Longitudinal Transcriptomic Analysis Identifies Persistent Immune-Related Signature Associated With Restrictive Left Ventricular Filling Patterns After Heart Transplantation.

BACKGROUND: Diastolic dysfunction is a recognized chronic allograft complication, and a restrictive left ventricular filling pattern is associated with adverse outcomes. However, the underlying pathophysiological mechanisms remain unclear. METHODS AND RESULTS: This study included 32 heart transplant recipients with a normal filling pattern at 1-year after transplantation. Five-year echocardiography classified patients into restrictive (n=12) and non-restrictive (n=20) groups. All patients underwent right heart catheterization and right ventricular endomyocardial biopsy at 1 and 5 years. Bulk RNA sequencing was performed on paired biopsy samples from 10 patients with available tissue. From 1 to 5 years, the restrictive group demonstrated significantly greater increases in pulmonary artery wedge pressure and the E/A and E/e' ratios, with no histopathological evidence of rejection and similar myocardial interstitial fibrosis in the 2 groups (P=0.81). Transcriptome analysis demonstrated that there was significant enrichment of immune and inflammatory pathways, including gene sets annotated as allograft rejection and T cell receptor signaling (Padjusted<0.05), in the restrictive group at 5 years. Temporal analysis revealed that these pathways were downregulated from 1 to 5 years in the non-restrictive group but remained persistently activated in the restrictive group. CONCLUSIONS: The development of a restrictive filling pattern is associated with elevated intracardiac pressures and a persistent immune-related transcriptome signature, despite no histological evidence of rejection.