Regional Neuroinflammation in a Porcine Model of Post-Cardiac Arrest Syndrome

Objective: Post–cardiac arrest syndrome (PCAS) stems from systemic ischemia–reperfusion injury following resuscitation from cardiac arrest and is marked by a robust inflammatory response. Based on a growing body of evidence that neuroinflammation plays a pivotal role in poor neurological outcomes among PCAS patients, the development of immunomodulatory therapies targeting the brain has been suggested as a novel treatment approach. However, key aspects of post-resuscitation neuroinflammation, including the spatial distribution of inflammatory gene expression and inflammatory cell infiltration across key brain regions, remain poorly characterized, particularly in clinically relevant large animal models of PCAS. To address this, we utilized a porcine model of PCAS to 1) characterize regional variability in neuroinflammatory gene expression and leukocyte infiltration after resuscitation from sudden cardiac arrest (SCA), and 2) determine whether the duration of ischemia influences these responses. Methods: Swine (n=10) underwent 7-mins (brief-SCA) or 10-mins (prolonged-SCA) of electrically-induced VF SCA before initiation of mechanical CPR, defibrillation, and intravenous epinephrine (0.015 mg/kg) to achieve return of spontaneous circulation (ROSC; sustained MAP>60 mmHg). Hemodynamic and echocardiographic measurements were performed at baseline (pre-SCA), 1hr, and 4hr post-ROSC. Likewise, circulating leukocyte levels (CBC/flow cytometry) and inflammatory cytokines (IL-6, TNFα; ELISA) were assessed before and throughout the ROSC period. At 4hr post-ROSC, the frontal cortex, caudate nucleus, and hippocampus were excised to examine proinflammatory gene expression (qPCR) and leukocyte infiltration (flow cytometry). An additional subset of swine (n=5) served as controls for comparison with healthy non-ischemic brain tissue. Results: Compared to the brief-SCA cohort, the prolonged-SCA group experienced a significantly longer ischemic/low-flow interval (963±77 vs. 655±121 secs; p<0.05), despite similar CPR durations between groups (235±54 vs. 363±34 secs; p=0.42). The circulating neutrophil-to-lymphocyte ratio increased similarly from pre-SCA to 4hr post-ROSC in both groups, indicating a heightened inflammatory response regardless of SCA duration. Interestingly, post-SCA inflammatory gene expression was consistently higher within the caudate nucleus compared to other brain regions, regardless of SCA duration. For example, expression of CCL2 was markedly increased in the caudate nucleus of the brief-SCA group (69±20 fold-change) and prolonged-SCA group (53±19 fold-change) compared with controls (both p<0.001). Increased expression of IL-1β and TNFα was also evident in various brain regions after SCA, but expression of CCR2 and CD68 was not significantly different in either SCA group relative to controls. Post-mortem analysis of leukocyte infiltration revealed increased levels of cells expressing CD172 (inflammatory adhesion molecule), pro-inflammatory granulocytes, and pro-inflammatory dendritic cells across brain regions compared to controls (all p<0.01), with similar responses regardless of SCA duration. Conclusion: These findings reveal distinct regional heterogeneity in post-ROSC neuroinflammation, with the caudate nucleus exhibiting a pronounced elevation in proinflammatory gene expression, particularly CCL2, regardless of SCA duration. This observation underscores the dorsal striatum’s vulnerability to ischemic stress and highlights the need for targeted interventions to mitigate post-ROSC neuroinflammation, with the goal of ultimately improving neurologic outcomes in PCAS. Supported by funding from the NIH, US Department of Veteran's Affairs, and American Heart Association. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.