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American Heart Association

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Final ID: Tu059

Single-Nucleus Transcriptomics Demonstrates Endothelial Cell Expansion in Failing Human Right Ventricles

Abstract Body: 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 to validate the causal nature of these observed changes in pathogenesis of RVF are currently ongoing.
  • Kuznetsov, Ivan  ( University of Pennsylvania , Philadelphia , Pennsylvania , United States )
  • Edwards, Jonathan  ( Childrens Hospital of Philadelphia , Philadelphia , Pennsylvania , United States )
  • Li, Kristina  ( University of Pennsylvania , Philadelphia , Pennsylvania , United States )
  • Simonson, Bridget  ( Massachusetts General Hospital , Boston , Massachusetts , United States )
  • Chaffin, Mark  ( Massachusetts General Hospital , Boston , Massachusetts , United States )
  • Guedira, Yasmine  ( Massachusetts General Hospital , Boston , Massachusetts , United States )
  • Bedi, Kenneth  ( University of Pennsylvania , Philadelphia , Pennsylvania , United States )
  • Margulies, Kenneth  ( University of Pennsylvania , Philadelphia , Pennsylvania , United States )
  • Ellinor, Patrick  ( Massachusetts General Hospital , Boston , Massachusetts , United States )
  • Arany, Zoltan  ( University of Pennsylvania , Philadelphia , Pennsylvania , United States )
  • Author Disclosures:
    Ivan Kuznetsov: DO NOT have relevant financial relationships | Jonathan Edwards: DO NOT have relevant financial relationships | Kristina Li: DO NOT have relevant financial relationships | Bridget Simonson: No Answer | Mark Chaffin: DO NOT have relevant financial relationships | Yasmine Guedira: No Answer | Kenneth Bedi: DO NOT have relevant financial relationships | Kenneth Margulies: No Answer | Patrick Ellinor: No Answer | Zoltan Arany: DO NOT have relevant financial relationships
Meeting Info:

Basic Cardiovascular Sciences

2024

Chicago, Illinois

Session Info:

Poster Session and Reception 2

Tuesday, 07/23/2024 , 04:30PM - 07:00PM

Poster Session and Reception

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