Adenosinergic Signaling in the Immunoinflammatory Response After Cardiac Arrest

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Abstract Of the ~600,000 annual cardiac arrest events in the USA, <7% result in survival with a good neurological outcome. Patient heterogeneity and variations in emergency care affect ischemia time, rates of resuscitation, and post-resuscitation outcomes. The early hours after resuscitation are a critical window to promote cell recovery. This project builds upon a robust post-resuscitation clinical program and our prior work identifying unique neutrophil populations and their interactions with lymphocytes in “post-cardiac arrest syndrome” in humans. In our patients, low numbers of CD73-expressing (CD73+) lymphocytes after resuscitation and a high neutrophil to CD73+ lymphocyte ratio are each associated with worse outcomes. CD73 is a key enzyme in the generation of adenosine, which is neuroprotective and regulates vasoreactivity. Because increased duration of ischemia also increases risk of poor outcome, we predict that the longer ischemic times associated with cardiac arrest in patients living in rural areas will be reflected in fewer CD73+ circulating lymphocytes post- resuscitation. We expect regional differences in emergency care to contribute to heterogeneity of the inflammatory response, emphasizing the importance of diversity and inclusion in cardiac arrest research. In addition to our clinical observations, our studies show critical immunomodulatory effects of CD73+ lymphocytes on neutrophil activation, specifically on a novel subpopulation of highly inflammatory neutrophils we have named cardiac arrest-associated neutrophils (CAANs). We will characterize molecular signaling associated with CD73+ lymphocytes with respect to neutrophil and endothelial cell function. We hypothesize that activation of CD73+ lymphocytes is an acute protective response to whole-body ischemia-reperfusion injury that dampens the inflammatory consequences of global ischemia. Further, we predict that low numbers of CD73+ lymphocytes correlate with pathological neutrophil activation and impaired endothelial function, leading to decreased blood flow at end-vascular territories and tissue infarction in the brain and other vulnerable organs. Our aims are to: 1) determine the inflammatory profiles and associated clinical phenotypes in cardiac arrest patients with varying levels of CD73+ lymphocytes, and 2) characterize the effects of CD73+ lymphocytes against neutrophil-mediated injury to the endothelial cell barrier. This is the first major attempt to characterize the cellular immune response after resuscitation from cardiac arrest, and represents a novel translational research direction for Dr. David Seder, an experienced clinical trialist. Dr. Seder will expand his clinical research skills into laboratory-based skills in molecular phenotyping of human-derived inflammatory cells, and receive mentorship from senior physician-scientists with successful careers in patient care, academic medicine, and clinical and translational research (C. Rosen and D. Sawyer). The completion of this study will set the stage for novel interventional trials to improve cardiac arrest outcomes.