Abstract 12474: Nicotinamide Restores Tissue Nad+ and Improves Outcomes in a Murine Model of Cardiac Arrest
Introduction: Metabolic suppression in the ischemic heart is characterized by reduced levels of NAD+ and ATP.
Hypothesis: Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide (NAM) restore of tissue NAD+ and improve cardiac function and survival in a mouse model of cardiac arrest.
Methods: Cardiomyocytes isolated from 1-2-day old C57BL6 mice were exposed to 30 min ischemia and 90 min reperfusion. Contraction recovery was measured by phase contrast imaging without and with 0.1mM NAM given at reperfusion. Adult C57BL6 mice were subjected to an established KCL-induced 8 min cardiac arrest protocol, randomly assigned to receive saline or 500 mg/kg NAM after cardiopulmonary resuscitation (CPR). Survival, MAP, ETCO2, and continuous ECG were recorded until 4 h after successful CPR.
Results: We first tested the effect of NAM on NAD+ recovery in heart cells exposed to the simulated ischemia and reperfusion. NAD+ content was decreased from 4.51 ± 0.03 nMol/g before ischemia (equilibration) to 2.69 ± 0.42 nMol/g at the end of ischemia. Treatment with 0.01 mM NAM completely restored the cellular level of NAD+ by 15 min reperfusion (4.63 ± 0.45 nMol/g), while there was no significant recovery of NAD+ in untreated cells. This rescue of NAD+ depletion was associated with improved contractile recovery by 10 min reperfusion (58.1 ± 7.3% return of baseline contractile velocity vs.18.5 ± 3.7% in control cells, n=5, p<0.05) that could be augmented further using isoproterenol treatment (83.3 ± 3.5% vs. 58.0 ± 2.9% in control cells. p<0.05). We then tested the effect of NAM (500 mg/kg) on mouse SCA 4 h survival and cardiovascular recovery. NAM administered IV after CPR resulted in a trend toward improved mouse SCA survival, with 9/10 survival at 4 h as compared to 5/10 in the saline (NS) group. Compared to saline treated mice, NAM-treated mice displayed improved NAD+ content in hearts obtained at 4 h post-ROSC compared to saline treated SCA hearts (2.4 ± 0.1 nMol/g vs. 4.5 ± 0.1 nMol/g, p<0.05).
Conclusions: NAM is CPR medication that can rapidly restore cardiac tissue NAD+ and promote contractile recovery, with improved early survival demonstrated in a mouse model of cardiac arrest.
Author Disclosures: X. Zhu: None. J. Li: None. H. Wang: None. C. Lee: None. T. Vanden Hoek: None.
- © 2016 by American Heart Association, Inc.