Transcriptomic Analysis of Right Ventricular Adaptation and Failure in a Novel Ovine Model of Pulmonary Hypertension

Abstract

<h3>Purpose</h3> Right ventricular failure (RVF) is a large contributor to morbidity and mortality in pulmonary hypertension (PH). Molecular understanding of RVF may facilitate identification of novel drug and device therapy targets. Using our previously published large animal model of PH-RVF, we performed RNA-seq analysis of RV tissues sampled from healthy sheep, PH sheep, and PH sheep that received mechanical circulatory support (MCS). <h3>Methods</h3> We assessed RV gene expression in adult sheep prior to and after completion of a previously described PH model. Three PH sheep subsequently underwent acute MCS for 3-6 hours. Right ventricular (RV) free wall tissues were collected prior to PA banding and at termination of MCS (pre-PH vs post-PH, N=3 each). One subject experienced severe maladaptive RVF and expired prior to MCS. This maladaptive characterization was based on its mixed venous saturation below 30% and several liters of ascites and pleural effusion found at necropsy. The pre-PH and post-PH RV tissue samples were analyzed for gene expression profile with RNAseq and studied with over-representation analysis to elucidate enriched pathways. <h3>Results</h3> RNAseq identified 358 genes with differential expression between pre-PH and post-PH tissue samples (p < 0.01, >2-fold change). Enrichment analysis showed that these genes were related to cardiomyocyte muscularization and proliferation, indicating adaptation to RV loading. The maladaptive RV sample, even when compared to the other PH sheep that received MCS, demonstrated markedly reduced expression of metabolic genes, especially in fatty acid oxidation. <h3>Conclusion</h3> RV load stress coincides with differential expression of genes related to cardiomyocyte muscularization and proliferation. Observations of reduced expression of fatty acid oxidation genes in a maladaptive subject with RVF warrants further investigation. The role of mechanical support on RV gene expression needs to be further studied in longer-term settings.