Abstract

Introduction: Myocardial transcriptional changes in the right ventricle (RV) during stress and failure are poorly understood. We hypothesized that myocardial transcriptomic signatures would differ among decompensated (d-RV), compensated (c-RV), and healthy RV (h-RV) myocardium. Methods: We obtained RV free-wall myocardial samples from pts undergoing transplant for end-stage HF (n=33). Control samples were obtained from unused donor hearts. We defined d-RV by pulmonary arterial pulsatility index </= 2.0 (10/33, 30%). We performed RNA-seq using the Illumina NovaSeq6000 with pair-wise differential gene expression using DESeq2 (FDR <0.05) and Gene Set Enrichment Analysis (GSEA) using WebGestalt to identify differentially regulated pathways (FDR <0.1). Results: Controls (n=8) were 44 years [IQR 39-57] and 50% male. HF pts were 53 years [44-61], 63% male, 13 ischemic and 22 non-ischemic, with median LVEF 21% (IQR 16-28%). Principal component analysis demonstrated distinct expression for h-RV vs c-RV and d-RV, but poorly differentiated between c-RV and d-RV ( Figure 1A ). Volcano plots for pairwise comparisons with differentially expressed genes (DEGs) are displayed in Figure 1B-D . Notable upregulated genes in d-RV and c-RV vs h-RV included NPPA, NPPB, and MYH6. Of the 4171 DEGs of d-RV vs h-RV, 3625 were also identified comparing c-RV vs h-RV. There were 39 DEGs differentiating d-RV vs c-RV. GSEA identified increased transcription of immune pathways, metabolism, and protein synthesis related pathways in c-RV and d-RV vs h-RV (Figure 2A ). c-RV vs d-RV featured increased protein synthesis and decreased immune system and catabolism related pathways ( Figure 2B ). Conclusions: The RV response to stress in end-stage HF features transcriptional increases in immune pathways and protein synthesis along with metabolic changes in fatty acid synthesis, insulin signaling, and steroid biosynthesis. These findings warrant further mechanistic investigation of the implicated pathways.