Tumor necrosis factor in congestive heart failure: A mechanism of disease for the new millennium?

Tumor necrosis factor alpha (TNF-α), a protein belonging to the family of cytokines, is one of the leading mediators of the immune response to inflammation. Its widespread biological effects are modulated by two circulating binding proteins corresponding to the extra-cellular domain of the membrane receptors, namely soluble TNF receptors. TNF-α was first supposed to be linked with congestive heart failure (CHF) on a cachexiainducing basis. In patients with advanced CHF, elevated levels of circulating TNF-α and soluble TNF receptors have been found. The pathophysiological implications of activation of the TNF system in CHF seem to rely mainly on its effects on the heart and the endothelium. TNF-α exerts a negative inotropic effect both directly and indirectly, this latter being mediated by enhancement of nitric oxide production. Moreover, TNF-α has been suggested to trigger the apoptotic process in cardiac myocytes. There is consensus on the detrimental role played by TNF-α in CHF further supported by the evidence of a temporal association between TNF activation and transition from asymptomatic to symptomatic CHF.