| Title: |
Abstract Tu059: Single-Nucleus Transcriptomics Demonstrates Endothelial Cell Expansion in Failing Human Right Ventricles |
| Authors: |
Kuznetsov, Ivan; Li, Kristina; Simonson, Bridget; Chaffin, Mark; Guedira, Yasmine; Bedi, Kenneth; Margulies, Kenneth; Ellinor, Patrick; Arany, Zoltan; Edwards, Jonathan |
| Source: |
Circulation Research ; volume 135, issue Suppl_1, page ATu059-ATu059 ; ISSN 0009-7330 1524-4571 |
| Publisher Information: |
Ovid Technologies (Wolters Kluwer Health) |
| Publication Year: |
2024 |
| Description: |
Background: Right ventricular failure (RVF) is most commonly observed as a sequela of left ventricular failure (LVF)—for which it more than doubles the risk of mortality. Moreover, isolated RVF is the most common cause of death in pulmonary hypertension and is a leading cause of major adverse events in systemic right ventricle congenital heart diseases. Therapies which effectively treat LVF show poor efficacy for RVF. For example, beta blockade, a cornerstone of LVF therapy, has no efficacy in RVF. Therefore, there is a need for broader exploratory research to identify pathways which are dysregulated in RVF and which could serve as targets for future therapies. Methods/Results: To this end, we performed single-nucleus RNA sequencing (N=11) on RV myocardium from nonfailing or dilated cardiomyopathy (DCM) hearts subgrouped by preserved systolic and diastolic RV function (pRV) or RVF. After cell-type assignment and differential expression analysis, we find a progressive upregulation of pro-angiogenic signaling in vascular endothelial cells (ECs) from nonfailing to pRV and RVF. There is a concomitant expansion of the EC pool from nonfailing to pRV and RVF (EC percentage 5%, 9%,15% for NF, pRV, and RVF; p < 0.05 for one-way ANOVA). We find increased HIF-mediated and VEGF-mediated signaling in these ECs, which may be mediating this expansion. Surprisingly, there is also increased expression of genes regulated by type 1 interferon signaling, which is thought to be anti-angiogenic. Discussion: In summary, we have conducted a single-nuclei transcriptomic study of human RVF and found evidence for increased angiogenic signaling and EC expansion. These findings are significant, as the balance of pro-angiogenic and anti-angiogenic factors in RVF is still unclear, with studies in animal models showing conflicting results in terms of changes in macro/microvasculature in RVF. Here, we provide evidence that in human RVF the balance tends to lead toward a pro-angiogenic phenotype, even in dysfunctional RVs. Orthogonal studies ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1161/res.135.suppl_1.tu059 |
| DOI: |
10.1161/res.135.suppl_1.Tu059 |
| Availability: |
https://doi.org/10.1161/res.135.suppl_1.tu059; https://journals.lww.com/10.1161/res.135.suppl_1.Tu059 |
| Accession Number: |
edsbas.9EBDFE2B |
| Database: |
BASE |