Abstract A059: Upregulated Immune Responses in Children with Arteriopathic and Cardioembolic Stroke

Introduction: The inflammatory response to infection likely plays a prominent role in the pathogenesis of childhood arterial ischemic stroke (AIS), particularly arteriopathic and cardioembolic strokes. Prior analyses in the “Vascular effects of Infection in Pediatric Stroke” study (VIPS II) demonstrated that the infections themselves were not unusual. In this analysis, we measured peripheral gene expression to test the hypothesis that children with arteriopathic and cardioembolic stroke have a greater inflammatory host response than those with idiopathic stroke. Methods: From 2017-2022, 22 multinational VIPS II centers collected peripheral blood from 205 children (28 days-18 years old) within 72 hours of centrally confirmed AIS (iatrogenic strokes excluded). We performed bulk RNA sequencing on blood from AIS cases and 100 stroke-free well children (controls). A central team classified AIS subtype. Differential gene expression analysis and pathway analysis were used to identify gene expression patterns and dysregulated biological pathways associated with AIS and stroke subtypes. Results: Median age was 11.6 years for AIS cases (45% female) and 11.8 for controls (53% female). Bulk RNA sequencing data was available in 190 cases and 91 controls. Among AIS cases, 67 were classified as definite arteriopathy, 74 as probable arteriopathy, 23 as cardioembolic, and 26 as idiopathic; there was no significant difference in age, gender, or infarct size across subtypes. With a false discovery rate (FDR) <0.05, 2,755 genes were differentially expressed between AIS cases and controls; 47 had a log2 fold-change >1. Significantly upregulated signaling pathways in AIS correlated with proinflammatory innate immune responses. Stratification by stroke subtype revealed that this inflammatory host response was present only after arteriopathic and cardioembolic stroke (Figure A, B ), while gene expression after idiopathic stroke was similar to controls ( C ). The only differentially expressed gene across all subtypes was CD177, a neutrophil surface antigen upregulated during inflammation. Conclusions: This is the first large-scale transcriptomic analysis exploring gene expression profiles in childhood AIS. Our findings demonstrate significant immune dysregulation within 72 hours of arteriopathic and cardioembolic stroke, but not idiopathic stroke. These insights may inform future diagnostic biomarkers and immunomodulatory therapeutic strategies in childhood stroke.