Location and etiology modulate fibroblast activation in the failing human heart

Cardiac fibrosis is a major contributor to heart failure (HF), yet its therapeutic targeting remains limited due to the complexity of fibrosis types and distributions. This study investigates fibroblast heterogeneity and spatial organization in the left ventricle of human hearts from non-failing donors and HF patients with ischemic or dilated cardiomyopathy. Using single-nucleus RNA sequencing and spatial transcriptomics, distinct fibroblast subpopulations were identified, with resident fibroblasts being depleted in HF and replaced by disease-associated states. Differences in activation ligands, transcriptional trajectories, and spatial localization revealed divergent fibroblast transitions between scar and interstitial fibrosis, and between HF subtypes. These results provide insight into fibroblast dynamics and offer potential targets to modulate fibrosis in heart failure.