A Step Toward Growth-Adaptive Pediatric Heart Valve Transplantation: Novel Functional And Single Nuclei Genomic Analysis Of Extracellular Matrix Tricuspid Valve Replacements In Sheep
Zachary Pickell, BS, Sam Raredon, MD, PhD., Micah Wolfsohn, BS, Navya Sinha, Eva Luna, MD, PhD, Peter J. Gruber, MD, PhD.
Yale School of Medicine, New Haven, CT, USA.
Objective(s): Currently, there are no growth-adaptive pediatric valve replacements other than pulmonary autografts. Recently, an acellular extracellular matrix (ECM) derived from a porcine small intestinal submucosa has been employed to successfully replace the tricuspid valve (TV). Despite some clinical success, there are limitations. Our objective is to understand the biology of ECM valve remodeling.
Methods: Sheep underwent CorMatrix ECM TV replacement with sacrifice at 3, 4, 5, and 10 months. Valves were analyzed for longitudinal function using TTE and subsequently harvested and divided for histological analysis using light microscopy and single nuclei RNA sequencing.
Results: Functionally, TTEs demonstrated excellent leaflet coaptation and trace tricuspid regurgitation. Histology demonstrated a dynamic flux of discrete cell types: first an infiltration of inflammatory cells followed by a reduction of inflammatory cells that begin at the annulus and spread towards the leaflets. Genomic analysis revealed distinct cell clusters that are consistent with an initial hypercellular inflammatory immune response, initially displaying large clusters of macrophages, and inflammatory fibroblasts which subsequently decreased while clusters of B-cells, T-cells, and endothelial cells emerged more prominently. Dynamic immune cell changes appeared to mediate valvular maturation and key formation of valvular endothelial cells and interstitial cells.
Conclusions: T-cell and B-cell emergence may represent a critical shift from an initial inflammatory response to immune cell mediated tissue repair, driving valvular maturation. Acellular ECMs may become a promising approach to growth adaptive valve replacements. Understanding the basic biology is required to design rational therapies to enhance valve maturation and prevent valve degradation.
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