Endothelins: pathophysiology and treatment implications in chronic heart failure

Less than 20 years after its discovery, endothelin is recognized as playing a central role in the pathogenesis of chronic heart failure. Endothelin is not only one of the most potent known vasoconstrictors; it also has multiple other actions. It mediates pathologic hypertrophy and fibrosis of both ventricular and vascular tissues, it potentiates the effects of other neurohormones, and it acts as a proarrhythmic. Endothelin receptor antagonists have been developed to investigate the hypothesis that these adverse effects could be prevented, and experimental studies showed promise in this regard. Clinical studies have confirmed the ability of these new agents to improve hemodynamics, but beneficial effects on clinical outcomes have been more difficult to demonstrate. Further analysis of the data from these trials, as well as other ongoing studies, may provide insight into these disparate findings and guidance for future investigations.