Abstract Wed165: Spatial transcriptomic signatures of cardiac sarcoidosis in myocardial tissue

Introduction: Cardiac sarcoidosis (CS) is traditionally characterized by the presence of granulomas within myocardial tissue. The impact of CS granulomas on surrounding non-granulomatous myocardium is unknown. To better identify the impact of granulomatous inflammation on the surrounding microenvironment, we sought to identify transcriptional signatures in explanted CS myocardial tissue in comparison to other non-CS cardiomyopathies with a similarly high prevalence of heart failure and arrhythmias. Methods: We performed 10X Genomics Visium Spatial Transcriptomics on 9 CS and 10 non-CS (1 Chagas disease and 9 HCM) available explants with diagnostic overlap to identify CS-specific signatures within spots enriched for cardiomyocytes (CMs) and fibroblasts (FBs). We assessed: transcriptional pathways with Kyoto Encyclopedia of Genes and Genomes (KEGG), differentially expression genes (DEGs), cell-cell communication (CCC) and weighted gene co-expression network analysis (WGCNA) to compare CMs and FBs in CS to non-CS. Results: Consistent with prior studies, in CS we observed upregulation of CHIT1 and FOXP3 in CM-enriched spots. Furthermore, WNT9A is a DEG in CM-enriched spots. CCC indicated enrichment of interactions between WNT9A and WNT11 with FZD8, 7, 6, 4 and 1, suggesting activation of the Wnt pathway. WNT gene-related CCC was only present in CS. Surprisingly, WNT was increased in CS relative to non-CS and was negatively correlated with immune activation genes including HLA isotypes, CD24, CD59, CCL2 and CCR10. Conclusions: Spatial transcriptomics of CS peri-granulomatous tissue in CS revealed upregulation of WNT9A coupled with downregulation of genes involved in immune response. CCC further suggests activation of the Wnt pathway via interactions in CM-enriched spots involving FZD receptors. These findings suggest that key pathologic pathways involving fibrosis, hypertrophy, and inflammation remain active in CS, even in late stage disease.