Having said this, it is very interesting to then find a significant upregulation of ACE exclusively in the subgroup of patients with the lowest left ventricular ejection fraction at baseline in our study, since this could indicate a strengthening of the detrimental ACE-mediated axis, which counterbalances the activated and protective ACE2-mediated site of the RAS as soon as heart failure has reached its most advanced stages. This evidence concerns the gene ACE and heart failure.