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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
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.).
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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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
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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 others6 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.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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.
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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.
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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.
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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.
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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.
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P<.05 vs control subjects;
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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.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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
others6 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.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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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.
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Footnotes |
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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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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol. 1992;20:248-254.[Abstract]
2.
Abel RM, Fischer J, Buckley MJ, Barnett GO, Austen
WG. Malnutrition in cardiac surgical patients.
Arch Surg. 1976;111:45-50.
3. Katz AM, Katz PB. Diseases of heart in works of Hippocrates. Br Heart J. 1962;24:257-264.
4. Pittman JG, Cohen P. The pathogenesis of cardiac cachexia. N Engl J Med. 1964;271:403-409.
5. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;323:236-241.[Abstract]
6.
McMurray J, Abdullah I, Dargie HJ, Shapiro D.
Increased concentrations of tumor necrosis factor in `cachectic'
patients with severe chronic heart failure. Br Heart
J. 1991;66:356-358.
7.
Dutka DP, Elborn JS, Delamere F, Shale DJ, Morris
GK. Tumor necrosis factor a in severe congestive cardiac
failure. Br Heart J. 1993;70:141-143.
8. Tracey KJ, Morgello S, Koplin B, Fahey TJ III, Fox J, Aledo A, Manogue KR, Cerami A. Metabolic effects of cachectin/tumor necrosis factor are modified by site of production: cachectin/tumor necrosis factor-secreting tumor in skeletal muscle induces chronic cachexia, while implantation in brain induces predominantly acute anorexia. J Clin Invest. 1990;86:2014-2024.
9. Himms-Hagen J. Thyroid hormones and thermogenesis. In: Girardier L, Stock MJ, eds. Mammalian Thermogenesis. London, UK: Chapman & Hall; 1983:141-177.
10.
Poehlman ET, Danforth E. Endurance training
increases metabolic rate and norepinephrine
appearance rate in older individuals. Am J
Physiol. 1991;261:E233-E239.
11.
Poehlmann ET, Scheffers J, Gottlieb SS, Fisher ML,
Vaitekevicius P. Increased resting metabolic rate in
patients with congestive heart failure. Ann Intern
Med. 1994;121:860-862.
12.
Anand IS, Ferrari R, Kalra GS, Wahi PL, Poole-Wilson
PA, Harris PC. Edema of cardiac origin: studies on body water
and sodium, renal function, hemodynamic indexes, and
plasma hormones in untreated congestive cardiac failure.
Circulation. 1989;80:299-305.
13.
Swan JW, Walton C, Godsland IF, Clark AL, Coats AJS,
Oliver MF. Insulin resistance in chronic heart failure.
Eur Heart J. 1994;15:1528-1532.
14. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector TS. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819-823.[Abstract]
15.
Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L, for
the CONSENSUS Trial Study Group. Hormones regulating
cardiovascular function in patients with severe
congestive heart failure and their relation to mortality.
Circulation. 1990;82:1730-1736.
16. Francis GS, Cohn JN, Johnson G, Rector TS, Goldman S, Simon A, for the V-HeFT VA Cooperative Studies Group. Plasma norepinephrine, plasma renin activity, and congestive heart failure: relations to survival and the effects of therapy in V-HeFT II. Circulation. 1993;87(suppl VI):VI-40-VI-48.
17.
Volterrani M, Clark AL, Ludman PF, Swan JW,
Adamopopoulos S, Piepoli M, Coats AJS. Predictors of exercise
capacity in chronic heart failure. Eur Heart J. 1994;15:801-809.
18. Engelberts I, Stephens S, Francot GJM, Van der Linden CJ, Buurman WA. Evidence for different effects of soluble TNF-receptors on various TNF measurements in human biological fluids. Lancet. 1991;338:515-516.[Medline] [Order article via Infotrieve]
19. National Center for Health Statistics. Weight by height and age for adults 18-74 years: United States 1971-1974. Vital and health statistics. Series 11. No. 208. Washington DC: Government Printing Office; 1979. DHEW publication PHS 79-1656.
20. Carr JG, Stevenson LW, Walden JA, Heber D. Prevalence and hemodynamic correlates of malnutrition in severe congestive heart failure secondary to ischemic or ideopathic dilated cardiomyopathy. Am J Cardiol. 1989;63:709-713.[Medline] [Order article via Infotrieve]
21.
Otaki M. Surgical treatment of patients with
cardiac cachexia: an analysis of factors affecting operative
mortality. Chest. 1994;105:1347-1351.
