Drugs

Prevention of the deterioration of CHF, such as occurs with the onset of cachexia, is one of the main goals of therapy. Increasing knowledge about the pathophysiology of CHF and its sequelae has led to an increasing number of therapeutic options. However, there is no specific drug therapy for cachexia associated with CHF. Most of the drugs currently in use, particularly ACE inhibitors, p-blockers, and aldosterone antagonists, have an effect on the neurohormonal system. For instance, ACE inhibitors reduce circulating levels of atrial and brain natriuretic peptides (ANP, BNP) [57,58], TNF-a [59], and IL-6 [60]. The effects on cate-cholamines, other neurohormones, and endothe-lial function mediated by ACE inhibitors are thought to improve the nutritional status of tissues and reduce ischaemia and oxidative stress. Thus, these drugs prevent tissue damage and apoptosis in patients with heart failure [4]. It was demon

Fig.4. The development of cachexia due to a complex interaction of different body systems and an imbalance of catabolic and anabolic systems. ET-1, endothelin-1. (Adapted from [56])

strated that treatment with the ACE inhibitor enalapril reduced the risk of over 6% weight loss by 19% [4]. Also, it has been shown that ACE inhibitors can restore depressed levels of circulating IGF-1 in CHF patients by reducing angiotensin II activity [61]. A further option is therapy with an angiotensin II type-1 receptor antagonist itself, which resulted in reduced plasma levels of TNF-a, IL-6, and BNP [62]. Angiotensin II is a potent stimulator of the immune and neurohormonal axis.

Recently, p-blockers were found to act beneficially in CHF and to prevent or even partially reverse cachexia [63]. In a study with CHF patients, after therapy with carvedilol or metoprolol for 6 months, subjects with baseline cachexia gained significantly more weight gain than subjects in the non-cachectic group [64]. The p-blocker carvedilol is thought to have an inhibitory effect on reactive oxygen species and apoptosis [65]. All-cause mortality was lower in the metoprolol group in a study enrolling 3991 patients [66]. Also, carvedilol therapy led to a reduced overall mortality rate of 3.2% (n = 696) vs 7.8% in the placebo group (n = 398) [67]. However, there was no difference between cachectic and non-cachectic patients in this study.

The importance of high levels of cytokines favours implementation of an anti-cytokine therapy. Although anti-cytokine treatment is established in other diseases [68-70], its value in the management of CHF remains controversial [71]. The effects of two drugs, etanercept, which reduces the bioactivity of TNF-a, and infliximab, an anti-TNF-a antibody, have been studied. Contradictory to the initial favourable effects in early pilot studies [72, 73], larger studies failed to show a benefit for either drug [74-76].

Interestingly, phosphodiesterase inhibitors (e.g. amrinone, vesnarinone, pimobendan), which have short-term haemodynamic benefits in heart failure, can inhibit the production of TNF-a and other cytokines from stimulated human lymphocytes [77]. Furthermore, it has been suggested that another phosphodiesterase inhibitor, pentoxi-phylline, reduces TNF-a plasma concentrations [78], but in a well-controlled study pentoxifylline therapy did not reduce TNF-a levels in CHF patients [79].

Blocking the inflammatory activation is also possible with the anti-cytokine anti-IL-6. It was shown that proteolysis, muscle atrophy, and weight loss were prevented by anti-IL-6 antibody therapy in animal models [80].

Recombinant human GH can be considered as another option for the treatment of cardiac cachex-ia. Since normal doses had no significant clinical benefits compared to placebo [81], high doses of GH may be necessary to overcome GH resistance, which is present in patients with cardiac cachexia [82]. In fact, case reports involving three cachectic patients showed an increase of muscle mass and strength and an improvement of exercise capacity with high dose (about 6-8 times higher than normal) GH therapy [83, 84]. The use of anabolic steroids to increase muscle mass in cardiac cachex-ia is limited due to negative side effects on other organs, e.g. kidney function [15, 85]. Recently, ghrelin was found to improve ventricular function and increase body weight in animal studies [86]. Therefore, the GH-releasing peptide ghrelin, which has been isolated from the stomach, presents another option for the treatment of cardiac cachex-ia and therefore merits further research. Ghrelin causes a positive energy balance by stimulating food intake, and it also exhibits cardiovascular effects, e.g. inhibition of apoptosis by cardiomy-ocytes and endothelial cells [87].

The above-mentioned endotoxin hypothesis implies further therapeutic strategies. Drugs directed against endotoxin-producing bacteria in the bowel or endotoxin itself, or its binding to cells could prevent the effect of cytokine release due to endotoxin. However, further research on the benefits of this approach is needed.

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