Abstract Body: Introduction: Nicotinamide phosphoribosyltransferase (Nampt) is a rate limiting enzyme that converts nicotinamide (NAM) to nicotinamide mononucleotide (NMN), which is then converted to nicotinamide adenine dinucleotide (NAD⁺) by nicotinamide mononucleotide adenylyltransferase (Nmnat). NAD⁺ serves as an adenosine donor and source of high energy phosphate for the synthesis of ATP and regulates NAD⁺-dependent key cellular enzymes. Given its critical role in metabolism and energetic recovery, which is significantly associated with cardiac arrest outcomes, we hypothesized that Nampt deficiency could affect cardiac arrest survival in a mouse asystole arrest model.
Methods: C57BL6 wild type and Nampt^+/- mice underwent 8 min of KCl-induced asystole arrest and were monitored for up to 4-h following return of spontaneous circulation. NAM (100 mg/kg) or NMN (100 mg/kg) were administered during CPR in wild type and Nampt^+/- mice and survival was assessed by Log Rank analysis. Levels of Nampt and NAD⁺ in critical organs, heart and brain, were measured. A p < 0.05 was considered as statistically significant.
Results: Compared to wild type mice, survival was decreased from 60% to 20% in Nampt^+/- mice (N=10 each group, p < 0.05). The reduced Nampt expression was observed in Nampt^+/- mice. NAD⁺ content was decreased in the heart and brain of Nampt^+/- mice at baseline and 30 min post-ROSC (n=5, p<0.05). NAM administration did not improve Nampt^+/- mice survival. In contrast, NMN which bypasses Nampt for NAD⁺ supplementation, significantly improved 4-h survival of Nampt^+/- mice.
Conclusions: Nampt deficiency decreases mouse cardiac arrest survival. NMN may serve as a new therapeutic strategy for improving cardiac arrest survival.