Z Möller-Ramon(1,2), A Kaltenbach(1,2), F Sicklinger(3), I Kwok(4), K Nitz(1), M Schloss(1), C Weber(1,2), LG Ng(4,5), MY Chan(6), F Leuschner(3), SL Puhl(1,2,7), S Steffens(1,2), J Duchêne(1,2)

1. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Germany; 2. German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Germany; 3. University Hospital Heidelberg, Heidelberg, Germany; 4. Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network, Singapore; 5. Shanghai Immune therapy Institute, Shanghai Jiao Tong University School of Medicine, Renji Hospital, China; 6. Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 7. Comprehensive Heart Failure Center, University Clinic Würzburg, Germany

Background: Myocardial infarction (MI) remains a leading cause of mortality worldwide. Neutrophils are among the first immune responders to myocardial injury, and recent evidence indicates that circulating immature neutrophil subset (iNeu) expands in MI patients. However, the functional significance of this subset remains unclear, partly due to limitations in traditional murine MI models.

Methods: We analyzed neutrophil subsets in the blood of MI patients between 24h and 48h after MI. In parallel, we employed two murine MI models: (1) a surgical ligation model (SLM) of the left anterior descending artery and (2) a minimal invasive MI (MiMI) model.

Results: In human, 20% of circulating neutrophils exhibit an immature phenotype post MI. In mice, SLM triggered a significant shift in bone marrow neutrophil composition and mobilization, resulting in 80% of circulating iNeu at 24 hours. Further analysis revealed that these effects were driven by the surgical procedure itself rather than MI. In contrast, MiMI model had minimal impact on bone marrow neutrophils and led to 25% circulating iNeu. We showed that iNeu infiltrate the infarcted heart and exacerbate cardiac dysfunction by exhibiting an increased pro-inflammatory phenotype.

Conclusion: The surgical procedure of SLM masks the effects of MI on iNeu. We propose that MiMI is the more suitable model to study the role of iNeu after MI as it reflects the human neutrophil dynamics more accurately. iNeu display a pro-inflammatory phenotype within the infarcted heart suggesting a pathological role for these cells. Further studies are warranted to determine their therapeutic implications in MI recovery.