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