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Here we present a multi-modal atlas of human right ventricular pressure loading and failure, including bulk (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009142), single-nucleus (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200911) and Xenium spatial (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20099) transcriptomics in adults, plus pediatric (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200914) 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.\n                  <\/jats:p>","DOI":"10.1038\/s44161-026-00885-5","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T09:02:21Z","timestamp":1791536541000},"page":"1133-1158","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Human adult and pediatric multimodal transcriptomic atlas of progression from pressure-loaded to failing right ventricle"],"prefix":"10.1038","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0023-3405","authenticated-orcid":false,"given":"Ivan 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