Single-Nuclear RNA-Sequencing Identifies Cell-Specific Transcriptional Programs in Cardiac Allograft Vasculopathy

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<h3>Purpose</h3> Cardiac allograft vasculopathy (CAV) is the leading cause of late graft failure and mortality after heart transplantation (HT). Current therapies have limited efficacy in preventing or stalling the progression of CAV. Improved understanding of CAV biology is needed to identify novel therapeutics. <h3>Methods</h3> We performed single-nuclear RNA sequencing (snRNA-seq) on human cardiac tissue obtained by endomyocardial biopsy from the right ventricle of 3 HT recipients without CAV and at the time of heart explant in 3 HT recipients with severe CAV. Differentially expressed genes (DEGs) between cohorts were identified with DESeq2 using a 5% false discovery rate threshold for significant genes. <h3>Results</h3> Unsupervised clustering of 38,211 nuclei identified 15 major cell types (Figure A). Relative to cells from non-CAV hearts, endothelial cells and fibroblasts from hearts with severe CAV showed enrichment for genes and pathways associated with inflammation, angiogenesis, and extracellular matrix organization (Figure B and C; endothelial cells). Intersecting these DEGs with the druggable genome identified novel cell-specific drug targets. <h3>Conclusion</h3> We show feasibility of performing snRNA-seq from human endomyocardial biopsy samples and identify cell-specific transcriptional programs that are unique to patients with severe CAV. These data lay the groundwork for larger-scale studies that can accelerate mechanistic understanding of CAV development.