Tricuspid Valve Is Transcriptionally Active During Prolonged Pressure Overload, Right‐Sided Heart Failure, and Valve Regurgitation

Background Right‐sided heart failure (RHF), in the presence of tricuspid valve regurgitation, results from left‐sided heart failure, pulmonary hypertension (PH), or heart malformations. The occurrence of RHF and tricuspid regurgitation represents a critical indicator of hospitalization rates and all‐cause mortality. However, RHF has remained understudied, specifically with respect to the tricuspid valve. Methods Using the outbred sheep ( Ovis aries ) model of pulmonary artery banding that induces RHF and tricuspid regurgitation, we generated 3 batches of RNA sequencing for 354 samples containing right ventricle, left ventricle, each tricuspid and mitral valve leaflet, and the pulmonary artery representing both male and female sheep. The reads were assembled into a de novo sheep heart transcriptome for differential analysis. Results The de novo sheep heart transcriptome enhanced transcript mapping of reads by 43% to 45% in the heart valves relative to the reference transcriptome. Identified transcripts produce validated tissue‐specific pathways in ventricles (2756 isoforms), pulmonary arteries (535 isoforms), and valves (1215 isoforms), with transcript differences between the mitral and tricuspid valve involved in extracellular and endocrine signaling. Pulmonary artery banding resulted in the most significant transcriptional changes in the tricuspid valve with alterations in endocrine and immune pathway genes. Conclusions This project highlights the complexity of heart valve tissues and their transcriptional activity in a sheep model of RHF. It suggests potential therapeutic interventions in heart valve remodeling in pulmonary artery hypertension, RHF, and tricuspid regurgitation. This work highlights the need for further human and model organism research into the dynamic valve cells and genes.