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Pathophysiology of peripheral muscle wasting in cardiac
Gerasimos S. Filippatosa, Stefan D. Ankerb,c and Dimitrios T. Kremastinosa
Purpose of review
Many different mechanisms have been proposed to explain
muscle wasting in patients with heart failure; however, the
pathogenesis remains largely obscure. This manuscript
looks at current developments concerning the
pathophysiology of skeletal muscle wasting in cardiac
Recent findings
Many studies have shown that malnutrition, malabsorption,
metabolic dysfunction, anabolic/catabolic imbalance,
inflammatory and neurohormonal activation, and cell death
play an important role in the pathogenesis of wasting in
cardiac cachexia. However, the aetiology of the muscle
changes is not entirely clear. In biopsies of skeletal muscles
from animals with cardiac cachexia increased rates of protein
degradation have been observed, with increased activity of
the ubiquitin–proteasome proteolytic pathway. Skeletal
muscle apoptosis may also play a role in muscle atrophy and
wasting and can be partly prevented by neurohormonal
inhibition, but it has recently been reported that in cachectic
patients with chronic heart failure apoptosis is not the main
pathway of cell death and muscle loss.
Many hypotheses have been used to explain the
pathogenesis of muscle wasting in cardiac cachexia.
Cardiac cachexia is a multifactorial disorder, and the
targeting of different pathways will be necessary for
effective treatment. The immune and neurohormonal
abnormalities present in chronic heart failure may play a
significant role in the pathogenesis of the wasting process.
It has been suggested that common pathogenetic
mechanisms underlie the loss of muscle mass in different
cachectic states. More studies are needed to show whether
there is a common pathway in cardiac cachexia and the
other cachectic states.
apoptosis, cachexia, cytokines, heart failure, skeletal
muscles, wasting
Curr Opin in Clin Nutr Metab Care 8:249–254. # 2005 Lippincott Williams & Wilkins.
2nd University Department of Cardiology, Atticon University Hospital, Athens,
Greece; bDivision of Applied Cachexia Research. Department of Cardiology, Charité,
Campus Virchow-Klinikum, Berlin, Germany; and cClinical Cardiology, National Heart
and Lung Institute, Imperial College School of Medicine, London, UK
Correspondence to Gerasimos S. Filippatos, 2nd University Department of
Cardiology, Atticon University Hospital, Rimini 1, Haidari 12461, Athens, Greece
Tel: +30 210 8048427; fax: +30 210 8104367; e-mail: [email protected]
Current Opinion in Clinical Nutrition and Metabolic Care 2005, 8:249–254
angiotensin-converting enzyme
chronic heart failure
growth hormone
insulin-like growth factor
tumour necrosis factor
# 2005 Lippincott Williams & Wilkins
Cachexia is a syndrome of tissue wasting, which was first
described in chronic heart failure (CHF) by Hippocrates 2300 years ago, and is associated with significant
morbidity and mortality [1]. However, there is still no
widely accepted definition of cardiac cachexia. In the
past most clinicians used low body weight to define
cachexia, but a constitutionally low body weight should
not automatically qualify a patient as cachectic. In other
studies patients were classified according to body fat
content, lean body tissue or by anthropometric measurements [2]. Kotler [3] defined cachexia as ‘accelerated loss of skeletal muscle in the context of a chronic
inflammatory response’. This definition cannot be used
in research or in clinical practice, but it is important
because it shows that the development of cachexia in
CHF is a dynamic process that can only be proved by
documented non-intentional weight loss measured in a
non-oedematous state. It has thus been suggested that
in patients with CHF, cardiac cachexia can be diagnosed when non-intentional weight loss greater than 6%
of the previous normal weight is observed [4].
Although the cut-off value of 6% weight loss for the
definition of cardiac cachexia remains arbitrary, it is
very simple and quickly applicable in clinical practice.
