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

In summary, over a decade of investigation has demonstrated the pathophysiologic importance of TNF in the development and progression of cardiac dilatation and heart failure. Although the signaling pathways that regulate the cardiac production of TNF have not yet been identified and the potential benefits of TNF expression to the heart are not understood, the benefits of anticytokine therapy in animal models is marked. Unfortunately, these salutary effects in the laboratory have not transitioned to the bedside. To accomplish the translational portion of the cytokine story, we must identify the point in time during the transition from compensated to decompensated heart failure in which TNF is expressed. In addition, we must better understand the role that other down-stream and non-TNF-dependent cytokines play in the development of heart failure. Not all patients are the same; therefore, we must pursue clinical trials that will allow us to elucidate the optimal degree of TNF inhibition, identify the patients who are most likely to respond to TNF inhibition, and determine what the true, long-term effects of TNF inhibition may be. Finally, we must recognize that inflammatory activities can exist in tissues and organs in the absence of TNF. Thus, anticytokine strategies alone might not be effective in ameliorating the signs and symptoms of heart failure. It is hoped that the failure of recent studies to demonstrate salutary benefits in patients with class II to IV heart failure will not diminish enthusiasm for the long-term potential of anticytokine therapy.