J Cachexia Sarcopenia Muscle (2011) 2:135–142 [37], and activation of the inflammatory response is directly responsible for cardiac cell apoptosis [38] and depressed left ventricular systolic function [39]. These abnormalities can trigger a vicious circle in which impairment of one organ can negatively affect the function of the other. 3 Cachexia in chronic diseases: definition and epidemiology Cachexia is a complex syndrome associated with poor outcome, independently of the underlying primary disease. It is characterised by loss of skeletal muscle with or without loss of fat mass. Several definitions have been proposed, most of them focusing on the dominant feature of weight loss alone, and only a minority of authors recognised the importance of body composition changes over time. Other causes of weight loss include anorexia, sarcopenia and malnutrition, all of them possibly occurring both in HF and in CKD. Differentiation from other syndromes of weight loss is important to the early recognition and possible management of the syndrome. Carr et al. [40] defined cachexia as a body fat content of <15% in men and <22% in women, or a percentage of ideal weight <90%, whilst later cachexia was defined as a loss of >10% of lean tissue [41]. Nevertheless, these definitions depend on an evalua- tion of body composition, which is frequently not applica- ble in clinical practice. A previous definition, derived from the SOLVD database, appears to be the most appropriate to use in clinical practice since it does not require biochemical or skeletal muscle performance tests. Cachexia should therefore be defined as ‘a non-oedematous weight loss of >6% of total body weight over a period of 6 or more months’ [12]. More recently, a new definition has been proposed, which takes into account the concomitant clinical features associated with weight loss; according to the definition proposed by Evans et al. [42], cachexia is ‘a weight loss of 5% in twelve months or less (or a body mass index <20 kg/ m2) in a patient with underlying chronic disease and at least three of the following criteria: decreased muscle strength, fatigue, anorexia, low fat-free mass index and abnormal biochemistry (inflammation, anaemia, low serum albumin)’ (Table 1). Cachexia is frequently observed in association with many chronic disorders. Up to 60% of patients with end- stage renal disease (ESRD) present with malnutrition [43, 44], where this term does not only imply reduced energy intake, like in simple starvation, but also complex meta- bolic changes. This entity has been identified as malnutri- tion–inflammation–atherosclerosis (MIA) syndrome with potential genetic implications in its pathogenesis [45]. The prevalence of cardiac cachexia, in one of our initial studies, 137 Table 1 Diagnostic criteria for cachexia (adapted from Evans et al.) Chronic disease + Weight loss of ≥5% in 12 months or less (or BMI <20 kg/m2) + ≥3 of the following: –Decreased muscle strength –Fatigue –Anorexia –Low fat-free mass index –Abnormal biochemistry (↑CRP or IL-6; Hb <12 g/dL; s-albumin <3.2 g/L) was 16% [11]; subsequent observations [12] reported an incidence of cardiac cachexia of 35%. Interestingly, in recent years, an inverse association with all-cause mortality and BMI in patients on haemodialysis has been reported [46], and preliminary studies suggest that this ‘reverse epidemiology’ is also present in CKD patients who are not on dialysis [47], particularly in proteinuric CKD [48]. Paradoxically, patients with higher BMI have lower all- cause and cardiovascular mortality. The occurrence of cachexia has therefore important prognostic implications in CKD, similarly to other chronic diseases; the under- standing of the mechanisms that lead to cachexia might therefore help in improving the outcome of CKD patients. 4 Pathophysiological mechanisms of cachexia syndrome 4.1 Chronic HF In 1984, Braunwald [49] suggested that in cardiac cachexia, right ventricular failure could be predominant; interestingly, the only predictor of malnutrition in patients with severe CHF was an increased right atrial pressure [40]. In another study, cardiac output and systolic and diastolic arterial pressures were found to be significantly lower in cachectic patients as compared with non-cachectic patients [50]. These findings suggest that haemodynamic conditions may play a role in the genesis of cardiac cachexia. Nevertheless, the most important players are neurohormon- al and immune mechanisms. The trigger for immune activation has been reported to be pressure overload [51] and splanchnic venous congestion with consequent bacte- rial translocation from the gut into the bloodstream [52]. Levine et al. [53] were the first to demonstrate increased levels of tumour necrosis factor-alpha in cachectic patients. Other studies confirmed a marked immune activation in patients with cardiac cachexia [54] and the expression of cytokines in the myocardium of CHF patients [55]. Pro-