Abstract 19060: Single-Nuclei RNA-Seq Provides Novel Insights Into Cellular Composition and Transcriptional Changes in Human Right Ventricular Failure

Abstract

Introduction: Right ventricular failure (RVF) is a common consequence of pulmonary hypertension, but effective treatment options are currently lacking. To develop precise molecular and cellular targets for therapeutic development, a comprehensive investigation of cell type-specific responses and cellular heterogeneity in RVF is needed. Hypothesis: Cellular heterogeneity exists within the myocardium of RVF patients with pulmonary hypertension, and identifying specific genes contributing to failure can be aided by studying these distinct subpopulations. Methods: To test this hypothesis, we performed single-nucleus transcriptome analysis of 120,000 nuclei from ventricle samples of RVF patients with advanced or end-stage pulmonary hypertension with severe right heart failure undergoing heart double lung transplantation and normal control (NC) subjects. Single nuclei RNA sequencing was performed using 10x genomics, and bioinformatics tools were used for analysis. Results: Unsupervised clustering of 120,000 nuclei led to the identification of transcriptionally distinct subpopulations within 6 major cell types. We identified a unique fibroblast subpopulation expressing SERPINE1 in RVF and observed extensive crosstalk between the fibroblast cells and the other cardiac cell types through Visfatin signaling. In addition, other major cardiac cell types, such as cardiomyocytes, endothelial cells, and macrophages within the failing hearts also exhibited significant alterations in the signaling pathways compared with the control hearts. Conclusions: Our study provides novel insights into the single-cell landscape within the myocardium of RVF patients, revealing remarkable changes in the expression patterns of fibroblast genes. The identified sub-cluster of the fibroblast cell population could serve as a specific and potential therapeutic target in the clinic.