In 2014, the Prospective Comparison of ARNI with ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF)11 randomized clinical trial demonstrated that the combination of a neprilysin inhibitor (sacubitril) plus an ARB (valsartan) reduced heart failure hospitalizations and deaths compared to ACE-I (enalapril) monotherapy. This evidence concerns the gene MME and heart failure.