The frequency of body wasting in CHF is 12 –16% in
outpatients [4,5], but it is up to 50% in patients with
severe CHF [6]. In patients with a myocardial infarct
complicated by congestive heart failure, low body
weight is also a detrimental sign [7]. This article
discusses recent advances in the pathogenesis of skeletal muscle wasting in patients with cardiovascular
Pathogenesis of wasting in cardiac cachexia
Many different mechanisms have been proposed for
the pathogenesis of wasting in cardiac cachexia. It has
been suggested that malnutrition, malabsorption, metabolic dysfunction, anabolic/catabolic imbalance and the
250 Anabolic and catabolic signals
loss of nutrients via the urinary or digestive tracts are
important for the development of wasting, but the
mechanisms of the transition from heart failure to cardiac
cachexia are not known. Ajayi et al. [8] found that in
patients with CHF, tricuspid regurgitation is associated
with protein losing enteropathy, hypoalbuminemia and a
greater reduction in skinfold thickness. It has been
reported that right ventricular failure and tricuspid regurgitation are more common in patients with heart failure
and cardiac cachexia, and increased right atrial pressure
was the only predictor of malnutrition observed in
patients with severe CHF but this was not confirmed
in all studies [9]. Simple starvation and anorexia are often
considered to be responsible for cardiac cachexia. It is
known that patients with symptomatic heart failure and
nausea from intestinal oedema can be anorectic. In these
patients oral intake is usually inadequate as a result of
early satiety also caused by a lowered gastric volume
secondary to hepatomegalia and ascites. In addition,
anorexia may be exaggerated by drug therapy and
sodium-restricted diets. However, starvation would lead
to reduced plasma albumin levels. In most CHF studies
there is evidence of a general wasting process, and
cachectic patients suffer from fat, muscle, and bone tissue
loss, but albumin is not decreased in most of these
patients [10]. Moreover, increased nutritional intake does
not reverse cardiac cachexia. This would argue against a
major contribution of starvation, anorexia and gastrointestinal malabsorption in cardiac cachexia. However, it
has been reported that acetate provided by the oxidation
of free fatty acid increases the consumption of amino
acids in the tricarboxylic acid cycle, leading to muscular
wasting and cachexia. The optimization of substrate and
the administration of a specific formulation of amino acids
(mainly branched-chained with elevated amounts of leucine), calculated for matching energetic needs, has been
suggested to prevent wasting [11] by inducing the
hepatic synthesis of anabolic molecules such as growth
hormone (GH) and insulin-like growth factor (IGF), and
by modulating the catabolic neurohormonal-mediated
Cytokine and neuroendocrine activation
In CHF, neurohormones and cytokines are activated, as
a response to the impaired cardiac function. These
systems are acting, initially, as compensatory mechanisms, but eventually they contribute to the progression
of heart failure, haemodynamic deterioration and ventricular remodelling. Elevated plasma levels of neurohormones and cytokines predict mortality in patients
with CHF [12] and they interrelate [13]. Cachectic
CHF patients have markedly increased plasma levels
of tumour necrosis factor (TNF), IL-6, IL-1, norepinephrine, epinephrine, cortisol, angiotensin II and
aldosterone, with non-cachectic CHF patients having
near-normal levels [14,15].
Cytokine activation plays a central role in the pathogenesis of muscle wasting in cardiac cachexia. TNF is
one of the key cytokines important to the development
of catabolism, together with IL-1, IL-6 and transforming growth factor beta [14]. In-vivo experiments have
shown that IL-6 is capable of inducing proteolysis,
muscle atrophy and weight loss, all of which can be
prevented by IL-6 antibody therapy. TNF is increased
in patients in cardiac cachexia, and is the strongest
predictor of the degree of previous weight loss [10].
The site of production and action of TNF modifies its
effect. In animals, when TNF-producing cells are
implanted into skeletal muscle cachexia occurs,
whereas TNF-producing cells implanted in the brain
cause profound anorexia. TNF can also induce skeletal
muscle wasting, modulate collagen synthesis, and
induce IL-1 release and apoptosis in many cell types
[16]. It has recently been reported that TNF could
induce different signals within the same cell type [17].
