Incomplete Reverse Remodeling of the Tricuspid Valve Leaflets Following Relief of Pressure Overload

Abstract

Objective(s) Tricuspid valve (TV) remodeling and functional tricuspid regurgitation (FTR) progression during right ventricular (RV) pressure overload and reverse remodeling after resolution of RV afterload is poorly understood. We set out to investigate tricuspid leaflet tissue response to induction and subsequent alleviation of pressure overload in a large animal model of RV failure with FTR. Methods Fifteen healthy adult male Dorset sheep (72±4 kg) underwent pulmonary artery banding (PAB) to induce RV failure and FTR. After 8 weeks, 7 sheep (PAB, n=7) were terminated, and remaining 8 had the PAB removed (rPAB, n=8) and were followed for another 8 weeks before termination. Both groups underwent epicardial echocardiography and hemodynamic assessment during banding surgery and at terminal operation. Ten healthy sheep served as a control group (CTL, n=10) and underwent terminal procedure only. In all animals, TV leaflets and right ventricular (RV) tissue were harvested at terminal procedure and analyzed histologically and transcriptionally. Results TV leaflets in PAB animals showed increased cross-sectional area and ECM alterations, some of which persisted after resolution of RV pressure overload. rPAB valves exhibited distinct ECM composition, with notably altered mucin and fibrin content, suggesting a shift toward matrix stabilization, dissimilar to control and PAB. RNA sequencing uncovered a unique molecular state in rPAB valves, with persistent changes in PRG4, PDE3A, CXCL8, and HLA transcripts. RV tissue also demonstrated a separate remodeling trajectory, with sustained expression of stress-related genes including PDE3A, NAV2, ANFB, and ACTS. These findings indicate that both valve and ventricular tissues retain a persistent remodeled phenotype post-unloading. Conclusions TV leaflets actively remodel in response to hemodynamic stress and do not fully revert to a normal state after relief of pressure overload. This persistent altered phenotype may represent a biological contribution of the TV leaflets to recurrent TR with implications for long-term outcomes following treatment of FTR. Clinical Perspective What is new? Relief of right ventricular pressure overload, in a large animal model, resulted in substantial reverse remodeling of the right heart and reduction of tricuspid regurgitation severity, but tricuspid valve leaflets did not return to a normal state. Reverse remodeled leaflets remained enlarged despite normalization of hemodynamics with an altered extracellular matrix. Cellular proliferation and immune cell infiltration observed during pressure overload resolved after unloading, yet transcriptomic analysis identified a distinct molecular phenotype that differed from both healthy and diseased valves. Tricuspid valve leaflets are active biological participants in the remodeling process and exhibit persistent adaptation or maladaptation after resolution of the initiating hemodynamic stress. What Are the Clinical Implications? Secondary tricuspid regurgitation should be considered a disease involving both right heart geometry and leaflet biology. Resolution of the underlying cause of tricuspid regurgitation may not restore leaflet structure and molecular homeostasis. Persistent leaflet remodeling may contribute to residual or recurrent tricuspid regurgitation despite successful treatment of pulmonary hypertension or other inciting conditions. Therapies directed at leaflet remodeling may ultimately complement surgical and transcatheter strategies currently focused on annular and ventricular geometry.