Neutrophil Transcriptomic Changes in Severe Sterile Vasoplegic Syndrome Resemble a Distinct Molecular Subtype of Septic Shock

Background: Understanding early molecular events in systemic inflammation in sepsis is complicated by host-pathogen interactions and responses over time. Vasoplegic syndrome after cardiac surgery resembles septic shock but lacks pathogen-related variables and proceeds over a defined, reproducible time course. We hypothesized that human neutrophil transcriptomic changes in vasoplegic syndrome would resemble one or more molecular subtypes of septic shock. Methods: We compared dynamic human neutrophil transcriptomic changes during development of vasoplegic syndrome to 1) dynamic changes in uncomplicated cardiac surgery and 2) static transcriptomic profiles in septic shock. Vasoplegic syndrome was defined as vasopressor requirement to maintain MAP >60 mmHg, CI >2.2 L min -1 m -2 , and systemic vascular resistance index < 1970 d s cm -5 m 2 lasting at least 24 hours postoperatively. Septic shock was defined as acute refractory organ dysfunction due to infection. Neutrophil transcriptomics were correlated with clinical course and plasma cytokine levels. Results: In principal component analysis, neutrophil transcriptomes from surgical patients demonstrated core gene expression changes in response to cardiac surgery independent of outcome. Additionally, among vasoplegic patients, two marked and consistent neutrophil transcriptomic phenotypes were observed and associated with distinct clinical phenotypes. A subset of dynamic expression changes in severe vasoplegic syndrome which were not seen in surgical controls instead resembled expression in patients with septic shock with increased MMP8 mRNA. Conclusions: Dynamic gene expression in neutrophils from patients with severe vasoplegic syndrome includes both changes in response to surgery, and development of a gene expression phenotype resembling septic shock with elevated MMP8 expression. Our findings suggest a common neutrophil molecular program associated with multi-organ failure which may include common therapeutic targets for both sterile and septic systemic inflammatory states.