The main stimulus for the immune activation in CHF is
not known. It has been suggested that hypoxia is the
stimulus for increased proinflammatory cytokine production in CHF patients, and the failing heart itself may be
the main source of TNF [18]. Moreover, bowel wall
oedema, which occurs in CHF, may be responsible for
bacterial translocation with subsequent endotoxin release
and immune activation [19]. It has been proposed that
oedema can lead to altered gut permeability for bacteria
and endotoxin, which may subsequently enter the circulation and stimulate inflammatory cytokine activation.
This hypothesis is supported by the finding that there are
elevated concentrations of endotoxin in CHF patients
with oedema, which can be normalized by diuretic therapy [20]. In an animal model of gut-derived endotoxaemia, the angiotensin-converting enzyme (ACE)
inhibitor enalapril improved survival by reducing bacterial translocation and contributing to a preservation of
gastrointestinal functional and structural integrity [21].
As a consequence of the endotoxin hypothesis, lipoproteins may play a beneficial role in patients with CHF
by binding to endotoxin and protecting endothelial cells
from its toxic effects [22]. It has been shown in patients
with CHF that lower serum total cholesterol is independently associated with a worse prognosis, and higher
cholesterol levels are related to longer survival in both
cachectic and non-cachectic CHF patients [23]. However, it is not known whether cholesterol plays a pathophysiological role in CHF and cardiac cachexia or is only a
marker of the severity of the disease. Moreover, the exact
role of lowering cholesterol levels is not clear. In mice,
lowering cholesterol with 4-aminopyrolo-(3,4-D) pyrimide and with estradiol increased the susceptibility of
the mice to lipopolysaccharide [24]. However, in patients
with ischaemic and non-ischaemic CHF, statin use was
an independent predictor of improved survival although
Pathophysiology of peripheral muscle wasting in cardiac cachexia Filippatos et al. 251
the cholesterol levels were similar between treated and
non-treated patients [25].
Catecholamines can cause a catabolic metabolic shift, and
can lead to a graded increase in resting energy expenditure in patients with CHF [26]. An anabolic hormone that
is decreased in cachectic patients is dehydroepiandrosterone, also suggestive of a catabolic/anabolic imbalance
[10]. The abnormalities of sex steroid metabolism in
CHF are strongly and directly related to the immune
activation seen in cachectic CHF patients [13]. Attention
has recently focused on ghrelin, which is a novel GHreleasing peptide that has vasodilative effects, inhibits
sympathetic nerve activity, and stimulates food intake
through GH-independent mechanisms [27,28]. Besides
its effects on food intake and body composition [28], the
administration of ghrelin also appears to inhibit proinflammatory cytokine production [29]. In a pilot study
in patients with congestive heart failure [30], ghrelin
improved left ventricular function, exercise capacity, and
muscle wasting in patients with CHF. Moreover, ghrelin
negatively controls the plasma release of leptin and
leptin-induced cytokine expression [31], whereas TNF
increases the plasma concentrations of leptin in a dosedependent fashion [32]. Leptin, a product of the ob gene,
decreases food intake, increases resting energy expenditure, and upregulates transforming growth factor beta 1,
thereby augmenting the fibrogenic response. Plasma
levels of leptin have been shown to be elevated in
patients with CHF [33]; however, leptin serum levels
are decreased in patients with cardiac cachexia [34,35].
The exact role of leptin in the pathophysiology of cardiac
cachexia needs further clarification.
are mainly involved in the breakdown of proteins are the
lysosomal system, the calpain–calcium-dependent system, and the adenosine triphosphate-dependent ubiquitin proteasome pathway. In cachectic cancer patients, the
proteolysis-inducing factor induces the loss of skeletal
muscle and this effect is mediated by the upregulation
of the ubiquitin–proteasome proteolytic pathway [40].
