INTRODUCTION
- The incidence of CHF in the European and the United States
is about 0.1-0.5% per ear; while the prevalence of CHF is about 0.3-2.4% (~5
million people) in the United States.
- About half of the patients with chronic heart failure
(CHF) die within 4 years of diagnosis
- In unselected patients with CHF, mortality rates were as
high as 50% in the cachectic subset compared to 17% in the non-cachectic subset
at 18 months of follow-up.
- Cachexia is not only associated with poor outcomes, but
also with an unfavourable response to
drug treatment and poor quality of
life
DEFINITION OF CARDIAC
CACHEXIA
- Cardiac cachexia as a clinical entity is acknowledged as a
complex syndrome, which is associated with poor outcomes.
- No single reason for cachexia exists
- Patients usually experience progressive weight loss with
body composition alterations and disturbed homeostasis of several body systems.
- There is evidence for activation of neuroendocrine and inflammatory
systems, increased lipolysis, muscle wasting, lack of appetite, and
malabsorption whilst the importance of individual pathways and the exact
interplay remain unknown.
-The authors proposed definition:
non-oedematous weight loss of >6% of total body weight over a period of 6 or
more months (At this stage it is important to note that the severity of cardiac
cachexia may not always correlate with
classical criteria of disease severity as New York Heart Association [NYHA]
functional class, left ventricular ejection fraction, or exercise duration; Cardiac
cachexia even may not be associated with
morphological cardiac changes as seen by magnetic resonance imaging or
echocardiography)
- It might be necessary to add some laboratory, clinical and
functional parameters to be able to identify cachexia and body wasting in an
early phase.
- Ideally, patients at risk for the development of cachexia
should be identified as early as
possible, however, no effective
treatment of manifest cachexia is available yet.
- The definition by Evans 2008 may also be relevant.
Cautious with terms
such as “cachexia”, “anorexia”, “sarcopenia”, “malnutrition” and “hypercatabolism”
– they are not the same!
- Sarcopenia: age associated “normal” muscle wasting, may
not result in significant weight changes, because loss of muscle and increases
in fat mass are frequently balanced.
- Malnutrition and Anorexia: are associated with predominantly
loss of fat mass rather than muscle tissue; are reversible with adequate food
intake, but not cachexia
- Hypercatabolism cannot be evaluated during clinical
examination and neglects the other side of the coin, the anabolic processes
PATHOPHYSIOLOGICAL
ASPECTS OF CARDIAC CACHEXIA
1) Immune
Activation
- One key aspect of CHF and cardiac cachexia like many other
forms of cachexia is inflammatory immune activation
- Activation of the pro-inflammatory mediator tumour
necrosis factor-α (TNFα) is the final common pathway that links all forms of
cachexia.
- One of the most important signal transducers of many inflammatory
stimuli is nuclear factor-κB (NF-κB).
- Interestingly, over-activity of the NF-κB system has been
shown to occur in patients with CHF
2) Regulation of
Feeding
- Feeding is a key component of a satiety-hunger homeostaticmodel
(Fig.1).
- Although a simple but vital daily process, it is influenced
by many pathways and/or mechanisms, which are still not completely understood
(Table 2)
- The hypothalamus has been identified as the central
regulating site of appetite (Fig. 2).
- Two areas can be differentiated: a lateral “feeding area” and
a medial “satiety centre”
- Excessive fluctuations in feeding cause weight and body
composition changes which may develop into medical conditions or disease
- Cachexia of chronic illnesses shares several nutritional
features.
- Especially patients with cardiac cachexia experience
appetite problems and alterations in food intake, malabsorption of nutrients, metabolic
disturbances, and finally an anabolic/catabolic imbalance
- Malnourishment due to lack of appetite can occur in a
variety of chronic diseases and as many as half of the patients can be
affected.
- Disturbances in energy expenditure can contribute to
anorexia-mediated body wasting and eventually to cachexia.
- Therefore, it is a key element in treating chronic
illnesses that such patients receive
adequate nutrition in order to prevent further development of the disease,
to avoid potential side effects of treatment, and to recover from a state of
deterioration.
3) Mechanisms of
wasting in different body compartments
a) Skeletal muscle is lost due to an imbalance
of protein synthesis and proteolysis
- Typically proinflammatory cytokines induce proteolytic
systems, while simultaneously reducing the anabolic IGF-1 signalling.
- Additionally myostatin, a negative regulator of muscle
mass, is considered to be a key player, as it has been reported as up-regulated
in HIV cachexia and sarcopenia
b) Later in the course of the disease, wasting of bone and
fat mass is found
- Fat wasting can
be induced by numerous agents and the rate limiting step is the activity of the
enzyme hormone sensitivity lipase that can be activated by several receptors
including β-adrenergic and natriuretic peptides receptors.
- TNFα, which is
also over-expressed in both CHF and cardiac cachexia, plays a major role in fat
cell lipolysis and inhibiting insulin signalling. The latter is an important
aspect in the development of insulin resistance.
