Abstract
Introduction: To-date, there is no accurate means to identify which bAVMs will bleed and treatment remains controversial. Hypothesis: We developed an endovascular biopsy (EB) technique to isolate endothelial cells (ECs) from bAVMs in patients. We hypothesized this technique would allow RNA-seq analysis of relevant bAVM-related molecular pathways. Methods: EB was performed during angiography for bAVM patients undergoing resection. Cells were obtained from a bAVM juxta-nidal feeding artery and iliac artery (control) with a detachable coil and 0.035 inch wire. ECs were isolated with fluorescence assisted cell sorting (FACS). bAVM tissue was obtained from surgery, dissociated and underwent FACS sorting. Total RNA extraction and library preparation was performed, and samples sequenced on an Illumina HiSeq 4000 sequencer. Reads were aligned with Kallisto, and differentially expressed genes identified between bAVM and control with Sleuth using likelihood ratio tests. Correlations between EB and resected tissues were calculated with Pearson correlation coefficients. Principle Component Analysis (PCA) was used to assess for cell clustering. Results: EB was performed in 4 patients without complication or adverse event. PCA showed separation of bAVM ECs from controls. Analysis demonstrated 106 differentially expressed genes (FDR p ≤ 0.05). KEGG pathway analysis on these genes revealed enrichment in bAVM-related RAS/MAPK cell signaling functionally related to trophic factor, chemokine and gap junction signaling pathways. Detected genes were strongly correlated between EB and ECs isolated from resected tissues (R 2 = 0.77 for artery, nidus, and vein tissue). Results shown in Figure 1 . Conclusions: EB is a safe technique to permit non-invasive sequencing of bAVMs. These results implicate dysregulated KRAS/MAPK signaling in adult bAVMs. Whether this technique will allow for better natural history prediction or targeted medical therapies requires future study.
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