Abstract
Nearly 600,000 adults suffer from cardiac arrest in the United States each year, with the majority of events
occurring suddenly in an out-of-hospital setting in seemingly healthy individuals. Although advances in basic and
advanced life support have increased the likelihood of achieving return of spontaneous circulation (ROSC),
nearly 70% of patients that are admitted to the hospital following resuscitation from cardiac arrest will die before
hospital discharge. The high morbidity and mortality rate of patients who initially achieve ROSC has been
attributed primarily to systemic, multi-organ injury that accompanies prolonged whole-body ischemia and
reperfusion, a pathophysiological condition referred to as “post-cardiac arrest syndrome”. Although activation of
the innate immune system is recognized to be an important component of this syndrome, the mechanisms by
which the resulting inflammatory response contributes to post-resuscitation tissue injury remain poorly
understood. Unfortunately, this knowledge gap has hindered the development of effective treatment strategies
to provide multi-organ protection in patients with post-cardiac arrest syndrome.
The studies proposed in the present application aim to address this problem by testing the central hypothesis
that rapid leukocytosis and macrophage expansion are integral components of the systemic post-ROSC
inflammatory response that exacerbate multi-organ injury following resuscitation from cardiac arrest.
Using a highly translational porcine model of post-cardiac arrest syndrome, a combination of surgical and
pharmacological approaches will be employed to identify the mechanistic role of splenic leukocyte release in
post-ROSC inflammation and injury (Aim 1), determine whether this process is amplified by epinephrine-
mediated stimulation of ß2-adrenergic receptors during cardiopulmonary resuscitation (Aim 2), and evaluate the
therapeutic efficacy of a targeted approach to attenuate CCR2-dependent leukocyte infiltration in post-cardiac
arrest syndrome (Aim 3). An integrated research approach to address these aims has been developed by a
multi-disciplinary investigative team with expertise in cardiovascular physiology, large animal models of heart
disease, leukocyte biology, immunology, and neuroprotective therapies. Collectively, completion of the proposed
studies is expected to significantly advance our mechanistic understanding of innate immune system-mediated
injury following resuscitation from cardiac arrest and identify novel therapeutic interventions that mitigate multi-
organ damage by attenuating the post-resuscitation inflammatory response, ultimately facilitating the
development of novel strategies to improve the unacceptably low survival rate of patients with post-cardiac arrest
syndrome.