Abstract 110: Threshold Adjusted Vagus Nerve Stimulation After Asphyxial Cardiac Arrest Results In Reduction Of Endoplasmic Reticulum Stress And Apoptosis

Abstract

Background: Vagus nerve stimulation (VNS) has been shown to improve survival and neurological outcomes after cardiac arrest (CA) and resuscitation by improving mitochondrial function, increasing cerebral blood flow, and reducing inflammation. However, the therapeutic cellular and subcellular mechanisms of VNS are not clearly understood in CA injury. Endoplasmic reticulum (ER) stress after cardiac arrest also contributes to cell death and is an underexplored area. Objective: The aim of this study was to investigate the protective effects of customized threshold-adjusted VNS (tVNS) in a rat model of CA and resuscitation in reducing ER stress and cell apoptosis. Methods and Results: Sprague-Dawley rats underwent 12 min asphyxial-CA followed by resuscitation. Rats were assigned to either post-resuscitation tVNS for 2 h or no-tVNS (control). tVNS was applied by electrode placement in the left cervical vagus nerve immediately after resuscitation. The tVNS was determined by a 15-20% reduction from the immediate baseline heart rate as the effective and physiological threshold for each animal. This enabled customized parameters for individual animals. At 2 h post-ROSC, rats were perfused with normal saline, and the whole brain was removed. The whole brain was then processed for protein expression by western blotting. We also prepared sham rats that did not receive CA or tVNS. For measuring ER stress we evaluated the expression of p-IRE1α protein and for apoptosis, we measured p-BAD protein. We observed a significantly higher protein expression of p-IRE1α in whole brain tissue after CA in control groups in comparison to the sham (p<0.05). Applying tVNS significantly reduced the expression of brain p-IRE1α in comparison to the control group (p<0.05). CA also substantially increased de-phosphorylation of p-BAD protein compared to the sham group (p<0.05). By contrast, no significant increase in de-phosphorylation of p-BAD protein was observed between the tVNS and sham groups. Conclusions: Application of tVNS immediately after 12 minutes of CA and resuscitation results in reduced ER stress and apoptosis. This data suggests that the protective mechanism of tVNS on cell apoptosis involves a reduction in ER stress. tVNS may be a novel therapeutic approach in CA.