The lack of efficacy of Sac/Val in the LIFE trial for example, might be attributable to the desensitisation of natriuretic peptide receptors and high BNP levels causing inhibition of neprilysin, making patients enrolled in the trial less responsive to Sac/Val therapy [39] (although the evidence base for Sac/Val in advanced HF remains scarce, with few NYHA IV patients enrolled in other clinical trials). This evidence concerns the gene NPPB and hydrops fetalis.