Inflammatory mediators in chronic heart failure: an overview
2004; BMJ; Volume: 90; Issue: 4 Linguagem: Inglês
10.1136/hrt.2002.007005
ISSN2053-5864
Autores Tópico(s)Signaling Pathways in Disease
Resumohronic heart failure (CHF) represents a major public health burden, and its prognosis is comparable to that of different malignant diseases.Our understanding of CHF has developed from the rather simplistic model of mere pump failure to that of a multisystem disorder which affects not only the cardiovascular system but also the musculoskeletal, renal, neuroendocrine, and immune systems.Thus, the pathophysiology of CHF is exceedingly complex.Therapies to block excessive neuroendocrine activation have become a cornerstone of treatment.CHF progresses because of activation of neurohormones and pro-inflammatory cytokines following an initial cardiac injury or a mutation of the genetic programme. 1Virtually any heart disease can ultimately lead to heart failure, although the initial event leading to the development of this syndrome is in many cases unknown.However, CHF is always the result of some underlying process and the diagnosis cannot stand alone.The activation of the aforementioned systems maintains and worsens CHF.In particular, the activation of the immune system has received considerable interest in the last decade.There are several different components to this system which interact with each other in a complex manner.It is becoming increasingly apparent that inflammatory mediators play a crucial role in the development of CHF, and several strategies to counterbalance different aspects of the inflammatory response are considered.Possible targets involve pro-and anti-inflammatory cytokines and their receptors, endotoxin, adhesion molecules, nitric oxide and nitric oxide synthase, reactive oxygen species, and different types of leucocytes.The purpose of this review is to give a brief overview of the current understanding of the role of inflammation in CHF.Furthermore, we will discuss recent advances in the development of new therapeutic strategies in this field. ROLE OF PRO-INFLAMMATORY CYTOKINES cCytokines form a vast array of relatively low molecular weight, pharmacologically active proteins.These substances are secreted by different cell types for the purpose of altering either their own function (autocrine) or that of adjacent cells (paracrine).The most important cytokines implicated in the progression of CHF are tumour necrosis factor a (TNFa), interleukin (IL) 1, and IL-6.These cytokines share some of their major characteristics (redundancy), and all act in a proinflammatory sense.Among those, TNFa is the cytokine which has been studied in greatest detail.Several hypotheses have been suggested to describe the origin of immune activation in CHF (fig 1).The production of pro-inflammatory cytokines has mostly been attributed to secretion by mononuclear cells, although the myocardium seems to be another important source.Some evidence suggests that catecholamines augment this myocardial cytokine production.The concepts trying to explain increased production of pro-inflammatory mediators comprise response to myocardial injury 2 and underperfusion of peripheral tissues 3 (fig 1).We have proposed that increased bowel wall oedema causes translocation of bacterial endotoxin from the gut which eventually yields pro-inflammatory cytokine production from monocytes in the bloodstream and possibly other tissues. 4Indeed, endotoxin, also known as lipopolysaccharide (LPS), is one of the strongest inducers of TNFa and other pro-inflammatory mediators (fig 2A).Very small amounts of this substance are capable of inducing TNFa secretion. 5 Attempts to prove any of the aforementioned hypotheses, however, yielded only indirect evidence.Thus, the elevation of the plasma concentrations of several pro-inflammatory mediators in acute myocarditis and acute myocardial infarction may hint towards the tissue injury hypothesis. 2 Also, peripheral IL-6 spillover was found to be increased in patients with CHF when comparing arterial and venous plasma concentrations, thus indicating a peripheral cytokine production. 3This, however, has not been demonstrated for TNFa.Moreover, soluble CD14, a marker of endotoxin-cell interaction and shedding from the cell membrane (fig 2A), was found to be increased in some patients with CHF (controls: 2714 (121) ng/ml; CHF patients: 3401 (134) ng/ml, p = 0.0048), especially in those with cachexia. 4It was subsequently shown that LPS concentrations are raised in CHF patients 464 www.heartjnl.com
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