Abstract
Therapeutic hypothermia initiated during cardiopulmonary resuscitation (CPR) in pre-clinical studies appears to be highly protective against sudden cardiac arrest injury. Given the challenges to implementing CPR cooling clinically, insights into its critical mechanisms of protection could guide development of new CPR drugs that mimic hypothermia effects without the need for physical cooling. Here, we used Akt1-deficient mice that lose CPR hypothermia protection to identify hypothermia targets. Adult female C57BL/6 mice (Akt1+/+ and Akt1+/-) underwent 8 min of KCl-induced asystolic arrest and were randomized to receive hypothermia (30 ± 0.5°C) or normothermia. Hypothermia was initiated during CPR and extended for 1 h after resuscitation. Neurologically scored survival was measured at 72 h. Other outcomes included mean arterial pressure and target measures in heart and brain related to contractile function, glucose utilization and inflammation. Compared to northothermia, hypothermia improved both 2h mean arterial pressure and 72h neurologically intact survival in Akt1+/+ mice but not in Akt1+/- mice. In Akt1+/+ mice, hypothermia increased Akt and GSK3β phosphorylation, pyruvate dehydrogenase activation, and NAD+ and ATP production while decreasing IκBα degradation and NF-κB activity in both heart and brain at 30 min after CPR. It also increased phospholamban phosphorylation in heart tissue. Further, hypothermia reduced metabolic and inflammatory blood markers lactate and Pre-B cell Colony Enhancing Factor. Despite hypothermia treatment, all these effects were reversed in Akt1+/- mice. Taken together, drugs that target Akt1 and its effectors may have the potential to mimic hypothermia-like protection to improve sudden cardiac arrest survival when administered during CPR.
Highlights
Out-of-hospital sudden cardiac arrest (SCA) affects about 1000 people each day in the United States with an overall survival rate of about 7% [1]
Among Akt1+/+ mice, 9 out of 10 mice in the NT group and 10 out of 10 mice in the therapeutic hypothermia/cooling (TH) group achieved return of spontaneous circulation (ROSC), but only 1 mouse survived to 72 h in NT group while 5 out of 10 mice in TH group were alive at 72 h indicating TH confers protection against SCA injury (Fig 1A)
For Akt1+/- mice, 9 out of 10 mice in the NT group and 10 out of 10 mice achieved ROSC, similar to Akt1+/+ mice suggesting that TH had minimal effect on ROSC rates with this duration of cardiac arrest. 1 out of 9 mice in NT group survived to 72 h while 2 out of 10 mice in TH group lived to 72 h post-ROSC indicating a diminished TH protection in Akt1+/- mice (Fig 1B)
Summary
Out-of-hospital sudden cardiac arrest (SCA) affects about 1000 people each day in the United States with an overall survival rate of about 7% [1]. Significant mortality is due to a post-SCA syndrome consisting of myocardial stunning and hypotension, underlying metabolic injury demonstrated by decreased glucose utilization and lactic acidosis, and sepsis-like systemic inflammation. These hemodynamic, metabolic and inflammatory aspects of the post-SCA syndrome contribute to neurologic injury and death [2,3,4]. We and others have shown that TH induced earlier during CPR prior to ROSC is highly protective and potent enough to require only an hour of cooling to provide significant benefit [10, 12, 13] compared to 12–24 h of cooling required when initiated after ROSC. TH started at CPR is difficult to implement clinically
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