Moreover, in muscle wasting induced by severe injury
and sepsis there is increased gene expression and activity
of the calcium/calpain and ubiquitin–proteasome proteolytic pathways. It has recently been proposed that similar
transcriptional changes underlie the loss of skeletal
muscle in cachexia, and complementary DNA microarrays have been used to compare changes in the content
of specific mRNA in muscles atrophying from different
causes (fasted mice, rats with cancer cachexia, diabetes
mellitus, and renal failure). Animals with cardiac cachexia
have not been studied. It has been found that a common
set of genes, mainly of the ubiquitin–proteasome pathway (termed atrogins), were induced or suppressed in
atrophic muscles in all animals. Different types of muscle
atrophy thus share a common transcriptional programme,
which is activated in many systemic diseases, and the
proteolysis underlying muscle wasting is largely caused
by activation of the ubiquitin–proteasome pathway
[41]. Ubiquitin levels are increased in rats with CHF,
but the system has not been extensively studied in
human cardiac cachexia [42]. Moreover, in patients with
cardiac cachexia, the proteolysis-inducing factor has not
been isolated, and the differential elevation of circulating
IL-1, TNF-a, and IL-6 has been found in AIDS-associated cachectic states. Therefore, more studies are
urgently needed to show whether there is a common
pathway in the different cachectic states.
Wasting of skeletal muscle protein
According to the muscle hypothesis, changes in the
skeletal musculature are at the core of the deterioration
of patients with CHF [36]. Fatigue and muscle weakness
are two of the main symptoms experienced by CHF
patients. The loss of lean body mass, which mainly results
from the atrophy of skeletal muscle protein, is one of the
characteristics of cardiac cachexia. Muscle atrophy is
present in up to 68% of patients with CHF [37], and it
has been shown that skeletal muscle phenotype changes
occur during the transition from hypertrophy to heart
failure [38]. However, the aetiology of the muscle
changes in cardiac cachexia is not entirely clear.
It has been suggested that common pathogenetic
mechanisms underlie the loss of muscle mass in different
cachectic states [39]. In biopsies of skeletal muscle from
cachectic cancer patients, both reduced rates of protein
synthesis and increased rates of protein degradation have
been observed. This imbalance between protein synthesis and degradation is probably an important contributor
to muscle wasting in cardiac cachexia. The systems that
Muscle cell death in cardiac cachexia
Inflammatory cytokine and catabolic hormone levels are
known to correlate significantly with the reduction of
muscle, fat and bone tissue content in cachectic CHF
patients [43]. Insulin also plays a role in regulating the
balance between anabolism and catabolism. Experimental models have shown that insulin inhibits protein
degradation in skeletal muscle. Moreover, alterations
of the GH/IGF-1 axis may play an important role in
the pathogenesis of cachexia because patients with low
IGF-1 levels have evidence of muscle abnormalities [44].
The levels of GH are elevated and the levels of IGF-1 are
inappropriately low in cachectic CHF patients, suggesting the presence of GH resistance, but only local IGF-I
expression is significantly correlated with muscle crosssectional area [45,46]. It has been shown that IGF-1 can
inhibit a number of apoptotic pathways. The administration of GH at high but not at low doses in rats with
heart failure decreased not only muscle atrophy but also
serum levels of TNF and the number of apoptotic nuclei,
possibly by IGF-1 overexpression [47].
252 Anabolic and catabolic signals
Angiotensin II, which can induce wasting in animal
models, reduces circulating IGF-1 levels [48]. The coinfusion of angiotensin II and IGF-I did not prevent
muscle loss, suggesting that angiotensin II causes skeletal
muscle mass wasting by enhancing protein degradation,
probably via its inhibitory effect on the autocrine IGF-1
system [49]. The effects of angiotensin II are mediated
via the stimulation of two receptors, named type 1 and
type 2. Angiotensin II can also induce apoptosis [50] and
fibrosis through its type 1 receptor. Muscle atrophy
and apoptosis can be prevented by using angiotensin II
converting enzyme inhibitors and angiotensin II receptor
1 blockers [51,52,53,54–56]. In addition, the administration of the anti-inflammatory cytokine IL-15 completely reversed the apoptosis observed in the skeletal
muscle of tumour-bearing animals [57]. Anti-inflammatory effects of statins have also been reported, and have
led to the proposal that statins may be useful against
cachexia [58].
