The role of anticytokine therapy in heart failure: recent lessons from preclinical and clinical trials?

A decade ago, investigators first recognized that levels of the proinflammatory cytokine, tumor necrosis factor-alpha (TNFalpha), were elevated in patients with heart failure. Subsequent studies in isolated myocytes and in mice that overexpress TNF demonstrated that TNF could recapitulate the cellular biology and biochemistry of the failing human heart. In addition, anticytokine strategy in experimental models effected dramatic changes in the heart failure phenotype. The initial enthusiasm that was engendered by the studies in animal models has been tempered by a failure of these agents in phase II and III trials. The reassessment of basic and clinical science data regarding TNF pathobiology provides insight about these recent disparate results. To better understand this conundrum, this article reviews the basic pathobiology of TNF, the effects of anticytokine therapy in experimental and clinical studies, and an assessment of the future role of anticytokine therapy in the management of heart failure.