Besides activation of the immune system, neurohormonal abnormalities are also important in the pathophysiology of the development of cardiac cachexia. Attributed to impaired cardiac function, a general neurohormonal activation, in which the sympathetic nervous system, the renin-angiotensin-aldosterone axis, and the natriuretic peptide system are stimulated, occurs when heart failure deteriorates to a chronic disease state.
Fig. 3. The cardiorenal anaemia syndrome - anaemia as a cause and consequence of heart failure: anaemia, plasma volume and haemodynamic changes, sympathetic activation, vasoconstriction, tissue ischaemia, and tissue injury are components of a vicious circle. ADH, antidiuretic hormone; LV, left ventricular; LVH, left ventricular hyperthrophy; SNS, sympathetic neervous system. Adapted from 
Initially, these changes have a beneficial effect; however, later they contribute to increased vascular resistance, afterload, ventricular enlargement, and remodelling.
The overall sympathetic activity is demonstrated by an increased plasma norepinephrine level . Norepinephrine and epinephrine levels were markedly increased in a cachectic group of 53 CHF patients, who were stratified for LVEF, NYHA class, and presence of cachexia, compared to non-cachectic CHF patients and healthy subjects  (Fig. 2). Both of norepinephrine and epinephrine can cause a catabolic metabolic shift [25, 26] and lead to an increase in resting energy expenditure in CHF patients .
The importance of neuroendocrine activation in the development of cachexia in CHF is also reflected in increased aldosterone plasma levels and increased plasma renin activity . Adult patients with congenital heart disease have significantly higher levels of the neurohormones ANP, BNP, ET-1 (all p < 0.0001), norepinephrine, renin (p = 0.003), and aldosterone (p = 0.024) . Interestingly, there was a highly significant step-wise increase in the concentrations of ANP, BNP, ET-1, and norepinephrine with increasing disease severity. Angiotensin II- and aldosterone-activity explain the fibrosis of smooth muscle cells as well as the reduction of circulating insulin-like growth factor (IGF)-1 . Renin again stimulates the production of angiotensin II and norepinephrine (renin-angiotensin-system) .
Furthermore, the growth hormone (GH)/IGF-1 axis is involved in the pathogenesis of the wasting process [47, 48]. Abnormal GH/IGF-1 ratios and low testosterone levels correlate with the degree of weight loss in cachectic CHF patients .
The hormone cortisol is also considered to be part of the general stress response and exerts a catabolic effect. Increased cortisol was demonstrated in untreated patients with severe CHF (Fig. 2) , which was probably due to an elevated release of adrenocorticotropic hormone . This catabolic/anabolic imbalance was confirmed by a study in which the anabolic steroid dehy-droepiandrosterone was lowest in cachectic CHF patients and cortisol levels were particularly increased in cachectic CHF patients .
The protein leptin is involved in the regulation of food intake and energy balance , and it serves as an important signal from fat to brain. Raised levels of leptin can decrease food intake and increase resting energy expenditure . The role of leptin in the development of cardiac cachexia has not yet been elucidated, but it was reported that plasma leptin levels are increased in CHF  and higher leptin levels are associated with increased sympathetic activity . However, there are some contradictory reports on this issue [54,55].
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