Abstract 101: PHLPP Inhibitory Peptide Administered During CPR Improves Survival After Prolonged Cardiac Arrest

Abstract

Introduction: Active cooling is more effective than targeted temperature management in improving sudden cardiac arrest (SCA) survival, but can be difficult to implement clinically. We are developing drugs that mimic cooling effects without the need for physical cooling. Cooling protection is mediated by Akt activation. PH domain and Leucine rich repeat Protein Phosphatases (PHLPP) is a phosphatase that negatively regulates Akt. We developed a cell-permeable peptide TAT-PHLPP9c that inhibits PHLPP and reaches heart and brain within 5 min of intravenous administration. Hypothesis: We hypothesize that TAT-PHLPP9c improves outcomes following SCA. This protection involves the 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-PHLPP9c (7.5 mg/kg) via i.v. 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: Compared to control, TAT-PHLPP9c significantly improved ROSC rates. 3 ROSC mice in the control group died within 10 min while 8 out of 10 ROSC mice in the treatment group survived over 1 h and 4 mice survived to 4 h despite a 12-min arrest. Progressively increased CBF and metabolic CEST contrast were observed in the treated mice compared to controls. p-PDH was decreased by TAT-PHLPP9c (increased activity) at 15 min post-ROSC in both heart and brain. ATP generation was replenished with the peptide treatment. Plasma taurine and glutamate concentrations was reduced by TAT-PHLPP9c as early as 5 min post-ROSC. Further, higher levels of taurine and glutamate were detected in the non-survivors than the survivors. Conclusions: This novel treatment strategy may have a high translational potential to reproduce critical outcomes of CPR cooling without physical cooling.