Endothelin receptor antagonists in heart failure: current status and future directions

Experimental evidence suggests that endothelin substantially contributes to left ventricular remodelling and progression of heart failure. Plasma endothelin (ET)-1 levels are increased in patients with heart failure, independent of the aetiology, and correlate with the severity of the disease. Furthermore, tissue endothelin levels and endothelin receptors are upregulated in myocardium from animals and humans with heart failure. In several experimental models of left ventricular remodelling and/or heart failure, treatment with nonselective ET-A and -B as well as selective ET-A antagonists exerted beneficial cardiovascular effects. In patients with heart failure, short-term studies of treatment with endothelin antagonists demonstrated an improvement of haemodynamic parameters; however, long-term treatment with these drugs did not significantly improve combined morbidity/mortality endpoints. Furthermore, in the recently completed Endothelin-A Receptor Antagonist Trial in Heart Failure (EARTH) trial in patients with chronic heart failure, the selective ET-A receptor antagonist darusentan did not significantly affect left ventricular remodelling as assessed by cardiac magnetic resonance imaging. Potential reasons for the lack of beneficial effects of long-term treatment with ET antagonists in patients with heart failure include the following. Firstly, adverse effects on left ventricular healing have been observed when endothelin antagonist therapy was introduced early after myocardial infarction in rats. Secondly, the role of the ET-B receptor in the pathophysiology of heart failure and remodelling processes has not been clearly defined. Finally, for the detection of improvement in left ventricular remodelling, a study needs to be conducted in patients with recent myocardial infarction and signs of heart failure.