Is there any future for tumor necrosis factor antagonists in chronic heart failure?

Over the past decade, a large number of studies have demonstrated that tumor necrosis factor-alpha (TNFalpha) plays an important role in the development of heart failure. Indeed, administration of TNFalpha to experimental animals and transgenic over-expression of TNFalpha replicate the heart failure phenotype. Furthermore, attenuation of the biologic activity of TNFalpha abrogates the development of heart failure in model systems. These pre-clinical studies, suggested that anti-cytokine therapy could prove beneficial in the treatment of patients with heart failure. While early studies supported this hypothesis, anti-TNF strategies have not demonstrated salutary benefits in large, multicenter randomized and placebo-controlled clinical trials in patients with symptomatic heart failure. This finding was disappointing. However, recent studies might provide clarification of this conundrum. For example, the failure to elicit beneficial effects with anti-cytokine therapy might be explained by novel pharmacogenomic or pharmacodynamic effects, the design of the Phase III clinical trials, or discordance between animal models and the human condition. Thus, appropriately designed clinical trials and newer anticytokine agents may demonstrate benefit.