Regulatory and Communication Shifts in Dilated Cardiomyopathy: A Multimodal Single-Cell Analysis

Abstract

Abstract Dilated cardiomyopathy (DCM), a major cause of heart failure in young adults, is characterized by ventricular dilation and progressive heart muscle dysfunction. Cellular mechanisms driving DCM have not been elucidated despite advances in genomic medicine. This study performed comprehensive multimodal single-cell analysis integrating RNA sequencing, assay for transposase-accessible chromatin with sequencing, and spatial transcriptomics data of cardiac tissues from patients with DCM and control subjects. The complex cellular heterogeneity and a novel neuro-cardiac interface were identified in DCM. The neuronal signaling pathways, including GABA receptor signaling and WT1 transcription factor activity, were profoundly dysregulated in the cardiomyocytes of patients with DCM. Cell-cell signaling analysis revealed that the communication patterns were altered, especially the upregulation of IGF and NRG signaling, suggesting a redefined role of adipocytes and lymphatic cells in DCM pathogenesis. The results of neuronal marker immunostaining analysis were consistent with those of bioinformatics analysis and indicated a potential cross-talk between cardiomyocytes and neurons. The findings of this study provided novel insights into the molecular mechanisms of DCM and identified potential therapeutic targets for DCM, which will enable the development of precision therapeutic approaches for cardiomyopathies.