Review
Inflammatory mediators in heart failure

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Abstract

Cytokines have been identified as a major player in the pathogenesis and the functional status of patients with heart failure. Herein I review studies which are under way to assess the effects of anti-cytokine therapy, where soon we may see treatments directed against bacteria in the bowel, the translocation process, and endotoxin itself, the binding sites of bacterial endotoxin on immune competent cells, or both.

Introduction

It has become more clear over the past decade that many features of the syndrome of chronic heart failure can be explained by the known biological effects of inflammatory mediators. There has been a considerable increase in research in this area and it continues to remain a widely recognised and discussed field. Indeed, when expressed in experimental models at the concentrations that are observed in heart failure, inflammatory mediators such as tumour necrosis factor-α and nitric oxide can produce effects that mimic some clinical features of heart failure, including (but not limited to) progressive left-ventricular dysfunction, pulmonary oedema, left-ventricular remodelling, and cardiomyopathy [1], [2]. Thus, the elaboration of cytokines may be responsible, in part, for disease progression in patients with chronic heart failure [1].

Many cardiologists have learned and many more will need to increase their knowledge about what cytokines are. This is of increasing importance with the advent of anti-cytokine treatment as it has not only been successfully carried out in diseases such as rheumatoid arthritis [3], but for the first time this year in patients with chronic heart failure [4]. It appears that this is just the beginning of a new era of promising therapeutic options.

Section snippets

Inflammatory cytokines

It has become apparent that an ensemble of biologically active molecules termed cytokines, that are different from the better known neurohormons in many ways, are also expressed in the setting of heart failure. The term cytokine refers to a group of protein molecules with relatively small molecular weights (∼15–30 kDa) that are secreted by cells in response to a variety of different inducing stimuli. As opposed to cytokines, polypeptide hormones are generally produced by a specific cell type in

Interleukin-6

Interleukin-6 is a pro-inflammatory cytokine which has been shown to be elevated in patients with chronic heart failure [8], [9], and it is associated with severe symptoms of heart failure as demonstrated by a higher incidence of New York Heart Association (NYHA) functional class III and IV, worse left ventricular function, and a poorer prognosis [2], [10], [11].

In one study it was demonstrated that plasma IL-6 levels not only increased significantly from the femoral artery to the femoral vein

Tumour necrosis factor-α

In 1975, tumour necrosis factor-α (TNF-α) has been discovered in the search for an anti-cancer treatment [14]. While studying ‘haemorrhagic necrosis’ of tumours produced by endotoxin, it was found that the serum of bacillus Calmette–Guerin (BCG)-infected mice treated with endotoxin contained a substance, then termed tumour necrosis factor, which mimicked the tumour necrotic action of endotoxin itself. A variety of tests indicated that TNF was not residual endotoxin, but a factor released from

Cytokines in chronic heart failure

Cytokines have been shown to play a major role in the pathogenesis of various diseases, including chronic heart failure. Elevated levels of the pro-inflammatory cytokine TNF have been documented in patients with chronic heart failure, and this has been found to correlate with the severity of heart failure [18], [19]. Increased expression of tumour necrosis factor (TNF) has been found in cardiac tissue of patients with chronic heart failure undergoing heart transplantation and the failing heart

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