Post-cardiopulmonary bypass (post-CPB) vasoplegia syndrome (VS) is associated with a dysregulated inflammatory response and a higher morbidity and mortality, but the molecular pathways involved have been incompletely identified. We used multiplexed proteomic and transcriptomic analyses and targeted biochemical assays to identify the inflammatory and metabolic mediators that characterize post-CPB VS.

16 matched pairs of VS+ and VS- patients were analyzed pre-CPB and post-CPB for comparative proteomic and transcriptomic differences, with gene ontology (GO) pathway enrichment. Circulating NO metabolites (NOx), acetylcholine (ACh), and choline acetyltransferase (ChAT) levels were measured and correlated with VS.

Baseline proteomic analysis demonstrated elevated TNF, IL-1R1 and IL-17RA in VS+ patients, with the activation of inflammatory cytokine, leukocyte activation, and NO biosynthesis pathways. Analysis of temporal pre-to-post-CPB proteomic changes in VS+ patients demonstrated post-CPB elevation IL17A, CXCL2, and VEGFR/FLT, and decreased immune resolving proteins. Post-CPB proteomic analysis demonstrated differential activation of leukocyte trafficking, T-cell differentiation, IL-6, and IL-17 pathways in VS+ patients. Transcriptomic analysis demonstrated post-CPB activation of cellular response to hypoxia, cellular stress response, and decreased response to angiotensin pathways. Circulating NOx, ACh, and ChAT levels were elevated pre-CPB in VS+ patients and increased further post-CPB. Pre-CPB ACh had a 99% AUC correlation with post-CPB VS+.

We demonstrated increased baseline cardiovascular inflammation in VS+ patients, which predisposed them to a dysregulated response to CPB, and we identified CPB-induced activation of IL-17 skewed multi-cytokine inflammatory pathways and endothelial activation as mechanistic mediators of post-CPB VS. Circulating ACh was identified as a potential biomarker.