Single‐Cell Transcriptomic Reveals the Involvement of Cell–Cell Junctions in the Early Development of Hypertrophic Cardiomyopathy

ABSTRACT The relationship between the changes in endothelial cell–cell junctions and microvascular abnormalities in the progression of hypertrophic cardiomyopathy (HCM), as well as their potential as early biomarkers, remains unclear. Here, we analysed single‐nucleus RNA‐sequencing data from the left ventricles of 44 health donors and HCM patients. First, we observed that endothelial cell–cell junctions were significantly altered in HCM vascular endothelial cells (ECs), including tight junctions, gap junctions and adherens junctions, especially in capillary ECs. The proposed pseudo‐timing analysis predicted that endothelial cell–cell junctions abnormalities occurred in the early stages of HCM. Second, we verified that endothelial cell–cell junctions disorders occur at early stages of HCM disease progression in two time‐series single‐nucleus datasets of mice. The expression of eight cell–cell junction genes showed an initial increase in the early stage, followed by a slight decrease in the middle stage, and a sharp increase in the later stage. Subsequently, cell communication and transcription factor analysis were used to explore the underlying mechanisms. Furthermore, an early HCM prediction model was developed and independently validated using three mRNA datasets comprising 204 health individuals and HCM patients for the eight genes panel, the accuracy was 0.81 [0.63–0.98]. Finally, we validated this panel in HCM tissues. This study demonstrated in humans and mice that eight cell–cell junction genes were significantly elevated in the early stages of HCM and may be potential biomarkers for the early diagnosis of HCM.