Raising NAD in Heart Failure

It 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. 1,2NAD + 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. 2he 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(definition) in the failing heart.Stabilizing the intracellular NAD + level represents a promising therapeutic strategy to improve myocardial bioenergetics and cardiac function. 1,3,4In 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.In a genetic mouse model of dilated cardiomyopathy, induced by the deletion of serum response factor in the heart (SRF HKO ), Diguet et al 5 found that supplementation of NR in the diet significantly reduced left ventricular contractile dysfunction and chamber dilation.A similar, albeit moderate, effect was also observed in mice with pressure overload-induced hypertrophy and dysfunction.These observations are consistent with prior work demonstrating the beneficial effects of increasing NAD levels on cardiac hypertrophy and function in models of agonist-induced pathological hypertrophy, 6 chronic pressure overload, 7 and mitochondrial cardiomyopathy associated with Friedreich's ataxia. 7Therefore, this study adds support to the emerging concept of increasing NAD levels as a therapeutic strategy for heart failure.Despite the compelling evidence that expanding the intracellular NAD pool benefits the failing heart, the question of how it works remains not fully answered.8][9] Those studies suggested that protein hyperacetylation was attributable to impaired NAD + -dependent protein deacetylation by sirtuins, especially Sirt3, the mitochondria-localized sirtuin. 7,8The benefit