The molecular signature of degeneration in explanted decellularized allogeneic heart valves

The objective of this study was to gain insight into the molecular mechanisms leading to early degeneration of decellularized homografts.

Formalin-fixed and paraffin-embedded tissues from fresh explanted decellularized aortic (n = 7) and pulmonary (n = 8) valves were used. RNA was isolated and analyzed using panel-based transcriptomics, focusing on fibrosis- and inflammation-related genes. Differentially expressed genes were used as input parameters for biological pathway analysis using the Gene Ontology Biological Process and Hallmark databanks. Formalin-fixed and paraffin-embedded tissues from freshly explanted healthy donor aortic (n = 7) and pulmonary valves (n = 8) were used as controls.

Our analysis revealed 56 differentially expressed genes in decellularized aortic valves compared to donor aortic valves, of which 21 and 35 were up- and downregulated, respectively. Decellularized pulmonary valves showed 115 differentially expressed genes compared to donor pulmonary valves, 66 of which were up- and 49 downregulated. In both decellularized aortic and pulmonary valve explants, we found increased expression of fibrosis-, inflammation-, and endothelium-related genes and a decreased expression of genes encoding for complement factors in line with the observed biological pathway activity patterns.

We present a comprehensive transcriptome analysis of explanted decellularized heart valve homografts providing insights into the biological processes leading to continued degeneration and ultimately loss of function. The degeneration of decellularized homografts is driven by inflammation, fibrosis, and extracellular matrix (ECM) remodelling, reinforced by ongoing oxidative stress rather than by a mainly complement-driven humoral immune response.