What is the clinical evidence from this study?

Study design: Observational. Population: Pulmonary Arterial Hypertension (n=46). Primary outcome: Cell type-specific transcriptional programs associated with RV contractility (Ees) and ventriculo-arterial coupling (Ees/Ea).

What question did this study set out to answer?

This research aims to define the molecular programs involved in right ventricular (RV) remodeling in pulmonary arterial hypertension (PAH).

May 20, 2026

D16-03 Cell Type-specific Transcriptional Programs in the Human Right Ventricle Are Associated With Contractility and Ventriculo-arterial Coupling in Pulmonary Arterial Hypertension

Q: What does this research mean for the field?

In pulmonary arterial hypertension, maintenance of right ventricular contractility is associated with upregulated lipid metabolism and downregulated oxidative phosphorylation in cardiomyocytes. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

Key Result

In PAH, maintenance of right ventricular contractility is associated with upregulated lipid metabolism and downregulated oxidative phosphorylation in cardiomyocytes.

Key Points

This research aims to define the molecular programs involved in right ventricular (RV) remodeling in pulmonary arterial hypertension (PAH).
Applied single-nucleus RNA sequencing to RV biopsies from PAH patients (n=22) and controls (n=24).
Conducted differential expression analysis within each cell type using DESeq2, adjusting for age and sex.
Performed gene-set enrichment analysis against the human Reactome database.
PAH exhibited downregulation of oxidative phosphorylation and TCA cycle pathways in cardiomyocytes and other cell types.
Positive associations between contractility and lipid metabolism pathways, while oxidative phosphorylation was negatively associated.
Fibroblasts demonstrated ECM remodeling links, with TGF-β signaling negatively impacting coupling.

Study Design

Type

Observational (n=46)

Structured PICO

Population

Human right ventricular tissue from patients with pulmonary arterial hypertension (PAH) (n=22) and non-failing controls (n=24)

Comparator

Non-failing controls

Outcome

Cell type-specific transcriptional programs associated with RV contractility (end-systolic elastance, Ees) and ventriculo-arterial coupling (Ees/Ea)surrogate

Single-nucleus RNA sequencing of human right ventricular tissue reveals that adaptation and maintenance of contractility in PAH are associated with a shift toward lipid metabolism and reduced extracellular matrix remodeling.

Abstract

Abstract Rationale Right ventricular (RV) maladaptation drives morbidity and mortality in PAH, yet molecular programs underlying adaptive versus maladaptive RV remodeling remain incompletely understood. We applied single-nucleus RNA sequencing (snRNAseq) to human RV tissue obtained by endomyocardial biopsy to define cell type-specific transcriptional programs in PAH and to determine how these relate to gold-standard pressure-volume loop measures of RV contractility and ventriculo-arterial coupling. Methods snRNAseq was performed on RV endomyocardial biopsies from PAH patients (n = 22) and RV tissue from non-failing controls (n = 24). After standard quality control, clustering, and cell-type annotation in Seurat, differential expression analysis comparing PAH to controls was performed within each cell type. In PAH, pseudobulk gene counts were generated per subject and cell type, and DESeq2 was used to regress gene expression against RV contractility (end-systolic elastance, Ees) and coupling (Ees/Ea) with adjustment for age and sex. Gene-level statistics were used for gene-set enrichment analysis against the human Reactome database. Pathways significant at FDR 0.05 were summarized and clustered using EnrichmentMap. Results PAH was characterized by downregulation of oxidative phosphorylation and TCA cycle programs across cardiomyocytes, fibroblasts, and endothelial cells. PAH fibroblasts and stromal cells demonstrated enrichment of extracellular matrix (ECM) organization, TGFβ, and MAPK signaling, while PAH immune and endothelial populations exhibited upregulation of interferon, cytokine, and antigen presentation programs. Integration of functional traits revealed positive contractility associations with lipid handling and metabolism pathways and negative associations with oxidative phosphorylation and respiratory electron transport, with these themes emerging prominently in cardiomyocytes and to a lesser extent in fibroblasts and myeloid cells. In cardiomyocytes, coupling was associated with excitation-contraction programs, Rho GTPase signaling, and cytoskeletal regulation, while stromal populations demonstrated downregulated integrin and ECM programs. TGF-β receptor, SMAD, and related ECM-organization pathways showed negative associations with coupling across fibroblasts and pericytes/smooth muscle cells. Conclusions We present the first survey of single-cell transcriptomic associations with gold-standard measures of RV function in PAH. In comparison to non-failing controls, the human PAH RV appears energetically stressed and enriched for ECM remodeling programs. However, in PAH, maintenance of contractility is associated with upregulated lipid metabolism paired with downregulated oxidative phosphorylation, particularly in cardiomyocytes, suggestive of a substrate-flexible, metabolically efficient bioenergetic state. In PAH fibroblast and perivascular cells, RV adaptation appears linked to reduced ECM remodeling and restrained TGF-β/SMAD signaling. These findings highlight metabolic and stromal pathways that may be therapeutically modulated to promote RV adaptation in PAH. This abstract is funded by: NIH/NHLBI R01 HL114910 (PMH)

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