The tumor necrosis factor superfamily in heart failure

Numerous clinical studies have established that tumor necrosis factor (TNF)-alpha may play a pathogenic role in the development and progression of heart failure (HF). Recent reports suggest that other ligands in the TNF superfamily could also play a pathogenic role in chronic HF. TNF superfamily ligands are expressed predominantly by cells in the immune system, while the TNF receptor superfamily are expressed by a wide variety of cells, including myocardial cells. Several pathways are activated by ligand-receptor interactions, but of particular importance is the nuclear factor (NF)-kappaB pathway which is activated in the failing human heart. All ligands in the TNF superfamily have the potential to activate NF-kappaB, leading to transcription of genes involved in apoptosis, cell survival, proliferation, inflammation and hypertrophic signaling in cardiomyocytes. Among several TNF superfamily members that are activated in HF, the authors' have recentlyshown that CD40L-CD40 and OPG-RANK-RANKL interactions may be implicated in the pathogenesis of HF through different mechanisms, possibly representing new targets for therapy in this disorder.