Neurohormonal Abnormalities

Beta Switch Program

Beta Switch Program by Sue Heintze

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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 [41]

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 [42]. 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 [26] (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 [43].

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 [26]. 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) [44]. 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 [45]. Renin again stimulates the production of angiotensin II and norepinephrine (renin-angiotensin-system) [46].

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 [26].

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) [49], which was probably due to an elevated release of adrenocorticotropic hormone [50]. 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 [26].

The protein leptin is involved in the regulation of food intake and energy balance [51], and it serves as an important signal from fat to brain. Raised levels of leptin can decrease food intake and increase resting energy expenditure [52]. 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 [53] and higher leptin levels are associated with increased sympathetic activity [52]. However, there are some contradictory reports on this issue [54,55].

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