Lee and colleagues present one of the first high-resolution spatial transcriptomic atlases of human heart failure. Using GeoMx digital spatial profiling, they captured transcriptional data from cardiomyocytes, fibroblasts, immune cells, and other compartments within carefully annotated regions of ventricular myocardium. Samples were drawn from patients with end-stage heart failure of varying etiologies and compared against healthy controls, with tissue sections segmented into scar, border zone, and remote myocardium.

The analysis revealed marked heterogeneity. Scar tissue was enriched in fibrotic signatures, while border zones showed stress-response and metabolic reprogramming, and even remote myocardium displayed subtle activation of fetal gene programs. Immune infiltration was concentrated around fibrotic areas, suggesting active crosstalk between immune cells and fibroblasts. Changes in glucose and fatty acid pathways localized to border regions, reflecting the metabolic vulnerability of surviving myocardium. Network analyses further highlighted paracrine signaling, including TGF-β and chemokine pathways, as potential mediators of remodeling.

Taken together, these findings emphasize that heart failure is not a uniform process but a mosaic of region- and cell-specific alterations. By situating gene expression within histological context, this work bridges molecular data with pathological remodeling. While still primarily a research tool, spatial transcriptomics may ultimately help direct region-specific therapies—whether anti-fibrotic, immunomodulatory, or metabolic—tailored to the microenvironment of the failing heart.