Key result
Right ventricular failure progression follows a distinct two-phase trajectory marked by early protective loss then fibrosis.
Why the study?
Right ventricular failure independently predicts mortality in heart failure, yet its pathophysiology is poorly understood.
Observational (n=156)
This multi-modal transcriptomic atlas reveals a two-phase trajectory of right ventricular failure characterized by extensive multi-lineage microenvironment remodeling and highlights distinct metabolic responses between adult and pediatric disease.
Answers are grounded in this paper and cite their sources.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The result: most transcriptional changes happen before failure. While function is still preserved, the myocardium is already far from 'normal.' More broadly, I think this challenges the idea that RV failure is simply accompanied by progressively greater transcriptional changes.”
May inform phased mechanistic studies of RV failure; leaves open whether targeting early protective loss alters progression.
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.
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Kuznetsov et al. (2026) conducted an observational in Right ventricular failure (n=156). Right ventricular pressure loading and failure vs. Non-failing right ventricle was evaluated. Progression to right ventricular failure involves a two-phase molecular trajectory, characterized initially by widespread loss of tissue-protective programs and subsequently by spatially-resolved, multi-lineage fibrotic and cellular activation.
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