to cachexia (DHEA is reduced in most severely cachectic patients; testosterone does not increase) or appear to develop a resistance syndrome (growth hormone). This suggests that the syndrome of cardiac cachexia is characterized by a severe catabolic/anabolic imbalance in favor of catabolic metabolism, which may be a valid target for novel therapeutic interventions. It is unlikely that any single physical or biochemical disorder causes cardiac cachexia in all patients.

We found no marked reduction of albumin levels in our cachectic patients compared with control subjects, which is to some degree unexpected. The diuretic doses were similar in the two patient groups. The liver function of the cachectic and noncachectic CHF patients appeared to be normal. Therefore, we do not believe that the albumin results are likely to reflect impaired hepatic albumin synthesis accompanied by decreased blood volume due to diuretics. Taken together, the results argue against a major impact of anorexia and starvation in the majority of these cachectic CHF patients.

Limitations
The present study is a cross-sectional study. The differences have been described, but changes over time have not been shown. The proof of causality requires a prospectively designed longitudinal study. For clarity of presentation, we subdivided patients into categories of increasing severity. This was arbitrary, but similar conclusions can be drawn when the classification of severity was analyzed using all individual points in regression analysis. Table 5 shows strong inverse relationships between several increased hormones and TNF and reduced body weight that cannot be found with conventional severity markers (Table 6). One of the strengths of the present investigation is also one of its limitations: the multiple biochemical investigations. We chose 17 humoral factors that characterize heart failure severity, catabolism, or anabolism and investigated 69 subjects in three groups. Necessarily, we performed many statistical tests. We reduced the level of significance by a factor of 5 from 5% to 1%, protecting against chance findings. Because the results have a physiological explanation, we believe that our results are indicative. Finally, many other interesting and possibly causally important factors were not included in our analysis, for example, prostaglandins, interferons, interleukins and soluble TNF receptors, adhesion molecules, hGH- and IGF-binding proteins, sex hormone–binding globulin, atrial natriuretic peptide, and endothelins. This study was performed only in male CHF patients, because sex steroid levels are not comparable in men and women. Therefore, it is difficult to draw conclusions on the development of cardiac cachexia in women, but we have no reason to believe that the general pattern of stress responses and immune activation would be different in women. We are aware that several hormones intercorrelate, and this may influence the outcome of the statistical analysis. For instance, it is known that cytokines may inhibit testosterone synthesis,³⁵ which suggests an inverse relationship between these two parameters. This was not found when our population was analyzed as a whole, but it is indeed present in the subgroup of cachectic patients (data not presented).

Conclusions
Catabolic/anabolic disturbance and hormonal activation are relevant to the development of cardiac cachexia. In an extension of the neurohormonal hypothesis,¹ which postulates that heart failure progresses because activated endogenous neurohormonal systems exert a deleterious effect on the heart and circulation, this study suggests that the syndrome of heart failure progresses to cardiac cachexia when the normal metabolic balance of catabolism and anabolism is altered.

	Selected Abbreviations and Acronyms

 

CHF = chronic heart failure hGH = human growth hormone IGF-1 = insulin-like growth factor-1 LVEF = left ventricular ejection fraction PRA = plasma renin activity T3 = triiodothyronine TNF = tumor necrosis factor

	Acknowledgments

 
Dr Anker was supported by a grant from the Ernst und Bertha Grimmke–Stiftung, Düsseldorf, Germany, and by a fellowship from the European Society of Cardiology. Cardiac Medicine, National Heart and Lung Institute, Imperial College School of Medicine is supported by the British Heart Foundation and the Viscount Royston Trust.

	Footnotes

 
Reprint requests to Dr Stefan Anker, Cardiac Medicine, National Heart and Lung Institute London, Imperial College School of Medicine, Dovehouse St, London SW3 6LY, UK.

Received August 22, 1996; revision received February 4, 1997; accepted February 11, 1997.

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