Preliminary evidence indicates that inter-individual variables such as immune cell activity
and the production of pro-inflammatory factors may differentiate patients with the highest
risk of poor neurological outcome, and may reveal novel therapeutic approaches based on
promoting molecular pathways of inflammation-resolution and recovery to reduce the severity
of hypoxic ischemic encephalopathy (HIE). Additionally, there are intrinsic, modifiable
metabolic factors, such as the presence and metabolic activity of brown adipose tissue (BAT)
that may modulate injury and recovery.
Comparative analysis showed that cardiac arrest survivors have more CD73+ lymphocytes
compared to non-survivors. CD73 is the key enzyme in the generation of anti-inflammatory and
immunosuppressive adenosine. We have also identified novel populations of neutrophils
(CD14posCD16low and DEspR+) that had amplified response to inflammatory stimuli. The
investigators hypothesize that individual variability in the expression and signaling
profiles of white blood cells (lymphocytes, neutrophils, monocytes and macrophages) following
resuscitation affects inflammation and is independently associated with neurological outcome.
To test this hypothesis, investigators will determine levels of various immune cell
populations at different time points in peripheral blood of patients. Characterization of
blood circulating factors, clinical phenotypes, and neurological outcomes after cardiac
arrest is a second aim of this project, with a focus on understanding the heterogeneity of
cellular and humoral immune responses and how they relate to different clinical phenotypes of
post-resuscitation syndrome.
PCAS metabolism:
IT is known that hyperglycemia is an independent risk factor for poor outcome after cardiac
arrest, but it is not known if modification of hyperglycemia reduces this risk. Published
studies have not demonstrated benefit with intensive insulin therapy. Our preliminary data
suggest correlation between brown adipose tissue activity and good outcome. We have
postulated that BAT may be activated by therapeutic hypothermia and may act as a glucose sink
reducing the oxidative stress caused by hyperglycemia, and secondarily reducing injury to the
brain, heart, and other organs.
In these studies we will also investigate other actionable targets for new therapies.