Beiser DG, Wojcik KR, Zhao D, Orbelyan GA, Hamann KJ, Vander Hoek TL. Akt1 genetic deficiency limits hypothermia cardioprotection following murine cardiac arrest. Therapeutic hypothermia (TH) cardioprotection has recently been associated with increased Akt signaling in a rat model of cardiac arrest. However, it is not known whether Akt is required for this beneficial effect of TH. We used a mouse model of cardiac arrest demonstrating TH cardioprotection to study the response of mice deficient in an Akt1 allele. We hypothesized that Akt1 mediates TH cardioprotection and that decreases in Akt1 content would diminish such protection. Adult C57BL/6 wildtype (WT) mice underwent an 8-min cardiac arrest. After 6 min, the mice were randomized to normothermia (WTNT, 37°C) or TH (WTTH, 30°C). Following cardiopulmonary resuscitation and the return of spontaneous circulation (ROSC), the animals were hemodynamically monitored for 240 min (R240). At R240, cardiac tissue Akt content and phosphorylation were assayed. Studies were repeated in Akt1 heterozygous (Akt1 ϩ/Ϫ ) mice. As a result, baseline characteristics and ROSC rates were equivalent across groups. At R240, WTTH mice exhibited lower heart rate, larger stroke volume, and higher cardiac output than WTNT animals (P Ͻ 0.05). Cardioprotection in WTTH at R240 was associated with increased cardiac Akt phosphorylation at Ser473 and Thr308 compared with that in WTNT (P Ͻ 0.05). THassociated alterations in Akt phosphorylation, stroke volume, heart rate, and cardiac output were abrogated in Akt1 ϩ/Ϫ animals. In conclusion, TH improves post-ROSC cardiac function and increases Akt phosphorylation in WT, but not Akt1 ϩ/Ϫ , mice. The Akt1 isoform appears necessary for TH-mediated cardioprotection.sudden cardiac death; asystole; cardiopulmonary resuscitation; therapeutic hypothermia; protein kinase B SUDDEN CARDIAC ARREST is a leading contributor to cardiovascular disease mortality with only 5-7% of out-of-hospital cardiac arrest victims surviving hospital discharge (27). During the first minutes to hours following the return of spontaneous circulation (ROSC), patients often exhibit severe and lethal myocardial dysfunction than can occur in the absence of underlying focal coronary artery occlusion (8,16,25,38,41). The mechanisms of post-ROSC myocardial depression are likely related to factors associated with ischemia-reperfusion (I/R) injury including substrate depletion, acidosis, oxidative stress, mitochondrial injury, alterations in intracellular calcium handling and in circulating cytokines, and the posttranslational modification of contractile and mitochondrial proteins (6,20,23,24,28).The induction of mild to moderate therapeutic hypothermia (TH) has been demonstrated to improve survival and neurological outcomes in comatose survivors of out-of-hospital cardiac arrest, in part, by limiting cardiac dysfunction during the immediate post-ROSC period (3, 40). Researchers from our laboratory and others have previously demonstrated that intraarrest hypothermia attenuates cardiac dysf...