Nitrite elicits divergent NO-dependent signaling that associates with outcome in out of hospital cardiac arrest

Abstract

Brain and heart injury cause most out-of-hospital cardiac arrest deaths but limited pharmacotherapy exists to protect these tissues. Nitrite is a nitric oxide precursor that is protective in pre-clinical models of ischemic injury and safe in Phase I testing. Protection may occur by cGMP generation via the sGC pathway or through S-nitrosothiol and nitrated conjugated linoleic acid (NO2-CLA) formation. We hypothesized that nitrite provided during CPR signals through multiple pathways and that activation of signals is associated with OHCA outcome. To this end, we performed a secondary analysis of a phase 1 study of intravenous nitrite administration during resuscitation in adult out-of-hospital cardiac arrest. Associations between whole blood nitrite and derived plasma signals (cGMP and NO2-CLA) with patient characteristics and outcomes were defined using Chi-square or t-tests and multiple logistic regression. Whole blood nitrite levels correlated inversely with plasma NO2-CLA (p = 0.039) but not with cGMP. Patients with shockable rhythms had higher cGMP (p = 0.027), NO2-CLA (p < 0.0001) and trended towards lower nitrite (p = 0.077). Importantly, plasma cGMP and NO2-CLA levels were higher in survivors (p = 0.033 and 0.019) and in those with good neurological outcome (p = 0.046 and 0.021). Nitrite was lower in patients with good neurologic outcome (p = 0.029). cGMP (OR 4.02; 95% CI 1.04–15.54; p = 0.044) and NO2-CLA (OR 3.74; 95% CI 1.11–12.65; p = 0.034) were associated with survival. Nitrite (OR 0.20; 95% CI 0.05–0.08; p = 0.026) and NO2-CLA (OR 3.96; 95% CI 1.01–15.60; p = 0.049) were associated with favorable neurologic outcome. In summary, nitrite administration was associated with increased plasma cGMP and NO2-CLA formation in selected OHCA patients. Furthermore, patients with the highest levels of cGMP and NO2-CLA were more likely to survive and experience better neurological outcomes.