22. Buchanan N, Keen RD, Kingsley R, Eyberg CD. Gastrointestinal absorption studies in cardiac cachexia. Intensive Care Med. 1977;3:89-91.[Medline] [Order article via Infotrieve]
23. Thomas RD, Silverton NP, Burkinshaw L, Morgan DB. Potassium depletion and tissue loss in chronic heart disease. Lancet. 1979;310:9-11.
24.
Mancini DM, Walter G, Reichek N, Lenkinski R, McCully
KK, Mullen JL, Wilson JR. Contribution of skeletal muscle
atrophy to exercise intolerance and altered muscle
metabolism in heart failure.
Circulation. 1992;85:1364-1373.
25.
Vescovo G, Serafini F, Facchin L, Tenderini P,
Carraro U, Della Libera L, Catani C, Ambrosio GB. Specific
changes in skeletal muscle myosin heavy chains composition in cardiac
failure: differences compared with disuse atrophy as assessed on
microbiopsies by high resolution electrophoresis.
Heart. 1996;76:337-343.
26. Simioni A, Long CS, Yue P, Dudley GA, Massie BM. Heart failure in rats causes changes in skeletal muscle phenotype and gene expression unrelated to locomotor activity. Circulation. 1995;92(suppl I):I-259. Abstract.
27. Cohn AE, Steele JM. Unexplained fever in heart failure. J Clin Invest. 1934;13:853-868.
28.
Torre-Amione G, Kapadia S, Lee J, Durand J-B, Bies RD,
Young JB, Mann DL. Tumor necrosis factor- and tumor necrosis
factor receptors in the failing human heart.
Circulation. 1996;93:704-711.
29. Goldstein DS. Plasma norepinephrine as an indicator of sympathetic neural activity in clinical cardiology. Am J Cardiol. 1981;48:1147-1154.[Medline] [Order article via Infotrieve]
30. Landsberg L, Young JB. Catecholamines and the adrenal medulla. In: Wilson JD, Foster DW, eds. Williams Textbook of Endocrinology. Philadelphia, Pa: WB Saunders; 1992:621-705.
31. Chidsey CA, Harrison DC, Braunwald E. The augmentation of plasma norepinephrine response to exercise in patients with congestive heart failure. N Engl J Med. 1962;267:650-654.
32. Orth DN, Kovacs WJ, DeBold CR. The adrenal cortex. In: Wilson JD, Foster DW, ed. Williams Textbook of Endocrinology. Philadelphia, Pa: WB Saunders; 1992:489-619.
33. Nicholls MG, Espiner EA, Donald RA, Hughes H. Aldosterone and its regulation during diuresis in patients with gross congestive heart failure. Clin Sci Mol Med. 1974;47:301-315.[Medline] [Order article via Infotrieve]
34. Underwood LE, Van Wyk JJ. Normal and aberrant growth. In: Wilson JD, Foster DW, ed. Williams Textbook of Endocrinology. Philadelphia, Pa: WB Saunders; 1992:1079-1138.
35.
Xiong Y, Hales DB. The role of tumor necrosis
factor- in the regulation of mouse Leydig cell
steroidgenesis. Endocrinology. 1993;132:2438-2444.
