The Tricuspid Valve is Transcriptionally Active During Prolonged Pressure Overload, Right-Sided Heart Failure, and Valve Regurgitation

Abstract

BackgroundRight-sided heart failure (RHF), in the presence of tricuspid valve regurgitation (TR), can result from left-sided heart failure (LHF), pulmonary hypertension (PH), or heart malformations. The occurrence of RHF and TR represents a critical indicator of hospitalization rates and all-cause mortality. However, RHF has remained understudied, specifically with respect to the tricuspid valve, with few animal models to investigate the transformative processes and identify novel interventions. MethodsUsing the outbred sheep (Ovis aries) model of pulmonary artery banding (PAB) that induces RHF and TR, we generated three batches of ribosomal reduced RNA sequencing for 354 samples (NCBI SRA PRJNA1182691) containing right ventricle, left ventricle, each tricuspid valve leaflet, each mitral valve leaflet, and the pulmonary artery that represents both male and female sheep. The reads were assembled into a de novo sheep heart transcriptome for differential analysis. ResultsThe de novo sheep heart transcriptome enhanced transcript mapping of reads by 43-45% in the heart valves relative to the known sheep reference transcriptome. The identified transcripts produce validated tissue-specific pathways in ventricles (2,756 isoforms), pulmonary arteries (535 isoforms), and valves (1,215 isoforms), with transcript differences between the mitral and tricuspid valve involved in extracellular and endocrine signaling. The transcriptome also produced robust sex differences encoded by sex chromosomes and autosomes, highlighting epigenetic and sex hormone differences in the heart. Echocardiography and differential expression suggest that 8 weeks after PAB, the right ventricle has extensive morphological changes and known stress-induced lipid processing dysregulation. At 16-weeks post-PAB, tricuspid valve leaflets show the most significant transcriptional changes, with alterations in endocrine and immune pathway genes involved in cellular and extracellular remodeling. Genes within the tricuspid valve with differential expression and known human or mouse heart phenotypes include FLNA, LTBP4, VDR, CR2, PIGQ, CENPF, ACKR3, CR1, KLF2, and HIF3A. ConclusionsThis 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 PAH, RHF, and TR. This work highlights the need for further human and model organism research into the dynamic valve cells and genes. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABS- Improved cardiac and valve specific transcriptome mapping through de novo transcriptome for clinically relevant ovine model. - Tricuspid valves show a sex dependent and active transcriptional response to pulmonary artery banding induced pulmonary hypertension and right sided heart failure. - Transcriptional phenotypes in ovine model mirror known human heart disease phenotypes. - Several transcripts identified with therapeutic potential for treating pressure overload conditions such as pulmonary hypertension. What Are the Clinical Implications?- Tricuspid valve remodeling due to pulmonary hypertension is accompanied by transcriptional alterations, and mechanical alterations alone may not be sufficient to address valve insufficiency. - Valve and ventricle sex specific gene expression changes following pulmonary hypertension indicate a potential role for hormonal influences and a need for personalized treatment strategies. - Improved patient outcomes for right heart failure, including diagnosis, early detection, and improved treatment strategies can be elucidated through the ovine model and supported through expanded interrogation of human tissues.