Human adult and pediatric multimodal transcriptomic atlas of progression from pressure-loaded to failing right ventricle

Abstract Right ventricular failure (RVF) independently predicts mortality in heart failure, yet its pathophysiology is poorly understood. Here we present a multi-modal atlas of human right ventricular pressure loading and failure, including bulk ( n = 142), single-nucleus ( n = 11) and Xenium spatial ( n = 9) transcriptomics in adults, plus pediatric ( n = 14) and mouse pulmonary artery banding cohorts. Subclustering resolved 34 cell subtypes across 12 lineages along a two-phase trajectory. Phase 1 (non-failing to pressure-loaded) accounts for most of the transcriptional change detectable by bulk and single-nucleus RNA sequencing and is marked by loss of resident macrophage identity, fibroblast activation, endothelial expansion and erosion of tissue-protective programs. Phase 2 (pressure-loaded to RVF) produces little change in bulk RNA sequencing but is resolved by spatial transcriptomics, engaging multi-lineage fibrotic, endothelial-activation and cardiomyocyte-reactivation programs, with a gain of extracellular matrix (collagen, laminin, thrombospondin) signaling over a stable cell contact adhesion baseline. Mitochondrial respirometry revealed respiratory dysfunction in adult and mouse RVF but not pediatric RVF. Multi-lineage remodeling of the cardiac microenvironment emerges as the central molecular program of RVF, meriting further study as possible disease-modifying targets.