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|
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|
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|
|
|
|
 |
|
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|
|
|
|
 |
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
A Heidland, K Sebekova, A Frangiosa, L S De Santo, M Cirillo, F Rossi, M Cotrufo, A Perna, A Klassen, R Schinzel, et al. Paradox of circulating advanced glycation end product concentrations in patients with congestive heart failure and after heart transplantation Heart, November 1, 2004; 90(11): 1269 - 1274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 M E Onwuamaegbu, M Henein, and A J Coats Cachexia in malaria and heart failure: therapeutic considerations in clinical practice Postgrad. Med. J., November 1, 2004; 80(949): 642 - 649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
K. Kalantar-Zadeh, G. Block, T. Horwich, and G. C. Fonarow Reverse epidemiology of conventional cardiovascular risk factors in patients with chronic heart failure J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1439 - 1444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. K Shieh, E. Kotlyar, and F. Sam Aldosterone and cardiovascular remodelling: focus on myocardial failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1): 3 - 13. [Abstract] [PDF]
|
|
|
|
 |
|
 J.R. Keys and W.J. Koch The Adrenergic Pathway and Heart Failure Recent Prog. Horm. Res., January 1, 2004; 59(1): 13 - 30. [Abstract] [Full Text]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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R. Aquilani, C. Opasich, M. Verri, F. Boschi, O. Febo, E. Pasini, and O. Pastoris Is nutritional intake adequate in chronic heart failure patients? J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1218 - 1223. [Abstract] [Full Text] [PDF]
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K. T Weber, Yao Sun, L. A Wodi, A. Munir, E. Jahangir, R. A Ahokas, I. C Gerling, A. E Postlethwaite, and K. J Warrington Toward a broader understanding of aldosterone in congestive heart failure Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 155 - 163. [Abstract] [PDF]
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S. Aker, S. Belosjorow, I. Konietzka, A. Duschin, C. Martin, G. Heusch, and R. Schulz Serum but not myocardial TNF-{alpha} concentration is increased in pacing-induced heart failure in rabbits Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R463 - R469. [Abstract] [Full Text] [PDF]
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I. C. Gerling, Y. Sun, R. A. Ahokas, L. A. Wodi, S. K. Bhattacharya, K. J. Warrington, A. E. Postlethwaite, and K. T. Weber Aldosteronism: an immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H813 - H821. [Abstract] [Full Text] [PDF]
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R. Debigare, K. Marquis, C. H. Cote, R. R. Tremblay, A. Michaud, P. LeBlanc, and F. Maltais Catabolic/Anabolic Balance and Muscle Wasting in Patients With COPD Chest, July 1, 2003; 124(1): 83 - 89. [Abstract] [Full Text] [PDF]
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 P. Y. Liu, A. K. Death, and D. J. Handelsman Androgens and Cardiovascular Disease Endocr. Rev., June 1, 2003; 24(3): 313 - 340. [Abstract] [Full Text] [PDF]
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 W. L. Holman, B. K. Rayburn, D. C. McGiffin, B. A. Foley, R. L. Benza, R. C. Bourge, L. J. Pinderski, and J. K. Kirklin Infection in ventricular assist devices: prevention and treatment Ann. Thorac. Surg., June 1, 2003; 75(90060): S48 - 57. [Abstract] [Full Text] [PDF]
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R. Persinger, Y. Janssen-Heininger, S. S. Wing, D. E. Matthews, M. M. LeWinter, and M. J. Toth Effect of heart failure on the regulation of skeletal muscle protein synthesis, breakdown, and apoptosis Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E1001 - E1008. [Abstract] [Full Text] [PDF]
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 A. Y.-M. Wang, J. Sanderson, M. M.-M. Sea, M. Wang, C. W.-K. Lam, P. K.-T. Li, S.-F. Lui, and J. Woo Important factors other than dialysis adequacy associated with inadequate dietary protein and energy intakes in patients receiving maintenance peritoneal dialysis Am. J. Clinical Nutrition, April 1, 2003; 77(4): 834 - 841. [Abstract] [Full Text] [PDF]
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J. Francis, R. M. Weiss, A. K. Johnson, and R. B. Felder Central mineralocorticoid receptor blockade decreases plasma TNF-alpha after coronary artery ligation in rats Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R328 - R335. [Abstract] [Full Text] [PDF]