- It is tempting to speculate that increased levels of catecholamines and possibly natriuretic peptides may be responsible
for the loss of adipose tissue that has been observed in such patients
- The bone
density in patients with cardiac cachexia is lower, and lower calcium and
vitamin D levels have been reported, although no mechanisms have been identified
so far
- These alterations in body composition have their reasons
in profound metabolic perturbations, which are initially meant to isolate and neutralize the insult that caused the
heart to fail.
- However, at a later stage, they contribute to the
development and the progression of cardiac cachexia.
THERAPEUTIC APPROACHES
TO CARDIAC CACHEXIA
- Currently there are no approved therapies to treat of
weight loss as such in cardiac cachexia
1) Prevention of
Weight Loss
a) ACE Inhibitors
& Beta-blockers
- Angiotensin Converting Enzyme (ACE) inhibitors and
beta-blockers have both clinically shown their potential to delay and possibly
prevent the onset of cardiac cachexia.
2) Nutrition
a) Feeding
- Although feeding alone, the reversal of the clinically
observed anorexia, does not reverse cachexia, nutrition itself still seems to
be a major factor in treatment strategies
- Often patients have deficiencies in micronutrients such as
vitamins and a supplementation of branched-chain amino acids has shown to be
beneficial
- An overall induction of food intake to battle anorexia in
these patients is considered supportive.
b) Nutritional
Consideration
- However, the daily sodium intake should be restricted to 2
g in all patients with advanced CHF or cardiac cachexia
- Prolonged periods of fasting are potentially harmful, and
cachectic patients should be advised to eat small, frequent meals
- Fluid intake should be restricted to 1.5–2.0 l/day,
especially in patients with severe symptoms or those requiring high doses of
diuretics
- At least one study suggests that multiple micronutrient
supplementation is potentially beneficial. Such supplements should contain
anti-oxidant supplements and B-group vitamins
- Avoid food and
lifestyle factors that trigger the acute phase response such as an excess of
carbohydrates or saturated fats, alcohol, and smoking
- Food that counteracts inflammatory responses, can be recommended.
This includes fish oil supplements, olives, walnuts, flaxseed oil, any fruits
or vegetables, garlic, ginger, turmeric, sunflower seeds, eggs, herring, or
nuts
- Enteral nutrition should always be given preference over
parenteral nutrition, however, if the latter cannot be avoided, the general
guidelines can be followed: 35 kcal per kg of bodyweight per day,1.2 g of
protein per kg per day, and a 70:30 glucose:lipid ratio for the non-protein
energy (ZYL note: I recommend to start slow while monitor for refeeding syndrome; increase calorie intake slowly as tolerated and prevent overfeeding)
3) Pharmacotherapy
I) Appetite
Stimulants
a) Megestrol Acetate
- Megestrol acetate has been shown to stop weight loss in
hormone responsive cancer and has recently been approved for AIDS cachexia in
the United States.
- The closely related
compound, medroxyprogesterone acetate, has similar effects, but a trend towards
peripheral oedema was observed. Cannabinoids
b) Cannabinoids
- Cannabinoids are known inducers of food intake, but have
clinically shown contradictory results.
- While positive effects on appetite were seen in patients
with AIDS and cancer, there was no concomitant weight gain.
II) Anabolic agent
a) Anabolic Steroids
- The use of anabolic steroids in cachexia patients is
limited to chronic obstructive pulmonary disease and AIDS, where positive
effects on weight have been observed
- In CHF, there was an improved cardiac function, but no
effect on weight
b) Beta-adrenergic
agonist
- Beta-adrenergic, especially β2-adrenergic agonists are
also known for their anabolic properties and have shown some beneficial effects
in degenerative muscle diseases.
- Although short-lived, positive cardiac effects have been
reported in CHF, but there was no improvement in the functional capacity of the
patients
III) Anti-inflammatory
strategies
- a) Neutralizing antibodies like eternacept and infliximab,
which showed a lack of efficiency in CHF,
- b) Statins, which show beneficial pleiotropic effects like
the reduction of pro-inflammatory cytokines in some settings and
- c) Thalidomide, which potently reduces TNFα
IV) Inhibition of
major proteolysis pathway
- The use of proteasome inhibitors to inhibit major
proteolysis pathway, the ubiquitin-proteasome pathway is in its early stages
and has so far only been tested in cancer, where weight gain has been reported.
- While pentoxifylline reduced the activity of muscle proteolytic
systems in a rat model of cancer cachexia, it failed to improve weight in
patients with cancer cachexia.
CONCLUSION
- The pathophysiology of cardiac cachexia is exceedingly
complex, and we still do not understand when and how CHF progresses into this syndrome
- Pro-inflammatory cytokines and especially TNFα certainly play
an important part. However, therapies that targeted specific single cytokines
have largely failed, and it appears that broader approaches are required.
- We are currently not able to interfere with appetite
regulation in a promising way, although initial steps have been undertaken.
- Nutritional recommendations for cardiac cachexia remain
speculative, and no large-scale randomized, controlled trials have been
performed
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