Endothelin expression and the progression of heart failure: exemplifying the vagaries of therapeutic development.

Increased expression of endothelin (ET)–1 has been well described in heart failure and has been thought to potentiate the progression of this disorder through hemodynamic effects as well as vascular and cardiac remodeling.1,2 Investigations of heart failure animal models3,4 as well as early clinical studies5–7 supported a potential beneficial effect of ET-1 blockade in heart failure. On the basis of these observations, it is surprising that larger-scale clinical trials failed to support the value of chronic endothelin receptor blockade in reducing symptoms or adverse clinical outcomes for patients with heart failure.8,9 In fact, there was evidence for harm, in part mediated through increased fluid retention. The study by Schirger et al10 in this issue provides us with important new insights into the role of ET-1 in the progression of cardiovascular remodeling to clinical heart failure. This study also reminds us of the caution required in navigating the complex road from a partial understanding of pathophysiology to achieving clinical benefit through pharmacological intervention.