Neurohormonal Inhibition in Heart Failure: Insights from Recent Clinical Trials

Heart failure (HF) is a clinical syndrome characterized by chronic, persistent activation of the neuroendocrine system, which has been assumed to be linked to disease progression and adverse outcomes. Clinical trials have shown that adrenergic modulators, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone blockers, and β-blockers, improve long-term outcomes in patients with HF. These findings have led to the hypothesis that inhibition of a single neurohormonal or cytokine pathway may continue to provide incremental benefits. However, the results of recent clinical trials, using centrally acting agents-endopeptidase inhibitors or endothelin and cytokine antagonists-suggest that selective inhibition of neurohormonal systems may not be advantageous and actually may have serious adverse effects. The reasons for this lack of benefit may be ascribed to the fact that long-term mortality benefits in patients with chronic HF are primarily the result of treatment of the diseases that have caused HF in the first place rather than treatment of neurohormonal abnormalities.