Other Organs and Mediators in Chronic Heart Failure It is now clear that the syndrome of heart failure is a multisystem disease, affecting not only the heart but also many other organs and processes including the sympathetic nervous system, the kidney, the gastrointestinal system and nutrition,31 hemopoiesis,32,33 the brain,34 and skeletal muscle.35 Of these only a few will be considered here Sympathetic Nervous System It is now widely acknowledged that activation of the sympathetic nervous system plays a central role in the pathogenesis of congestive heart failure This activation occurs early in the course of the disease, even before the onset of symptoms,36 and as the syndrome evolves may play both adaptive and maladaptive roles It appears that in the early stages of the syndrome, before the onset of symptoms, activation of the sympathetic nervous system occurs selectively within the heart37 and kidneys It has been suggested that this initially selective activation occurs secondary to ventricular dilation, which stimulates the release of natriuretic peptides and activation of the cardiac sympathetic nervous system This initially adaptive response to ventricular dysfunction may preserve myocardial function However, with worsening heart failure as cardiac output and systemic blood pressure fall, this selective activation of the sympathetic nervous system becomes generalized as the high-pressure baroreceptors within the heart and the carotid sinus become unloaded.38,39 Although activation of the sympathetic nervous system may play an important role in maintaining cardiac output and arterial blood pressure in the early stages of the condition (adaptive response), with time catecholamines may have detrimental effects Elevated levels of catecholamines in the plasma40 have been shown to correlate with decreased survival; this may be secondary to myocardial hypertrophy or activation of the renin-angiotensin system Catecholamines are also known to be toxic to the myocyte41 through their effects on the intracellular levels of calcium.42,43 Retention of Sodium and Water From the time that the condition was known as dropsy, retention of salt and water has been recognized to be a prominent feature of heart failure Recent decades have considerably improved our understanding of the mechanisms responsible for the retention of sodium and water and in particular have highlighted the contributions of activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the role of arginine vasopressin, aquaporins, and the natriuretic peptide systems.44 A pivotal trigger in the development of sodium and water retention has been posited to be arterial underfilling secondary to a reduction in cardiac output Unloading of the baroreceptors in the arterial tree results in the activation of sympathetic nervous activity, including effects on the kidneys, where it may not only directly cause the retention of sodium and water but also stimulate the renin-angiotensin system.45 Activation of the sympathetic nervous system within the supraoptic and paraventricular nuclei of the hypothalamus results in the release of vasopressin, which further contributes to the retention of water by the kidney Activation of the renin-angiotensin system occurs early in the evolution of heart failure, with levels of renin within the plasma being observed before the onset of symptoms in patients with subclinical ventricular dysfunction Angiotensin plays a number of roles in the pathogenesis of heart failure Although its synthesis is stimulated by sympathetic stimulation, angiotensin, in turn, enhances activity of the sympathetic nervous system through a positive feedback loop Angiotensin II has important vasoconstrictor properties as well as contributing directly to the development of cardiac hypertrophy and fibrosis.46 It plays a central role in retaining sodium and water through its direct effects on the tubular absorption of sodium as well as indirectly through its effects of the secretion of aldosterone by the adrenal gland The natriuretic peptide system, which is activated in heart failure, is also important in the retention of sodium and water In normal subjects, natriuretic peptides increase the rate of glomerular filtration and sodium excretion by the kidney Although the secretion of natriuretic peptides is increased in the early stages of the evolution of heart failure, it is now known that heart failure is associated with considerable resistance to their actions.44,47 This resistance to natriuretic peptides―which may contribute substantially to the retention of sodium―has been attributed to a number of factors including a downregulation of the receptors for natriuretic peptide in the kidney, the secretion of biologically inactive natriuretic peptide, or the enhanced degradation of natriuretic peptide by the enzyme neutral endopeptidase or by phosphodiesterase.48 Although for decades it was thought that vasopressin contributed little to the retention of water in patients with heart failure, it has been shown more recently that vasopressin, through its actions on aquaporins within the collecting duct of the renal tubule, may play a central role.49 In animal models of congestive heart failure, the expression of aquaporin-2 is increased,50 and in clinical studies antagonists of vasopressin may result in a dose-related increase in water excretion.51