Abstract 13675: New Treatments for Myocardial Stunning: Creating an Optimal Drug Cocktail for CPR
Introduction: Myocardial stunning following sudden cardiac arrest resuscitation increases morbidity and mortality. Previous work suggests that intra-ischemic cooling protects against stunning by enhancing Akt survival signaling, with related enhancement of glucose utilization and NAD+ recovery. New or existing drugs that mimic these effects could improve cardiac arrest outcomes. Here we test agents known to activate PI3K/Akt signaling, increase pyruvate dehydrogenase activity, and enhance NAD+ content. They were tested for their ability to improve contractile recovery in a mouse cardiomyocyte stunning model.
Methods: Primary neonatal cardiomyocytes were exposed to 30 min ischemia and 90 min reperfusion followed by 10 min isoproterenol (1μM). Therapeutic hypothermia (TH) using intra-ischemic cooling (32 ± 0.5°C), the PTEN inhibitor VO-OHpic (VO, 1μM), insulin (0.01U/ml), intralipid (ILE, 0.25%), dichloracetate (DCA, 2 mM), and the NAD+ augmentation agents NAM (10 μM), and Nampt peptide (1-200 nM) were administered at reperfusion. Akt phosphorylation was detected by Western blot. ATP content was measured by a fluorescent assay kit.
Results: Compared to control cells, spontaneous contractions ceased within 5 min of ischemia and upon reperfusion recovered to less than 40% of baseline contractions despite isoproterenol treatment. Comparable to TH, the use of VO, DCA, NAM, insulin or ILE all induced a rapid and strong contractile recovery with the most significant sustained effect seen with VO and ILE. Both VO and TH improved recovery of ATP after reperfusion to comparable levels. NAM resulted in a rapid recovery that was not sustained with one dose, while Nampt had no effect. The most synergistic cocktail of two-drug combinations tested was VO plus NAM. VO increased Akt phosphorylation while NAM treatment did not, suggesting that the complementary protective effect of NAM was downstream of Akt activation.
Conclusions: Treatment of contractile stunning after cardiac ischemia can be achieved by drugs that mimic critical aspects of cooling protection, including Akt activation and NAD+ supplementation. Further work is needed to test drug combinations during cardiopulmonary resuscitation (CPR) that improve myocardial recovery.
Author Disclosures: J. Li: None. Z. Shao: None. C. Li: None. X. Zhu: None. T.L. Vanden Hoek: None.
- © 2015 by American Heart Association, Inc.