Spatial Transcriptional Landscape of Human Heart Failure

Heart failure (HF) poses a major clinical challenge with diverse underlying causes. Despite advances, the intricate molecular alterations specific to distinct cell types and histological patterns during HF progression remain inadequately characterized. Using the GeoMx whole human transcriptome digital spatial profiler, we discerned gene expression dynamics in failing human hearts, integrating cell type, clinical, and histological nuances. We demonstrated the cellular composition of the left ventricle myocardium and validated the GeoMx platform's compartmentalization efficiency, showing high accuracy for cardiomyocytes but limitations for endothelial cells and fibroblasts. Gene regulation in HF was influenced by cellular context, with contrasting patterns across cell types. Differentially expressed genes, such as UCHL1, IGFBP2, CCL14, ACKR1, and PLVAP, were linked to specific histologic features like degeneration and fibrosis. Multiplex immunohistochemistry confirmed the co-localization of PLVAP and ACKR1 in endothelial cells, correlating with fibrosis severity. Furthermore, our data highlight pronounced inflammatory responses in end-stage HF. Integrative analysis, combining histological and clinical perspectives, spotlighted CRIP3, PFKFB2, and TAX1BP3 as potential contributors to HF progression. Our findings underscore the pivotal role of cell enriched and histology-specific transcriptome mapping in understanding the complex pathophysiological landscape of failing hearts, unveiling potential therapeutic targets and molecular insights. Overall design: Nanostring GeoMx Digital Spatial Profiler sequencing was performed using human heart samples from various cardiomyopathy patients. (e.g. Ischemic cardiomyopathy (ICMP), hypertrophic cardiomyopathy (HCMP), Dilated cardiomyopathy (DCMP))