Potential Mechanisms of Benefit with Thalidomide in Chronic Heart Failure

This review considers the recent clinical and relevant preclinical evidence that thalidomide may have therapeutic benefit in chronic heart failure (HF), and considers some of the mechanisms by which thalidomide may elicit potentially beneficial effects. Persistent inflammation, involving increased levels of inflammatory cytokines, seems to play a pathogenic role in chronic HF by influencing heart contractility, inducing matrix degradation and fibrosis, and promoting apoptosis, contributing to myocardial remodeling. On the basis of these issues, immunomodulating therapy has emerged as an option in the management of chronic HF. Failure of anti-tumor necrosis factor (TNF) therapy has lead to further interest in a more general immunomodulatory approach, directed against the imbalanced cytokine network rather than at one particular cytokine.Some recent studies suggest that thalidomide, a glutamic acid derivative with proposed antiangiogenic, anti-inflammatory, and immunomodulatory properties, should be added to the list of potential immunomodulating agents in chronic HF. Thus, in a recent double-blind, placebo-controlled study in patients with chronic HF, thalidomide was found to significantly improve left ventricular ejection fraction. Although thalidomide has been regarded as an anti-TNF drug, it was found to increase plasma levels of TNFalpha in a placebo-controlled study in patients with HF, suggesting that other mechanisms may contribute to its beneficial effects. Such mechanisms could involve inhibition of neutrophils, matrix stabilizing, and antifibrotic effects, as well as a thalidomide-mediated decrease in the heart rate. However, our knowledge of the mechanisms of action of this drug is still scarce and will have to be further examined in forthcoming studies. Such studies should include experiments in animal models of HF as well as further preclinical trials, attempting to identify the potential mechanisms by which thalidomide may be beneficial in human HF.