Associate editor: P.C. MolenaarCardiac cachexia: A systematic overview
Introduction
The treatment of chronic heart failure (CHF) has made significant advances over the last two decades. This applies likewise for the establishment of the diagnosis of this syndrome using different single and multi-biomarker approaches (Cowie et al., 1997, Kempf et al., 2007, von Haehling et al., 2007b). Even more so, our understanding of the disease has developed from the rather simplistic model of mere pump failure to that of a complex disease that affects multiple body systems. Despite this, the clinical perspective remains poor, because about half of the patients with CHF die within 4 years of diagnosis (Remme & Swedberg, 2001). This truly devastating prognosis is comparable to that of some types of cancer (Stewart et al., 2001). Overall, the incidence of CHF is steadily increasing in most European countries and in the United States. Current estimates amount to an incidence of 0.1–0.5% per year, and the numbers are doubling with each decade to reach 3% in those over the age of 75. The prevalence of CHF has been estimated at around 0.3–2.4%, which implies that 5 million people in the United States are affected (American Heart Association, 2005). Heart failure accounts for 970,000 hospitalizations and 12–15 million outpatient office visits in this country per year. This causes health-care associated costs of 28 billion US-dollar.
The situation worsens considerably once cardiac cachexia has been diagnosed. Although the definition of this clinical entity has been subject to debate over years (see below), all researchers have unanimously agreed on the poor prognosis of the cachectic patient. 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 (Anker et al., 1997, Anker et al., 1997, Anker et al., 1997). Cachexia is not a unique feature of CHF, but is also seen in terminal stages of other chronic illnesses, including cancer, sepsis, rheumatoid arthritis, and acquired immunodeficiency syndrome (AIDS).
Cachexia is not only associated with poor outcomes, but also with an unfavourable response to drug treatment and poor quality of life. It has been observed in patients with cancer that survival is impaired already at a weight loss of 5% (Dewys et al., 1980). Weight loss exceeding 30% is incompatible with life (Fearon et al., 1992). It is among the most common misconceptions that one of the underlying causes of cachexia is anorexia, i.e. loss of appetite. Although anorexia is certainly a common feature of the diseases leading to the development of cachexia, this feature alone cannot explain the metabolic changes observed during this perturbation. Importantly, nutritional supplementation cannot reverse the process of losing weight in patients with genuine cachexia, which is possible in patients who suffer from starvation or anorexia. Still, nutritional aspects have to be considered when treating patients with cachexia.
Weight loss in the cachectic patient predominantly affects muscle protein, however, bone and fat tissue are likewise affected later in the course of the disease. The factors that trigger the progression from clinically and body weight stable, ambulatory CHF to cardiac cachexia remain poorly understood. The timelines differ widely between patients. The aim of this review is to provide a broad overview of the current knowledge of cardiac cachexia. This includes the ongoing discussion about how to define cachexia, intracellular and extracellular signalling, and potential therapeutic approaches.
Section snippets
Definition of cardiac cachexia
Body weight is a dynamic parameter, and it has a certain rhythm over the lifespan (Wallace & Schwartz, 2002). Currently, public opinion is more concerned with weight gain than weight loss, and therefore most of the programs in adults are aiming at the reduction of body size (Dansinger et al., 2007). However, weight loss due to body wasting may reflect serious disease and has to be considered with particular attention. Cachexia (Greek: kakós – bad; hexis – condition) constitutes its terminal
Immune activation
One key aspect of CHF and cardiac cachexia like many other forms of cachexia is inflammatory immune activation. This has been first described by Levine and associates in 1990 (Levine et al., 1990). Indeed, it may well be that activation of the pro-inflammatory mediator tumour necrosis factor-α (TNFα) is the final common pathway that links all forms of cachexia. Since the initial description of TNFα activation in CHF, at least five different hypotheses have been suggested to explain the origin
Brief summary
In this section, both positive and negative key modulators of appetite will be reviewed. Feeding is a key component of a satiety-hunger homeostatic model (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) (Brunetti et al., 2005). However, 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
Brief summary
This section gives an overview of the wasting process seen in cardiac cachexia, which does not only involve lean tissue, i.e. skeletal muscle, but also fat tissue and bone. Skeletal muscle is lost due to an imbalance of protein synthesis and proteolysis. Typically pro-inflammatory cytokines induce proteolytic systems, while simultaneously reducing the anabolic IGF-1 signaling. Lean body mass depletion is one of the major characteristics of cachexia. Indeed, up to 68% of patients with CHF have
Brief summary
There are currently no approved therapies to treat of weight loss as such in cardiac cachexia. This section aims to give an overview of the different treatment strategies that might be pursued in preventing or treating loss of tissue. Some of these have been shown to provide benefit, as data from retrospective analyses show, some have even shown their efficacy in clinical studies. Others, however, may prove less effective although they have therapeutic appeal from a theoretical point of view.
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. One potential therapeutic aim is the inhibition of intracellular signalling pathways like NF-κB, which is also likely to inhibit
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