Immune Activation

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There is evidence that neurohormonal changes and immune activation in CHF patients play a major role in the pathogenesis of cardiac cachexia. While tumour necrosis factor-a (TNF-a) is increased in cardiac cachexia as a sign of immune activation [6, 7, 24], the levels of this cytokine are not increased in all CHF patients [25]. Keeping the definition of cardiac cachexia as > 7.5% weight loss in 6 months, the TNF-a plasma level is higher in cachectic (Fig. 2), than in non-cachectic CHF patients. TNF-a level is also the strongest predictor of the degree of previous weight loss [26]. In animal experiments, TNF-a-producing cells implanted in the brain caused profound anorexia [27]. When TNF-a-producing cells were implanted in skeletal muscle, cachexia occurred, which proves a causative role for increased levels of TNF-a in the genesis of cachexia. Other important cytokines in CHF are interleukin (IL)-1, IL-6, interferon (IFN)-y, and transforming growth factor (TGF)-p. Besides cytokines, there are other elevated inflammatory markers, e.g. erythrocyte sedimentation rate, which also relate adversely to the prognosis [28].

The exact mechanism for the activation of the immune system is not clear and several possibilities have been discussed, including a role for TNF-a since it is a validated marker for immune activation in cardiac cachexia. Hypoxia has been suggested as the main stimulus for increased TNF-a production in CHF patients [29]. As the failing myocardium is capable of producing TNF-a [30], another hypothesis assumes that the heart itself is the main source of inflammatory cytokines [31]. Nevertheless, treatment of patients with ventricular assistance devices failed to provide long-term beneficial anti-inflammatory effects [32]. Also,

Fig. 2. Tumour necrosis factor alpha (TNF-a), epinephrine, norepinephrine and Cortisol plasma levels in 53 chronic heart failure (CHF) patients and 16 healthy controls. Patients are sub-grouped according to: (1) cachectic state (nc, non-cachectic [n = 37]; cach, cachectic [n = 16]): (2) maximal oxygen consumption (peak VO2) (< 14 [n = 17] vs 14-20 [n = 24] vs >20 ml/kg per min [n = 12]; (3) New York Association class (NYHA) (class 1/2 [n = 16] vs class 3/4 [n = 37]); (4) left ventricular ejection fraction (LVEF) (< 20% vs 20-35% [n = 17] vs > 35% [n = 12]). Data presented as mean ± SEM P-values for Fisher's test are given if ANOVA showed significant inter-group variation. Adapted from [26]

Fig. 2. Tumour necrosis factor alpha (TNF-a), epinephrine, norepinephrine and Cortisol plasma levels in 53 chronic heart failure (CHF) patients and 16 healthy controls. Patients are sub-grouped according to: (1) cachectic state (nc, non-cachectic [n = 37]; cach, cachectic [n = 16]): (2) maximal oxygen consumption (peak VO2) (< 14 [n = 17] vs 14-20 [n = 24] vs >20 ml/kg per min [n = 12]; (3) New York Association class (NYHA) (class 1/2 [n = 16] vs class 3/4 [n = 37]); (4) left ventricular ejection fraction (LVEF) (< 20% vs 20-35% [n = 17] vs > 35% [n = 12]). Data presented as mean ± SEM P-values for Fisher's test are given if ANOVA showed significant inter-group variation. Adapted from [26]

endotoxin stimulates inflammatory cytokine production [33]. Therefore, bacterial translocation due to bowel-wall oedema in CHF with subsequent endotoxin release represents a possible mechanism to activate the immune reaction (endotoxin hypothesis) [34]. There is evidence that endotoxin-mediated inflammation is important in cardio-genic shock [35]. Furthermore, an increased sensitivity of peripheral monocytes to lipopolysaccha-rides (LPS) and high levels of neopterin (a marker of monocyte activation) indicate monocyte activation in CHF patients [36]. In contrast,lipids play a beneficial role in patients with CHF by binding to and detoxifying the effects of endotoxin [37]. High lipoprotein levels were found to be inversely related to low plasma levels of TNF and other inflammatory cytokine variables [38]. Furthermore, it may explain why low, but not high serum lipopro-tein levels are associated with a poor prognosis in CHF patients [39,40].

Another aspect is anaemia, which can be the cause of heart failure, but also its consequence

(Fig. 3) [41]. Reduced haemoglobin is frequently seen in inflammatory conditions, and pro-inflammatory cytokines may be pivotal triggers of anaemia in CHF. Studies also document that lower plasma haemoglobin levels in CHF are related to female gender, older age, poor kidney function, lower body weight, greater inflammation, and advanced disease status (based on left ventricular ejection fraction, exercise capacity, and mortality analyses) [41].

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