195 - Role for Nitro-Conjugated Linoleic Acid and cGMP in Nitrite-Mediated Neuroprotection in Out-of-Hospital Cardiac Arrest

Abstract

Every year in the US 350,000 people suffer out-of-hospital cardiac arrest (OHCA) but despite recent advances, survival rates remain below 10%. Successful resuscitation is inescapably associated with ischemia-reperfusion injury (IR) resulting from uncontrolled free radical generation, microcirculatory dysfunction and sterile inflammation. Animal studies of nitrite (NO2‒) administered during cardiopulmonary resuscitation (CPR) have shown promising results driving an ongoing phase I/II clinical trial (NCT02987088) of NO2‒ after OHCA. Nitro-conjugated linoleic acid (NO2-CLA) is generated from the reaction of nitrogen dioxide with conjugated linoleic acid, and is both a potent inducer of Nrf2-dependent antioxidant responses and an inhibitor of TLR4/NF-κB pro-inflammatory signaling. Data in humans and animal models show that NO2-CLA levels are modulated by dietary NO2‒ intake as well as by iNOS-dependent nitric oxide (NO) formation during inflammatory responses. We hypothesized that intravenous NO2‒ during CPR would result in downstream signaling via NO2-CLA and/or cGMP resulting in improved outcomes after OHCA and sought to identify clinical characteristics of responders. Plasma was obtained under exception from informed consent from patients receiving NO2‒ (25 and 60 mg) within 60 minutes of resuscitation. Circulating levels of NO2‒, NO2-CLA and cGMP were determined and correlated with indices of clinical presentation and Cerebral Performance Category (CPC), a functional outcome scale. Surrogate ischemic burden markers were not correlated with NO2‒ levels (p = 0.141-0.372) however NO2‒ consumption was correlated with NO2-CLA formation (p=0.039). NO2‒ consumption was not associated with successful resuscitation or survival to discharge (p=0.16-0.24) but was associated with improved neurological outcome (CPC 1 or 2; p=0.029). Increased levels of both NO2-CLA and cGMP were positively associated with better neurological outcome (p = 0.022, n = 82 and p = 0.046, n = 74, respectively) and survival to discharge (p = 0.020 and p = 0.034, respectively). Levels of NO2-CLA did not correlate with cGMP (p = 0.99). Both NO2-CLA and cGMP were increased in patients presenting with ventricular fibrillation. These results, though limited by power and the unadjusted use of multiple comparisons, suggest that NO2‒ administration is neuroprotective after OHCA via both NO-dependent cGMP formation and cGMP-independent NO2-CLA signaling thus opening the door for the development of interventions aimed at curbing both morbidity and mortality in OHCA.