We believe that this is the largest-ever study of the association between circulating ET-1 and a range of outcomes in HFrEF.25 We confirmed the prognostic importance of this peptide in a well-treated, contemporary population, provided novel information about the incremental predictive value of ET-1 when added to NT-proBNP and hs-TnT (particularly for HF hospitalization), and showed a previously unknown association between ET-1 and progressive worsening of kidney function over time in patients with HFrEF. This evidence concerns the gene EDN1 and hydrops fetalis.