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The accepted paradigms and treatment strategies for heart failure have changed during the past 50 years. Traditionally, patients with CHF were treated with diuretics, vasodilators and inotropic drugs, resulting in improvement in functional status and symptoms, but with no decrease in long-term mortality [1,2]. However, the initial haemodynamic dysfunction of CHF has downstream effects on cardiovascular reflexes, and systemic organ perfusion and function. The arterial under-filling is sensed by baroreceptors that activate powerful neurohormones, which act as effectors of vasoconstriction and of avid sodium and water retention. Recognition of neurohormones as important substances in the pathogenesis of CHF has resulted in several new treatment modalities, including angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists and β-blockers, which yield marked improvements in morbidity and mortality of CHF patients [3,4,5,6,7].
Despite 'state of the art' cardiovascular treatment, CHF is still a progressive disease with high morbidity and mortality, suggesting that important pathogenic mechanisms remain active and unmodified by the present treatment modalities. Persistent immune activation and inflammation may represent such 'unmodified mechanisms'. Attention has focused on mediators that are classically associated with innate immunity, including inflammatory cytokines [8].
Cytokines as pathogenic mediators of chronic heart failure
Cytokines are peptides that mediate cell-to-cell interactions via specific cell-surface receptors. They regulate activation, differentiation, growth, death and acquisition of effector functions of various cell types [9]. As a result, they are increasingly recognized as important factors in the pathophysiology of CHF (Fig. 1).
Figure 1 [Images not available. See PDF.]
Overview of potential inflammatory mechanisms that are involved in the development of chronic heart failure (CHF). Various stimuli, including autoimmunity, chronic infections, mechanical overload, ischaemia and oxidized low-density lipoprotein (LDL)-cholesterol, may induce production of inflammatory cytokines in CHF. Inflammatory cytokines may further negatively influence contractility and contribute to the remodelling process in the failing myocardium (e.g. hypertrophy and apoptosis of cardiomyocytes), resulting in a cardiomyopathy-like phenotype with cardiac dilatation and fibrosis. IL=interleukin; MCP=monocyte chemoattractant protein; TNF=tumour necrosis factor.
Several studies have demonstrated that CHF patients are characterized by persistent immune activation in vivo. This is reflected in increased circulating levels of inflammatory cytokines (TNF-α, IL-1β and IL-6) and chemokines (monocyte chemoattractant protein [MCP]-1 and IL-8), as well as enhanced expression of various inflammatory mediators (TNF-α, IL-6 and adhesion molecules) within the...