The role of endothelin in the pathogenesis of heart failure.

In fewer than than 15 years since its discovery, endothelin is now recognized as playing a central role in the pathogenesis of chronic heart failure. This review examines the signaling pathways and mechanism of action of endothelin in relation to the studies that have elucidated this role. Early investigations observed that the endothelin system is markedly upregulated in heart failure, whereas others demonstrated that endothelin is the most potent vasoconstrictor. However, it has multiple other actions, including mediating pathologic hypertrophy and fibrosis of both ventricular and vascular tissues, acting as a proarrhythmic, and potentiating the effects of other neurohormones. Endothelin receptor antagonists were developed to investigate the hypothesis that these adverse effects could be prevented and experimental studies showed promise in this regard. Clinical studies to date have not fulfilled this promise. Further analysis of these trials will hopefully provide insight into these disparate findings and guidance for future investigations.