Altered Intercellular Communication and Extracellular Matrix Signaling as a Potential Disease Mechanism in Human Hypertrophic Cardiomyopathy

Abstract Objectives To understand Hypertrophic Cardiomyopathy-associated alterations in gene expression and intercellular communication at the single cell level in left ventricular outflow tract lesions. Background Human hypertrophic cardiomyopathy (HCM) is considered a disorder of the sarcomere (i.e., cardiomyocytes) but the paradoxical association of nonmyocyte phenotypes such as fibrosis, mitral valve anomalies and microvascular occlusion is unexplained. Methods To understand the interplay between cardiomyocyte and nonmyocyte cell types in human HCM, single nuclei RNA-sequencing (snRNA-seq) was performed on myectomy specimens from HCM patients with left ventricular outflow tract obstruction and control samples from donor hearts free of cardiovascular disease. Results Clustering analysis identified a total of 34 distinct cell populations, which were classified into 10 different cell types based on marker gene expression. Differential gene expression analysis comparing HCM to Normal datasets revealed differences in sarcomere and extracellular matrix gene expression. Analysis of expressed ligand-receptor pairs across multiple cell types indicated profound disruption in HCM intercellular communication, particularly between cardiomyocytes and fibroblasts, fibroblasts and lymphocytes and involving integrin β1 and its multiple extracellular matrix (ECM) cognate ligands. Conclusions These findings provide evidence for intercellular interactions in HCM that link sarcomere dysfunction with altered cardiomyocyte secretion of ECM ligands, altered fibroblast ligand-receptor interactions with a variety of cell types and increased fibroblast to lymphocyte signaling, which can further alter the ECM composition, disrupt cellular function and promote nonmyocyte phenotypes.