Abstract 4595: Intra-arrest Hypothermia Preserves Heart Akt Phosphorylation And Cardiac Function Following Cardiac Arrest In Wild-type But Not Akt(+/−) Mice

Abstract

OBJECTIVE: To establish the role of Akt signaling in hypothermia protection following cardiac arrest. METHODS: Cardiac arrest was induced in anesthetized C57B6 wild-type (WT) and Akt1(+/−) heterozygous mice with an intravenous bolus of KCl. Animals were randomized to normothermia ( NT , 37°C) or hypothermia ( HT , 30°C) induced after 6 minutes of arrest and continued for 1 hour following return of spontaneous circulation (ROSC). After 8 minutes, resuscitation was attempted with chest compressions, mechanical ventilation, and fluid administration. Following ROSC, resuscitated animals were monitored for up to 4 hours. Total Akt and phosphorylated Akt (pAkt at Ser473 and Thr308) levels were measured by Western blot analysis in whole heart lysates from 4-hour survivors and shams (n=4 each group). RESULTS: In WT animals, 4-hour survival (HT = 7 of 8, NT = 3 of 8, p < 0.04), cardiac output (p<0.001) and left-ventricular dP/dt max (p<0.001) were significantly improved in HT versus NT animals. In addition, hearts from WT animals randomized to HT displayed increased pAkt (Ser473) levels and over 8-fold higher pAkt(Thr308) levels compared to NT and sham groups (p<0.001). These pAkt changes occurred despite total Akt levels remaining unchanged. Baseline hemodynamics prior to arrest were similar between WT and Akt(+/−) animals, while heart Akt1levels were decreased by approximately 40% in Akt(+/−) heterozygous mice. In contrast to WT mice, HT compared to NT had no effect on Akt(+/−) mouse 4-hour survival rates and left-ventricular hemodynamic measures. Compared to HT treated WT mice, Akt(+/−) animals treated with HT displayed significantly lower maximum left-ventricular pressure, stroke volume, and dP/dt max by 4 hours post-ROSC (p<0.05). CONCLUSIONS: HT improves short-term cardiovascular outcomes and induces signficant heart Akt(Thr308) phosphorylation during the immediate post-ROSC period. The therapeutic benefit of intra-arrest HT on post-ROSC hemodynamics is greatly attenuated in Akt(+/−) animals, suggesting that Akt signaling may play a critical role in mediating HT protection.