BS45 Transcriptomic analysis of differential ventricular gene expression patterns in response to phosphodiesterase 5 inhibition in heart failure

Introduction There is little data on the differentially expressed genes and transcription factors in heart failure. As such, this study aimed to utilise RNA sequencing analysis to identify differentially expressed genes in ventricular cardiac myocytes in 4-week paced, heart failure and tadalafil (phosphodiesterase 5 inhibitor)-treated sheep compared with control. Methods This study used a sheep model of tachypacing induced heart failure; where, samples were extracted from left ventricular myocardial tissue at 4 weeks and 8 weeks (heart failure) post pacing and following treatment with tadalafil. Samples were also extracted from myocardial tissue of sheep which didn't undergo pacing (control). RNA sequencing data was obtained from these samples for each group. Ingenuity Pathway Analysis (IPA) software and DESeq2 analysis were then used to analyse conical pathways and differentially expressed genes and transcription factors in each group. Results Our work highlighted that there were 1720 common differentially expressed genes (DEGs) between heart failure (HF) v control and 4-week paced (4wk) v control. Comparing these 1720 common DEGs with the Tadalafil v HF group (159 DEGs), 132 common genes were found between these groups. Of these 132 genes, 92 genes were upregulated in HF/4wk v control, and 40 genes were downregulated. Of these 92 genes which were upregulated in HF/4wk v control, 89 genes (97%) were conversely downregulated in Tadalafil v HF. Of the 40 genes which were downregulated in HF/4wk v control, 36 genes (90%) were conversely upregulated in Tadalafil v HF. Among these SERPINE1 and TGFb1 were among significantly altered genes which were upregulated in both HF and 4wk v control and downregulated in Tadalafil v HF. SERPINE1 is an inhibitor of tissue plasminogen activator (tPA), and IPA analysis demonstrated a direct link between SERPINE1 and cardiac fibrosis. TGFB1 is thought to a driver of EDN1/ETI also known as endothelin 1 (a potent vasoconstrictor) which upregulated ABRA signalling pathway which is implicated in cardiac myocyte hypertrophy. Conclusions In summary, our work highlighted common differentially expressed genes which were upregulated in heart failure and 4-week paced v control which were conversely downregulated in Tadalafil v heart failure of which two significant genes included SERPINE 1 and TGFB1. Future work would benefit from investigation of the mechanistic pathways of SERPINE1 and TGFB1 to investigate a causal relationship between these genes and mechanisms taking place in cardiac tissue contributing to heart failure. Conflict of Interest No conflict of interest declared.