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P. C. Schulze, J. Kratzsch, A. Linke, N. Schoene, V. Adams, S. Gielen, S. Erbs, S. Moebius-Winkler, and G. Schuler Elevated serum levels of leptin and soluble leptin receptor in patients with advanced chronic heart failure Eur J Heart Fail, January 1, 2003; 5(1): 33 - 40. [Abstract] [Full Text] [PDF]
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P. J. Pugh, R. D. Jones, T.H. Jones, and K. S. Channer Heart failure as an inflammatory condition: potential role for androgens as immune modulators Eur J Heart Fail, December 1, 2002; 4(6): 673 - 680. [Abstract] [Full Text] [PDF]
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 Y. Sun, J. Zhang, L. Lu, S. S. Chen, M. T. Quinn, and K. T. Weber Aldosterone-Induced Inflammation in the Rat Heart : Role of Oxidative Stress Am. J. Pathol., November 1, 2002; 161(5): 1773 - 1781. [Abstract] [Full Text] [PDF]
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 J. R. Keys, E. A. Greene, W. J. Koch, and A. D. Eckhart Gq-Coupled Receptor Agonists Mediate Cardiac Hypertrophy Via the Vasculature Hypertension, November 1, 2002; 40(5): 660 - 666. [Abstract] [Full Text] [PDF]
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P.R. Kalra, P.P. Ponikowski, and S.D. Anker Sympathetic activation and malignant ventricular arrhythmias: a molecular link? Eur. Heart J., July 2, 2002; 23(14): 1078 - 1080. [Full Text] [PDF]
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A. P. Bolger, R. Sharma, W. Li, M. Leenarts, P. R. Kalra, M. Kemp, A. J.S. Coats, S. D. Anker, and M. A. Gatzoulis Neurohormonal Activation and the Chronic Heart Failure Syndrome in Adults With Congenital Heart Disease Circulation, July 2, 2002; 106(1): 92 - 99. [Abstract] [Full Text] [PDF]
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R. Hambrecht, P. C. Schulze, S. Gielen, A. Linke, S. Mobius-Winkler, J. Yu, J.u. Kratzsch, G. Baldauf, M. W. Busse, A. Schubert, et al. Reduction of insulin-like growth factor-I expression in the skeletal muscle of noncachectic patients with chronic heart failure J. Am. Coll. Cardiol., April 3, 2002; 39(7): 1175 - 1181. [Abstract] [Full Text] [PDF]
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 R Ferrara, F Mastrorilli, G Pasanisi, S Censi, N D'aiello, A Fucili, M Valgimigli, and R Ferrari Neurohormonal modulation in chronic heart failure Eur. Heart J. Suppl., April 1, 2002; 4(suppl_D): D3 - D11. [Abstract] [PDF]
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R Sharma and S.D Anker From tissue wasting to cachexia: changes in peripheral blood flow and skeletal musculature Eur. Heart J. Suppl., April 1, 2002; 4(suppl_D): D12 - D17. [Abstract] [PDF]
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 S. Benedini, R. Fiocchi, A. Battezzati, P. Scifo, L. P. Sereni, A. Gamba, C. Mammana, A. Del Maschio, G. Perseghin, and L. Luzi Energy Metabolism in Diabetic and Nondiabetic Heart Transplant Recipients Diabetes Care, March 1, 2002; 25(3): 530 - 536. [Abstract] [Full Text] [PDF]
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M. Imazio, M. Bobbio, F. Broglio, A. Benso, V. Podio, M.R. Valetto, G. Bisi, E. Ghigo, and G.P. Trevi GH-independent cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to dilated and ischemic cardiomyopathy Eur J Heart Fail, March 1, 2002; 4(2): 185 - 191. [Abstract] [Full Text] [PDF]
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A. Nohria, E. Lewis, and L. W. Stevenson Medical Management of Advanced Heart Failure JAMA, February 6, 2002; 287(5): 628 - 640. [Abstract] [Full Text] [PDF]
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K. T. Weber Aldosterone in Congestive Heart Failure N. Engl. J. Med., December 6, 2001; 345(23): 1689 - 1697. [Full Text] [PDF]
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A.L. Clark, M. Loebe, E.V. Potapov, K. Egerer, C. Knosalla, R. Hetzer, and S.D. Anker Ventricular assist device in severe heart failure. Effects on cytokines, complement and body weight Eur. Heart J., December 2, 2001; 22(24): 2275 - 2283. [Abstract] [PDF]
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C.-W. Kong, T.-G. Hsu, F.-J. Lu, W.-L. Chan, and K. Tsai Leukocyte mitochondria depolarization and apoptosis in advanced heart failure: clinical correlations and effect of therapy J. Am. Coll. Cardiol., November 15, 2001; 38(6): 1693 - 1700. [Abstract] [Full Text] [PDF]
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A. J S Coats HEART FAILURE: What causes the symptoms of heart failure? Heart, November 1, 2001; 86(5): 574 - 578. [Full Text] [PDF]
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N. Nagaya, M. Uematsu, M. Kojima, Y. Date, M. Nakazato, H. Okumura, H. Hosoda, W. Shimizu, M. Yamagishi, H. Oya, et al. Elevated Circulating Level of Ghrelin in Cachexia Associated With Chronic Heart Failure: Relationships Between Ghrelin and Anabolic/Catabolic Factors Circulation, October 23, 2001; 104(17): 2034 - 2038. [Abstract] [Full Text] [PDF]
