TNF alpha—Still a Therapeutic Target

For over a decade a wealth of scientific information suggested that the proinflammatory cytokine tumor necrosis factor‐α (TNF‐α) could serve as a target for the treatment of patients with heart failure. While the normal mammalian heart (including the human heart) does not produce TNF‐α, hearts with compromised function reexpress significant amounts of TNF‐α, which is released into the peripheral circulation. Indeed, circulating levels of TNF‐α correlate inversely with functional capacity and with survival in patients with heart failure. Furthermore, in the basic science laboratory, investigators found that both infusion of TNF and transgenic overexpression in rodent models recapitulated the heart failure phenotype as animals exposed to TNF demonstrated diminished cardiac function, cardiac dilatation, extracellular matrix remodeling and fibrosis, ventricular tachyarrhythmias, abnormal calcium homeostasis, apoptosis, and early death. Furthermore, discontinuation of infusions of TNF‐α, inhibition of the bioactivity of TNF by overexpression of the TNF‐soluble receptor or infusion of an anti‐TNF antibody or genetic ablation of the TNFR1 (but not the TNFR2) receptor prevented or rescued the heart failure phenotype in experimental animals. Based on this wealth of basic science information, investigators assessed the efficacy of etanercept, a recombinant dimer consisting of two moieties of TNF‐soluble receptor linked by human IgG. In early phase II studies, etanercept improved functional capacity and inhibited maladaptive cardiac remodeling in patients with heart failure. However, in a large study, etanercept proved ineffective—leaving investigators to wonder why an approach that proved so successful in animal models was not viable in humans. In the accompanying report, Dr. Mann and his colleagues provide one explanation for the ineffectiveness of TNF‐soluble receptors in improving outcomes in patients with heart failure. This work points out the inherent difficulties in translating scientific discoveries in the laboratory to effective therapies in the clinical arena. Furthermore, it points out the fact that translational medicine is a two‐lane highway—and not a one‐way street. By going back to the bench to ask, try, and understand why etanercept did not work, investigators have now identified an explanation for the lack of effectiveness of etanercept. More importantly, this work supports the concept that in studying etanercept for the therapy of heart failure—we chose the wrong drug—and not the wrong target. Thus, the proinflammatory cytokine pathway may still be an effective target in the treatment of patients with heart failure—if we can identify better therapeutic agents.