HMGCS2 and heart failure: SIRT3 is the major deacetylating enzyme, itself dependent on the NAD+/NADH ratio.35,53 In addition to its role in deacetylating HMGCS2, there are other roles of SIRT3, which are important to consider in the context of heart failure and HFpEF, including maintaining mitochondrial function54–56 and preventing cardiac hypertrophy.54