Raising NAD in Heart Failure

t has long been known that cellular NAD levels are a critical regulator of metabolism and bioenergetics. The intracellular NAD pool consists of both oxidized (NAD + ) and reduced forms (NADH). NAD + is the main hydride acceptor in intermediary metabolism. Electrons derived from substrate catabolism are carried by NADH and used for oxidative phosphorylation and biosynthetic reactions. These reduction-oxidation reactions are not only essential for mitochondrial function and cell metabolism but also serve as important modulators of cell signaling. 1,2 NAD + functions as a cosubstrate for sirtuin deacylases, ADP-ribose transferases, and cyclic ADP-ribose synthases that govern posttranslational modification of proteins, DNA repair, and inflammatory responses. he cellular NAD + level is determined by the NAD(H) pool size (total NAD + and NADH concentration) as well as its reduction-oxidation state. The former is dependent on cellular NAD + consumption and regeneration, whereas the latter is regulated by cell metabolism and mitochondrial function (Figure). Emerging evidence suggests that derangements in the myocardial NAD pool are causally linked to metabolic remodeling and mitochondrial dysfunction in the failing heart. Stabilizing the intracellular NAD + level represents a promising therapeutic strategy to improve myocardial bioenergetics and cardiac function. In this issue of Circulation, Diguet et al 5 report exciting data suggesting that supplementation with a NAD + precursor, nicotinamide riboside (NR), reduces cardiac dysfunction in preclinical models of heart failure.