Introduction:
Cardiac arrest (CA) is a leading cause of death in the United State, affecting 600,000 people annually with overall survival rate of less than 10%. CPR and cooling are the few effective treatments that improve CA survival. No drugs are currently available to improve survival. Active cooling is more effective than targeted temperature management in improving survival, but can be difficult to implement clinically. We have developed a novel peptide (TAT-PHLPP) that inhibits PH domain and Leucine rich repeat Protein Phosphatases (PHLPP). When this peptide was administered intravenously (i.v.) during CPR, it expresses in both heart and brain within 5 min of intravenous injection and significantly improved 4 h survival in a 12 min mouse asystole arrest model.
Hypothesis:
We hypothesize that TAT-PHLPP improves neurologically intact long-term survival following SCA with improved early metabolic recovery.
Methods:
C57BL6 mice (n=20) were randomized to receive peptide treatment and appropriate blinding was ensured. A 12 min asystolic arrest was induced with KCl. CPR was started along with TAT-PHLPP (7.5 mg/kg) via i.v. Three day Survival was evaluated. Cerebral blood flow (CBF) and metabolic chemical exchange saturation transfer (CEST) contrast were measured with endogenous and dynamic arterial spin labeling (ASL) and CEST MRI respectively. Glucose utilization was assessed by pyruvate dehydrogenase (PDH) phosphorylation and ATP generation. Further, blood taurine and glutamate were measured.
Results:
Baseline characteristics including weight, temperature, heart rate, MAP were indistinguishable between the control (normal saline, NS) and peptide group. Compared to NS, TAT-PHLPP significantly improved 3-day survival with better neurological function. It progressively increased CBF and metabolic CEST contrast. It decreased p-PDH (increased activity) at 15 min post-ROSC and enhanced ATP generation in both heart and brain. It also reduced plasma taurine and glutamate concentrations as early as 5 min post-ROSC. Further, high levels of taurine and glutamate were detected in non-survivors.
Conclusions:
This novel therapy may have a high translational potential to reproduce critical outcomes of CPR cooling without physical cooling.
Predictors of long-term survival in patients treated with targeted temperature management after cardiac arrest
