First full-heart spatial transcriptomic analysis of giant cell myocarditis reveals transmural immune - metabolic gradients

Background Giant cell myocarditis is a rare but highly aggressive inflammatory cardiomyopathy frequently presenting with rapidly progressive heart failure. Despite treatment with intensive combined immunosuppression, many patients progress to advanced heart failure, transplantation, or death. A deeper understanding of the immunological pathways driving myocardial injury is therefore urgently needed to enable more effective and targeted therapeutic strategies. Purpose To characterize the transmural immune and metabolic organization of giant cell myocarditis across the human cardiac wall using whole-transcriptome spatial profiling of explanted heart tissue. Methods Whole-transcriptome spatial RNA sequencing was performed on explanted human cardiac tissue obtained at heart transplantation for fulminant giant cell myocarditis. Twenty tissue sections from twelve predefined ventricular regions were analyzed. Spatial clustering, cell-type deconvolution, and layer-resolved pathway analyses were applied along a continuous epicardial-to-endocardial axis to characterize immune, stromal, and cardiomyocyte programs. Results Layer-resolved pathway analysis revealed marked epicardial enrichment of IL-6/JAK/STAT3 and TNF-α/NF-κB signaling, identifying a dominant pro-inflammatory signaling niche at the outer myocardial layer. Spatial profiling demonstrated cardiomyocytes, fibroblasts, endothelial cells, and immune populations arranged in distinct transmural patterns, with immune cells concentrated in epicardial inflammatory regions dominated by activated myeloid populations. Lymphoid compartments exhibited a continuum from IgM-expressing B cells to IgG4-secreting plasma cells, consistent with sustained humoral immune activation. These spatial immune–metabolic gradients were conserved across ventricular regions despite marked regional heterogeneity. Conclusion First full-heart spatial transcriptomic analysis of giant cell myocarditis identifies dominant epicardial IL-6/JAK/STAT3 signaling as a central feature of the disease-associated immune landscape. This first spatial multi-region profiling of a human GCM explant reveals a layered immune–metabolic organization linking epicardial inflammatory niches to myocardial injury and highlights potential therapeutic targets.