This review highlights the complex role of inflammatory cytokines in heart failure pathogenesis and the challenges in developing effective immunomodulatory therapies.
Evidence from both experimental and clinical trials indicates that inflammatory mediators are of importance in the pathogenesis of chronic heart failure (HF) contributing to cardiac remodeling and peripheral vascular disturbances. Several studies have shown raised levels of inflammatory cytokines such as tumor necrosis factor (TNF)α, interleukin (IL)-1β and IL-6 in HF patients in plasma and circulating leukocytes, as well as in the failing myocardium itself. There is strong evidence that these mediators are involved in processes leading to cardiac remodeling such as hypertrophy, fibrosis and apoptosis. Some of these cytokines can also give useful prognostic information as reliable biomarkers in this disorder. In general, immunomodulating treatments have, with a few exceptions, been neutral or even harmful. However, the negative results of anti-TNF studies, for instance, do not necessarily argue against the ‘cytokine hypothesis’. These studies just underscore the challenges in developing treatment modalities that can modulate the cytokine network in HF patients and result in beneficial net effects. Future studies should identify the crucial actors and their mechanisms of action in the immunopathogenesis of chronic HF and, in particular, clarify the balance between adaptive and maladaptive effects of these molecules. Such studies are a prerequisite for the development of new treatment strategies that target inflammatory and immunopathogenic mechanisms in HF. In this review article, these issues are thoroughly discussed, and we also argue for the possibility of future therapeutic targets such as mediators in innate immunity, chemokines and mediators in matrix remodeling.
Gullestad et al. (Sun,) studied this question.