Splenic Modulation of Early Post-Resuscitation Inflammation in a Porcine Model of Sudden Cardiac Arrest
Authors: Rolland Tyler J , Zahra Sumbule , Cucinotta Daniel , Hudson Emily R , Graser Luke , Young Rebeccah , Weil Brian 
Published: May 2024

Objective: The spleen has been implicated as a potential therapeutic target for acute anti-inflammatory intervention via modulation of splenic nerve activity, but the translational viability of this approach is unclear due to limited mechanistic understanding of splenic leukocyte mobilization in clinically relevant models. In contrast to prior rodent studies, we recently demonstrated that the spleen is not required for leukocyte mobilization after focal myocardial ischemia/reperfusion in swine. However, the spleen's role in the early inflammatory response to whole-body ischemia/reperfusion following resuscitation from sudden cardiac arrest (SCA) remains unexplored. Therefore, we used a surgical approach to investigate the spleen's contribution to early post-resuscitation inflammation in a porcine model of SCA. Methods: Eighteen swine were randomized to splenectomy (SPLX; n=9) or sham surgery (SHAM; n=9), and subsequently underwent 8 minutes of electrically-induced ventricular fibrillation SCA one week later. Mechanical CPR with defibrillation and intravenous epinephrine (EPI; 0.015 mg/kg) was performed to achieve return of spontaneous circulation (ROSC; defined as sustained MAP>60mmHg). Hemodynamic parameters, cardiac function, circulating biomarkers of injury (cTnI) and inflammation (IL-6, TNF-⍺), and blood leukocyte levels were assessed for 4 hours post-ROSC, at which time the heart and brain were collected for post-mortem analysis of leukocyte infiltration via flow cytometry. Results: SPLX and SHAM animals were resuscitated at a similar rate (SHAM vs SPLX: 56% vs. 44%) and required a similar number of defibrillation attempts (4.3±0.8 vs. 5.2±1.3), but SPLX required more EPI boluses during CPR (3.3±1.3 vs. 1.4±0.2; p<0.05) and took longer to achieve ROSC (779±196 vs. 455±37 sec; p<0.05). After ROSC, SPLX animals required more EPI (43±10 vs. 13±10 μg/kg; p<0.05) to maintain MAP >60mmHg and tended to have higher circulating cTnI levels compared to SHAM (19.5±4.4 vs. 5.8±4.4 ng/mL; p=0.07). A significant elevation in circulating leukocytes was observed from pre-SCA to 4-hours post-ROSC in both SPLX (19.5±1.3 to 32.0±2.6 103/μl; p<0.05) and SHAM (from 15.1±1.3 to 23.7±2.9 103/μl; p<0.05), along with an increase in circulating IL-6 and TNF-α vs. pre-SCA values that tended to be higher in SPLX. Flow cytometry revealed post-ROSC leukocyte infiltration that was particularly evident in the brain, with an increased number of inflammatory granulocytes (CD172+CD163-) and dendritic cells (CD172+CD16+) in multiple brain regions of SPLX and SHAM animals compared with healthy controls. Conclusion: These results demonstrate that, in swine, the spleen is not required for the robust early inflammatory response to resuscitation from SCA. This observation provides further evidence that, in contrast to rodents, the spleen is not a primary contributor to sterile inflammation following ischemia/reperfusion injury in large animals. This translational study suggests that neuromodulation of splenic leukocyte mobilization may not be a viable therapeutic strategy for mitigating acute inflammation in clinical post-cardiac arrest syndrome. Supported by funding from the NIH and US Department of Veteran's Affairs. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.