Apoptosis contributes to cell loss in the failing human
heart and to the expansion of fibrotic foci [59]. Apoptosis
has also been found in the skeletal myocytes of patients
with CHF and cachexia, and has been associated with
impaired exercise capacity [60,61]. Moreover, structural
alterations and increased collagen content have been
found in peripheral skeletal muscles after experimental
myocardial infarction. It has been suggested that the
apoptosis of muscle nuclei can play a role in muscle
atrophy and wasting. It is known that there is a ratio
between the size of a muscle fibre and the number of
nuclei within a given fibre. Each nucleus regulates metabolism and protein expression within a given muscle fibre
volume. The loss of myonuclei through apoptosis thus
results in fibre atrophy [62]. However, it has been
reported that skeletal muscle apoptosis is not different
between CHF patients with and without cachexia,
whereas the collagen content is increased in the biopsies
of skeletal muscles of patients with cardiac cachexia
Inflammatory cytokine and neurohormonal activation
lead to cell death and fibrosis. These systems are particularly activated in CHF patients with cachexia. It can be
confirmed that during the disease progression from compensated heart failure to cachexia the form of cell death
changes from apoptosis to necrosis and collagen deposition [54–56]. A decrease in the apoptotic index has also
been reported in the late stages of cancer cachexia. In
rabbits with cancer cachexia, there is an increase in the
apoptotic index in the early stages of cachexia but a
decrease at higher losses [63]. The expression of Bax,
which promotes apoptosis, is also increased in the early
stage of weight loss, but thereafter declines. Moreover, it
has already been suggested that death involving skeletal
muscles may occur by other routes that differ at least
morphologically [64], and the increased proteolytic
activity of ‘proapoptotic’ enzymes without evidence of
apoptosis has been found in mice with cancer cachexia
In clinical trials in patients with CHF, treatment with an
ACE inhibitor reduced the risk of weight loss and bblocker therapy induced weight gain, showing that cardiac cachexia is partly mediated by activation of the
renin–angiotensin and sympathetic nervous systems
[4,66]. However, cachexia is a complex syndrome,
and not only b-blocker therapy but also the administration of the b2-agonist formoterol in animals with cancer
cachexia resulted in an important reversal of the musclewasting process [67]. According to the different pathophysiological mechanisms studied, different management strategies have been used to treat muscle
wasting [68,69,70] (see Table 1).
All these differences could be the result of differences
between animal models and human cachexia, differences
between different cachexia states, differences in the
Table 1. Agents that can be considered for the management of
muscle wasting in experimental models and clinical cachexia
Anabolic agents
Recombinant human GH
Recombinant IGF-1
IGF–IGFBP3 combinations
Synthetic anabolic steroids
(nandrolone decanoate,
Cytokine inhibition
D-9 Tetrahydrocannabinol
Antisense therapy directed
at NFkB
Anti-IL-6 receptor antibody
Anti-TNF antibody
(infliximab and others)
TNF receptor fusion protein
Hypercaloric feeding
Appetite stimulants
Megestrol acetate
Proteasome inhibitors
Eicosapentaenoic acid
Peptide aldehydes
Vinyl sulfones
Dipeptide boronic
acid analogues
Resistance exercise training
Metabolic regulators
Lipoprotein lipase activators
Serotonin type 3
receptor antagonists
Inhibition of myostatin
GH, Growth hormone; IGF, insulin-like growth factor; IGFBP3, insulinlike growth factor binding protein 3; NFkB, nuclear factor kappa B; TNF,
tumour necrosis factor. Some of these agents have never been tested.
Many of these agents are in testing in experimental studies or clinical
cachexia trials. Very few of these drugs are agency-approved for use in
certain types of human cachexia. Most of these agents have never been
tested in cardiac cachexia. Modified from Filippatos [68].
Pathophysiology of peripheral muscle wasting in cardiac cachexia Filippatos et al. 253
populations studied, in the definition of cardiac cachexia,
or in the time the patients were studied after the ‘beginning’ of cardiac cachexia. Further studies are needed to
examine the effect of cachexia in different categories of
patients with heart disease [68].
Cachectic patients represent a significant proportion of
patients with CHF. Cardiac cachexia is a multifactorial
disorder, and it is unlikely that any single agent will be
completely effective in treating this condition; the targeting of different pathways will be necessary. Improved
prognosis of cardiac cachexia and the reversal of the
wasting process will have a significant influence on the
quality of life and may improve the long-term prognosis
of patients with CHF.
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