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 A. A. EID, A. A. IONESCU, L. S. NIXON, V. LEWIS-JENKINS, S. B. MATTHEWS, T. L. GRIFFITHS, and D. J. SHALE Inflammatory Response and Body Composition in Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): 1414 - 1418. [Abstract] [Full Text] [PDF]
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 J. W. A. Smit, Y. J. H. Janssen, H. J. Lamb, E. E. van der Wall, M. P. M. Stokkel, E. Viergever, N. R. Biermasz, J. J. Bax, H. W. Vliegen, A. de Roos, et al. Six Months of Recombinant Human GH Therapy in Patients with Ischemic Cardiac Failure Does Not Influence Left Ventricular Function and Mass J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4638 - 4643. [Abstract] [Full Text] [PDF]
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N. Nagaya, M. Uematsu, M. Kojima, Y. Ikeda, F. Yoshihara, W. Shimizu, H. Hosoda, Y. Hirota, H. Ishida, H. Mori, et al. Chronic Administration of Ghrelin Improves Left Ventricular Dysfunction and Attenuates Development of Cardiac Cachexia in Rats With Heart Failure Circulation, September 18, 2001; 104(12): 1430 - 1435. [Abstract] [Full Text] [PDF]
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Task Force for the Diagnosis and Treatment of Chro, W. J. Remme, and K. Swedberg Guidelines for the diagnosis and treatment of chronic heart failure Eur. Heart J., September 1, 2001; 22(17): 1527 - 1560. [PDF]
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S. HEINDL, M. LEHNERT, C.-P. CRIEE, G. HASENFUSS, and S. ANDREAS Marked Sympathetic Activation in Patients with Chronic Respiratory Failure Am. J. Respir. Crit. Care Med., August 15, 2001; 164(4): 597 - 601. [Abstract] [Full Text] [PDF]
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P. R Kalra, S. D Anker, and A. J.S Coats Water and sodium regulation in chronic heart failure: the role of natriuretic peptides and vasopressin Cardiovasc Res, August 15, 2001; 51(3): 495 - 509. [Full Text] [PDF]
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S. D. Anker, M. Volterrani, C.-D. Pflaum, C. J. Strasburger, K. J. Osterziel, W. Doehner, M. B. Ranke, P. A. Poole-Wilson, A. Giustina, R. Dietz, et al. Acquired growth hormone resistance in patients with chronic heart failure: implications for therapy with growth hormone J. Am. Coll. Cardiol., August 1, 2001; 38(2): 443 - 452. [Abstract] [Full Text] [PDF]
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A. Jacobsson, E. Pihl-Lindgren, and B. Fridlund Malnutrition in patients suffering from chronic heart failure; the nurse's care Eur J Heart Fail, August 1, 2001; 3(4): 449 - 456. [Abstract] [Full Text] [PDF]
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G. Akner and T. Cederholm Treatment of protein-energy malnutrition in chronic nonmalignant disorders Am. J. Clinical Nutrition, July 1, 2001; 74(1): 6 - 24. [Abstract] [Full Text] [PDF]
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K. K. A. Witte, A. L. Clark, and J. G. F. Cleland Chronic heart failure and micronutrients J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1765 - 1774. [Abstract] [Full Text] [PDF]
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A.Q. Adigun and A.A. L. Ajayi The effects of enalapril-digoxin-diuretic combination therapy on nutritional and anthropometric indices in chronic congestive heart failure: preliminary findings in cardiac cachexia Eur J Heart Fail, June 1, 2001; 3(3): 359 - 363. [Abstract] [Full Text] [PDF]
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 A. Bolger, W. Doehner, and S. D Anker Insulin-like growth factor-I can be helpful towards end of life BMJ, March 17, 2001; 322(7287): 674b - 674. [Full Text]
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Recommendations for exercise training in chronic heart failure patients Eur. Heart J., January 2, 2001; 22(2): 125 - 135. [PDF]
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M. Rauchhaus, W. Doehner, D. P. Francis, C. Davos, M. Kemp, C. Liebenthal, J. Niebauer, J. Hooper, H.-D. Volk, A. J. S. Coats, et al. Plasma Cytokine Parameters and Mortality in Patients With Chronic Heart Failure Circulation, December 19, 2000; 102(25): 3060 - 3067. [Abstract] [Full Text] [PDF]
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 B. Bozkurt Activation of cytokines as a mechanism of disease progression in heart failure Ann Rheum Dis, November 1, 2000; 59(90001): i90 - 93. [Full Text] [PDF]
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 P.J. Pugh, K.M. English, T.H. Jones, and K.S. Channer Testosterone: a natural tonic for the failing heart? QJM, October 1, 2000; 93(10): 689 - 694. [Full Text] [PDF]
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