TNF and congestive heart failure: therapeutic possibilities

TNF-alpha is a cytokine that may play a role in the pathogenesis of heart failure. In patients with heart failure, increased levels of TNF-alpha were observed that were high enough to reduce cardiac contractility in vitro. The mortality of heart failure patients increases with higher levels of TNF-alpha. For these reasons, inhibition of TNF-alpha appears to be a valid target for the improvement of heart failure therapy beyond the current practice of inhibiting neurohormonal activation with beta-blockade, angiotensin-converting enzyme (ACE) inhibition and aldosterone antagonism. However, whilst this strategy (using soluble TNF receptor or TNF antibodies) was successful in smaller short-term studies, larger longer-term studies have not revealed any beneficial effect of this therapy (RENAISSANCE, RECOVER, RENEWAL, ATTACH). In contrast, the mortality tended to be higher in the treated groups giving rise to questions about the overall strategy. The reasons for this failure of the clinical studies to show a longer-term benefit from TNF-alpha inhibitors are unclear, but they may include an error of the general concept, individual adverse effects of the agents used for the studies, incorrect dosage and the fact that the current therapy of heart failure with beta-blockade, ACE inhibitors and aldosterone antagonists cannot be further improved by additional blockade of neurohormones or cytokines.