Rationale : Mutations in glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) protein reduce cardiac Na + current ( I Na ) and cause Brugada Syndrome (BrS). GPD1-L has >80% amino acid homology with glycerol-3-phosphate dehydrogenase, which is involved in NAD-dependent energy metabolism. Objective : Therefore, we tested whether NAD(H) could regulate human cardiac sodium channels (Na v 1.5). Methods and Results : HEK293 cells stably expressing Na v 1.5 and rat neonatal cardiomyocytes were used. The influence of NADH/NAD + on arrhythmic risk was evaluated in wild-type or SCN5A +/− mouse heart. A280V GPD1-L caused a 2.48±0.17-fold increase in intracellular NADH level ( P <0.001). NADH application or cotransfection with A280V GPD1-L resulted in decreased I Na (0.48±0.09 or 0.19±0.04 of control group, respectively; P <0.01), which was reversed by NAD + , chelerythrine, or superoxide dismutase. NAD + antagonism of the Na + channel downregulation by A280V GPD1-L or NADH was prevented by a protein kinase (PK)A inhibitor, PKAI 6–22 . The effects of NADH and NAD + were mimicked by a phorbol ester and forskolin, respectively. Increasing intracellular NADH was associated with an increased risk of ventricular tachycardia in wild-type mouse hearts. Extracellular application of NAD + to SCN5A +/− mouse hearts ameliorated the risk of ventricular tachycardia. Conclusions : Our results show that Na v 1.5 is regulated by pyridine nucleotides, suggesting a link between metabolism and I Na . This effect required protein kinase C activation and was mediated by oxidative stress. NAD + could prevent this effect by activating PKA. Mutations of GPD1-L may downregulate Na v 1.5 by altering the oxidized to reduced NAD(H) balance.